Osteogenesis Imperfecta: From Diagnosis to Treatment 9781685074999, 9781685075194, 1685074995

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ORTHOPEDIC RESEARCH AND THERAPY

OSTEOGENESIS IMPERFECTA FROM DIAGNOSIS TO TREATMENT

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ORTHOPEDIC RESEARCH AND THERAPY

OSTEOGENESIS IMPERFECTA FROM DIAGNOSIS TO TREATMENT

DMITRY A. POPKOV, MD, PHD AND

SERGEY RYABYKH, MD, PHD EDITORS

Copyright © 2022 by Nova Science Publishers, Inc. DOI: https://doi.org/10.52305/BNDY1848 All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470

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Library of Congress Cataloging-in-Publication Data Names: Popkov, Dmitry A., editor. | Ryabykh, Sergey, editor. Title: Osteogenesis imperfecta : from diagnosis to treatment / Dmitry A. Popkov, MD, PHD, Professor, National Ilizarov Medical Research Centre for Traumatology and Orthopaedics, Kurgan, Russia; Associated member of Medical Academy of France, Sergey Ryabykh, MD, PHD, Priorov National Medical Research Center of Traumatology and Orthopedics, Moscow, Russia, editors. Description: New York : Nova Science Publishers, [2022] | Series: Orthopedic research and therapy | Includes bibliographical references and index. | Identifiers: LCCN 2021061111 (print) | LCCN 2021061112 (ebook) | ISBN 9781685074999 (hardcover) | ISBN 9781685075194 (adobe pdf) Subjects: LCSH: Osteogenesis imperfecta. Classification: LCC RC931.O68 O88 2022 (print) | LCC RC931.O68 (ebook) | DDC 616.7/16--dc23/eng/20211214 LC record available at https://lccn.loc.gov/2021061111 LC ebook record available at https://lccn.loc.gov/2021061112

Published by Nova Science Publishers, Inc. † New York

Contents

Foreword

........................................................................................ ix Alexander Gubin

Acknowledgments ................................................................................xiii Chapter 1

Definition, Pathogenesis, and Genetic Classification of Osteogenesis Imperfecta ................... 1 Tatiana Markova, Tatiana Nagornova, Elena Merkurieva and Ekaterina Zakharova

Chapter 2

Сlinical Classification of Osteogenesis Imperfecta: Somatic Issues in Children with Osteogenesis Imperfecta. Medical Treatment for Children with Osteogenesis Imperfecta .............. 29 Nato Vashakmadze, Natalia Zhurkova, Anastasia Rykunova, Tatiana Ryabykh and Leyla Namazova-Baranova

Chapter 3

The Current State of Molecular Genetic Diagnostics in Various Forms of Osteogenesis Imperfecta ......................................... 61 Sergey Khalchitsky, Marina Sogoyan, Alina Li, Lavrentii Danilov, Vladislav Muldiyarov, Dmitry Buklaev and Sergey Vissarionov

vi

Contents

Chapter 4

Physical Therapy Management in Osteogenesis Imperfecta ......................................... 91 Nadezhda Epishina

Chapter 5

Orthotics and Assistive Devices for Osteogenesis Imperfecta ..................................... 109 Dmitry Okhapkin

Chapter 6

Anesthetic Management in Osteogenesis Imperfecta ....................................... 125 Vadim Evreinov

Chapter 7

Management of Pain in Patients with Osteogenesis Imperfecta During Operations on the Lower Limb................................ 137 Vadim Evreinov and Elena Raznoglyadova

Chapter 8

Osteogenesis Imperfecta: The Role and Place of Orthopedic Surgery of the Lower Extremities ........................... 151 Dmitry A. Popkov, Eduard Mingazov, Pierre Journeau, Alexander Gubin, Nikita Gvozdev and Arnold Popkov

Chapter 9

Sliding Transphyseal Flexible Intramedullary Nailing in Children with Osteogenesis Imperfect .................................... 175 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich and Arnold Popkov

Chapter 10

Surgical Correction of Limb Deformities in Children with Osteogenesis Imperfecta: Experience of Turner Center ................................... 197 Dmitry Buklaev and Sergey Vissarionov

Contents

vii

Chapter 11

Use of Titanium Telescopic Rods in Osteogenesis Imperfecta Patients: Combined Technique and 3D Gait Analysis in OI Children ............................................ 217 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov, Pierre Journeau, Dmitry Dolganov, Nikita Gvozdev and Arnold Popkov

Chapter 12

Spinal Pathology in Children and Adults with Osteogenesis Imperfecta ............... 241 Sergey Ryabykh, Elena Schurova, Polina Ochirova, Olga Sergeenko, Tatiana Ryabykh and Oleg Chelpachenko

Chapter 13

Surgical Correction of Spinal Pathology in Patients with Osteogenesis Imperfecta ............... 255 Sergey Ryabykh, Elena Schurova, Polina Ochirova, Olga Sergeenko and Dmitry Savin

Chapter 14

Quality of Life and Outcomes of Reconstructive Surgery in Children with Osteogenesis Imperfecta .................................. 267 Dmitry A. Popkov, Eduard Mingazov, Fedor Hoffman, Anatoly Korkin, Nikita Gvozdev and Siniša Ducic

Conclusion

..................................................................................... 283

About the Editors ................................................................................ 285 Index

..................................................................................... 287

FOREWORD Alexander Gubin, MD National Priorov Medical Research Centre for Traumatology and Ortopaedics, Moscow, Russia

Osteogenesis imperfecta (OI) is a general term for a group of hereditary bone disorders with primary changes in type 1 collagen formation which causes bone fragility. There are four well known OI phenotypes of Sillence classification [1]. Genetic heterogeneity in osteogenesis imperfecta becomes more and more understandable from the genetic point of view and gets more subtypes based on research and collecting more data. Recently type V as a type IV variant with the formation of volumetric hypertrophied and not prone to remodeling calluses after fractures was described [2,3]. Expanded by genetics Sillence classification consists of many subtypes and can be expanded more and more in the near future [4]. In Russian Federation patients with OI are managed mostly in a few big federal clinics which are located in Kurgan, Saint-Petersburg and Moscow. The progress in research and treatment of OI as in other rare diseases is greatly driven by state support and activity of patient’s 

Corresponding Author’s E-mail: [email protected].

x

Alexander Gubin

societies. This helps to create the clinical continuity and multidisciplinary teams which results in preparing this publication. The global task of orthopedic surgical treatment of OI deformities is to maintain physical activity, autonomy, the ability to acquire and develop motor skills, and facilitate care. This is achieved through an increase in the mechanical strength of bones throughout their entire length by surgical intervention, prevention of recurrence of deformities and a decrease in the frequency of fractures. Spine surgery is indicated in some rare cases to avoid cord compression, instability and stature imbalance. The classical orthopedic approaches in OI patients are used only in I type. In all other cases the main challenges are poor bone quality, quick recurrence of multiplanar skeletal deformities and growth in pediatric patients. The optimal moment for surgical correction is the age when the child is physiologically ready for vertical posture and walking. New kind of hardware as telescopic intramedullary steel or titanium rods make it possible to control the deformities and decrease fractures during child’s growth. The technique of telescopic rods application is well known but it has many tricks and a lot of obstacles and complications. The main idea of this book is to collect the best experience for multidisciplinary treatment of OI patients. The unique data includes highly professional descriptions of OI from different points of view. The publication includes general information about OI, new genetic research, therapeutic approach for treatment and management and special surgical up-to-date issues. Orthopedic chapters include orthosis usage, surgical indications and techniques. Two chapters are dedicated to spine and craniocervical manifestations of OI and back up the importance of wide view on OI for prevention of mostly dangerous and not well-known among the orthopedic surgeons complications. Anesthetic management and pain control in OI patient are two very important issues which have their tricks and must be taken into consideration. The main strategy and quality of life assessment are reflected in most practical way which makes the publication a OI textbook. We hope that this brilliant collection of authors will decrease the level of suffering of OI patients and their families.

Foreword

xi

REFERENCES [1] Sillence, D.O., Senn, A., Danks, D.M. (1979). Genetic heterogeneity in osteogenesis imperfecta. J Med Genet., 16:101-116. [2] Cho, T.J., Lee, K.E., Lee, S.K., Song, S.J., Kim, K.J., Jeon, D., et al. (2012). A single recurrent mutation in the 50 -UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet., 91:343– 348. [3] Balasubramanian, M., Parker, M.J., Dalton, A., Giunta, C., Lindert, U., Peres, L.C., Wagner, B.E., Arundel, P., Offiah, A., Bishop, N.J. (2013). Genotype-phenotype study in type V osteogenesis imperfecta. Clin Dysmorphol., 22(3):93-101. [4] Chetty, M., Roomaney, I.A., Beighton, P. (2021). The evolution of the nosology of osteogenesis imperfecta. Clinical Genetics, 99:4252.

ACKNOWLEDGMENTS We dedicate this book to children and adults with osteogenesis imperfecta, their families, as well as to charitable foundation for helping patients with osteogenesis imperfecta. We are grateful to all colleagues who agreed to participate in this international project. Without their research studies, experience, scientific reputation and hard work the birth of this book could never have happened.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 1

DEFINITION, PATHOGENESIS, AND GENETIC CLASSIFICATION OF OSTEOGENESIS IMPERFECTA Tatiana Markova, MD, PhD, Tatiana Nagornova, MD, Elena Merkurieva, MD and Ekaterina Zakharova*, MD Research Centre for Medical Genetics, Moscow, RUSSIA

ABSTRACT Introduction Osteogenesis imperfecta (OI) or brittle bone disease is a genetic heterogeneous bone disease characterized by bone fragility, low bone mass, and increased rate of bone fractures and deformities.

Materials and Results Here, we present an overview of the genetic heterogeneity and pathophysiological background of OI. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects *

Corresponding Author’s E-mail: [email protected].

2

Tatiana Markova, Tatiana Nagornova, Elena Merkurieva et al. in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Thus far, 19 genes have been identified to cause OI. These genes play a critical role in the processing and post-translational modification of type I collagen, the genes that modify mineralization and take part in osteoblast differentiation. In this сhapter, we summarized information on the results of studies in the field of genetic aspects of osteogenesis imperfecta and reflected the current state of the classification criteria for diagnosing the disease.

Conclusion Numerous causative genes complicated the classical classification of the disease and, due to new advances in the molecular basis of the disease, the classification of the disease is constantly being improved.

Keywords: osteogenesis imperfecta, collagen, bone fragility, multiple fractures, pathophysiology, genetic heterogeneity

INTRODUCTION Osteogenesis imperfecta (OI) or brittle bone disease is a genetic heterogeneous bone disease characterized by bone fragility, low bone mass, and increased rate of bone fractures and deformities. Clinical presentation of OI shows wide variability ranging from mild to severe and early lethal forms. The term “osteogenesis imperfecta” was coined by Vrolick in the 1840s. OI patients may exhibit dentinogenesis imperfecta (abnormal tooth development), craniofacial abnormalities and joint hypermobility, as well as extra-skeletal manifestations including blue sclerae, hearing impairment, and intrinsic and extrinsic lung abnormalities [1].

Definition, Pathogenesis, and Genetic Classification …

3

Table 1. Classification of osteogenesis imperfecta [7] Type Clinical findings MOI I Blue sclerae, moderate bone fragility AD II Lethal in the perinatal period AR III White sclera, severe with progressive deformity AR IV White sclera, variable bone fragility AD AD - autosomal dominant; AR - autosomal recessive; MOI - mode of inheritance.

CLASSIFICATION OF OSTEOGENESIS IMPERFECTA The classification of OI has been revised repeatedly during last 40 years. The original classification was developed by Sillence et al. in 1979. In the publication titled “Genetic Heterogeneity in Osteogenesis Imperfecta”, based on clinical features, disease severity and the mode of inheritance of 180 patients, four different types of the disease were distinguished: (I) Dominantly inherited OI with blue sclerae, (II) Lethal perinatal OI with radiographically crumpled femora and beaded ribs, (III) Progressively deforming OI, and (IV) Dominantly inherited OI with normal sclerae (Table 1) [2]. The numbers OI types I–IV were inserted in a table following a meeting with Dr. Victor McKusick who wanted to be able to put these syndromes into the computerized database, Mendelian Inheritance in Man (MIM). As such, the initial types I–IV reflected the order of appearance of the OI groups in the manuscript [3]. Over the last four decades, the knowledge generated through advances in biochemical, molecular genetics, and more recently, genomics, has allowed to demonstrate that these phenotypes and several special syndromes with phenotypic features overlapping with those in OI result from mutations in at least 24 distinct gene loci. In the last five years, genetic and functional studies have resulted in even more insights into the pathogenic mechanism responsible for bone fragility [4].

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Tatiana Markova, Tatiana Nagornova, Elena Merkurieva et al.

The growing list of genes associated with rarer forms of OI gave rise to a classification system that determines OI subtypes based on the causative gene, and it is now up to XXI types of OI according to the Online Mendelian Inheritance in Man database (https://www.omim.org/). To date, 19 genes have been identified that are responsible for the development of OI (Table 2). The latest addition, mutations in KDELR2 resulting in a progressive deforming OI phenotype occurred relatively recently [5]. Also, according to the international classification of genetic skeletal disorders, adopted in 2019, a group of OI is included in the “Osteogenesis Imperfecta and decreased bone density group” category 25. It includes genetic variants of skeletal dysplasias associated with OI, accompanied by low bone mineral density and similar clinical symptoms. Two well-known examples are Bruck syndrome (MIM 259450 and 609220), previously known as “OI with congenital joint contractures,” and osteoporosis-pseudoglioma syndrome (MIM 603506), first described as “ocular form of OI.” In 1986, Cole and Carpenter described two infants with bone deformities and multiple fractures reminiscent of OI who also had ocular proptosis with orbital craniosynostosis, hydrocephalus, and distinctive facial features (MIM 112240) [6]. Another very useful classification divided OI in five functional groups based on mutation genes and pathogenetic mechanisms: group A, primary defects in collagen structure or processing (COL1A1, COL1A2, and BMP1); group B, collagen modification defects (CRTAP, LEPRE1, PPIB, and TMEM38B); group C, collagen folding and cross-linking defects (SERPINH1, FKBP10, and PLOD2); group D, ossification or mineralisation defects (IFITM5 and SERPINF1); and group E, defects in osteoblast development with collagen insufficiency (WNT1, CREB3L1, and SP7). Most physicians agree that functional genetic classification could be usefully supplemented by a parallel clinical classification of OI and in clinical practice OI phenotypes are still classified according to Sillence [7, 8].

Definition, Pathogenesis, and Genetic Classification …

5

EPIDEMIOLOGY Osteogenesis imperfecta (OI) is one of the most common inherited bone disorders. Studies from Europe and the United States have found a birth prevalence of OI of 0.3–0.7 per 10,000 births [9, 10]. The population frequencies of type I OI have been reported to range between 2.35 to 4.7 in 100,000 worldwide.

Figure 1. Proteins and genes involved in the pathogenesis of OI. [From: Etich, J., Leßmeier, L., Rehberg, M., Sill, H., Zaucke, F., Netzer, C., Semler, O. (2020). Osteogenesis imperfecta-pathophysiology and therapeutic options. Mol Cell Pediatr., 7(1):9]. This figure is licensed under a Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/.

Gene MIM 120150

120160

614757 172860

605497

610339

123841

600943

Gene COL1A1

COL1A2

IFITM5

SERPINF1

CRTAP

P3H1

PPIB

SERPINH1

X

IX

VIII

VII

VI

OI type I II III IV II III IV V

613848

259440

610915

610682

613982

Phenotype MIM 166200 166210 259420 166220 166210 259420 166220 610967

AR

AR

AR

AR

AR

AD

AD

Inheritance AD

Table 2. Genetic classification of OI

Collagen alpha-2(I) chain fibrillar collagen found in most connective tissues, including cartilage. Interferon-induced transmembrane protein 5 Required for normal bone mineralization. Serpin F1 The protein inhibits angiogenesis and it is a neurotrophic factor involved in neuronal differentiation. Cartilage-associated protein Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues. Prolyl 3-hydroxylase 1 The enzyme catalyzing the posttranslational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts. Peptidyl-prolyl cis-trans isomerase B The enzyme catalyzing the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding. Serpin H1 Protein binds specifically to collagen. May be involved as a chaperone in collagen biosynthesis

Protein and functions Collagen alpha-1(I) chain fibrillar collagen found in most connective tissues, including cartilage.

Gene MIM 607063

606633

112264

611236

164820

616215

Gene FKBP10

SP7

BMP1

TMEM38B

WNT1

CREB3L1

XVI

XV

XIV

XIII

XII

OI type XI

616229

615220

615066

614856

613849

Phenotype MIM 610968

AR

AR

AR

AR

AR

Inheritance AR

Protein and functions Peptidyl-prolyl cis-trans isomerase FKBP10 PPIases accelerating the folding of proteins during protein synthesis. Transcription factor Sp7 The bone specific transcription factor required for osteoblast differentiation and bone formation. Bone morphogenetic protein 1 Roles in ECM formation include cleavage of the C-terminal propeptides from procollagens such as procollagen I, II and III or the proteolytic activation of the enzyme lysyl oxidase LOX, necessary for the formation of covalent cross-links in collagen and elastic fibers. Trimeric intracellular cation channel type B Monovalent cation channel required for maintenance of rapid intracellular calcium release. May act as a potassium counter-ion channel that functions in synchronization with calcium release from intracellular stores. Proto-oncogene Wnt-1 The protein plays a significant role in osteoblast function, bone development and bone homeostasis Cyclic AMP-responsive element-binding protein 3-like protein 1 Plays a critical role in bone formation through the transcription of COL1A1, and possibly COL1A2, and the secretion of bone matrix proteins. Directly binds to the UPR element (UPRE)-like sequence in an osteoblast-specific COL1A1 promoter

Gene MIM

182120

611357

300294

607783

609024

Gene

SPARC

TENT5A

MBTPS2

MESD

KDELR2

XXI

XX

XIX

XVIII

XVII

OI type

619131

618644

301014

617952

616507

Phenotype MIM

AR

AR

XLR

AR

AR

Inheritance

Table 2. (Continued) Protein and functions region and induces its transcription. Does not regulate COL1A1 in other tissues, such as skin. SPARC Binds calcium and copper, several types of collagen, albumin, thrombospondin and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca2+ with a low affinity and an EF-hand loop that binds a Ca2+ ion with a high affinity. Terminal nucleotidyltransferase 5A Probable nucleotidyltransferase acts as a non-canonical poly(A) RNA polymerase. Membrane-bound transcription factor site-2 protease involved in intramembrane proteolysis during bone formation LRP chaperone MESD The chaperone specifically assisting the folding of beta-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs). KDEL endoplasmic reticulum protein retention receptor 2, which recycles ERresident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport.

Definition, Pathogenesis, and Genetic Classification …

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Reports of the incidence of type II OI range between 1 in 40,000 to 1.4 in 100,000 live births [1]. The exact incidence of types III and IV OI is unknown, although the incidence is much less than OI type I. The incidence of severe forms recognizable at birth is 1:15-20,000 [1, 11]. The actual prevalence could be even higher because milder variants often remain unrecognized.

ETIOLOGY AND PATHOGENESIS Bone is a dynamic tissue undergoing constant process of formation and resorption, which is balanced under normal conditions. In OI patients, bone resorption exceeds bone formation, which ultimately leads to reduction in total bone mass. In the last 10 years, advances in molecular genetics have led to improved understanding of complexity of the pathogenesis and extreme genetic heterogeneity of OI. Approximately 85–90% of OI patients harbor heterozygous mutations in genes COL1A1 (MIM: 120150) or COL1A2 (MIM: 120160), encoding the α1(I) and α2(I) chain of type I collagen, respectively. It is estimated that alterations in genes other than those encoding type I collagen are responsible for about 15–25% of OI cases were all identified after 2006. Thus far, 19 genes have been identified to cause OI (Table 2). These genes play a critical role in the processing and post-translational modification of type I collagen, the genes that modify mineralization and take part in osteoblast differentiation [12]. It should be mentioned that discovery of the new gene groups has critically changed the paradigm of the pathogenesis of OI, turning it from a disease associated exclusively with collagen defects into a group of disorders the underlying mechanisms of which are much more heterogeneous and diverse. The description of individual proteins and genes involved in the pathogenesis of OI, is given below and in Figure 1 [16].

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DEFECTS IN COLLAGEN SYNTHESIS, STRUCTURE OR PROCESSING OF COL1A1 AND COL1A2 Collagen type I is the most abundant protein in connective tissue constituting 80-90% of the organic bone matrix. It is a heterotrimer composed of two α1- and one α2-chains. The three pro-alpha chains consist of a central helical region containing uninterrupted Gly-X-Y repeats (where X and Y can be any amino acid, but are often proline (Pro) and lysine (Lys) respectively [13] The complex biosynthesis of type I procollagen involves a large number of post-translational modifications. For correct collagen formation, the presence of glycine in certain positions of aminoacid sequence is essential. Glycine is the smallest residue that can occupy the axial position of the triple helix. Each alpha chain consists of an aminoterminal pro-peptide and carboxyl-terminal pro-peptide and a central propeptide consisting of 338 repeats of glycine. The helical region of the collagen molecule is also rich in proline residues, which are arranged in repetitive sequences. After translating the procollagen into the rough endoplasmic reticulum (ER), one of the first steps in the posttranslational modification is the hydroxylation of proline residues in the helical region to hydroxyproline. The hydroxylation leads to greater stability of the collagen triple helix. The three alpha-chains of collagen type I form disulphide bonds at the C-terminus end of the molecule. The procollagen thus formed is excreted by the osteoblast into the extracellular space and converted into collagen by cleaving off the propeptides [14].

DEFECTS OF COL1A1 И COL1A2 At least 90% of OI patients have a genetic defect resulting in quantitative and qualitative (or both) abnormalities in type I collagen molecule. Аn autosomal dominant mutation in collagen type I alpha 1 chain (COL1A1) or collagen type I alpha 2 chain (COL1A2) leads to the

Definition, Pathogenesis, and Genetic Classification …

11

structure changes in of one of the alpha chains of type I collagen. The large size of these genes explains the numerous known mutations and the diversity of the clinical symptoms [12, 13]. OI is most caused by a quantitative defect with reduced amount but structurally normal collagen I due to «loss-of-function mutations» [1518]. This can be a consequence of a premature termination codon or a frame-shift mutation after an insertion, deletion or splice site mutation, all variants leading to nonsense mediated decay of COL1A1 mRNA. Stop mutations usually lead to reduced collagen amount resulting in a mild phenotype, while missense mutations mainly provoke structural alterations in the collagen protein and entail a more severe phenotype. Exchange of glycine for any other amino acid leads to qualitative alterations of the extracellular matrix (ECM), since the collagen molecules and later fibrils cannot assemble properly. Qualitative mutations of collagen also include a splicing defect, mutations in the X or Y position and N- and C-terminal mutations that lead to similar dysfunctional pathways. The qualitative disturbance and the inadequate stability of the collagen also stimulate bone resorption, since the body tries to break down disturbed bone. The mutations reported so far delineate a complex relationship between genotype and phenotype, e.g., the proposed “increased severity gradient from N- to C-terminal” theory initially presented has been modified to lethal regions in both chains while it still holds true that N-terminal mutations are generally nonlethal.

DEFECTS IN C-TERMINAL PROPEPTIDE CLEAVAGE Once the procollagen molecules are secreted into the extracellular space, they undergo an extracellular maturation process in which the Nand C-propeptides are removed by specific proteases. Mutations in the BMP1 gene, which codes for the protease BMP1 (bone morphogenetic protein 1) responsible for the extracellular cleavage of C-propeptides, result in deficient proteolytic cleavage and a very variable phenotype ranging from mild to severe. Procollagen processing and the ability to

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Tatiana Markova, Tatiana Nagornova, Elena Merkurieva et al.

generate mature collagen fibrils are limited in cells of these patients. Processing defects of the C-propeptide have a dominant form caused by substitutions in the cleavage site and a recessive form caused by defects in the processing enzyme; both lead to high bone mass OI (OI XIII) [19, 20].

DEFECTS OF THE POST-TRANSLATIONAL MODIFICATION OF TYPE I COLLAGEN During collagen synthesis, nascent type I procollagen molecules are translocated into the ER where they are subject to various posttranslational modifications, including formation of inter- and intra-chain disulfide bonds, isomerization of peptidyl-prolyl bonds, hydroxylation of prolyl and lysyl residues, and glycosylation of hydroxylysine residues. Thus, numerous molecules assisting procollagen synthesis are present in the ER- several enzymes and molecular chaperons [5, 21].

HYDROXYLATION OF PROLINE AND LYSINE RESIDUES IN COLLAGEN MOLECULE Hydroxylation of proline and lysine residues are important for proper collagen synthesis, transport and stability. These modifications are subsequently used as substrates for lysyl oxidases to convert specific lysine residues to lysyl-pyridinoline (LP) or hydroxylysine residues to hydroxylysyl-pyridinoline (HP) to generate inter-collagen cross-links. The activity of Lysyl hydroxylase 2 (LH2) is regulated by the molecular chaperones HSP47 and FKBP65 in the ER [14]. Protein disulfide isomerase (PDI) is an ER-resident multifunctional enzyme that catalyzes the oxidation of thiol groups, as well as reduction and rearrangement of disulfide bonds in various cell surface and secreted proteins. The hydroxylation of proline residues on α chains of type I procollagen in the helical region to hydroxyproline leads to greater

Definition, Pathogenesis, and Genetic Classification …

13

stability of the collagen triple helix. This reaction is performed by the tetrameric prolyl-4-hydroxylase complex. A subunit of this complex, the protein PDI (protein disulfide isomerase), is encoded by the P4HB gene. PDI also has important functions during the posttranslational modification of procollagen type I, acting as a chaperone to prevent aggregation of procollagen alpha chains. Mutations in P4HB gene lead to type 1 Cole Carpenter syndrome but are also clinically described as moderate to severe OI [21]. CRTAP (cartilage-associated protein), P3H1 (prolyl-3-hydroxylase 1), and PPIB (peptidyl-prolyl-cis-trans-isomerase B or cyclophilin B) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the α1 chains of collagen type I. Mutations lead to a delay in collagen folding, accompanied by an excessive modification [22, 23]. Deficiency of CRTAP or P3H1 causes a very severe to lethal bone dysplasia. Null mutations in CRTAP or LEPRE1 cause OI types VII and VIII, respectively, both of which result in over modification of the full collagen helical region [24-26, 29]. Lysyl hydroxylases catalyze hydroxylation of collagen lysines and sustain essential roles in ECM maturation and remodeling. Modification of collagen lysines enables subsequent glycosylation and formation of extracellular cross-links, leading to fibrillary or meshwork superstructures [28]. The PLOD2 gene encodes the protein lysyl hydroxylase 2 (LH2), which belonging to the family of collagen lysyl-hydroxylases (LH or PLOD) catalyzes lysine hydroxylation of collagens molecule. Mutations in the PLOD2 gene cause Bruck syndrome type 2 and OI type XI with progressive joint contractures [22].

Collagen Folding and Crosslinking SERPINH1 and FKBP10 are two genes encoding ER resident chaperones known to have triple helical procollagen molecules as preferred substrates. SERPINH1 encodes the heat shock protein 47

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(HSP47). HSP47 is essential for the correct folding of types I–V procollagens in the ER. In the absence or deficiency of HSP47, type I procollagen molecules have a shorter residence time in the ER and are quickly transported to the Golgi complex. Mutations in SERPINH1 cause moderate and severe forms of OI type X, some with severe deformities and prenatal fractures, but some with fractures only in the first months of life. FKBP10 encodes FKBP65 a chaperone with prolyl cis-trans isomerase activity (PPIase) crucial for normal collagen synthesis. Mutations in FKBP10 result in a range of phenotypes that includes OI type XI, Bruck syndrome type 1, and a contracture syndrome with osteopenia (Kuskokwim disease) [22, 30].

OTHER ALTERATIONS OF COLLAGEN MODIFICATION AND VESICULAR TRANSPORT TMEM38B (Transmembrane Protein 38B) is a gene coding for a monovalent cation channel (TRIC-B, trimeric intracellular cation channel type B). Ca2+ release from the ER and sarcoplasmic reticulum regulates important cellular functions. Two trimeric intracellular channels, TRIC-A and TRIC-B are localized to ER, sarcoplasmic reticulum, and nuclear membranes. The molecular mechanism through which the absence of TRIC-B causes an OI phenotype has not been well understood. It is hypnotized that disturbed intracellular Ca2+release leads to an incorrect regulation of collagen modification by various enzymes in the ER. Mutations in this transmembrane protein are inherited in an autosomal recessive manner and are associated with OI Type XIV [22]. The mesoderm development gene (MESD) encodes the protein MESD (low-density lipoprotein receptor chaperone MESD), which plays a central role in embryogenesis by acting predominantly as a chaperone for the low-density lipoprotein receptors LRP5 and LRP6 in the ER [31]. Specifically, MESD enables the correct folding of β-propeller/epidermal growth factor (EGF) modules as well as its trafficking to the сomplex

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Golgi (cG), which are crucial steps for further maturation. The OI type XX caused by MESD mutations was characterized by an increased incidence of fractures and a progressively deforming phenotype [31].

ANTEROGRADE VESICLE TRANSPORT After the posttranslational modifications and the triple helix folding have been completed in the ER, procollagen is transported to the ER and cG via vesicle transport. However, the transport of the procollagen triple helix is different than most other proteins due to the large size of the triple helix, which is estimated to reach 400 nm. For this reason, it has been hypothesized that procollagen secretion takes place in large coat protein II (COPII) vesicles with a diameter between 400 and 1200 nm [32]. SEC24D encodes a protein of the COPII-dependent ER-to-Golgi transport, defects in this protein leads to molecular retention of procollagen in the ER. Mutation in SEC24D gene lead to syndromic form of OI (Cole-Carpenter syndrome 2) [6].

RETROGRADE VESICLE TRANSPORT Newly synthesized proteins are transported from the ER to the cG, however, some of these proteins have to be transported back to the ER where they exert their function; this happens by retrograde transport. Sorting of proteins back to the ER is based on the presence of the common retrograde KKXX motif. In addition, certain proteins such as the KDEL receptor, also mediate the sorting of ER proteins by binding large coat protein I (COPI) and functioning as an adaptor [32]. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which is one of the receptors that cycle between the cG and the ER, returning proteins containing the KDEL signal to the ER. Defects

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in KDELR2 that lead to impaired KDELR2-dependent retrograde transport, result in a progressively deforming OI phenotype XXI [33]

DEFECTS IN INTRAMEMBRANE PROTEOLYSIS AND IMPAIRMENT OF OSTEOBLAST DIFFERENTIATION AND FUNCTION In OI patients, bone resorption is more intensive than formation, which ultimately leads to reduction in total bone mass. Recently, some genes involved in OI have been identified which affect the differentiation as well as the function of osteoblasts. For most of them, the underlying pathomechanism is not yet fully elucidated [34]. MBTPS2 is an X-linked gene located on chromosome Xp22.11p22.13 and encodes a membrane-bound zinc metalloprotease (S2P, site-2 protease). This protease is associated with various intracellular signaling cascades, including regulated intramembrane proteolysis (RIP). RIP involves cleavage of membrane-spanning regulatory proteins by proteases within the plane of the membrane [35, 36]. Only a few patients have been identified carrying mutation in this gene and present with a moderate to severe OI phenotype (OI XIX) [37]. The cyclic adenosine monophosphate (AMP) responsive element binding protein 3-like 1 (CREB3L1) gene codes for the ER stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. It is a basic leucine zipper (bZIP) transcription factor which belongs to the conserved family of the cyclic AMP responsive element binding protein/activating transcription factor (CREB/ATF) genes. OASIS is processed by regulated RIP in response to ER stress and is highly expressed in osteoblasts. Мutations in this gene result in reduced collagen production in bone but not in the skin cells of affected patients. This is partly accompanied by an altered composition and hypermineralization of the bone matrix. Patients with a biallelic mutation

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usually present a moderate to a severe clinical course, often with prenatal fractures and shortening of the long bones (OI XVI) [37]. Furthermore, it was demonstrated that deficiency of OASIS affects transcription of several bone-associated genes (COL1A1, COL1A2, ALPL, IBSP and OPN), reduces glycosaminoglycan levels in bone EСM and has negative effects on osteoblasts [38, 39]. The SPARC gene encodes osteonectin, a monomeric glycoprotein that binds collagen and other ECM proteins (activin, inhibin, heparin, and proteoglycans). On collagen binding, SPARC undergoes a conformational change in its EC domain, creating a deep pocket that accommodates the phenylalanine residue of the trailing collagen chain (‘‘Phe pocket’’). The SPARC variants gave rise to type XVII OI phenotype. SPARC was proposed to cooperate with HSP47, ensuring that only properly folded procollagen molecules exit the ER. The protein is expressed mainly in cells with high rates of ECM production in bone [40]. In the extracellular space, SPARC mediates EСM-cell interactions and promotes mineralization of the EСM by binding to collagen and hydroxyapatite. Thus, SPARC fulfills multiple roles in maintaining bone mass and quality. SP7 gene encodes the osteoblast-specific transcription factor SP7 (or osterix). Osterix initiates the differentiation of preosteoblasts into osteoblasts as well as osteocytes. Mutations in SP7 is associated with OI type XII. These patients show increased bone porosity, which could possibly be attributed to increased trabecular bone remodeling due to impaired balance between bone formation by osteoblasts and bone resorption by osteoclasts [41]. WNT1 gene codes the Wingless Type MMTV Integration Site Family, Member 1 (WNT1). In bone, WNT signaling pathways are involved in the differentiation of MSC progenitors into osteoblasts. Though not all aspects of WNT signaling in bone are fully understood, recent work in a conditional mouse model suggesting suggests that the osteocytes are the primary source of WNT1 in bone and that WNT signaling from osteocytes to osteoblasts is disturbed by OI-causing

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WNT1 variants [42]. Variants in WNT1 causes the OI (OI Type XV) with a very heterogeneous clinical severity [43].

REGULATION OF EXTRACELLULAR MATRIX MINERALIZATION OR OSTEOCLAST FUNCTION Mutations in three genes that have been linked to OI are implicated in the regulation of EСM mineralization or osteoclast function. In contrast to the bone-forming osteoblasts, a disturbed balance of bone formation and resorption inevitably will result in defective bone homeostasis. The collagen fibers form a scaffold on which, with the help of proteoglycans, hydroxyapatite crystals mineralize [44]. IFITM5 encoding for the homonymous protein interferon-induced transmembrane protein-5, also known as bone-restricted IFITM-like (BRIL) - bone-restricted interferon-induced transmembrane protein-like protein), is a member of the IFITM family. It has a single transmembrane domain with an extracellular C-terminus and localized predominantly to the osteoblast plasma membrane. BRIL is highly expressed in osteoblasts and developing bone and is not detectable in either chondrocytes or osteocytes; low expression occurs in fibroblast. The first known and most common mutation in humans (5′-non-translated region, new start codon), which results in gain-of-function, is responsible for the typical OI type V clinical symptoms, however a de novo IFITM5 mutation was reported in a child with clinical features of type III/IV OI. The function of IFITM5 is still not fully understood but it supposedly plays a role in osteoblast differentiation and bone mineralization. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a 50kDa secreted glycoprotein. PEDF belongs to the Serpin family of serine protease inhibitors but does not have protease inhibitory activity. It is a potent anti-angiogenic factor expressed by a wide range of cells, including chondrocytes throughout the growth plate, osteoblasts, and mesenchymal stem cells.

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In bone, it induces the expression of osteoprotegerin, a physiological inhibitor of osteoclastogenesis, through blockade of RANKL functions at many levels to maintain bone homoeostasis and regulate osteoid mineralization. PEDF interacts with two sites on type I collagen. A lossof-function mutation in SERPINF1 leads to an increased differentiation and activation of osteoclasts, mediated by the misregulated RANKL/osteoprotegerin system. Thus, an increased degradation of bone mass takes place. Patients with PEDF deficiency have a recessively inherited severe skeletal phenotype due to a mineralization defect, referred to as type VI OI. PLS3 codes for the cytoskeletal protein plastin-3 (also known as Tplastin) that is ubiquitously expressed, including all bone cell types, and appears to play a role in bone formation, mineralization, and resorption. In 2013, mutations in PLS3 were identified in five families with X‐linked osteoporosis [44]. Recently, several cases of OI with classical clinical manifestations in hemizygous men and a variable phenotype in heterozygous women, but without an obvious link to collagen, were attributed to mutations in PLS3 gene. The underlying molecular mechanism for its roles in the regulation of skeletal development remains unknown [44, 45]. More recently, PLS3 has been suggested to have a role in the mineralization process and the overactivity of osteoclasts as a partial reason for the developing of this phenotype. TENT5A encodes the terminal nucleotidyltransferase 5A [45]. The expression of the gene in osteoblasts suggests a role in bone homeostasis and a previously unknown function of this enzyme in mineralized tissue was described [46]. Mutations in the gene TENT5A (formerly known as FAM46A), were described as disease-causing in three moderately to severely affected patients with OI XVIII [47]. TENT5A may regulate the expression of secreted proteins in osteoblasts, presumably involved in bone formation, dysfunction of which could lead to a bone-related phenotype.

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CONCLUSION In this chapter, we summarized information on the results of studies in the field of genetic aspects of OI and reflected the current state of the classification criteria for diagnosing the disease. It is a well-established fact that OI is mainly caused by mutation in collagens genes, however more than 20 causative genes have been described to date and the list will be growing constantly. The study of these genes has also provided novel insights into our understanding of the process of bone formation and mineralization. Clarification of the biochemical and molecular mechanisms underlying the pathogenesis of OI and OI-related diseases could significantly impact novel drug discovery for targeted-mechanism based treatments. Further research will help to guide genetic counseling, as well as therapeutic decision-making.

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[29] Ward, L. M., Rauch, F., Travers, R., Chabot, G., Azouz, E. M., Lalic, L., Roughley, P. J. & Glorieux, F. H. (2002). Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone., 31(1), 12-18. [30] Alanay, Y., Avaygan, H., Camacho, N., Utine, G. E., Boduroglu, K., Aktas, D., Alikasifoglu, M., Tuncbilek, E., Orhan, D., Bakar, F. T., Zabel, B., Superti-Furga, A., Bruckner-Tuderman, L., Curry, C. J., Pyott, S., Byers, P. H., Eyre, D. R., Baldridge, D., Lee, B., Merrill, A. E., Davis, E. C., Cohn, D. H., Akarsu, N. & Krakow, D. (2010). Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet., 86(4), 551-559. [31] Lu, W., Liu, C. C., Thottassery, J. V., Bu, G. & Li, Y. (2010). Mesd is a universal inhibitor of Wnt coreceptors LRP5 and LRP6 and blocks Wnt/beta-catenin signaling in cancer cells. Biochemistry., 49(22), 4635-4643. [32] Claeys, L., Storoni, S., Eekhoff, M., Elting, M., Wisse, L., Pals, G., Bravenboer, N., Maugeri, A. & Micha, D. (2021). Collagen transport and related pathways in Osteogenesis Imperfecta. Hum Genet., 140(8), 1121-1141. [33] van Dijk, F. S., Semler, O., Etich, J., Köhler, A., Jimenez-Estrada, J. A., Bravenboer, N., Claeys, L., Riesebos, E., Gegic, S., Piersma, S. R., Jimenez, C. R., Waisfisz, Q., Flores, C. L., Nevado, J., Harsevoort, A. J., Janus, G. J. M., Franken, A. A. M., van der Sar, A. M., Meijers-Heijboer, H., Heath, K. E., Lapunzina, P., Nikkels, P. G. J., Santen, G. W. E., Nüchel, J., Plomann, M., Wagener, R., Rehberg, M., Hoyer-Kuhn, H., Eekhoff, E. M. W., Pals, G., Mörgelin, M., Newstead, S., Wilson, B. T., Ruiz-Perez, V. L., Maugeri, A., Netzer, C., Zaucke, F. & Micha, D. (2020). Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. Am J Hum Genet., 107(5), 989-999.

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[34] Stürznickel, J., Jähn-Rickert, K., Zustin, J., Hennig, F., Delsmann, M. M., Schoner, K., Rehder, H., Kreczy, A., Schinke, T., Amling, M., Kornak, U. & Oheim, R. (2021). Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX. J Bone Miner Res., 36(6), 1077-1087. [35] Murakami, T., Kondo, S., Ogata, M., Kanemoto, S., Saito, A., Wanaka, A., Imaizumi, K. (2006). Cleavage of the membranebound transcription factor OASIS in response to endoplasmic reticulum stress. J Neurochem., 96(4), 1090-1100. [36] Lindert, U., Cabral, W. A., Ausavarat, S., Tongkobpetch, S., Ludin, K., Barnes, A. M., Yeetong, P., Weis, M., Krabichler, B., Srichomthong, C., Makareeva, E. N., Janecke, A. R., Leikin, S., Röthlisberger, B., Rohrbach, M., Kennerknecht, I., Eyre, D. R., Suphapeetiporn, K., Giunta, C., Marini, J. C. & Shotelersuk, V. (2016). MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun., 7, 11920. [37] Symoens, S., Malfait, F., D’Hondt, S., Callewaert, B., Dheedene, A., Steyaert, W., et al. (2013) Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J Rare Dis., 8(1), 154. [38] Lindahl, K., Åström, E., Dragomir, A., Symoens, S., Coucke, P., Larsson, S., Paschalis, E., Roschger, P., Gamsjaeger, S., Klaushofer, K., Fratzl-Zelman, N. & Kindmark, A. (2018). Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASISdeficiency to survive infancy. Bone., 114, 268-277. [39] Guillemyn, B., Kayserili, H., Demuynck, L., Sips, P., De Paepe, A., Syx, D., Coucke, P. J., Malfait, F. & Symoens, S. (2019). A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta. Hum Mol Genet., 28(11), 1801-1809.

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[40] Mendoza-Londono, R., Fahiminiya, S., Majewski, J., Care4Rare Canada Consortium, Tétreault, M., Nadaf, J., Kannu, P., Sochett, E., Howard, A., Stimec, J., Dupuis, L., Roschger, P., Klaushofer, K., Palomo, T., Ouellet, J., Al-Jallad, H., Mort, J. S., Moffatt, P., Boudko, S., Bächinger, H. P. & Rauch, F. (2015). Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet., 96(6), 979-985. [41] Fiscaletti, M., Biggin, A., Bennetts, B., et al. (2018). Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone., 110, 66-75. [42] Joeng, K. S., Lee, Y. C., Lim, J., Chen, Y., Jiang, M. M., Munivez, E., Ambrose, C. & Lee, B. H. (2017). Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest., 127, 2678-2688. [43] Kubota, T., Michigami, T. & Ozono, K. (2009). Wnt signaling in bone metabolism. J Bone Miner Metab., 27, 265-271. [44] van Dijk, F. S., Zillikens, M. C., Micha, D., Riessland, M., Marcelis, C. L., de Die-Smulders, C. E., Milbradt, J., Franken, A. A., Harsevoort, A. J., Lichtenbelt, K. D., Pruijs, H. E., RubioGozalbo, M. E., Zwertbroek, R., Moutaouakil, Y., Egthuijsen, J., Hammerschmidt, M., Bijman, R., Semeins, C. M., Bakker, A. D., Everts, V., Klein-Nulend, J., Campos-Obando, N., Hofman, A., te Meerman, G. J., Verkerk, A. J., Uitterlinden, A. G., Maugeri, A., Sistermans, E. A., Waisfisz, Q., Meijers-Heijboer, H., Wirth, B., Simon, M. E. & Pals, G. (2013). PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med., 369(16), 1529-1536. [45] Gewartowska, O., Aranaz-Novaliches, G., Krawczyk, P. S., Mroczek, S., Kusio-Kobiałka, M., Tarkowski, B., Spoutil, F., Benada, O., Kofroňová, O., Szwedziak, P., Cysewski, D., Gruchota, J., Szpila, M., Chlebowski, A., Sedlacek, R., Prochazka, J. & Dziembowski, A. (2021). Cytoplasmic polyadenylation by TENT5A is required for proper bone formation. Cell Rep., 35(3), 109015.

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[46] Kamioka, H., Sugawara, Y., Honjo, T., Yamashiro, T. & TakanoYamamoto, T. (2004). Terminal differentiation of osteoblasts to osteocytes is accompanied by dramatic changes in the distribution of actin-binding proteins. J Bone Miner Res., 19(3), 471-478. [47] Doyard, M., Bacrot, S., Huber, C., Di Rocco, M., Goldenberg, A., Aglan, M. S., Brunelle, P., Temtamy, S., Michot, C., Otaify, G. A., Haudry, C., Castanet, M., Leroux, J., Bonnefont, J. P., Munnich, A., Baujat, G., Lapunzina, P., Monnot, S., Ruiz-Perez, V. L. & Cormier-Daire, V. (2018). FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet., 55(4), 278-284.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 2

СLINICAL CLASSIFICATION OF OSTEOGENESIS IMPERFECTA: SOMATIC ISSUES IN CHILDREN WITH OSTEOGENESIS IMPERFECTA. MEDICAL TREATMENT FOR CHILDREN WITH OSTEOGENESIS IMPERFECTA Nato Vashakmadze1,2,, MD, PhD, Natalia Zhurkova2, MD, PhD, Anastasia Rykunova2, MD, Tatiana Ryabykh3, MD and Leyla Namazova-Baranova1,2, MD, PhD 1

Pirogov Russian National Research Medical University, Moscow, Russia 2 Central Clinical Hospital of the Russian Academy of Sciences, Moscow, Russia 3 National Ilizarov Medical Research Centre for Traumatology and Orthopaedics, Kurgan, Russia



Corresponding Author’s E-mail: [email protected].

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ABSTRACT The chapter describes classification of osteogenesis pathology. In the second part of management for osteogenesis exposed as well.

the pathogenesis, modern clinical imperfecta, and semiotics of somatic the chapter, the modern therapeutic imperfecta in children and adults are

Keywords: osteogenesis imperfecta, somatic issues, cardiopulmonary dysfunction, therapy bisphosphonate treatment

INTRODUCTION Osteogenesis imperfecta (OI) – is a genetically heterogeneous group of rare hereditary diseases arising from impaired synthesis of bone and connective tissue, which caused by mutations in genes encoding collagen synthesis, post-translational collagen modification, bone mineralization, and impaired osteoblast differentiation.

Pathogenesis Collagen type I consists of three polypeptide chains: 2 - α1, 1- α2, which form a triple helix. In order for its structure to form correctly, collagen chains must have glycine in the third position (Х-Y-Gly). When mutations occur in the COL1A1 or COL1A2 genes, the collagen structure changes [1]. The cells produce both abnormal and normal collagen. Depending on the abnormal forms of collagen amount, which of the chains, α1 or α2, is more affected, as well as which section of the triple helix has an abnormal structure, severe, lethal clinical forms of osteogenesis imperfecta arise, and lighter ones, with a relatively favorable course. Collagen fibers should be in a certain direction, and the crystals of hydroxyapatite, which are between them, should ensure the

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strength and stability of this structure. In mild types of osteogeneses imperfecta, electron microscopy reveals deformation of the endoplasmic reticulum and a decrease in the size of collagen fibers, while the number of osteoclasts and osteocytes remains within normal limits [2]. In severe types of osteogeneses imperfecta, collagen bundles of various diameters are formed, the structure of osteoblasts is disturbed, hyperosteocytosis, thinning of the cortical layer and defect in growth plates [3]. When the structure of type I collagen is disturbed, patients show not only increased bone fragility and frequent fractures, but also otosclerosis, imperfect dentinogenesis, and blue sclera.

CLASSIFICATION Over the past 15 years, as a result of studying the genome of patients with OI, new causes of the disease development have been established: mutations in the genes of proteins involved in post-translational modification, chaperone attachment, folding and cross-linking of collagen. The discovery of new genes has significantly improved understanding of the cellular and biological pathogenesis of OI development [4]. In patients with OI, changes were also found in the process of bone tissue formation, which are associated not with collagen, but with impaired bone mineralization, differentiation, and functioning of osteoblasts. Autosomal recessive, X-linked and additional autosomal dominant inheritance pathways were identified. In 2000, the first mutation in the IFITM5 gene with an autosomal dominant inheritance pathway was discovered which characterized by the formation of hypertrophic callus and ossification of the interosseous membrane [5-7]. In 2006, Morello et al. described the first mutation with an autosomal recessive inheritance in the CRTAP gene [8]. Now discovered that mutation in 18 genes can lead to phenotypic manifestations of OI. Disturbance of post-translational collagen modification and hydroxylation defect are caused by genes CRAPT, LEPRE1, PPIB;

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violation of bone formation and mineralization - IFITM5, SERPINF1; terminal propeptide cleavage defect - BMP1; violation of interaction with chaperones and collagen crosslinking - SERPINH1, FKBP10, PLOD2; impaired differentiation and functioning of osteoblasts - SP7, TMEM38B, WNT1, CREB3L1, SPARC, MBNPS2. Over 1500 mutations found, all of them are listed in the OI variability database. According to OMIM (Online Mendelian Inheritance in Man) database, there are 21 types of osteogenesis imperfecta. OI, type I. The disease caused by mutations in the COL1A1 and COL1A2 genes. Inheritance - autosomal dominant. The main clinical manifestations: multiple fractures, onset in period active movements and walking of the child, fractures often cure without deformities, blue sclera, dentinogenesis imperfecta, progressive hearing loss, and otosclerosis. OI, type II. The disease caused by mutations in the COL1A1 and COL1A2 genes. Inheritance - autosomal dominant. The main clinical manifestations: nonimmune hydrops, premature birth, short stature, sort limbs, blue sclera, beaked nose, multiple fractures at birth, absent calvarial mineralization, large fontanelles, wormian bones, beaded ribs, severe spine, chest, ribs, femurs, limbs deformities, platyspondyly, pulmonary insufficiency, cardiac anomaly. Perinatal lethal or early lethal disease [9]. OI, type III. The disease caused by mutations in the COL1A1 and COL1A2 genes. Inheritance - autosomal dominant. The main clinical manifestations: short stature, triangular face, micrognathia, blue sclera, which become of a normal color as they grow older, dentinogenesis imperfecta, multiple fractures at birth, scoliosis, kyphosis, codfish vertebrae, Short deformed femurs, pulmonary hypertension. OI, type IV. The disease caused by mutations in the COL1A1 and COL1A2 genes. Inheritance - autosomal dominant. The main clinical manifestations are short stature, hearing loss, otosclerosis, dentinogenesis imperfecta, multiple fractures, kyphosis, and scoliosis, flattened vertebrae, bowing of lower and upper extremities. A mild course of the disease described in some patients.

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OI, type V. The disease caused by mutations in the IFITM5 gene. Inheritance - autosomal dominant. The main clinical manifestations: blue sclera, multiple and frequent fractures, moderate to severe bone fragility, wedge-shaped vertebrae, biconcave vertebrae, deformity of the limbs of varying severity, with the formation of hyperplastic callus, after fractures and ossification of the interosseous membrane on the forearm, which can lead to secondary dislocation of the head radius bone [10]. OI, type VI. The disease caused by mutations in the SERPINF1 gene. Inheritance - autosomal recessive. The main clinical manifestations: short stature, bowing and shortening of upper and limbs, multiple fractures, humerus and femurs, osteopenia, increased alkaline phosphatase. The severity of the disease ranges from severe to mild. Blue sclerae. OI, type VII. The disease caused by mutations in the CRTAP 1 gene. Inheritance - autosomal recessive. The main clinical manifestations are normal weight and height at birth, then - short stature, platyspondyly, vertebral compression fractures, shortening of the limbs, impaired skull mineralization, multiple fractures, deformation of the chest, ribs and spine, osteopenia, blue sclera, developmental delay, respiratory failure. In some cases - death in the neonatal. OI, type VIII. The disease caused by mutations in the P3H1 gene (LEPRE1). Inheritance - autosomal recessive. The main clinical manifestations: short stature, shortening of the limbs, impaired skull mineralization, multiple fractures, deformity of the chest and spine, osteopenia, blue sclera, developmental delay. OI, type IX. The disease caused by mutations in the PPIB gene. Inheritance - autosomal recessive. The main clinical manifestations: short stature, shortening of the limbs, multiple fractures at birth, deformity of the limbs, kyphosis, gray sclera. OI, type X. The disease caused by mutations in the SRPINH1 gene. Inheritance - autosomal recessive. The main clinical manifestations: delayed physical development, triangular face, relative macrocephaly, bitemporal narrowing, midface hypoplasia, blue sclerae, micrognathia, narrow chest, multiple fractures, severe skeletal deformities, osteopenia,

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blue sclera, dentinogenesis imperfecta, skin abnormalities, inguinal hernias, kidney stones. OI, type XI. The disease caused by mutations in the FKBP10 gene. Inheritance - autosomal recessive. The main clinical manifestations: Brachycephaly, triangular face, multiple fractures, deformation of long bones, compression fractures of the spine, osteopenia, increased blood alkaline phosphatase. The severity of skeletal deformities ranges from mild to severe. OI, type XII. The disease caused by mutations in the BMP1 gene. Inheritance - autosomal recessive. The main clinical manifestations: short stature, chest deformity, clavicle deformity, multiple fractures, curvature, limb shortening, hypermobility syndrome, umbilical hernia, increased bone density. The severity of skeletal deformities ranges from mild to severe. OI, type XIII. The disease caused by mutations in the SP7 gene. Inheritance - autosomal recessive. The main clinical manifestations: short stature, chest deformity, deformity of the clavicles, multiple fractures, curvature, shortening of the limbs, hypermobility syndrome, umbilical hernia, increased bone density. OI, type XIV. This disease caused by mutations in the TMEM38B gene. Inheritance - autosomal recessive. The main clinical manifestations: multiple fractures of the limbs, osteopenia. OI, type XV. The disease caused by mutations in the WNT1 gene. Inheritance - autosomal dominant, autosomal recessive. The main clinical manifestations Severe deformities of the skeleton, multiple fractures of upper and lower limbs, spine, thinning of the ribs, platyspondyly, impaired mineralization of the cranial vault, decreased bone density. Development delay, brain malformation: unilateral cerebellar hypoplasia, pontine hypoplasia, optic chiasm hypoplasia, hypoplasia of the hypothalamus, chizencephaly, congenital absence of the vermis. OI, type XVI. The disease caused by mutations in the CREB3L1 gene. Inheritance - autosomal recessive. The main clinical manifestations: short stature, pronounced deformities of the chest, spine,

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limbs, impaired skull mineralization, shortening and curvature of the limbs, callus formation, tooth agenesis. OI, type XVII. The disease caused by mutations in the SPARC gene. Inheritance - autosomal recessive. The main clinical manifestations are scoliosis, compression fractures of the spine, platyspondyly, multiple fractures, curvature of long bones, joint hypermobility, muscle hypotonia, muscle weakness. OI, type XVIII. The disease caused by mutations in the TENT5A gene. Inheritance - autosomal recessive. The main clinical manifestations: blue sclera, multiple fractures, poor mineralization, thin cortex of bones, bowing of long bones, motor developmental delay. OI, type XIX. The disease caused by mutations in the MBTPS2 gene. Inheritance - X-linked recessive. The main clinical manifestations: blue sclera, rib and clavicular fractures, often - prenatal, chest deformity, scoliosis, flat biconcave vertebral bodies, shortening of the upper and lower extremities, short stature, osteopenia, calcification of the epiphyses. The severity of the disease ranges from severe to milder. OI, type XX. The disease caused by mutations in the MESD gene. Inheritance - autosomal recessive. The main clinical manifestations: features of the phenotype, multiple fractures of the ribs (at birth, in the neonatal period), narrow chest, spinal fractures, rhizomelia, deformation of the limbs, extremities, impaired skull mineralization, impaired tooth growth. OI, type XXI. The disease caused by mutations in the KDELR2 gene. Van Dijk F.S. [11] described the disease in 2020. The type of inheritance is autosomal recessive. The main clinical manifestations: short stature, small, crumbling teeth, caries, barrel-shaped deformity of the chest, multiple fractures, impaired skull mineralization, deformity and fractures of the spine, curvature and shortening upper and lower limbs, flat feet, joint hypermobility, impaired bone mineralization, muscle hypotonia. Bruck syndrome, type 2. The disease caused by mutations in the PLOD2 gene. The type of inheritance is autosomal recessive. The main clinical manifestations of the disease: short stature, chest deformity, multiple fractures, bone fragility, congenital joint contractures, joint

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hypermobility, progressive spinal deformity, osteoporosis, femoral bowing, limb deformities, knees, elbows pterygium.

Cardiovascular System Issues in Children with OI Damage to the cardiovascular system was described in patients with type II OI. Chronic heart failure is more common. Children diagnosed as OI type VII showed the absence of a pulmonary artery and hypoplasia of the pulmonary veins. In several patients with type XII, pulmonary venous hypoplasia was revealed. In children with osteogenesis imperfecta, type I, mitral valve prolapse was detected [12]. According to several studies, in adult patients with OI, valvular insufficiency, including mitral valve insufficiency and aortic root dilatation are often detected. Several adult patients, who required aortic valve replacement, are described in the literature [13]. In another study, echocardiogram and ECG were carried out in 46 children and young adults aged from 3 to 23 years old with OI type III (progressive) and OI type IV (moderately severe) [14]. In particular, 23 patients (11 boys, 12 girls) represented osteogenesis imperfecta, type III and 23 cases (8 boys, 15 girls) with type IV OI. The defeat of the heart valves was detected in 78% (18/23) of cases in patients of both groups. The most common regurgitation was the tricuspid valve. Two patients with type III osteogenesis imperfecta and 10 patients with type IV showed regurgitation on the mitral, aortic and pulmonary artery valves in combination with tricuspid regurgitation. Isolated mitral regurgitation was diagnosed in two patients. In three children with OI, type II, ASD and pulmonary valve regurgitation were detected. Mild left atrial hypertrophy was diagnosed in two patients with type III. Cardiac arrhythmias were also found in patients of the examined groups: in one patient with type III and in three patients with type IV, premature atrial contraction was revealed, in seven patients (5 of them with type III) sinus tachycardia with right ventricular overload. For this reason, the

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echocardiogram is needed for all patients with OI to detect early any pathology of the cardiovascular system and prescribe adequate therapy.

Lung Involvement in Patients with OI Lung pathology is quite common in patients with moderate and severe forms of OI [14]. Patients show pronounced deformities of the chest and spine, as well as changes in the structure of the lung parenchyma due to a violation of the structure of collagen. Obstructive pulmonary disease, breathing disorders during sleep, chronic bronchopulmonary infections, often leading to bronchiectasis are frequent conditions in patients with OI. Multiple chest deformities and low stature of patients present additional difficulties in the diagnosis and treatment of bronchopulmonary infections. According to the OMIM database, lung pathology is most often described in patients with type II OI, type III OI, and type X OI. Patients with OI type III have pulmonary hypertension. Thiele et al. [14] studied the state of lungs in children with severe and moderate OI. The study was carried out in 46 patients with types III (23 people) and IV types (23 people) at the age of 3-23. Scoliotic deformity of the spine > 10 ° according to Cobb, that required surgical correction, was discovered in 36 patients. This group of patients showed a progressive decrease in the forced vital capacity of the lungs and the vital capacity of the lungs as scoliosis progressed. A decrease in lung function was also detected in patients with scoliosis A mutation in the COL1A2 gene was identified in her. The girl who received the MSC felt well enough. Until the age of 8, she sustained 5 hip fractures, 2 clavicles, 1 shoulder fracture and 1 skull fracture and 11 compression fractures of the vertebrae, with an increase in their number by the age of 8. She continued to have low growth, although growth rates were normal during the first 6 years and worsened by 8 years. At the age of 8, she underwent a second MSC transplant. In the next 2 years, no new fractures were noted. At the age of 11-13, to improve growth performance, the patient received another dose of MSC from the same donor, improved mobility and linear growth (-6 SD). The patient assesses her well-being at the age of 17 as good [52]. In another case, MSCs were transplanted to a fetus with type IV OI, who had multiple fractures prenatally at 26 weeks of gestation. The fetus and the pregnant woman tolerated the procedure well; no new fractures found in the fetus during the entire pregnancy. In the first month of her life, the girl started therapy with bisphosphonates due to impaired bone mineralization. A molecular genetic examination was carried out a c.659G> A mutation in the COL1A2 gene was detected. In the first year of life, the patient's height was just below the 3rd percentile. Retransplantation of MSCs was performed at the age of 1 year and 6 months, after which growth normalized. The patient is 10 years old now [53]. A clinical survey is currently underway in Europe to study increased fragility of bones before birth (BOOSTB4). This is a study investigating MSC transplantation as a treatment for severe forms of OI (type III and severe type IV). At the first stage (phase I/II), a multicenter study carried out to assess the safety and tolerability of this method of therapy in the fetus, pregnant woman, and newborn. At the second stage, the effectiveness of treatment will be assessed: the frequency of fractures, the severity of fractures, the number of fractures at birth, height, bone

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mineral density, biochemical markers of bone tissue disorders and the clinical condition of patients. The study included three groups of patients: 1 child who received four doses of MSCs during labor at a dose of 3 × 10 6 MSCs/kg body weight (n = 15); 2 children who received one dose prenatally and three doses after birth at a dose of 3 × 10 6 MSC/kg body weight (n = 15); 3 anamnestic and prospective controls (n = 30 - 150). All patients taking part in the study will receive MSCs; there will be no group randomization.

Calcium and Vitamin D In a controlled randomized trial, calcium and vitamin D supplementation is associated with a reduced risk of fracture. T. Edouard et al. proved that the content of vitamin D in blood serum positively correlates with bone mineral density (BMD). Consumption of 1300 mg of calcium and 600-800 IU of vitamin D per day is sufficient in most cases, according to international recommendations [46].

Growth Hormone The use of osteoanabolic agents in children with OI is of great interest because of their frequent short stature. Despite the normal parameters of growth hormone (GH) in the blood, when it was used in children with OI types I and IV, an increase in growth parameters and the volume of formed bone tissue was recorded, in contrast to patients with type III, who did not have significant changes [47].

TGF-β Inhibitor Transforming growth factor beta regulates the function of osteoclasts and osteoblasts. The experimental study showed that an increased activity

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of TGF-β plays an important role in the formation of the OO phenotype, and antibodies to TGF-β had an inhibitory effect on osteoclasts [48].

Сombination Therapy Currently, the synergistic effect of anabolic and antiresorptive therapy is being actively studied [49].

Cell Therapy Transplantation of mesenchymal stem cells (MSCs) in patients with OI is a promising method of treatment that can be performed in the neonatal period, as well as, according to a number of studies, prenatally for severe types of OI [50]. The high efficiency of MSCs in severe types of OI prenatally or at an early age is associated with the possibility of normal collagen production after infusion. Study of models of bone tissue in mice shows that 2% of grafted donor cells lead to the synthesis of 20% collagen of normal structure [50, 51, 52, 53].

CONCLUSION Osteogenesis imperfecta represented by a heterogeneous group of rare hereditary diseases resulting from an impaired synthesis of bone and connective tissue. Their phenotypic expression determines the clinical manifestation. Like any systemic disease, OI affects all organs and systems, the damage of which varies depending on the type and severity. The target for OI is damage to the skeleton, cardiovascular system, lungs and eyes. Moreover, all patients with OI require clinical screening for the manifestation of somatic pathology, especially at the stages of orthopedic surgical treatment. Therapeutic approaches are currently investigated;

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bisphosphonate therapy is the basic therapy with proven efficacy. Other approaches are in clinical trials or have limitations.

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[42] Biggin, A., Zheng, L., Briody, J. N., Coorey, C. P., Munns, C. F. (2015). The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta. Horm Res Paediatr., 83(3):183-189. [43] Orwoll, E. S., Shapiro, J., Veith, S., Wang, Y., Lapidus, J., Vanek, C., Reeder, J. L., Keaveny, T. M., Lee, D. C., Mullins, M. A. (2014). Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. Journal of Clinical Investigation, 124:491498. [44] Glorieux, F. H., Devogelaer, J. P., Durigova, M., Goemaere, S., Hemsley, S., Jakob, F., Junker, U., Ruckle, J., Seefried, L., Winkle, P. J. (2017). BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial. J Bone Miner Res., 32(7):1496-1504. [45] Mammadova, E. O., Grebennikova, T. A., Belaya, Zh. E., Rozhinskaya, L. Ya. (2018). Antibodies to sclerostin as a new anabolic therapy for osteoporosis. Osteoporosis and osteopathies., 21(3):21-29. [46] Edouard, T., Glorieux, F. H., Rauch F. (2011). Predictors and correlates of vitamin D status in children and adolescents with osteogenesis imperfecta. J Clin Endocrinol Metab., 96(10):31933198. [47] Antoniazzi, F., Monti, E., Venturi, G., et al. (2011). GH in combination with bisphosphonate treatment in osteogenesis imperfecta. Eur J Endocrinol., 163(3):479-487. [48] Grafe, I., Yang, T., Alexander, S., Homan, E. P., Lietman, C., Jiang, M. M., Bertin, T., Munivez, E., Chen, Y., Dawson, B., Ishikawa, Y., Weis, M. A., Sampath, T. K., Ambrose, C., Eyre, D., Bächinger, H. P., Lee, B. (2014). Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med., 20(6):670-675. [49] Antoniazzi, F., Monti, E., Venturi, G., Franceschi, R., Doro, F., Gatti, D., Zamboni, G., Tatò, L. (2010). GH in combination with

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[50]

[51]

[52]

[53]

[54]

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bisphosphonate treatment in osteogenesis imperfecta. Eur J Endocrinol., 163(3):479-487. Götherström, C., Walther-Jallow, L. (2020). Stem Cell Therapy as a Treatment for Osteogenesis Imperfecta. Curr Osteoporos., 18: 337343. Horwitz, E. M., Prockop, D. J., Gordon, P. L., Koo, W. W., Fitzpatrick, L. A., Neel, M. D., et al. (2001). Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood., 97(5):1227–1231. Horwitz, E. M., Gordon, P. L., Koo, W. K., Marx, J. C., Neel, M. D., McNall, R. Y., et al. (2002). Isolated allogeneic bone marrowderived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA., 99(13):8932–8937. Götherström, C., Westgren, M., Shaw, S. W., Aström, E., Biswas, A., Byers, P. H., Mattar, C. N., Graham, G. E., Taslimi, J., Ewald, U., Fisk, N. M., Yeoh, A. E., Lin, J. L., Cheng, P. J., Choolani, M., Le Blanc, K., Chan, J. K. (2014). Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a twocenter experience. Stem Cells Transl Med., 3(2):255-264. Le Blanc, K., Götherström, C., Ringdén, O., Hassan, M., McMahon, R., Horwitz, E., Anneren, G., Axelsson, O., Nunn, J., Ewald, U., Nordén-Lindeberg, S., Jansson, M., Dalton, A., Aström, E., Westgren, M. (2005). Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation., 79(11):1607-1614.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 3

THE CURRENT STATE OF MOLECULAR GENETIC DIAGNOSTICS IN VARIOUS FORMS OF OSTEOGENESIS IMPERFECTA Sergey Khalchitsky*, MD, Marina Sogoyan, Alina Li, Lavrentii Danilov, Vladislav Muldiyarov, Dmitry Buklaev, MD, PhD and Sergey Vissarionov, MD National Turner Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery, Saint-Petersburg, Russia

ABSTRACT Osteogenesis imperfecta (OI) is the most common hereditary form of bone fragility, a genetically and clinically heterogeneous disease with a wide range of clinical severity, often leading to disability from early childhood. It is based on genetic disorders leading to a violation of the structure of bone tissue, which leads to frequent fractures, impaired growth, and posture, with the development of characteristic disabling bone deformities and related problems, including respiratory, neurological, cardiac, renal failure, and hearing loss. OI occurs in both men and women; the disease is inherited both in an autosomal dominant *

Corresponding Author’s E-mail: [email protected].

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S. Khalchitsky, M. Sogoyan, A. Li et al. and autosomal recessive manner; there are sporadic cases of the disease caused by de novo mutations, as well as X-linked forms. Extensive molecular studies of the etiology of OI have been carried out over the past decade, and these advances are of direct relevance to the medical treatment of this disorder. In this chapter, we consider the history of the classification of OI depending on clinical, biochemical, and molecular genetic studies and the state of molecular genetic diagnostics of various forms of the disease from the first studies to the present.

Keywords: osteogenesis imperfecta, bone fragility, classification, molecular genetic research

INTRODUCTION Obviously, in modern orthopedic science at the present time, there is nothing more controversial and confusing than the classification of OI. Clinicians, biochemists, and geneticists argue about this. Here we will try to do our bit to clarify the truth in this debate. So, where did this problem come from, and how has its research and solution evolved? Osteogenesis imperfecta (ICD-10 code-Q78.0) is a genetic disease of bone tissue with genetic and clinical heterogeneity. The main cause is the disorder of bone tissue structure and physical quality determined by genetics, resulting in frequent fractures that are accompanied by the development of disabling bone deformities and related problems of the respiratory system, cardiovascular system, and neuromuscular system. OI occurs in both sexes; the incidence of the disease ranges from 1:10 000 to 1:30 000 newborns in different countries of the world. OI is the most common genetic bone disease in Russia: one case per 10–20 thousand newborns. The disease is inherited both in an autosomal dominant and autosomal recessive mode with a predominance of an autosomal dominant mode of inheritance with familial mosaicism; however, there are also sporadic cases of the disease caused by de novo mutations, and X-linked forms have also been found [1].

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Currently, 21 genes responsible for developing different forms of OI have been identified, and the search for new genes involved in the pathogenesis of the disease continues. Over the past some years, seven new genes have been identified that are involved in the pathogenesis of OI. The last gene was identified in 2020, and it is still not clear to what extent this disease is clinically and genetically heterogeneous. Genetic defects in OI cause defects in collagen synthesis, the structure of its chains, post-translational collagen modification, its correct folding into a triple helix, and stitching [2]. With OI, defects in bone mineralization and osteoblast differentiation are also observed. In connection with discovering new molecular causes of the disease, the diagnostic criteria are constantly being improved, and the classification of osteogenesis incomplete is being revised.

HISTORICAL ASPECTS OF THE OSTEOGENESIS IMPERFECTA CLASSIFICATION FROM CLINIC TO MOLECULAR DIAGNOSTICS Apparently, the earliest of the described cases of the disease were identified during the study of the mummified skeleton of a child from ancient Egypt, located in the British Museum in London, approx. 1000 BC [3]. Medical publications on the study of fragile bones and associated hearing loss began to appear as early as the 17th century. In 1788, Olaus Jacob Elkman described a family with the fragility of the skeletal system, which had features similar to the OI and named “Osteomalaciae Sistens.” But in fact, the first who described this disease in sufficient detail and gave it a name was J.F. Lobstein and W. Vrolik. In 1825 J.F. Lobstein cited information about three sick children of different ages who had long bone fractures for no apparent reason. He proposed to call this disease osteopsatirosis and devoted a whole chapter to it in his treatise on pathological anatomy.

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In 1849 W. Vrolik described under the name “osteogenesis imprfecta” a syndrome of the fragility of bones with multiple fractures that occurred in the prenatal period or immediately after birth. When studying the literature on this issue, one can trace how gradually the congenital fragility of bones stood out from the concept of rickets into an independent nosological form, and since 1900, many authors began to point out the genetic nature of this disease. Later, in 1906, E. Looser divided the state of OI into “early” or “congenital” and “later.” In 1896 J. Spurway drew attention to the fact that some patients with fragile bones also had blue sclera. E. Bronson, in 1917 noted the presence of familial deafness in people with fragile bones and blue sclera. In 1918, J. Hoeve and A. Kleyn described the presence of fragile bones in combination with the blue sclera and early deafness as a separate hereditary syndrome. In 1926 J. Key added to the symptoms of the disease also hypertonicity of the ligaments and hypermobility of the joints, which basically made up a complete clinical picture of OI. A group of experts in genetics, pediatrics, and pediatric radiology, at a meeting of the European Society of Paediatric Radiology, gathered in 1970 in Paris, developed the first “Nomenclature of Constitutional Diseases of Bone”, known as the Paris Nomenclature [4], and it was widely accepted and published. The purpose of this nomenclature was to standardize the terminology used to refer to the various entities that make up the group of constitutional or intrinsic bone diseases. Thereafter, the Paris Nomenclature was regularly updated and supplemented in 1977, 1983, 1992, 1997, 2001, 2005, 2010, 2015, and 2019. The first attempt at classification of OI was made by Sillence et al. [5] (1979) when it was proposed to subdivide the disease into four main types. This numerical classification was based on an analysis of clinical presentation and presumed inheritance pattern (Table 1). The types range from the lightest to the most severe. Since 1979, this classification system has become generally accepted throughout the world and continues to evolve as new information on the molecular pathogenesis of the disease becomes available.

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Table 1. Classification of OI by Sillence Type Clinical Features I Blue sclera, moderate bone fragility II Lethal in the perinatal period III White sclera, severe with progressive deformity IV White sclera, variable bone fragility MOI: Mode of Inheritance

MOI AD AR AR AD

By the 1980s, discoveries in collagen biochemistry and later in molecular biology had convincingly shown that the OI-congenita phenotype is usually the result of new dominant mutations [6, 7]. At that time, the accidental appearance in siblings was explained on the basis of gonadal mosaicism. Most cases of AD OI are caused by mutations in the COL1A1 and COL1A2 genes. These genes are located on chromosomes 17 and 7, respectively, and encode type I collagen polypeptide chains. A multiple-exon deletion in the collagen gene COL1A1 was discovered in 1983 [8], and in 1986 a heterozygous single nucleotide substitution in COL1A1 was identified as the cause of a form of OI that was lethal in infants and young children. The 2nd official revision of the Paris Nomenclature took place in 1991 at the International Working Group meeting on Bone Dysplasia in Bad Honnef [9]. At this time, the classification of OI was focused on radiological and morphological criteria and was based on the Sillence classification of four main types. The third official revision of the 1972 Paris Nomenclature for Constitutional Bone Diseases took place in 1997 in Los Angeles. In this version of the revised nomenclature, groups of disorders were grouped based on etiopathogenetic information regarding the gene and/or protein defect. 32 groups of conditions were listed, and OI was included in group 23, designated as low bone density dysplasias. The Sillens classification of 4 main types was retained, and mutations in the COL1A1 and COL1A2 genes were documented. Following the creation of the International Skeletal Dysplasia Society (ISDS) in 1999, corrections were prepared by a group of experts within the ISDS, and the term “nomenclature” was replaced by “nosology”.

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The next official revision took place in 2001 at Oxford and was published in 2002. This version included 33 groups of disorders, of which OI was placed in group 24. Two new subtypes of OI were included, namely type V, which was characterized by the presence of dislocations of the radial head and the formation of hyperplastic callus, as well as type VI, diagnosed with bone histology [10]. An extended Sillence classification was published in 2004 [11]. These authors added OI Types V-VII, in which the underlying genetic defects were initially unknown. Thereafter, following a comprehensive rediographic, bone morphologic, and molecular genetic analyse, an extended classification was published. In August 2009, in Boston, the Nosological Committee of the International Skeletal Dysplasia Society identified 456 genetic conditions and divided them into 40 groups, which were determined by molecular, biochemical, and/or radiographic criteria [12]. OI was given special attention in this session and was placed in group 25. At this stage, confusion arose, which was caused by the etiological complexity of various forms of OI. Therefore, the Nosological Committee proposed to adhere to the Sillence classification, which defines and classifies OI according to clinical characteristics and mode of inheritance, rather than molecular data, and this has been recommended in clinical practice [12]. Was also introduced “Working nosology”, where instead of Roman numerals, Arabic numerals are used. With the discovery of each new genetic determinant and the subsequent revision of the nomenclature, the Sillence classification expanded to include the documented types of OI to 15 [13]. The categories of OI I - OI IV were determined according to the radiological and clinical manifestations of the disorder, while OI V - OI XV were determined based on molecular data. However, it is important to note that the clinical manifestations of OI I - OI IV and OI V - OI XV are largely the same. In the 9th edition of Nosology, published in 2015, 436 diseases are listed in 42 groups and 364 determinant genes are registered [14]. OI remains in group 25 and the phenotype-based Sillence classification is

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still maintained. Type 5 OI has been added because it differs radiologically from other forms of OI. The nomenclature used for NFR is recommended in 2011. The number of genes documented in type 1 OI and type 2 OI remains the same as in 2011. Conversely, the number of genes involved in type 3 OI increased from 7 in 2011 to 15, while in type 4 OI the number of genes increased from 5 to 8. The gene and its associated protein in type 5 OI were identified [15]. The 2015 Nosology Committee concluded that OI is a classic skeletal disease in which molecular diagnostics depends on next-generation sequencing, although the prognosis is based on phenotypic observations. At this point, it became apparent that a detailed understanding of the molecular events required for collagen synthesis (COL1A1 and COL1A2), post-translational processing/modification (CRTAP, LEPRRE1, PPIB, and TMEM38B), folding, and crosslinking (SERPINH1, FKBP10, and PLOD2) is needed. Many key genes/proteins involved in the pathogenesis of OI have also been elucidated. It also became apparent that other non-collagen genes, especially CREB3L1 and SP7, play a role in osteoblast differentiation. To account for the rapidly growing list of novel genes associated with OI, Forlino, and Marini [16] proposed a functional metabolic classification scheme. It included both clinical and genetic information to determine the subtype of the pathological condition based on changes in intracellular or extracellular metabolic pathways. Disease classification based on molecular pathogenesis of the disease complicated the work of clinical doctors, and in 2016 the International Nomenclature Committee constitutional disorders of the skeleton (INCDS) has reduced the classification to 5 forms, retaining the 4 types that were originally described D. Sillence, and adding the 5th type. A total of five disease groups using Arabic numeric a system that indicates unifying phenotypes technical characteristics, and individual (inherent specific type) the changes are still saved its original Roman designation (Table 2). This classification leaves room to include new genes found as

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the causes of OI until it is identified the degree of heterogeneity of the disease. In the latest edition of Nosology (2019), pathogenic variants were listed for 92% (425/461) of the disorders that were included [17]. Previously, the percentage of diseases in which the causative gene was identified was 58% (215/372) in the 2006 revision [18], 69% (316/456) in the 2010 revision, and 88% (385/436) in the 2015 revision [14]. Unlike previous versions, the protein is not listed as it can be identified by the gene. The reference list of clinically confirmed conditions and their causative genes, presented in this 2019 edition of Nosology, can help clinicians make accurate diagnoses for their patients and help expand research in skeletal biology. Table 2. Classification of osteogenesis imperfecta Type I II

Type name Non-deforming type with blue sclera Perinatally fatal, severe

III

Progressively deforming, moderately severe

IV

Variable OI with blue sclera, medium heavy

V

Moderate OI with ossification of the interosseous membrane of the forearm MOI: Mode of Inheritance

Gene COL1A1, COL1A2, SP7, BMP1, P3H1, PLS3 COL1A1, COL1A2, CRTAP, P3H1, CREB3L1, PPIB, BMP1 COL1A1, COL1A2, BMP1, CRTAP, FKBP10, P3H1, PLOD2, PPIB, SERPINF1, SERPINH1, TMEM38B, WNT1, CREB3L1, FAM46A COL1A1, COL1A2, WNT1, CRTAP, PPIB, SP7, PLS3, TMEM38B, FKBP10, SPARC IFITM5

MOI AD, X-linked AD, AR AD, AR

AD, AR, Xlinked AD

OI is included in category 25, “Osteogenesis imperfecta and low bone density” (Table 3). Although the phenotypically based Sillence classification persists, the OI classification has expanded to twenty types with the latest addition of mutations in MESD, resulting in a progressive deforming OI phenotype. Two new genes have been identified, SPARC [19] and TENT5A [20], which are included as causal genes in OI 3.

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Table 3. Category 25: Osteogenesis imperfecta and decreased bone density group [17] Name of Disorder

MOI

OMIM No.

Gene

OI type 1 OI type 2

AD AD AR AR AR AR AD AR AR AR AR AR AR AR AR AR/AD AR AR AR AR AD AD AR AR AR AR AD XL XL

166200 166200 610854 610915 259440 607723 259240 613982 610682 610915 259440 613848 610968 615066 112264 615220 616229 616507 617952 607783 166220 615220 610854 259440 610968 606633 610967

COL1A1, COL1A2 COL1A1, COL1A2 CRTAP LEPRE1 PPIP SUCO COL1A1, COL1A2 SERPINF1 CRTAP LEPRE1 PPIB SERPINH1 FKBP10 TMEM38B BMP1 WNT1 CREB3L1 SPARC TENT5A(FAM24A) MESD COL1A1, COL1A2 WNT1 CRTAP PPIB FKBP10 SP7 IFITM5 PLS3 MBTPS2

OI type 3

OI type 4

OI type 5 Osteoporosis X-linked form Osteporosis AD AD form AD MOI: Mode of Inheritance

300294 615220

WNT1 LRP5

Molecilar Diagnosis OMIM OI type I OI type II OI type VII Oi type VIII OI type IX SUN1 OI type III OI type VI OI type VII OI type VIII OI type IX OI type X OI type XI OI type XIII OI type XIV OI type XV OI type XVI OI type XVII OI type XVIII OI type XX OI type IV OI type XV OI type VII OI type IX Oi type XI OI type XII OI type V OI type XIX OI type XV

Clinical forms of X-linked osteoporosis and AD forms of osteoporosis are also included in group 25 [17]. In addition to the clinical form associated with the PLS3 gene, the recently identified MBTPS2 gene, in which mutations are now diagnosed as type XIX OI, is also implicated in the X-linked osteoporosis group [21]. The WNT1 and LRP5 genes are listed as participating in the pathogenesis of OI type XV and X-linked forms of AD osteoporosis, respectively [17]. The clinical

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form of OI with lesions of the calvarial doughnut lesions was found as a result of mutations in the SGMS2 gene [22]. Another rare type of familial osteoporosis, previously known as Levine-type OI, has been confirmed as a result of mutations in ANO5 gene [23].

Molecular Genetic Concepts of the Etiology and Pathogenesis of Osteogenesis Imperfecta OI is characterized by wide clinical and genetic heterogeneity. Previously, the disease was referred to as collagenopathies, since in most cases, the structure and function of the main protein of bone tissue, type I collagen, and its stability, are impaired. Later, in patients with OI, mutations were found in genes not involved in forming the structure and folding of collagen [24]. Currently, 21 genes have been identified that are responsible for the development of OI. Defects in most cases cause the autosomal dominant mode of OI inheritance in the COLIA1 or COLIA2 genes of type I collagen chains encoding the α1 (I) and α2 (I) peptide chains of type I collagen, respectively [25]. Autosomal dominant variants of inheritance of the disease have also been described in several patients in the case of mutations in the IFITM5 (MIM: 614757) and P4HB (MIM: 176790) genes. P4HB encodes the beta subunit of prolyl-4-hydroxylase, which involves prolyl hydroxylation and folding of procollagen [26]; and IFITM5 is an osteoblast-specific gene associated with matrix mineralization [27]. The IFITM5 gene is localized on chromosome 11 (p15.5) in a cluster of related genes (IFITM1, 2, 3, 10). It belongs to the family of genes encoding proteins containing two transmembrane domains that perform various significant cellular functions [28].

III, IV V

III

3p22.3 17q21.2 11p15.5

1p34.2

CRTAP – cartilage-associated protein

FKBP10 – 65kDa FK506-binding protein IFITM5 – bone-restricted interferoninduced transmembrane protein-like protein (BRIL; also known as IFM5) P3H1 – prolyl-3-hydroxylase 1

III

III, IV

15q22.31

17p13.3

PPIB – peptidyl-prolyl cis–trans isomerase B (PPIase B) SERPINF1 – pigment epitheliumderived factor (PEDF)

I, III, IV

8p21.3

IV

12q13.12

BMP1 – bone morphogenetic protein 1

IV

9q31.2

TMEM38B – trimeric intracellular cation channel type B (TRIC B; also known as TM38B) WNT1 – proto-oncogene Wnt-1 (WNT1)

III

12q13.13

SP7 – transcription factor SP7 (also known as osterix)

III, IV

I, II, III, IV

27q21.3

COL1A2 – collagen α2(I)

Type OI I, II, III, IV

Localization 17q21.33

Genes and their protein products COL1A1 – collagen α1(I)

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive

Autosomal recessive Autosomal recessive

Inheritance type Autosomal dominant Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant

Involved in bone mineralization

Involved in the functioning of osteoblasts and bone development Participates in the C-terminal processing of both procollagen protein chains Participates in post-translational modification of type I collagen

Participates in post-translational modification of collagen I Involved in the regulation of bone cell differentiation Involved in the transfer of divalent Ca

Expressed in skeletal tissue and is involved in bone formation

Participates in post-translational modification of collagen I Serves as collagen chaperones

Part of collagen type I

Function Part of collagen type I

9

5

20

4

6

5

16

2

11

7

52

Exons 52

38

17

11

36

6

2

69

2

39

32

604

Mutations 1035

Table 4. Characterization of genes and their protein products responsible for development of OI

5q33.1

6q14.1

IV

4q26

SEC24D – SEC24 homolog D, COPII coat complex component SPARC – osteonectin

FAM46A – family of similar sequences 46A 3 3

III, IV

3q24

PLOD2 – lysyl hydroxylase 2 (LH2)

III

III, IV

III

17q25.3

P4HB – prolyl 4-hydroxylase, subunit beta

II

I

Xq23

11p11.2

Type OI III, IV

Localization 11q13.5

CREB3L1 – old astrocyte specifically induced substance (OASIS; also known as CR3L1)

Genes and their protein products SERPINH1 – serpin H1 (also known as HSP47) PLS3 (plastin 3) – plastin 3

Autosomal recessive

Autosomal recessive Autosomal recessive Autosomal recessive

Autosomal dominant

Autosomal recessive

Inheritance type Autosomal recessive X-linked type

Table 4. (Continued)

Regulates the proliferation and interaction of cells and matrix by binding calcium ions with hydroxyapatite Function is not fully understood

Participates in the hydroxylation of lysine residues in collagen fibers; catalyzes the hydroxylation of proline residues in X-Pro-Gly repeats in the spiral domain of procollagen Participates in the hydroxylation of lysine residues in collagen fibers Function is not fully understood

The molecular function of plate-3 is not fully understood, may play a role in the differentiation of bone cells Regulates the formation of type I collagen in the process of bone formation

Function Is a collagen chaperone

3

10

25

23

11

13

21

Exons 7

3

2

7

10

2

4

11

Mutations 9

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OI is also transmitted by an autosomal recessive mode of inheritance, which is caused by mutations in the following genes: BMP1 (MIM: 112264) [29], CRTAP (MIM: 605497) [30], FKBP10 (MIM: 607063) [31], P3H1 (MIM: 610339) [32], PLOD2 (MIM: 601865) [33], PPIB (MIM: 123841) [34], SEC24D (MIM: 607186) [35], SERPINH1 (MIM: 600943) [36] and TMEM38B (MIM: 611236) [37] involved in posttranslational modifications, processing, coagulation, secretion, and crosslinking of type I procollagen. However, another group of OI loci has an autosomal recessive inheritance, which is not recognized as directly involved in the biosynthesis of type I collagen but plays a role in the mineralization or development of osteoblasts. This group of genes includes CREB3L1 (MIM: 616215) [38], SERPINF1 (MIM: 172860) [39], SP7 (MIM: 606633) [40], SPARC (MIM: 182120) [41] and WNT1 (MIM: 164820) [42;43]. Finally, mutations in the PLS3 (MIM: 300131) [44] and MBTPS2 (MIM: 300294) genes have been associated with two different forms of X-linked forms of OI. It is known that there are two genes encoding proteins that are part of the metabolic chain that regulates intramembrane proteolysis (RIP) in osteoblasts, leading to the formation of the OI phenotype. During intramembrane proteolysis, endopeptidases S1P (encoded by the MBTPS1 gene) and S2P (encoded by the MBTPS2 gene) in the Golgi membrane sequentially cleave regulatory proteins transported from the membrane of the endoplasmic reticulum during endoplasmic reticulum stress or sterol metabolite deficiency. In patients with mutations in the MBTPS2 gene, the hydroxylation of lysine in the α1 (I) and α2 (I) chains is reduced, collagen crosslinking is altered, and the strength of bone tissue is impaired. One of the transcription factors activated by RIP is a substance specifically induced by astrocytes (OASIS, encoded by CREB3L1). A deficiency of this substance has been reported in association with a family with severe OI. OASIS is an endoplasmic reticulum stress transducer that regulates the transcription of genes involved in the development, differentiation, and maturation of osteoblasts. CREB3L1 knockout mice showed severe osteopenia with

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spontaneous fractures and decreased production of type I collagen in the bone [45]. In 2018, another gene, FAM46, was discovered, leading to OI with an autosomal recessive mode of inheritance. FAM46A belongs to the superfamily of nucleotidyl transferase fold proteins, but its exact function is unknown. However, there is some evidence to suggest a corresponding role for FAM46A in bone development. Specific expression of FAM46A in human osteoblasts was detected by RT-PCR analysis and, interestingly, a nonsense mutation in FAM46A in mice was recently identified; this change is characterized by reduced body length, limbs, deformities of the ribs, pelvis, and skull, and reduced cortical a layer of tubular bones [46] (Table 4). Recently Van Dijk et al. (2020) [47] reported 6 patients from 4 families with OI, all of whom had been given a clinical diagnosis of progressively deforming OI type 2B/3. Four patients (P1, P2-1, P2-2, and P3) showed disproportionate short stature and had experienced multiple fractures from early childhood, leading to progressive skeletal deformation and requiring recurrent surgical interventions. In P2-1, P2-2, and P3, progression led to wheelchair dependence, in childhood for P2-1 and P2-2 and at 18 years for P3. In 6 patients from 4 families with OI, who were negative for mutation in known OI-associated genes, van Dijk et al. identified homozygosity or compound heterozygosity for mutations in the KDELR2 gene (609024.0001-609024.0004). Moreover, by family-based exome sequencing, Efthymiou et al. (2021) [48] identified homozygous missense variants in the KDELR2 gene in 3 children with progressively deforming OI and neurodevelopmental delay: an R5W substitution (609024.0005) in 2 Pakistani sibs, and a Y162C change (609024.0006) in a Turkish boy. The mutations segregated with disease in each family and were not found in the gnomAD database. These facts indicate the discovery of a new genetic type of osteogenesis imperfecta – XXI (Table 5). OI type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients

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exhibit disproportionate short stature and scoliosis and are often wheelchair-bound by adulthood [47]. However, approximately 90% of patients with OI have changes in the COL1A1 or COL1A2 gene, and the remaining 10% have homo- or heterozygous mutations in other genes involved in the pathogenesis of OI. However, major sequencing centers offering a panel of causative mutations associated with OI identify a lower frequency of structural mutations in the COL1A1 and COL1A2 genes in patients with moderate to severe clinical disease. For example, 77% of 598 OI patients from the Schreiners Clinic (Montreal, Canada) had heterozygous mutations in the COL1A1 or COL1A2 genes, 9% had one mutation IFITM5 gene, and the rest had homozygous or heterozygous mutations in other genes that cause OI. Lethal mutations in the collagen gene may not have been included in this study. In populations with a high level of consanguinity, the incidence of OI is higher; for example, among African Americans in the United States of America, the frequency of a mutant variant in the P3H1 gene (formerly called LEPRE1, which encodes spilled 3-hydroxylase 1) is about 1 in 240 people. Homozygosity for this so-called West African allele accounts for 25% of all cases of lethal OI in this population, which may be clinically erroneously classified as type II OI. Among West Africans in Ghana and Nigeria, the frequency of this allele is 1.5%, which can lead to a frequency of lethal recessive OI equal to the frequency of de novo mutations in type I collagen. Despite many mutations, each population has its own spectrum, consisting of a small number of mutations, and each researcher finds mutations previously undescribed in the literature. Table 5. XXI type of osteogenesis imperfecta Location

Phenotype

7p22.1

Osteogenesis imperfecta 21

Phenotype MIM number 619131

Inheritance

AR

Phenotype mapping key 3

Gene/Locus

KDELR2

Gene/Locus MIM number 609024

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In Russia, in the genetic laboratory of the H. Turner National Medical Research Center for Children's Orthopedics and Trauma Surgery, since the beginning of 2021, work has also been carried out on molecular genetic diagnostics of patients with OI. With the help of PCR diagnostics and sequencing, various polymorphic regions of the COl1A1 gene, both in exon and intron regions, are totally investigated to determine the most characteristic mutations in OI patients in the Northwestern region of Russia. This work has not yet been completed, but some characteristic features of the distribution of polymorphisms among about 100 patients with a confirmed diagnosis of OI have already been identified, they reflect the population characteristics of our region and will be published shortly. As with other recessive diseases, some populations have single mutations in rare genes that are not found in other populations: an exon deletion in the TMEM38B gene is found in a family from Saudi Arabia; a frameshift in the FKBP10 gene was found in patients from Turkey; missense mutations in the WNT1 gene - in the Hmong ethnic group from Vietnam and China [1]. Among the Northern Ontario (Canada) population, the intronic variant leads to destabilization of the mRNA of the CRTAP gene encoding a protein associated with cartilage and the development of the type VII OI phenotype. The clinical picture of OI and the severity are diverse, lethal variants with obvious skeletal anomalies in children are possible, or there may be a slight manifestation in people of mature age. The severity of the disease is determined by the frequency of fractures, progressive deformity, chronic bone pain, and loss of mobility. Due to the clinical heterogeneity of the disease, there are difficulties in diagnosis and verification of the diagnosis. In children with OI, retardation of physical development, scoliosis, progressive deformities of long bones, hearing loss, pathology of teething are revealed. Therefore, only identifying the molecular cause of the disease allows an accurate diagnosis to be made.

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DISCUSSION The original classification, published by Sillence in 1979, consisted of four subtypes defined by severity, phenotype, and radiological findings. Thereafter, the evolution of molecular genetics led to the discovery of additional genes, mutations that determine the clinical picture of OI. Identifying these new genes has greatly expanded the understanding of the cellular and biological pathways involved in OI. However, the rapid pace of these discoveries has resulted in the publication of many classifications that are often difficult to understand for both clinician and patient. It is well known that an imbalance in the activity of osteoblasts and osteoclasts can lead to abnormalities in bone density. The understanding of the molecular basis of bone development and remodeling has improved significantly in recent years. Some newly identified OI candidate genes may be involved in one of three major signaling pathways, depending on their function. These are type I collagen biosynthesis, WNT, and TGFβ signaling pathways. Most recently identified pathogenic variants encode proteins involved in the posttranslational modification of collagen and genetic changes that cause defects in osteoblast development. However, some of the disease-causing genes involved in bone formation are still unknown and do not belong to the previously mentioned signaling pathways. Collagen, in particular type I collagen, is the most abundant and important organic component of the extracellular matrix, which gives bones flexibility and strength. Therefore, a mutation in one of the genes responsible for the synthesis and assembly of type 1 collagen may be a causative factor of OI. About 90% of AD forms of OI have been identified, which arise as a result of mutations in COL1A1 and COL1A2. The remaining 10% of AR types of OI result from mutations in CRTAP, LEPREI1, PLOD2, CREB3L1, PPIB, SERPINH1, SERPINF1, FKBP10, TMEM38B, MBTPS2, SPARC, and BMP. These genes are directly or indirectly involved in synthesizing and assembling type I collagen (Figure 1).

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Figure 1. A schematic representation of the he most important signaling pathways regulating bone remodeling which have been identified through the investigation of monogenic bone disorders such as OI. [From: Lindert, U., Cabral, W. A., Ausavarat, S. et al. (2016). MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nature Commun, 7:11920.]. This figure is licensed under a Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0/.

In addition to genes involved in collagen 1 biosynthesis, mutations have been identified in genes involved in other pathways related to bone formation. Mutations in WNT1, a ligand of the WNT signaling pathway, and mutations in Sp7, which encodes osterix, an important regulator of mesenchymal stem cell differentiation, have been described [49, 42]. Finally, type V OI is caused by mutations in the IFITM5 gene, the function of which is still largely unclear [50]. Homozygous mutations in WNT1 cause OI types III and XV. Heterozygous inactivating mutations in WNT1 and heterozygous loss of function mutations in LRP5 have also been identified in juvenile osteoporosis [51] both in vivo and in vivo. In vitro and in vivo studies have shown that the TGFβ signaling pathway can influence bone formation and resorption and is an important regulator of bone remodeling. Using exome sequencing, mutations in PLS3 have been identified in the X-linked osteoporosis family, although the role of PLS3 in bone remodeling is unclear. Based on the ability of PLS3 to bind actin and PLS3 expression in osteocytes, its role in mechanosensitivity has been suggested [52]. Osteocytes induce increased bone growth by suppressing

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SOST expression as a result of adaptation to mechanical stress. Thus, mutations in PLS3 may explain the osteoporotic phenotype in patients [53]. For many years, the diagnosis of OI has depended on the correlation of clinical findings with analysis of the corresponding radiographs and biochemical findings. Until recently, molecular genetic confirmation was often the final step in the diagnostic process. However, there is a significant overlap in clinical presentation caused by various molecular defects. This means that a molecular cause cannot be inferred from the patient's clinical picture [54]. A notable exception is the distinctive features of AD associated with IFITM OI [55, 56]. In addition to the difficulty of attempting to correlate molecular diagnosis with clinical presentation, the previously established relative frequencies of OI types seem to be in reality inadequate despite the large number of recent studies using next-generation sequencing, especially in developing countries [57, 58]. 85-90% of OI cases are thought to be caused by COL1A1 and COL1A2 defects [1, 59], and AD IFITM5 defects are the most common non-collagenous form of OI [27]. However, studies in China [60], Malaysia [61], India [62], and Brazil [50] showed that COL1A1 and COL1A2 defects cause only 49% to 73% of OI. There may be several reasons for this, including the relative distribution of mild, moderate, and severe samples. Mild to moderate OI is usually associated with collagen defects, while more severe forms of the disease are associated with non-collagen defects [63, 54]. This discrepancy may also be due to using a more efficient NGS method compared to Sanger sequencing, which was mainly used in previous studies. Finally, these data may indeed reflect population differences in the molecular diversity of defects in OI. These contradictions between the previous literature and more recent research indicate that the more we learn about OI, the more questions arise. With the availability and reduced cost of next-generation sequencing, a “genotype first - phenotype later” approach may soon become a more desirable approach. The “genotype first - phenotype later” approach has limitations in predicting clinical outcomes since genotype-phenotype

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correlations in patients with OI are still not well established. It has been shown that families with the same pathological variant of the genotype have heterogeneous clinical features, and conflicting results are often encountered in OI studies. For example, a study of Swedish patients with OI [64] showed that patients without collagen I mutations had no dentinogenesis disorders, while a large study of Italian patients with OI showed that 33.3% of patients with a similar genotype had dentinogenesis imperfecta [65]. These are sharply opposite results. New genetic variants are constantly being discovered that do not belong to known pathogenic variants, but patients have similar phenotypes. A study of a Palestinian sample of 77 patients with OI revealed 11 new pathogenic variants of unknown disease-causing genes, while 10% of patients in this sample did not have pathogenic variants in known disease-causing genes [66]. If the mechanism of genotype-phenotype correlation is clarified and understood, then it will become clinically useful and informative for clinicians, patients, and geneticists. It would be desirable for the research process to give equal attention to both genotyping and phenotyping. The ever-evolving nosologies are useful reference materials for diagnosis and genetic counseling. However, the limitations of these reference guides should be recognized due to their rapid obsolescence. The genetic classification currently developed has been extended based on the original Sillence classification, and a new subtype has been proposed for each defective gene. The OMIM genome database currently lists 21 types of OI, types I to XXI. This numerical list is a combination of 5 original clinical types with 16 additional genotypes resulting from dominant, autosomal recessive, or sex-linked inheritance. It is expected that this classification will constantly evolve as new genes are discovered.

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CONCLUSION Summarizing the above, we can conclude that there has been a breakthrough in the identification of molecular pathogenesis of OI, which is due to the introduction of modern next-generation sequencing technologies (NGS). Nevertheless, questions about the prevalence of the disease in general and its individual clinical forms in various populations of the world are still far from complete. The degree of molecular heterogeneity of OI is still unknown, the identification of new pathogenetic mechanisms of the formation of the disease phenotype continues on the basis of the identification of new genes involved in the pathogenesis of OI. At present, attempts are being made to develop targeted therapy for the disease, taking into account new knowledge about the clinical and genetic aspects of OI, but there are still many conflicting results and the solution to the problem of adequate treatment of the disease lies in the future.

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[64] Maioli, M., Gnoli, M., Boarini, M., et al. (2019). Genotype– phenotype correlation study in 364 osteogenesis imperfecta Italian patients. Eur J Hum Genet, 27(7), 1090-1100. [65] Essawi, O., Symoens, S., Fannana, M., et al. (2018). Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families. Molecular genetics & genomic medicine, 6(1), 15-26.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 4

PHYSICAL THERAPY MANAGEMENT IN OSTEOGENESIS IMPERFECTA Nadezhda Epishina, MD Fragile People Charitable Foundation; St. Petersburg, Russia

ABSTRACT The chapter describes contemporary approaches to physical rehabilitation of patients with Osteogenesis imperfecta (OI) based on a review of scientific research, together with the case of the Mobile Rehabilitation Service (MRS) of the Fragile People Charitable Foundation.

Keywords: osteogenesis imperfecta, physical therapy, International Classification of Functioning, quality of life, interdisciplinary approach

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Corresponding Author’s E-mail: [email protected].

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INTRODUCTION Osteogenesis imperfecta (OI) is a hereditary disease of connective tissue manifested in bone brittleness and bone loss and characterized by a clinical and genetic heterogeneity. Due to a qualitative and quantitative deficiency of type-I collagen, the skeletal system is affected, as well as any bodily structures containing connective tissue, including muscle, tendons, ligaments, sclera, skin, teeth, auditory organs. The thorax becomes deformed which contributes to the development of breathing disorders and respiratory infections. Specifically, cardiopulmonary complications are a common cause of death among the patients with OI [1, 2, 3]. The prevalence of the disease, according to various sources, is one per 10,000 or 20,000 live births [2, 3, 4, 5]. However, it may be higher since mild cases of the disease often remain undiagnosed [6]. This pathology is identified universally, regardless of race and gender. Nonetheless, the extent of medical staff’s awareness of it remains low, especially at the local level, whereas the quality of life of people with the brittle bone disease is directly related to early detection and timely initiation of treatment. The approach to the treatment is comprised of a comprehensive therapeutic, surgical, rehabilitative, and psychological aid designed to lower the number of bone fractures, to increase bone density and to maximize the functionality and the acquisition of necessary life skills. The collaborative work of professional pediatric, orthopedic, surgical, traumatological, rehabilitative, psychological, and other related medical staff also plays a key role in case management. Only the coordinated effort of an interdisciplinary group of professionals with the education and the support of the parents can allow the affected children to fully utilize their potential, to retain maximal mobility and independence from outside help, to improve their quality of life [7]. Rehabilitation specialists also feature prominently in the planning and the assistance of people with OI.

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PURPOSE To present a review of existing approaches to physical rehabilitation of patients with OI, to consider the challenges related to the organization of rehabilitation assistance of patients with OI, to the choice of strategy and techniques of rehabilitation treatment.

MATERIALS AND TECHNIQUES Following is a review of the existing research regarding the methods of physical therapy in patients with OI, including the developments achieved under the Mobile Rehabilitation Service project of the Fragile People Charitable Foundation.

RESULTS AND DISCUSSION The World Confederation for Physical Therapy (WCPT) describe physical therapy as: “Providing services to individuals and populations in order to develop, maintain and restore maximum movement and functional ability throughout the lifespan. This includes providing services in circumstances where movement and function are threatened by ageing, injury, disease or environmental factors.” Physical therapy is highly important for the treatment of people with OI and the improvement of their quality of life. The patients who possess a decent level of mobility undergo fewer surgeries throughout life. The rehabilitation should start from an early age to help the child to overcome their fear of bone fractures in acquiring new motor skills and adapting to the conditions of their environment. In addition, rehabilitation is a critical stage in the treatment of trauma, bone fractures and post-operative care [4]. It has been proven that the strengthening of core muscles, verticalization, and extensive mobility facilitate the increase in bone density and the decrease in the risk of bone fractures. However, when

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outlining the treatment plan specialists should consider that children with OI face pain and fear of new movements on a daily basis. Kinesiology leads to hypodynamic condition, and this produces an adverse effect both on the physical and the mental condition of the patients. Insufficient physical activity is compounded by the clinical symptoms of Osteogenesis imperfecta: due to the absence of axial load on the skeletal structure, osteoporosis, muscle weakness and atrophy, as well as problems with cardiovascular and respiratory systems become aggravated. Besides, the sedentary lifestyle contributes to psychological problems: depression and anxiety are commonly encountered. That is why a comprehensive approach to treatment is important, including therapy if necessary. In 2017 an expert group convened in Oslo to develop an international document in relation to the physical therapy of children and teenagers with Osteogenesis imperfecta. The experts exchanged expertise and drawn the conclusion that regular physical therapy is essential for people with OI. It was also noted that consistency in doing physical exercises is more important than a specific set of them, and that the exercises should correspond to the interests of patients. The 2018 consensus statement on the physical therapy of children and teenagers with Osteogenesis imperfecta emphasizes that the general aim of the treatment of children is maximizing mobility, functionality, activity and participation. It was also underlined that the fear of bone fractures is the single most limiting factor preventing the full utilization of the patient’s potential. In a significant number of families fear is the most considerable obstacle to independent exercising. At the same time the majority of children suffering from mild and moderate cases can move on their own with the use of technical aids if necessary. The technical aids should be tailored to the needs of the individual child, e.g., a motorized wheelchair should be used in case of short stature or weakness in the arms. Specialists take into account the decreased muscle strength and bone density, short stature, lung capacity, aerobic capacity, endurance, loss of balance and coordination, pain and mental state of the child to develop an adequate rehabilitation plan. A successful strategy breaks the aims into smaller achievable targets. This

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allows a person to succeed at relatively easy objectives and progress stepby-step until the skill is acquired [8]. The main aim of developing the rehabilitation strategy is upholding the highest possible level of physical activity without trauma [9]. Diminished physical activity is often accompanied by overweight which has a negative effect on the health and vitality of the patients. Several reports have been published on the increased prevalence of overweight among the patients with OI, which further demonstrates the significance of encouraging physical activity in this social group. It is important to prevent overweight by maintaining physical activity and healthy diet [10, 11, 12]. Children with OI may find aquatic exercises beneficial, especially if those activities are presented voluntarily and through play [12]. It is an excellent form of aerobic training. However, since aquatic exercises alone do not exert much influence on growth and bone density, adults should include other forms of exercise with weights [13]. A research conducted by Monpetit et al. shows that in the course of regular exercising throughout 12 weeks children with OI gained muscle strength and intensified their mobility. The patients with a good level of mobility undergo fewer surgeries throughout life, and they are mostly type-I OI patients [4]. Rehabilitation should begin with early intervention. In case of severe forms of OI the rehabilitation is aimed at educating the parents on careful treatment of the child with brittle bones. It has been noted that deformations resulting from using soft movement-restricting surfaces for laying the child down are more frequent among patients with OI. In order to prevent those conditions, the position of the child should be frequently changed. When lying on the stomach the cervical spine and the upper limbs become straightened, while hip flexor muscles become stretched. This helps the child to learn how to roll over and consequently to sit. A physical therapy exercise session is begun with correcting the head and neck position, balancing in a sitting position and verticalization. With older children the main focus is on gaining muscle strength, functional development and fostering self-reliance.

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Often the children with severe forms of OI have not walked independently, either for a long period of time or ever. After reconstructive surgery lower limbs become able to support body weight but the patients are often afraid to stand up. In order to complete this difficult task, rehabilitation departments use special verticalizers and individual leg braces that stabilize lower limbs with weak muscles and hypermobile joints. After correcting lower limb deformations FassierDuval take casts of the patient intraoperatively and manufacture individual hinged leg braces [9, 14]. A recent study investigated an approach to rehabilitation that combined training with weights, training on a treadmill with whole-body weight support and exposure to alternating whole-body vibration in 53 persons with OI (age 2,5–24,8 years) for 6 months. The patients indicated an improved mobility, as well as an increase in muscle mass. However, 46 of the patients had been receiving treatment with bisphosphonates for years, and the program included varied approaches to treatment. Further research is required, included targeted therapy, collection of specific clinical data and evaluating physical therapy in short- and long-term intervention courses [15]. Among the rehabilitation methods for children with OI the literature also describes the use of whole-body vibration methods. Namely, for example, in case of using a vibration platform for three minutes twice a day in the course of 6 months a positive shift in bone mass was observed [16]. Still, in a similar research no positive effect of such method on bone mass was observed [17]. A recent review that contained only 3 relevant studies concluded that whole-body vibration can be an alternative treatment method for the improvement of mobility and functional parameters. However, to evaluate the effectiveness of whole-body vibration on bone mass and bone health in the pediatric population, further and broader prospective research over the period of more than 6 months is required. An investigation into the side effects and the negative influence of vibration on the organism should be conducted [18]. In 2015 Veronica Balkefors in her thesis titled Living with Osteogenesis imperfecta described, based on the ICF, the constraints

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faced in everyday life by people with type-I and type-IV OI. In particular, disturbances of structure or function of the body were addressed: fractures and deformation of bones, bone pain, short stature, hypermobility, spinal and thorax deformity, breathing problems, hearing and vision loss, Dentinogenesis imperfecta, etc. The following disturbances of activity and functionality are observed: inability to run and jump, inability of some patients to walk, lift heavy objects, wear backpacks, perform hard labor, do contact sports, go outside in winter when it is slippery and the road conditions worsen; avoidance of unknown routes, lines and gatherings. The patients experience a decrease in the quality of life in connection to health. The thesis underlines the supportive and barrier roles of the environment: the use of aids and assistive equipment such as canes, walkers, wheelchairs, tailoring the home environment, hearing aids, special footwear, as well as supportive family and friends, a mobility service, social care, transfers, medical assistance, access to health care, environmental accessibility, regular physical therapy, the lack of safe environment for exercising, uneven surface, winter, etc. Several idiosyncrasies of people with OI are described: the convictions and the attitude of the person towards their condition, mental health, socio-economic status, professional life, working conditions, satisfaction with the job and the education, selfactualization, marital status and others [19]. In their work the specialists comply with the International Classification of Disability, Functioning and Health (ICF), a unified and standardized classification of health and condition. This classification is outlined on the corresponding website (http://apps.who.int/ classifications/icfbrowser/Default.aspx). The ICF enables us to understand how the disturbances of the structures and functions of the organism are affecting a person’s activity and their participation in social life. In addition, the ICF allows us to view the health problems in their entirety, taking into account the specific features of the patient and their environment. The ICF also ensures interdisciplinary continuity because people with brittle bones often require assistance of various rehabilitation specialists: physical therapists, ergotherapists, psychotherapists, speech

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therapists, social workers, etc. The classification enables the use of individual treatment approaches for each patient and an effective professional continuity. The task of the physical therapist is to set the goals of rehabilitation in order to increase the involvement of the patient in their everyday life activities. Within the framework of activities of the Fragile People Charitable Foundation a Mobile Rehabilitation Service (MRS) project is in progress. The project works in several key areas: physical therapy, ergotherapy, and psychological support. Meetings with the mentees take place on the premises of G. Turner National Medical Research Center for Pediatric Orthopedics and Trauma Surgery in St. Petersburg, as well as online (Figure 1 and 2). The project connects participants from over 20 regions of Russia, from the CIS and the EU. Comprehensive assistance is given, including the evaluation of the physical condition, tailoring the environment, consultation on early childhood care and physical rehabilitation of people with OI. Educational projects and webinars are held, useful materials are published, a knowledge base on the issues of rare bone diseases is formed. Within the project 65 children aged 0-18 have been under regular management from August 2020 to July 2021, and there are over 700 mentees diagnosed with OI who also apply to the project for advisory assistance [20]. In their work, the project specialists create an individual intervention program, outline major problems, set goals in accordance with the S.M.A.R.T. principle (Specific, Measurable, Achievable, Relevant, Time), employ the methods of physical rehabilitation with proved effectiveness, conduct clinical observations with a record of the client base, assist with the choice of technical aids and utilities that improve the child’s self-reliance and with tailoring the environment. They also provide advice on appropriate care, managing family relations and the psychological and emotional development of the child.

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Figure 1. Online consultations allow you to maintain continuous communication with family and children with specialists. This allows you to quickly respond to changes, adjust the course of rehabilitation intervention.

Figure 2. Online workouts help children engage in regular physical activity in any situation.

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By using the patient-centric approach the team of specialists is able to facilitate interaction within the family, create a positive attitude and an optimistic vision of the future to focus on analysis and search for the solutions for various motor disturbances. Specialists run an initial diagnostic, evaluate the disturbances of the structure and functions, consider the impairments of activity and involvement of the patient, the environmental factors and the idiosyncrasies of the mentee within the framework of the ICF. The involvement in social situations and the functionality of the patient in everyday life are evaluated, as well as mobility, recreation and leisure, family values and traditions, the level of adaption to the educational and professional milieu. The following supportive and barrier environmental factors are considered: 

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Falling and traumatization (surface elevation, floor unevenness, including floor covering, sharp edges and corners, precariously standing objects, slippery floor, etc.) Aggravation of secondary disturbances (unsuitable furniture among which the child is present for a long period of time, inadequately selected technical aids which put the child in incorrect positions, etc.) Movement and free choice restraint (overprotective parents, dependance on adults, soft pillows in the cradle, object inaccessibility).

Rehabilitation is divided into two functional types: course and continuous. Course rehabilitation in hospital is aimed at convalescence after surgery and periods and immobility. Within the framework of the project the continuous type of rehabilitation is realized accompanied by long-term cooperation with the family. Together with the course rehabilitation it allows for the most effective assistance in the acquisition of necessary motor and self-reliance skills. In their work the employers of the Fragile People Charitable Foundation use a trial classification of the patients that includes 5 levels of everyday functionality:

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1. people with mild disturbances capable of independent movement and self-reliance without outside help. 2. people with mild disturbances capable of independent movement and self-reliance with an occasional use of technical aids (e.g., after surgery, when going outside, etc.). 3. people capable of movement with the help of technical aids and of self-reliance. 4. people capable of movement with the help of technical aids and of sitting without assistance but incapable of complete selfreliance. 5. bedridden patients requiring constant care. The task of rehabilitation is also to increase the level of a patient’s functionality. Physical therapists outline a set of exercises based on the level of functionality.

I and II Group Strengthening exercises, exercises with equipment (balls, poles, expanders, low-weight dumbbells, elastic bands, etc.), swimming, walkabouts, cycling / exercise bike, ladder, stepper, safe physical games, adaptive sport. Young children and patients after a period of immobility learning motor skills. Tailoring the environment if necessary.

III Group physical exercises with a lighter load, in a sitting and standing position (with the use of technical aids and leg braces if necessary), in a supine position (possibly in the aquatic environment). Exercises with equipment (balls, poles, etc.), body weight exercises, exercises with

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measured resistance, swimming pool, exercise bike, walking on the bars, walkabouts, adaptive sport. Tailoring the environment if necessary.

IV Group 20-30 minutes long exercise sessions, repeated 2-3 times a day; it is essential on include breathing exercises aimed at strengthening the exhaling muscles of the thorax. Learning accessible motor skills and selfreliance skills. Swimming, exercise bike, walking on the bars. Handpowered wheelchairs.

V Group The main aim is postural management and support of the active state of the organism, prevention and treatment of the complications caused by induced immobility, stimulation of respiratory resources (Position treatment, position change, cardiorespiratory rehabilitation). Assistance in the acquisition of accessible motor skills (the patient takes different positions throughout the day with the use of technical aids, learns new movements, acquires self-reliance skills), swimming. This category of patients also widely uses motorized wheelchairs [20]. The exercises that the sets include on each level: active joint exercises, muscle strength, flexibility and endurance training, balance and coordination training, as well as tailoring the environment and selecting the technical aids (Figure 3, 4, 5). During those exercises the patients should avoid large levers, sudden movements, jumping, twisting, applying force off the bone axis, any exercises connected to the risk of bone fractures and joint dislocation due to excessive force. Safer strength training exercises are done in a sitting and supine position. Balance and coordination, walking skills are trained in a standing position, as well as postural balance.

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Figure 3. Physical therapists do morning exercises at a summer rehab camp. According to the experts’ conclusion in the Oslo consensus document in 2017, the set of exercises is not as important as the regular exercise.

Figure 4. Exercises to strengthen the muscle corset are very important for children with osteogenesis imperfecta. Group training increases children’s motivation and also encourages communication with each other. Socialization is very important for children who spend a lot of time in isolation.

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At the same time the primary goal of the majority of the patients is verticalization and walking but the approach to the choice of the rehabilitation method should be individualized. Disease severity must be taken into account, as well as VO2 max, the presence of metal bonereinforcing constructions and other factors.Thus, physical therapy in the setting of Osteogenesis imperfecta should start from birth or the confirmation of the diagnosis and continue for a lifetime. The types of physical therapy depend on the age of the method choice: early intervention for age 0-3, physical activity through play should be encouraged for pre- and early school-aged children, fitness approach for teenagers and adults, as well as the acquisition of motor and self-reliance skills after long periods of immobility.

Figure 5. For a child with a severe clinical course of the disease, specialists picked up an electric wheelchair.

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In the course of early intervention, the zone of potential development is determined as the specialist focuses on the curve of motor development, evaluates not only the motor development but every aspect of the child’s life, such as speech and communication or cognitive functions. The sessions are presented as play. It is important to create a milieu for the child’s development, therefore the family-centricity of the approach is of significance. Care and positioning are brought to the forefront. An individual goal is set for each child. Weight shifting is important while in any position, with the goal of achieving the standing position and participation in everyday activities (washing, dressing, etc.) Independent activity should be encouraged. In the course of the child’s growth tailoring the environment, exercising through play for young children, encouragement of active independent movement and learning the safety rules all remain relevant. Teenagers must learn to understand the features and the potential of their bodies. If necessary, specialists assist in choosing technical aids depending on the needs, with the main choice criteria being a sufficient minimal support for the encouragement of mobility and independence. Complications may arise with age, such as arthritis (often osteoarthritis, including of the tuberculosis etiology) or joint instability, which cause pain and immobility, complications in the cardiovascular and respiratory systems, etc. It is for this reason that the patients should work out regularly with the inclusion of individually selected aerobic exercises, e.g., endurance and strength training. Accounting for painfulness is of paramount importance. This includes protecting joints, using technical aids, medications and other means. Aside from the age, planning the intervention program should consider the disease severity, diagnostic results, data from densitometry and X-ray imaging, related diseases, as well as previous drug and surgical treatment. In case of milder types of treatment (I) the patient should lead an active lifestyle, participate in safe types of physical activities, appropriate aerobic exercises, endurance and strength training. In case of more severe types (III, IV) motor and self-reliance skills should be

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developed, as well as muscle strength and endurance. Eradication of painfulness and fear comes in focus, while the main aim of therapy is maximizing the independence of the patient. Thus, the key factors of planning the program of physical therapy are: 1. safe movement and assuming safe positions for the duration of the day with the aim of preventing aggravation of secondary disturbances; 2. physical activity, including physical exercises, adaptive sports; 3. adaptive equipment, technical aids; 4. tailoring the environment and tools.

CONCLUSION As of today, protocols of the physical therapy treatment of children and adults with OI do not exist. Further research is required, including the collection of clinical data and the results of physical therapy in shortand long-term intervention courses. The general approach to effective physical therapy for the patient with OI will improve, provided that more experience is gained through the publishing of an increased number of reports about the cases and the cohort studies aimed at the evaluation of results.

REFERENCES [1] [2]

Farkhutdinova, L. M. (2017). Osteogenesis Imperfecta [in Russian]. Vrach, 8: 6-8. Marini, J., Smith, S. M. (2015). Osteogenesis Imperfecta. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279109/#osteo genesis-imperfe.toc-introduction.

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Subramanian, S., Viswanathan, V. K. (2019). Osteogenesis Imperfecta. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK536957/. [4] Burtzev, M. E., Frolov, A. V., Logvinov, A. N. et al., (2019). Modern Approach to Diagnostic and Therapy in Children with Osteogenesis Imperfecta [in Russian]. Ortopediya, Travmatologiya I Vosstanovitelnaya Khirurgiya Detskogo Vozrasta, 7(2):87–102. [5] Ignatovich, O. N. (2018). Phenotypic Features of Children with Osteogenesis Imperfecta [in Russian]. Rossiiskii Periatricheskii Zhurnal, 5:266-271. [6] Ignatovich, O. N., Namazova-Baranova, L. S., Margieva, T. V. et al., (2018). Osteogenesis Imperfecta: Peculiarities of Diagnostic. Pediatricheskaya Farmakologiya, 15(3): 224-232. [7] Marr, C., Sesman, A., Bishop, N. (2017). Managing the patient with osteogenesis imperfecta: a multidisciplinary approach. J. Multidiscip. Healthc., 10:145-155. [8] Mueller, B., Engelbert, R., Baratta-Ziska, F., et al., (2018). Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis., 13: 158. [9] Kruger, K. M., Caudill, A., Rodriguez, C. M., et al., (2019). Mobility in osteogenesis imperfecta: a multicenter North American study. Genet. Med., 21:2311-2318. [10] Germain-Lee, E. L., Brennen, F. S., Stern, D., et al., (2016). Crosssectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care. Pediatr. Res., 79:489495. [11] Chagas, C. E., Roque, J. P., Santarosa Emo Peters, B., LazarettiCastro, M., Martini, L.A. (2012). Do patients with osteogenesis imperfecta need individualized nutritional support? Nutrition, 28:138-142. [12] Zambrano, M. B., Brizola, E. S., Refosco, L., Giugliani, R., Felix, T.M. (2014). Anthropometry, nutritional status, and dietary intake

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[13]

[14]

[15]

[16]

[17]

[18]

[19] [20]

Nadezhda Epishina in pediatric patients with osteogenesis imperfecta. J. Am. Coll. Nutr., 33:18-25. Cho, T. J., Ko, J. M., Kim, H., Shin, H. I., Yoo, W. J., Shin, C. H. (2020). Management of Osteogenesis Imperfecta: A Multidisciplinary Comprehensive Approach. Clin. Orthop. Surg., 12(4): 417-429. Popkov, D. (2015). Combined Stimulation Methods of Reconstructive Surgery in Pediatric Orthopedics. Nova Science Publishers, Inc. 2015. Brizola, E., Félix, T. M., Shapiro, J. R. (2016). Pathophysiology and therapeutic options in osteogenesis imperfecta: an update. Research and Reports in Endocrine Disorders, 6:17-30. Hoyer-Kuhn, H., Semler, O., Stark, C., Struebing, N., Goebel, O., Schoenau, E. (2014). A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. J. Musculoskelet. Neuronal Interact., 14(4):445-453. Högler, W., Scott, J., Bishop, N., et al., (2017). The effect of wholebody vibration training on bone and muscle function in children with osteogenesis imperfecta. J. Clin. Endocrinol. MeTable, 102(8):2734-2743. Sa-Caputo, D. C., Dionello, C. D. F., Frederico, E., et al., (2017). Whole-body vibration exercise improves functional parameters in patients with osteogenesis imperfecta: a systematic review with a suitable approach. Afr. J. Tradit. Complement Altern. Med., 14(3): 199-208. Balkefors, V. (2015). Living with Osteogenesis Imperfecta. Stockholm. Yepishina, N. V., Luchkevich, V. S., Marinicheva, G. N. (2019). Peculiarities of Medical Care Organization and Curation Tactic in Patients with Osteogenesis Imperfecta. Materials of Conference “Prophylactic Medicine,” St. Peterburg, pp.146-153.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 5

ORTHOTICS AND ASSISTIVE DEVICES FOR OSTEOGENESIS IMPERFECTA Dmitry Okhapkin, MD “Doctor Okhapkin’s OrthoSpace”, Moscow, Russia

ABSTRACT The therapeutic objectives in patients with Osteogenesis Imperfecta are aimed to improve the functional capacity of the child or adult with OI and to optimize their independence. Thus, the use of different orthoses and assistive technology are important for achieving these objectives. Assistive technology (AT) is a term for devices containing specialized technical solutions used for adaption to or elimination of persistent disability in persons with Osteogenesis imperfecta (OI). In this chapter we shall consider the AT intended for verticalization and movement of patients, as well as the AT pertaining to orthotics and its utility in the rehabilitation program of patients with OI.

Keywords: assistive technology, orthotics, Osteogenesis Imperfecta

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Corresponding Author’s E-mail: [email protected].

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INTRODUCTION Individual needs of OI patients determine indications and use of lower and upper extremity orthotics [1, 2]. The use of bisphosphonates reduced conditions requiring bracing. This medical treatment provides stronger bone. The actual trend is represented by less bracing if possible [3, 4]. Nevertheless, bracing is indicated [4-6] in 

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progressive bowing in children who are not ready for reconstructive surgery. Thus, circumferential orthotics supporting bone are able to reduce fracture rate while waiting for operation; hypermobility related to tendon laxity requires custom-molded orthotics adding support to internal foot longitudinal arch preventing plano-valgus deformity; early postoperative period while m.quadriceps is still weak, the GRAFO enable up-right standing posture

The assistive technology intended for patients with OI is chosen based on the mobility and degree of independence of a patient. The current status of the patient should also be accounted for, i.e., whether any mobility-restricting factors (e.g., recent bone fractures) have revealed. In this chapter we review the main orthotics and assistive devices used in OI.

MATERIAL AND RESULTS The wheelchair is an assistive device used for the movement of patients. The wheelchair is required in the circumstances when independent walking is impossible or temporarily impaired by the orthopedic status of the patient.

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There are several types of wheelchairs used by patients with Osteogenesis imperfecta. In manual self-propelled wheelchairs the wheels are moved with the patient’s own muscle power. When selecting a wheelchair of this type, the physical capabilities of the patient and their range of arm movement should be accounted for. There are mass-produced wheelchairs, as well as custom-made models tailored to the user’s individual features. The materials used to manufacture the wheelchair play an important role in its selection. There exist lightweight models made from composite materials such as carbon (Figure 1). Nevertheless, this device Requires good upper body strength to manage community distances. The powered wheelchair (Figure 2) is designed for patients with low levels of physical activity, pronounced bone deformities and loss of upper-limb functions.

Figure 1. An active-type wheelchair manufactured with the use of composite materials.

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Figure 2. Powered wheelchair.

An adaptive van is needed to move the chair. Without elevator access in public transportation, the chair can only be used on even surface. The verticalizer (standing support, Figure 3) is an orthopedic device which enables the patient to assume, in whole or in part, the upright position. This type of device is used for patients who do not have the capacity for independent standing, as well as in elective surgery, trauma recovery, and rehabilitative treatment. Current models of the verticalizer offer extensive functionality. They allow to adjust the spread angle and the position of lower limbs, or to change the tilt of the patient therefore decreasing or increasing the load on the musculoskeletal system. There are mass-produced and custom-made verticalizers. The customized ones are manufactured from various materials using the plaster cast technique or 3D scanning (Figure 4).

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Figure 3. Verticalizer.

Mobility aids are orthopedic devices that assist the patient in enhancing their motor functions. They include walking canes, walkers and handrails. The devices are used for the independent movement of the patient and chosen based on their level of physical activity. When choosing the walking cane (Figure 5), the patient’s individual features should be accounted for.

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Figure 4. Verticalizer (custom-made).

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Figure 5. Walking canes.

It is important to give attention to the handle and its position, the type of grip, the base type (one-, three-, or four-pronged). They can be difficult to use if there is significant bowing of the upper extremity. The walker (Figure 6) is chosen based on the physical capabilities of the patient. In selecting the walker, special attention is paid to the type of upper-limb securing, the configuration, controllability and safety systems of the walker. In selecting the abovementioned assistive technology devices, it is important to consider the physical condition of the patient and their rehabilitation program, to follow the interdisciplinary approach as an attending physician and rehabilitation specialist.

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Figure 6. Walker.

The orthosis is an assistive technology device used to modify the structural and functional characteristics of the neuromuscular and skeletal systems, as well as to ensure, depending on the medical condition, orthopedic correction, unloading, securing, the enhancement of motor functions, or cosmetic effect. Applied to Osteogenesis imperfecta, orthotics is viewed as a supplementary aid that ensures orthopedic correction, unloading and securing. Through the example of orthopedic correction, we shall consider the options of employing orthoses in the form of an Articulated Ankle-Foot Orthosis (AAFO) (Figure 7).

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Figure 7. Articulated Ankle-Foot Orthosis (AAFO).

The AFO contains a hinge that enables it to retain the range of ankle joint movement and create the conditions for securing the joint in the right position. Through the example of unloading, we suggest considering the option of employing the Hip-Knee-Ankle-Foot Orthoses (HKAFO) (Figure 8). This orthosis design may be used with the aim of reducing the load on the femur.

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Figure 8. Hip-Knee-Ankle-Foot Orthoses (HKAFO).

Its structure creates points of pressure on the upper anatomical structures that decrease the load on the lower ones. It should be borne in mind that there remains a possibility of traumatization in the pressure zone, so X-ray data is used for risk mitigation. Additionally, soft atraumatic materials are used for the manufacturing of these orthoses. The purpose of employing this type of orthoses is retaining the mobility of the patient in the process of fracture healing (Figure 9).

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Figure 9. Articulated Knee-Ankle-Foot Orthosis (KAFO).

Orthoses are manufactured from various materials and their combinations. There are mass-produced and custom-made orthoses. Custom-made orthoses employ technologies that differ in the temperature of material heating in the production process (high- and low-temperature materials). High-temperature materials require heating up to 120 - 220°C

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depending on the structure of the material (polypropylene or polyethylene). The production of this type of orthoses requires industrial premises equipped with special thermal furnaces. Low-temperature materials can assume the required shape after heating up to 60 - 70°C and quickly solidify after cooling down. This feature of low-temperature materials allow them to be made at home (hot water is used for heating up the material).

Figure 10. Solid Ankle-Foot Orthosis (SAFO).

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Figure 11. Wrist-and-Hand Orthosis (WHO).

High-temperature materials enable the creation of more solid and multipurpose structures. Due to this, it is possible for the orthosis to be fitted with additional mechanisms (joints) that extend its functionality. This model of orthoses enables the verticalization of the patient due to the rigidity of the high-temperature materials being used. The disadvantages of the technology employing high-temperature plastic include a complicated orthopedic production process and a need for experts. However, it should be noted that technological complexity entails a wider range of opportunities of such models. Low-temperature materials enable the orthoses to be manufactured as quickly as possible (Figures 10 and 11). Such assistive technology devices do not require sophisticated equipment and a big team of experts

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but at the same time, this technology puts a limit on the rigidity of the material which sometimes prevents the medical problem from being solved completely. To ensure effective implementation of modern solutions in custom orthosis manufacturing, the entire range of available technologies should be applied.

CONCLUSION Being an additional (to bisphosphonate-therapy and physical therapy) option in management of OI, the use of assistive technology allows patients with Osteogenesis imperfecta to sustain or improve the functionality of their musculoskeletal system, to create a comfortable environment for mobility, correct body position, improve self-care and integrate into society.

REFERENCES [1]

[2]

[3]

[4]

Alguacil Diego, I. M., Molina Rueda, F., Gómez Conches, M. (2011). Orthotic management for patients with osteogenesis imperfecta. An Pediatr., (Barc), 74(2):131.e1 - 6. Bleck, E. E. (1981). Nonoperative treatment of osteogenesis imperfecta: Orthotic and mobility management. Clin. Orthop. Relat. Res., 159:111 - 122. Marr, C., Seasmon, A., Bishop, N. (2017). Managing the patient with osteogenesis imperfecta: A multidisciplinary approach. J. Multidiscip. Healthc., 10:145 - 155. Kruse, R. W. (Ed.). (2020). Osteogenesis Imperfecta: A Case-based Guide to Surgical Decision-making and Care. Springer Nature.

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Ruck, J., Dahan-Oliel, N., Montpetit, K., Rauch, F., Fassier, F. (2011). Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: Functional outcomes at one year. J. Child. Orthop., 5(3):217 - 224. Weintrob, J. C. (1995). Orthotic management for children with osteogenesis imperfecta. Connect. Tissue Res., 31:S41 - S43.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 6

ANESTHETIC MANAGEMENT IN OSTEOGENESIS IMPERFECTA Vadim Evreinov, MD, PhD National Ilizarov Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia

ABSTRACT Osteogenesis imperfecta is a collective term for a heterogeneous group of congenital syndromes caused by connective tissue maldevelopment and characterized primarily by the tendency to bone fractures. Operative orthopedic interventions in these patients are intended for increasing physical activity and preventing pathological fractures resulting in the improvement of the quality of life. Application of continuous regional methods of anesthesia, as the main analgesic component of anesthetic protection and postoperative pain therapy, makes it possible to solve the given tasks effectively.



Corresponding Author’s E-mail: [email protected].

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Vadim Evreinov The assessment of the coagulation potentials of the patient’s blood plasma and the prediction of critical incidents development associated with a comorbidity background define the strategy of treatment in the perioperative period.

Keywords: osteogenesis imperfecta, comorbidity background

perioperative

pain

therapy,

INTRODUCTION Osteogenesis imperfecta is a collective term for a heterogeneous group of congenital syndromes caused by connective tissue maldevelopment and characterized primarily by the tendency to bone fractures. The incidence of osteogenesis imperfecta (OI) in Europe and the United States ranges from 0.3 to 0.7 cases in 10,000 newborns [1]. In 90% of the cases, it is caused by mutation in the genes COL1A1 and COL1A2, encoding the A1 and A2 chains of type I collagen, respectively. The incidence in men and women is approximately the same. No relation to race is known [2]. Recurrent fractures and progressive deformities of the lower limbs lead to disability of patients, dramatically limiting their activity, and become the main reason for orthopedic interventions [3]. The concept of surgical treatment of this pathology includes corrective osteotomies of long bones followed by intramedullary transphyseal telescopic titanium nails and osteosynthesis with an external fixator [4, 5, 6]. Perioperative pain therapy against the background of aggressive surgical procedures is not an easy task for the anesthesiologist. This is caused by motor and behavioral disorders and severe accompanying somatic pathology of children with osteogenesis imperfecta. Thorough preoperative risk assessment allows to customize the technique of intraoperative pain protection and improve the patient care in the early postoperative period.

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COMORBIDITY BACKGROUND OF CHILDREN WITH OSTEOGENESIS IMPERFECTA According to Tauer J. T. et al., the pathology of the craniocervical transition in types I, III, IV of osteogenesis imperfecta is observed in 37% of the cases and the most frequent manifestations are basilar intussusception in 13% of the cases and platybasia in 29% [7]. Maldevelopment of the skull base can lead to compression of the structures of the posterior cranial fossa, Arnold-Chiari malformation, syringomyelia and hydrocephalus [8, 9]. Freya K. R. et al., (2011) and Kuurila K. et al., (2002) reported on bilateral symmetric hearing loss in 48.4% of the patients. Mixed hearing loss prevailed in 27.5% of the cases, conductive one was observed in 12.5% of the cases and sensorineural one in 8.4%. Significantly late onset (36.5 years; range: 10-60 years) is typical for pure cochlear neuropathy in comparison with conductive or mixed ones (19.0 years; range: 5-42 years). In 52.4% of the cases, hearing loss is combined with vestibular apparatus disorder and demonstrates dizziness [10, 11]. Bailleul-Forestier I. et al., (2008) pointed out the incidence of dentinogenesis imperfecta (DI) in more than 50% of children and adults with osteogenesis imperfecta. Change of the teeth color (gray, cloudy, yellow-brown) and the crown shape, enamel chipping, rapid dentin wear up to the gingival margin, brown staining of exposed dentine, dysplasia of the lower and upper jaws and deformity of the facial skull are the most common ND manifestations [12, 13]. The incidence of progressing spine curvature in this genetic pathology ranges from 25 to 80%. In 60% of patients, kyphoscoliotic changes are combined with deformities of the chest, followed by decrease of the pulmonary vital capacity [12, 14]. Bronheim R. et al., (2019) consider pulmonary pathology to be the evidence of qualitative type I collagen mutations but not the consequence of the axial skeleton curvature. In 68% of the cases, restrictive diseases are the main cause of death [15].

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Levy P. et al., (2015) reports on the sleep apnea in 1 to 6% of adults and in 2% of children with OI. Basing on Arponen H. et al., (2018) study, 15% of these patients require non-invasive respiratory ventilation during sleep [16, 17]. Patients with OI have an increased risk of cardiovascular diseases. Raphael E. Bonita et al., (2010), Balasubramanian M et al., (2019) revealed extension of the aortic root in 28% of the cases, thickening of the interventricular septum in 40% of the cases, thickening of the posterior wall of the left ventricle in 68%, aortic stenosis in 1.7%, atrial septal defect in 3.4%, Fallot’s tetralogy in 1, 7% and mitral valve prolapse in 6.9% of the cases [18, 19]. Chagas C. E et al., (2012) and Zambrano M. B. et al., (2014) present the data on the identified relationship between overweight and severe forms of osteogenesis imperfecta. For instance, alimentary obesity was registered in 46% of the cases in type III and required the selection of an individual diet. The main cause of overweight is physical inactivity due to frequent fractures and skeletal maldevelopment leading to the pain restricting activity [20-22]. Some authors indicate the disorders of blood coagulation potentials, demonstrated by an increase of bleeding time, decrease of factor VIII level and thrombocytic dysfunction, regardless of their normal number [23, 24].

ANAESTHESIOLOGICAL PROVISION OF ORTHOPAEDIC INVASIONS Considering the high predisposition to fractures and dislocations of limb bones in patients with OI, special care should be given while placing them on the operating table and applying a tourniquet before peripheral vein catheterization [25]. For the same reason, invasive arterial pressure measurement in this pathology is preferable to the oscillometric method [26].

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In tracheal intubation using direct laryngoscopy, anesthesiologists are faced with initially difficult respiratory tracts against the background of short neck, spinal scoliosis and the high risk of odontoaxial displacement, fractures of the cervical vertebrae, mandibulum and teeth. Hematomas or bleeding of the mucous membrane of the oral pharynx may also occur, making the situation more complicated [27]. Karabiyik et al., (2002) in his article describes the experience of providing respiratory tracts conductivity using a laryngeal mask against the background of total intravenous anesthesia [28]. In order to reduce the risk of developing possible adverse events, Elizabeth Vue et al., (2016) recommend performance of tracheal intubation using a fiberoptic bronchoscope on spontaneous breathing, without sedation, and after irrigation of the oropharynx with 4% lidocaine [26]. The advantages of the technique using fiberoptic laryngoscopy for tracheal intubation are also supported by Sahin A. et al., (2004) for the cases when motion in the cervical spine is undesirable [29]. Some authors offer to give up myoplegia with succinylcholine during induction in anesthesia due to the high probability of the limb fractures against the background of fasciculations [25, 30, 31]. Satoru Ogawa et al., (2009), in order to prevent malignant hyperthermia (MH), recommend total intravenous anesthesia with propofol combined with short-acting opioid analgesics, rather than halogen-containing inhalation anesthetics, although a direct connection of the latter with MH in this cohort of the patients was not proved [32, 33]. Rothschild L. et al., (2018), describe good intraoperative analgesic effect on the background of neuraxial blockade with a single or prolonged way of local anesthetic introduction in combination with general anesthesia and mechanical respiratory ventilation. The spinal or epidural anesthesia in children was performed in 87.5% of the cases, and only in 12.5% of the cases these techniques were rejected due to severe deformity of the spine [30]. On the other hand, Gupta D. et al., (2016) report on the rare application of central regional analgesia by anesthesiologists in patients with osteogenesis imperfecta due to the

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difficulty of predicting the spread of local anesthetics in a clinically significant scoliosis [34]. According to the results of many large-scale multicenter studies in the area of pediatric regional anesthesia, massive evidence base has been recorded in favor of neuraxial blockades safety produced under general anesthesia (the risk of complications is 0.66%, the risk of paralysis is 0.004%). Wong G. K. et al., (2013), after the performance of a 15-year retrospective review on the acute pain service databases of Academic Pediatric clinic in Canada, presented data on the incidence of complications of continuous epidural analgesia in accordance with age. Therefore, the complications’ rate in newborns is 4.2% compared to 1.4% in infants, 0.5% in children aged from one to eight years and 0.8% in children over eight years old [35-38]. Currently the number of serious catheter-associated infections in children has increased, which is associated with increased neuraxial analgesia applications. The infection incidence was higher in patients with chronic pain, i.e., 3.2% compared with the same with acute postoperative pain, i.e., 0.06%. In addition, Staphylococcus aureus and Streptococcus haemolyticus sensitive to methicillin were isolated in the operated children, and Staphylococcus aureus resistant to methicillin was cultured in children with chronic pain. Application of antibiotic therapy prior to epidural catheterization is controversial. An earlier prospective study in adults indicated no association between the incidence of colonization or infection of an epidural catheter in its 2-4 days use and administration of antibiotics in the perioperative period [39, 40]. Based on the studies carried out in the 1990s, the incidence of unintentional intravascular injections for epidural blockages in children ranged from 5.6 to 6.9%, according to various sources [41, 42]. The Pediatric Regional Anesthesia Network (PRAN), in its turn, reports 0.6% of cases. At the same time, the incidence of any adverse effects associated with neuraxial blockages does not depend on the technique of their performance and the degree of the patient’s sedation. Polaner D. M. et al., (2012) published 6 (1.3%) complication cases out of 450 epidural analgesia produced using ultrasound, and 307 (1.8%) complication cases

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out of 16 343 without ultrasound. In conscious patients, unfavorable effects were recorded in 4% of the cases and in 1.9% of children under general anesthesia [43].

CONCLUSION Operative orthopedic invasions in the patients with osteogenesis imperfecta are intended to increase motor activity and prevent pathological fractures resulting in the improvement of the quality of life. Application of continuous regional methods of anesthesia, being the main analgesic component of anesthetic protection and postoperative pain relief, makes it possible to effectively solve the given issues. Assessment of the coagulation properties of the patient’s blood plasma and prediction of the critical incidents associated with concomitant cardiovascular and pulmonary pathology are crucial objectives in the perioperative medicine. A multidisciplinary team of doctors should be involved in preparing these children for surgery to prescribe or correct a medication therapy for comorbid conditions, defining treatment strategy in the perioperative period.

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[2]

[3]

Shamit, S., Prabhu, K. F., Michael C. M., Uday N. R. (2018). Implant therapy for a patient with osteogenesis imperfecta type I: review of literature with a case report. Int J Implant Dent, 4: 36. Dijk, F. S., Sillence, D. O. (2014) Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A, 164(6): 1470-1481. Engelbert, R. H., Uiterwaal, C. S., Gulmans, V. A., Pruijs H., Helders P. J. (2000). Osteogenesis imperfecta in childhood: prognosis for walking. J Pediatr, 137(3):397-402.

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Riff, A., Smith, P. A. (2016) Transitional care in osteogenesis imperfecta: advances in biology, technology, and clinical practice. Chicago: Shriners Hospital for Children, 1(1): 27-48. [5] Celin, M. R., Kruger, K. M., Caudill, А., Nagamani, S. C. S., Harris, G F. Smith, P. A. (2020). A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta. JB JS Open Access, 5(3): e20.00031. [6] Mingazov, E. R., Gofman, F. F., Popkov, A. V., Aranovich, A. M., Gubin, A. V., Popkov, D. A. (2019). First use experience with titanium telescopic rod in pediatric limb deformity correction in osteogenesis imperfect. Genius orthopedics, 25(3):297-303. [7] Arponen, H., Mäkitie, O., Haukka, J., Ranta, H., Ekholm, M., Mäyränpää, M. K., Kaitila, I., Waltimo-Sirén, J. (2012). Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta. J Bone Miner Res, 27(5):1142-1149. [8] Ibrahim, A. G., Crockard, H. A. (2007). Basilar impression and osteogenesis imperfecta: a 21‐year retrospective review of outcomes in 20 patients. J Neurosurg Spine, 7:594-600. [9] Menezes, A. H. (2008). Specific entities affecting the craniocervical region: osteogenesis imperfecta and related osteochondrodysplasias: medical and surgical management of basilar impression. Childs Nerv Syst, 24:1169-1172. [10] Freya, K. R., Coucke, P. J., Paepe, A. M., Symoens, S., Malfait, F., Gentile, F. V., Sangiorgi, L., D’Eufemia, P., Celli, M., Garretsen, T., Cremers, C., Dhooge, I., Leenheer, E. (2011). Osteogenesis imperfecta: the audiological phenotype lacks correlation with the genotype. Orphanet J Rare Dis, 6: 88. [11] Kuurila, K., Kaitila, I., Johansson, R., Grénman, R. (2002). Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol, 111(10):939-46. [12] Bailleul-Forestier, I., Berdal, A., Vinckier, F., Ravel, T., Fryns, J. P., Verloes, A. (2008). The genetic basis of inherited anomalies of

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the teeth. Part 2: syndromes with significant dental involvement. Eur J Med Genet, 51(5):383-408. Tauer, J. T., Robinson, M. E., Rauch, F. (2019). Osteogenesis imperfecta: new perspectives from clinical and translational research. JBMR Plus, 3(8): e10174. Castelein, R. M., Hasler, C., Helenius, I., Ovadia, D., Yazici, M. (2019). Complex spine deformities in young patients with severe osteogenesis imperfecta: current concepts review. J Child Orthop, 13(1): 22-32. Bronheim, R., Khan, S., Carter, E., Sandhaus, R. A. (2019). Scoliosis and cardiopulmonary outcomes in osteogenesis imperfecta patients. SPINE, 44(15):1057-1063. Levy, P., Kohler, M., McNicholas, W. T. (2015). Obstructive sleep apnoea syndrome. Nat Rev Dis Primers, 1:15015. Arponen, H., Waltimo‐Siren, J., Valta, H., Makitie, O. (2018). Fatigue and disturbances of sleep in patients with osteogenesis imperfect - a cross‐sectional questionnaire study. BMC Musculoskelet Disord, 19(1):3. Bonita, R. E., Cohen, I. S., Berko, B. A. (2010). Valvular heart disease in osteogenesis imperfecta: presentation of a case and review of the literature. Echocardiography, 27(1):69-73. Balasubramanian, M., Verschueren, A., Kleevens, S., Luyckx, I., Perik, M., Schirwani, S., Mortier, G., Morisaki, H., Rodrigus, I., Laer, L., Verstraeten, A., Loeys, B. (2019). Aortic aneurysm/dissection and osteogenesis imperfecta: Four new families and review of the literature. Bone, 121:191-195. Chagas, C. E., Roque, J. P., Santarosa, E. P. B., Lazaretti-Castro, M., Martini, L. A. (2012). Do patients with osteogenesis imperfecta need individualized nutritional support? Nutrition, 28:138-142. Zambrano, M. B., Brizola, E. S., Refosco, L., Giugliani, R., Félix, T. M. (2014). Anthropometry, nutritional status, and dietary intake in pediatric patients with osteogenesis imperfecta. J Am Coll Nutr, 33 (1): 18-25.

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[22] Germain-Lee, E. L., Brennen, F. S., Stern, D., Kantipuly, A., Melvin, P., Terkowitz, M. S., Shapiro, J. R. Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care. Pediatric Research. 2016; 79: 489495. [23] Bhardwaj, M., Kar, K., Johar, S., Ruchi, S., D. A., Hooda, S. (2014). Anaesthetic management in a patient with osteogenesis imperfecta and a fractured femur. South Afr J Anaesth Analg, 20(2):132-135. [24] Singh, J., Sharma, P., Mitra, S. (2017). A novel approach to the anaesthetic management of a case of osteogenesis imperfecta. Indian J Anaesth, 61(6): 517-519. [25] Erdoğan, M. A., Sanli M., Ersoy, M. O. (2013). Anesthesia management in a child with osteogenesis imperfecta and epidural hemorrhage. Braz J Anesthesiol, 63(4):366-368. [26] Vue, E., Davila, J., Straker, T. (2016). Anesthetic Management in a Gravida with Type IV Osteogenesis Imperfecta. Case Rep Med, 2:1-6. [27] Dijk, F. S., Cobben, J. M., Kariminejad, A., Maugeri, A., Nikkels, P. G., Rijn, R. R., Pals, G. (2011). Osteogenesis Imperfecta: A Review with Clinical Examples. Mol Syndromol, 2(1):1-20. [28] Karabiyik, L., Parpucu, M., Kurtipek, O. (2002). Total intravenous anaesthesia and the use of an intubating laryngeal mask in a patient with osteogenesis imperfecta. Acta Anaesthesiol Scand, 46(5):618619. [29] Sahin, A., Salman, M. A., Erden, I. A., Aypar, U. (2004). Upper cervical vertebrae movement during intubating laryngeal mask, fibreoptic and direct laryngoscopy: a video-fluoroscopic study. Eur J Anaesthesiol, 21(10):819-823. [30] Rothschild, L., Goeller, J., Voronov, P., Barabanova, A., Smith, P. (2018). Anesthesia in children with osteogenesis imperfecta: Retrospective chart review of 83 patients and 205 anesthetics over 7 years. Paediatr Anaesth, 28(11):1050-1058.

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[31] Dinges, E., Ortner, C., Bollag, L., Davies, J., Landau, R. (2015). Osteogenesis imperfecta: cesarean deliveries in identical twins. Int J Obstet Anesth, 24(1):64-68. [32] Ogawa, S., Okutani, R., Suehiro, K. (2009). Anesthetic management using total intravenous anesthesia with remifentanil in a child with osteogenesis imperfect. J Anesth, 23(1):123-125. [33] Santos, M. L., Añez, C., Fuentes, A., Méndez, B.; Periñán, R., Rull, M. (2016). Airway Management with ProSeal LMA in a Patient with Osteogenesis Imperfecta. Anesthesia & Analgesia, 103(3):794. [34] Gupta, D., Purohit, A. Anesthetic management in a patient with osteogenesis imperfecta for rush nail removal in femur. Anesth Essays Res, 10(3): 677-679. [35] Walker, B. J., Long, J. B., De Oliveira, G. S., Szmuk, P., Setiawan, C., Polaner, D. M., Suresh, S. (2015). Peripheral nerve catheters in children: an analysis of safety and practice patterns from the pediatric regional anesthesia network (PRAN). Br J Anaesth, 115(3):457-462. [36] Suresh, S., Ecoffey, C., Bosenberg, A., Lonnqvist, P. A., Oliveira, G. S., Leon C. O., Andrés J., Ivani, G. (2018). The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine Recommendations on Local Anesthetics and Adjuvants Dosage in Pediatric Regional Anesthesia. Reg Anesth Pain Med, 43(2):211216. [37] Ecoffey, C., Lacroix, F., Giaufré, E., Orliaguet, G., Courrèges, P. (2010). Association des Anesthésistes Réanimateurs Pédiatriques d’Expression Française (ADARPEF). Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr Anaesth, 20: 1061-1069. [38] Wong, G. K., Arab, A. A., Chew, S. C., Naser, B., Crawford, M. W. (2013). Major complications related to epidural analgesia in children: a 15-year audit of 3,152 epidurals. Can J Anaesth, 60(4):355-363.

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[39] Sethna, N. F., Clendenin, D., Athiraman, U., Solodiuk, J., Rodriguez, D. P., Zurakowski, D. (2010). Incidence of epidural catheter-associated infections after continuous epidural analgesia in children. Anesthesiology, 113(1):224-232. [40] Yuan, H. B., Zuo, Z., Yu, K. W., Lin, W. M., Lee, H. C., Chan, K. H. (2008). Bacterial colonization of epidural catheters used for short-term postoperative analgesia: microbiological examination and risk factor analysis. Anesthesiology, 108(1):130-137. [41] Veyckemans, L. J. Obbergh, J. M. (1992). Gouverneur Lessons from 1,100 caudal blocks in a teaching hospital. Reg. Anesth. Pain Med, 17: 119-125. [42] Fisher, Q. A., Shaffner, D. H., Yaster, M. (1997). Detection of intravascular injection of regional anaesthetics in children. Can. J. Anesth, 44:592-598. [43] Polaner, D. M., Taenzer, A. H., Walker, B. J. (2012). Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth. Analg, 115(6):1353-1364.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 7

MANAGEMENT OF PAIN IN PATIENTS WITH OSTEOGENESIS IMPERFECTA DURING OPERATIONS ON THE LOWER LIMB Vadim Evreinov, MD, PhD and Elena Raznoglyadova, MD National Ilizarov Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia

ABSTRACT The method of choice for anesthetic support of orthopedic interventions on the hip in children is a combination of inhalation anesthesia and prolonged epidural analgesia. Nevertheless, there is no consensus in the medical community about the advisability of using neuraxial blockades in patients with osteogenesis imperfecta due to the risk of hemorrhagic complications, as well as increased intracranial pressure against the background of hydrocephalus, as a manifestation of an anomaly of the craniocervical junction.



Corresponding Author’s email: [email protected].

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Purpose of Study To assess the efficacy and safety of prolonged epidural blockade as the main component of anesthesia and postoperative pain relief in children with osteogenesis imperfecta during orthopedic correction of hip deformities.

Materials and Methods A retrospective analysis for the period from 2018 to 2020 included 40 children who underwent orthopedic interventions on the lower extremities. Considering a similar concomitant neurological pathology (epilepsy, hydrocephalus) and the severity of surgical interventions on the hip, 2 groups of 20 persons were formed: the main group – with osteogenesis imperfecta (OI) and the control group – with cerebral palsy (CP). Evaluated: hemodynamic parameters, perioperative need for analgesics, volume of external blood loss and need for blood transfusion, structure of complications.

Results Statistically significant differences in hemodynamic parameters were detected at the stage of tracheal intubation and at the end of the surgery, but they did not have clinical significance, since they were within the acceptable physiological values. The recorded differences in the hemoglobin level of capillary blood before surgery are probably due to the initial hypovolemia and hemoconcentration in the cerebral palsy group.

Conclusion Prolonged epidural analgesia in children with osteogenesis imperfecta during orthopedic correction of hip deformities is an effective and safe component of anesthesia and postoperative pain relief.

Keywords: osteogenesis imperfecta, childhood, hip surgery, prolonged epidural analgesia

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INTRODUCTION The clinical aspects of osteogenesis imperfecta (OI) are a decrease in bone mass, osteoporosis, and frequent fractures. Progressive deformities of the lower extremities, pain syndrome extremely limit the activity of patients, thereby reducing their quality of life [1, 2]. Currently, the concept of surgical treatment of this pathology consists in performing corrective osteotomies of long tubular bones with subsequent nailing by intramedullary titanium telescopic systems in combination with osteosynthesis by external fixators [3, 4]. The presence of motor, behavioral disorders and severe concomitant somatic pathology significantly complicate the perioperative management of such patients and dictate special requirements for the choice of anesthetic protection method [5-9]. The “gold standard” of anesthetic support for orthopedic hip surgeries in children is the combination of inhalation anesthesia with mechanical ventilation and prolonged epidural analgesia, the safety of which has been proven by a large number of studies [10-14]. At present, there is no consensus in the medical community about the advisability of using neuraxial blockades in patients with osteogenesis imperfecta due to the risk of hemorrhagic complications (epidural hematoma) and possible acute neurological disorders, due to the difficulty of predicting the spread of local anesthetics in severe kyphoscoliotic deformity of the spine [15, 16]. There is an open question regarding the increase in intracranial pressure, against the background of hydrocephalus, as a manifestation of anomalies of the craniocervical junction, and epidural analgesia [17–19]. The purpose of our study was to assess the efficacy and safety of prolonged epidural blockade as the main component of anesthesia and postoperative pain relief in children with osteogenesis imperfecta during orthopedic correction of hip deformities.

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MATERIALS AND METHODS The null hypothesis is based on the assumption that prolonged epidural analgesia is equally effective and does not affect the risk of perioperative complications in children with osteogenesis imperfecta compared to the patients with cerebral palsy, epilepsy, and hydrocephalus. The objects for our retrospective data analysis were children (40 persons) who underwent orthopedic surgery on the hip. The extraction of archival data was carried out for the period from 2018 to 2020. The study was carried out at the Federal State Budgetary Institution “NMRC TO named after academician G.A. Ilizarov” of the Ministry of Health of the Russian Federation. Data extraction criteria: 1. Age from 3 to 17 years old; 2. Osteogenesis imperfecta types I, III, IV according to Sillence [20], severe cerebral palsy (IV – V level according to the Gross Motor Function Classification System (GMFCS)) [21]; 3. Severe deformities or spastic dislocations and subluxations of the hips; 4. Orthopedic interventions on the hip with the application of intramedullary titanium telescopic systems, palliative or reconstructive surgery on the hip joint; 5. Concomitant epilepsy and/or compensated hydrocephalus (for patients in the control group); 6. Anesthetic aid – general inhalation anesthesia with mechanical ventilation in combination with prolonged epidural analgesia. All patients, depending on the main pathology, were divided into 2 groups, comparable with each other in terms of the main factors influencing the results of the analysis. The study groups included 9 boys and 11 girls (p > 0.05). The mean value (standard deviation – SD) of age in the groups was 7.4 (3.1) and 7.7 (2.3) years and did not statistically

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significantly differ (p = 0.65). The mean (SD) weight was 22.4 (10.7) kg and 21.2 (14.4) kg, respectively (p = 0.76). Of the 40 people included in the study, 20 (50%) were treated for osteogenesis imperfecta and were assigned to the main group (OI). Moreover, 7 children out of 20 (35%) had osteogenesis imperfecta type I according to Sillence, 5 (25%) had type III, and 8 (40%) – type IV. There were no anamnestic data for concomitant epilepsy and hydrocephalus. Considering the similar concomitant neurological pathology according to the literature data (hydrocephalus and epilepsy) with OI patients and the severity of surgical interventions on the hip, a control group was formed [22, 23]. The second group (cerebral palsy) included 20 out of 40 (50%) patients with cerebral palsy, concomitant epilepsy and hydrocephalus. All of them (100%) suffered from hydrocephalus, 8 out of 20 (40%) suffered from epilepsy and took anticonvulsants in the perioperative period. In accordance with the surgical and anesthetic risk for MSSAR in the OI group, 8 patients had grade III, 12 – IV, while in the cerebral palsy group 7 patients had grade III and 13 – IV (p > 0.05). All children were operated on under general inhalation anesthesia with mechanical ventilation in combination with epidural analgesia with ropivacaine 0.5% (Naropin®, Astra Zeneca, Sweden). The anesthetic was injected through a G 20 epidural catheter placed at the level of the dermatome corresponding to the surgery (L3-L4). A single-stage bolus injection of anesthetic at a dose of 2 mg/kg was carried out immediately after the installation of an epidural catheter. Repeated intraoperative injection was performed at ½ of the initial volume every next two hours. The average dose (SD) of the anesthetic during the surgery was: OI – 0.7 (0.1) mg/kg/h, cerebral palsy – 0.7 (0.3) mg/kg/h and did not statistically significantly differ (p = 0.82). Fentanyl, rocuronium bromide were used for induction anesthesia, in age-related dosages per body weight. Sevoflurane (Sevoran®, Abbott Laboratories, UK) was used as an inhalation agent. Fentanyl was injected once only for tracheal intubation, the average dosage (SD) of which in the groups was 5.6 (2.7) μg/kg, 5.9 (2.4) μg/kg in the OI and cerebral

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palsy groups respectively (p = 0.65). For the purpose of conservative hemostasis, tranexamic acid was administered intraoperatively and then 6 hours after the first injection at a dose of 15 mg/kg. At the end of the surgery, all patients were extubated on the operating table and transferred to the anesthesiology and reanimation department (A&R) on spontaneous breathing. Postoperative pain relief in A&R was carried out by the method of prolonged epidural analgesia (PEA) with ropivacaine 0.2% at the dose of 0.3 mg/kg/h using an elastomeric pump. Also, for the purpose of analgosedation, fentanyl was injected intravenously by micro-stream at the dose of 1.5 μg/kg/hour during their stay in the anesthesiology and reanimation department. Non-narcotic analgesics (paracetamol) in all groups were prescribed, if necessary, by the decision of the resuscitator. The volume of external intraoperative blood loss, determined by the gravimetric method, as well as the volume of intraoperative infusion therapy, did not statistically significantly differ between groups (p> 0.05). Laboratory control of the general blood test was carried out: during the surgery, 6 hours after the surgery and on the first postoperative day. The indications for transfusion of erythrocyte-containing components were blood loss of more than 25% of the circulating blood volume (CBV), a decrease in hemoglobin level below 80 g/l, hematocrit level below 25% and/or the occurrence of circulatory disorders. Criteria for evaluation: 1. hemodynamic parameters (mean arterial pressure (MAP)), heart rate (HR); 2. the volume of external blood loss; 3. the volume of infusion therapy; 4. capillary blood hemoglobin level; 5. the need for blood transfusion; 6. the number of complications; 7. the need for additional using of analgesics in the postoperative period;

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Study stages: 1. 2. 3. 4.

intraoperative; upon admission of the patient to the A&R; 6 hours after transfer to A&R; at 6 o’clock in the morning of the day following the surgery;

Mean arterial pressure was determined by the oscillometric method using an anesthetic monitor, and heart rate by means of a heart rate monitor. Statistical analysis was performed using StatPlus Pro 6. All sample data corresponded to normal distribution (Kolmogorov-Smirnov test). The parameters of the distribution of quantitative traits were described using the mean and standard deviation. To compare the groups, we used a special case of one-way analysis of variance – Student’s T-test. When comparing the proportions, the χ2 test was used. To compare qualitative features between the two groups, the odds ratio (OR) and its 95% confidence interval (CI) were calculated. In all cases, the significance level α at which the null hypothesis was rejected was taken equal to 0.05. The study was approved by the institution’s ethics committee and was conducted in accordance with the ethical standards set out in the Declaration of Helsinki.

RESULTS Statistically significant differences in hemodynamic parameters were recorded at the time of intubation (MAP) and after tracheal extubation (MAP, HR). However, these differences had no clinical significance, since they were within the acceptable values for this category of patients (data are presented in Table 1). Arterial hypotension, requiring correction by vasopressors, was not recorded in patients of the OI group, in the cerebral palsy group it occurred in one case (p > 0.05).

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The volume of external intraoperative blood loss was determined in the OI group – 121 (43) ml, in the cerebral palsy group – 118 (43) ml (p = 0.82), which in a fractional ratio of the circulating blood volume (CBV) was 8.5% (4.4%) and 8.9% (3.2%) respectively (p = 0.78).

CP

OI

Groups

Table 1. Intraoperative hemodynamic parameters (M ± SD) Hemodynamic indicators

Admission to the operating room 74(7)

MAP (mm Hg) HR per min. 127(19) MAP (mm 71 (7) Hg) HR per min. 125(12)

Tracheal After the injection Beginning of The main Tracheal intubatio of anesthetic into the surgery stage of extubation n the epidural space the surgery 73(6) 66(8) 61(9) 60(8) 62(6) 124(19) *67(8)

122(18) 61(9)

122(18) 57(8)

117(20) 56(7)

114(18) *58(6)

122(10)

119(11)

113(15)

110(14)

*102(12)

Note: * One-way analysis of variance; р < 0,05.

Intraoperative infusion, carried out with crystalloids, was 24 (8) ml/kg/h in the OI group, and 27 (12) ml/kg/h in the cerebral palsy group and did not differ significantly (p = 0.41). Analysis of hematological parameters revealed significant differences in the hemoglobin level of capillary blood in the groups at the stage of admission to the operating room and was determined at the level of 123 (8) g/l and 135 (11) g/l respectively (p < 0.05). After the main stage of the surgery, the level of hemoglobin decreased in all groups, which is due to intraoperative blood loss and hemodilution, was 105 (12) g/l in OI, and 101 (9) g/l in cerebral palsy (p = 0.22). The patients of the studied groups did not receive blood transfusion during the surgery. During early postoperative period, hemodynamic parameters did not statistically significantly differ in the study groups (p > 0.05), the data are presented in Table 2. Infusion therapy in the early postoperative period in the intensive care department was carried out with crystalloids amounting to 2.4 (1) ml/kg/h and 2.1 (0.7) ml/kg/h in the OI and cerebral palsy groups respectively (p > 0.05). The hemoglobin level at the time of transfer from

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A&R to the department was 109 (12) g/l in the OI group, 112 (11) g/l in the control group and did not differ significantly (p > 0.05). Patients of the studied groups did not receive blood transfusion in the intensive care department. Table 2. Hemodynamic indicators in A&R (M ± SD) Groups OI CP

Hemodynamic indicators MAP (mm Hg) HR per min. MAP (mm Hg) HR per min.

Admission to the A&R 80(8) 121(21) 76(11) 122(15)

6 hours after 71(9) 123(22) 72(14) 110(19)

When transferring to the department 70(10) 118(22) 73(10) 122(13)

Note: One-way analysis of variance; р > 0,05.

The need for narcotic analgesics, as well as the volume of anesthetic for PEA, did not statistically significantly differ in the study groups (p > 0.05) and amounted to: 34 (16) μg/ for fentanyl in the OI group and 28 (10) μg/h in the cerebral palsy group, for ropivacaine 0.2% – 6.8 (3.4) mg/h and 5.8 (2.3) mg/h in the main and control groups respectively. The number of prescriptions of paracetamol for additional anesthesia in the OI group was 7 times, in the cerebral palsy group – 8 times (p>0.05). The almost equal probability of using non-narcotic analgesics in the study groups is confirmed by the odds ratio OR = 0.808 with a 95% CI from 0.224 to 2.912. There were no complications during early postoperative period (0%, 95% CI from 0% to 13.9%).

DISCUSSION The registered statistical differences in the MAP values at the time of tracheal intubation in the cerebral palsy group are probably due to the initial hypovolemia, which, upon induction into anesthesia, contributed to a decrease in blood pressure. Low values of indicators (MAP, HR) at the end of the surgery (tracheal extubation) can be explained by impaired

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central hemodynamics characteristic of cerebral palsy [24, 25] and sympathetic block, but the statistical power of our study is insufficient to reveal such differences. Thus, prolonged epidural analgesia in the groups promoted hemodynamic stability in the perioperative period, and the revealed discrepancies at some stages of the surgery did not have clinical significance, since the values of MAP and HR were within the reference interval for this category of patients. Dysphagia, low nutritional status in children with cerebral palsy, and, as a consequence, reduced drinking, promoted hemoconcentration, which was reflected in statistically significant differences in capillary blood hemoglobin level between the comparison groups at the stage of admission to the operating room [26]. Adequate intraoperative fluid therapy led to moderate hemodelution and neutralized the differences in hematological parameters. Retrospective data analysis did not register any differences in the frequency of prescription of additional analgesics in the early postoperative period. This fact confirms the effectiveness of prolonged epidural analgesia in patients with osteogenesis imperfecta and cerebral palsy during hip surgery, and is consistent with the data of large studies in the field of pediatric anesthesiology [10-14]. When analyzing complications, it seems logical to assume a high probability of the brain stem penetrating the tentorial or foramen magnum in patients with hydrocephalus with the simultaneous injection of anesthetic into the epidural space due to compression of the dural sac and compression of the epidural veins. According to Hilt H. et al. (1986) and Hirabayashi Y. et al. (1990), a solution injected into the lumbar epidural space moderately increases intracranial pressure, the effect is short-term and lasts 3-7 minutes [27, 28]. A slow bolus injection of local anesthetic to patients with compensated or subcompensated hydrocephalus, and even more so long infusion, minimizes all possible complications [29, 30]. Our study did not register acute neurological or hemorrhagic complications, which confirms the safety of prolonged epidural analgesia

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when used in comparison groups, and with a high probability allows us to accept the null hypothesis.

CONCLUSION 



Prolonged epidural analgesia is an effective and safe component of anesthesia in children with osteogenesis imperfecta in nailing of the femoral bone by intramedullary titanium telescopic system. Prolonged epidural analgesia provides an adequate level of pain relief in the early postoperative period after orthopedic correction of hip deformities.

REFERENCES [1] [2]

[3]

[4]

[5]

Morello, R. (2018). Osteogenesis imperfecta and therapeutics. Matrix Biol., 71 - 72: 294–312. Marr, C., Seasman, A., Bishop, N. (2017). Managing the patient with osteogenesis imperfecta: a multidisciplinary approach. J. Multidiscip. Healthc, 10: 145 – 155. Mingazov, E. R., Gofman, F. F., Popkov, A. V., Aranovich, A. M., Gubin, A. V., Popkov, D. A. (2019). First use experience with titanium telescopic rod in pediatric limb deformity correction in osteogenesis imperfect. Genius orthopedics, 25(3):297 - 303. Rosemberg, D. L., Goiano, E. O., Akkari, M., Santili, C. (2018) Effects of a telescopic intramedullary rod for treating patients with osteogenesis imperfecta of the femur. J. Child Orthop., 12(1): 97 – 103. Anissipour, A. K., Hammerberg, K. W., Caudill, A., Kostiuk, T., Tarima, S., Zhao, H. S., Krzak, J. J., Smith, P. A. (2014). Behavior of scoliosis during growth in children with osteogenesis imperfecta. J. Bone Joint Surg. Am., 96(3): 237 – 243.

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Vadim Evreinov and Elena Raznoglyadova Bronheim, R., Khan, S., Carter, E., Sandhaus, R. A. (2019). Scoliosis and cardiopulmonary outcomes in osteogenesis imperfecta patients. SPINE, 44(15):1057 - 1063. Levy, P., Kohler, M., McNicholas, W. T. (2015). Obstructive sleep apnoea syndrome. Nat. Rev. Dis. Primers., 1:15015. Balasubramanian, M., Verschueren, A., Kleevens, S., Luyckx, I., Perik, M., Schirwani, S., Mortier, G., Morisaki, H., Rodrigus, I., Laer, L., Verstraeten, A., Loeys, B. (2019). Aortic aneurysm/d issection and osteogenesis imperfecta: Four new families and review of the literature. Bone, 121:191 - 195. Chagas, C. E., Roque, J. P., Santarosa, E. P. B., Lazaretti-Castro, M., Martini, L. A. (2012). Do patients with osteogenesis imperfecta need individualized nutritional support? Nutrition, 28:138 – 142. Ecoffey, C., Lacroix, F., Giaufré, E., Orliaguet, G., Courrèges, P. (2010). Association des Anesthésistes Réanimateurs Pédiatriques d’Expression Française (ADARPEF). Epidemiology and morbidity of regional anesthesia in children: a follow-up one-year prospective survey of the French-Language Society of Paediatric Anaesthesiologists (ADARPEF). Paediatr. Anaesth., 20(12):1061 1069. Taenzer A. H., Walker B. J., Bosenberg A. T., Martin, L., Suresh, S., Polaner, D. M., Wolf, C., Krane E. J. (2014). Asleep versus awake: does it matter? Pediatric regional block complications by patient state: a report from the Pediatric Regional Anesthesia Network. Reg. Anesth. Pain Med., 39(4):279 - 283. Walker B. J., Long J. B., Sathyamoorthy M. (2018). Complications in pediatric regional anesthesia: an analysis of more than 100,000 blocks from the Pediatric Regional Anesthesia Network. Anesthesiology, 129(4):721 – 732. Polaner, D. M., Taenzer, A. H., Walker, B. J. (2012). Pediatric Regional Anesthesia Network (PRAN): a multi-institutional study of the use and incidence of complications of pediatric regional anesthesia. Anesth. Analg., 115(6):1353 – 1364.

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[14] Merella, F., Canchi-Murali, N., Mossetti V. (2019). General principles of regional anaesthesia in children. BJA Educ., 19(10): 342 – 348. [15] Gupta, D., Purohit, A. Anesthetic management in a patient with osteogenesis imperfecta for rush nail removal in femur. Anesth. Essays Res., 10(3): 677 – 679. [16] Onal, O., Zora, M. E., Aslanlar E., Ozdemirkan, A., Celik J. B. (2018) Spinal Anesthesia in an Infant with Osteogenesis Imperfecta. Anesth Pain Med., 8(1): e65917. [17] Wong, C., Nathan, N., Brown D. L. (2009). Spinal, epidural, and caudal anesthesia: anatomy, physiology, and technique. In: R. D. Miller (Ed.), Miller’s anesthesia. 6th edition. Philadelphia: Elsevier Churchill Livingstone, 1289 – 1315. [18] Schulga, P., Grattan, R., Napier, C., Babiker M. O. (2015). How to use… lumbar puncture in children. Arch. Dis. Child. Educ., 100(5):264-271. [19] Grocott, H. P., Mutch, W. A. (1996). Epidural anesthesia and acutely increased intracranial pressure. Lumbar epidural space hydrodynamics in a porcine model. Anesthesiology, 85(5):10861091. [20] Sillence, D. O., Senn, A., Danks, D. M. (1979). Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet, 16(2):101116. [21] Palisano, R., Rosenbaum, P., Walter, S., Russell, D., Wood, E., Galuppi, B. (1997). Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev. Med. Child Neurol., 39(4):214 - 23. [22] Ibrahim, A. G., Crockard, H. A. (2007). Basilar impression and osteogenesis imperfecta: a 21‐year retrospective review of outcomes in 20 patients. J. Neurosurg. Spine, 7:594–600. [23] Menezes, A. H. (2008). Specific entities affecting the craniocervical region: osteogenesis imperfecta and related osteochondrodysplasias: medical and surgical management of basilar impression. Childs Nerv. Syst., 24:1169–1172.

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[24] Diordiev, A. V., Aizenberg, V. L., Yakovleva, E. S. (2015). Anesthesia in patients with cerebral palsy. Regional anesthesia and acute pain management. 9 (3): 29 - 36. [25] Shaikh S. I., Hegade, G. (2017). Role of anesthesiologist in the management of a child with cerebral palsy. Anesth. Essays Res., 11(3):544 - 549. [26] Kamalova, A. A., Rakhmaeva, R. F., Malinovskaya, Yu. V. (2019). Gastroenterological aspects of children management with cerebral palsy (literature review). RMJ Gastro., 5:30 - 35. [27] Hilt, H., Gramm, H. J., Link, J. (1986) Changes in intracranial pressure associated with extradural anesthesia. Anaesth., 58: 676680. [28] Hirabayashi, Y., Shimzu, R., Matsuda, I., Inoue, S. (1990). Effect of extradural compliance and resistance on spread of extradural analgesia. Br. J. Anaesth., –65:508-513. [29] Higuchi, H., Adachi, Y., Kazama, T. (2005). Effects of epidural saline injection on cerebrospinal fluid volume and velocity waveform: a magnetic resonance imaging study. Anesthesiology, 102:285 - 292. [30] Zabolotskikh, I., Trembach, N. (2015). Safety and efficacy of combined epidural/general anesthesia during major abdominal surgery in patients with increased intracranial pressure: a cohort study. BMC Anesthesiol., 15:76.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 8

OSTEOGENESIS IMPERFECTA: THE ROLE AND PLACE OF ORTHOPEDIC SURGERY OF THE LOWER EXTREMITIES Dmitry A. Popkov1,*, MD, PhD Eduard Mingazov1, MD, PhD, Pierre Journeau2, MD, Alexander Gubin3, MD, Nikita Gvozdev1, MD, PhD and Arnold Popkov1, MD 1

Ilizarov National Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia 2 Service de Chirurgie Orthopédique et Traumatologique Pédiatrique, Hôpital d'enfant, CHU Nancy, Vandœuvre-lès-Nancy, France 3 National Priorov Medical Research Center of Traumatology and Orthopedics, Moscow, Russia

ABSTRACT Introduction Surgical correction of orthopedic problems in children and adults with severe osteogenesis imperfecta (OI) is of interest to the medical community. The aim of this study was to review the current relevant literature on the role of orthopedic surgery in the treatment of *

Corresponding Author’s E-mail: [email protected].

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Dmitry A. Popkov, Eduard Mingazov, Pierre Journeau et al. children and adults with osteogenesis imperfecta and integrating surgery into a multidisciplinary team. Material and methods. To prepare the review, the scientific platforms such as PubMed, Scopus, ResearchGate, RSCI were used for information searching. Results and discussion This review includes a discussion of the clinical and radiological classification of OI, indications, features of the surgical technique and the early postoperative period, the role of early functional loading, and long-term treatment results of using telescopic transphyseal constructs in correction of deformities of limbs and aspects of the orthopedic surgery regarding bisphosphonate therapy. Conclusion Care for children and adults with severe and moderate types of osteogenesis imperfecta implies a multifactorial strategy including physical therapy, medical treatment, as well as the use of specialized implants, instrumentation and methods of surgery.

Keywords: osteogenesis imperfecta, limb orthopedic surgery, telescopic rods

INTRODUCTION Orthopedic surgery in children and adults with severe types of osteogenesis imperfecta (OI) is of permanent interest. The aim of this study was to review the current relevant literature about the role of orthopedic surgery in the treatment of children and adults with osteogenesis imperfecta as a part multidisciplinary approach in the treatment of patients with OI.

MATERIAL AND METHODS In this chapter, we summarize the definition, clinical and radiological classification of osteogenesis imperfecta, as well as role and methods of orthopedic and surgical management for fracture and deformity of limbs in pediatric and adults population. To prepare the review, we searched for information sources at the scientific platforms such as PubMed, Scopus,

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ResearchGate, RSCI, as well as other published products (Elsevier, Springer).

RESULTS AND DISCUSSION Definition Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous group of inherited bone dysplasias characterized by frequent fractures, bone deformities, low bone mineral density and osteopenia [1–5].

Clinical and Radiographic Classification The first (and classical!) clinical classification of OI was proposed by Sillence et al. in 1979 [1]. It includes types I, II, III and IV of the disease. This classification is based on clinical presentation, radiographic features and patterns of inheritance. Subsequently, the classification was expanded [3, 4]; in particular, type V was added (dominantly inherited OI with intraosseous membrane ossifications and hypertrophied calluses not prone to remodeling). However, the generally accepted classification of osteogenesis imperfecta has not been developed yet [6]. Currently, for clinical purposes associated with the surgical correction of orthopedic problems in OI (choice of method, prognosis), despite the progress in genetic studies and the identification of new genes responsible for the disease, the phenotypic classification remains relevant [9, 10]. This more clinically based approach put all types of OI including the new recessive types under the Sillence-type clinical umbrella.

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The Working Group of the International Skeletal Dysplasia Society recommends identifying the type of OI (I, II, III, IV, V) by clinical signs, defining subclasses depending on the type of inheritance and the genetic abnormality found [7, 11]. The decision on the method of surgical treatment is made on the basis of disease severity identified with a modified Sillence classification [9, 10]. Clinical and radiological classification [9] is used for purely practical purposes. Type I refers to a milder type of the disease, characterized by a relatively low frequency of fractures and a low risk of bone deformities. This types rarely requires a reconstructive surgery. Type II is the most severe OI type; children die at an early age, indications for surgical orthopedic treatment are not considered. Type III is the most severe type of OI in children who have survived the neonatal period, and in whom the frequency of fractures and deformities is the highest. Type IV includes moderate-to-severe OI; fractures and deformities are more common justifying indications for surgical treatment. Type V is of similar severity to type IV but the hypertrophied and not prone to remodeling calluses after fractures and osteotomies along with ossification of the interosseous membranes significantly limit the indications for operations.

Conservative Orthopedic Treatment Conservative orthopedic treatment, in fact, is part of a physical therapy program aimed at maintaining the child's physical activity, selfcare and muscle strength, acquiring skills of vertical posture [7, 8, 12– 14]. Orthoses applied on the lower extremities compensate the joint instability related to hyperlaxity of the ligaments and correct the position in the joints caused by muscle weakness, which is also a part of the program of postoperative management [13, 14].

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Limb Fracture Management in Patients with Osteogenesis Imperfecta The type and severity of osteogenesis imperfecta determine a method of fracture management in OI patients. In OI type I, bone union occurs within usual period. Thus, the duration of immobilization with a plaster cast should not be longer than in healthy children. Complicated and/or instable fractures justify indications for surgical treatment where an internal osteosynthesis is the most appropriated [8, 11]. In severe OI types (types III, IV), an increased rate of fractures manifests in the preschool and school age [15, 16]. The principal approach to treatment is to minimize duration of immobilization without functional limb loading in order to exclude the development of secondary disuse osteoporosis [8, 17–19]. Alignment of bone fragments is mandatory, since the malunion with angulation of over 20° predisposes to repeated pathological fractures at the deformed site of the bone [20–22]. For treating fractures over preexisting deformities (Figure 1), primary telescopic intramedullary osteosynthesis in combination with surgical deformity correction is recommended [10, 12, 16, 17, 23-29]. The primary use of telescopic intramedullary osteosynthesis for fracture treatment in OI children reduces the frequency of future interventions in comparison with regular non-telescopic implants [30]. Fixation with plates or screws is contraindicated in osteosynthesis in OI patients, since stress concentration results in bone fractures at the level of the proximal and distal edges of the plate because of different mechanical properties/elasticity of bone tissue and implant [8, 31–33]. We should note that the use of non-telescopic implants (Kirschner wires, Kuntcher nails, Rush or Ender rods) in the treatment of bone fractures provides good and excellent results in the short term. However, as the bone grows, risks of fractures and progressive deformities arise in the newly formed bone areas, outside the osteosynthesis zone [11, 17].

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Long-Bone Deformity Correction in Children with OI The primary target of orthopedic surgery in OI children is to maintain physical activity and self-care, autonomy, the ability to gain and develop motor skills including walking. Surgical intervention can achieve this through an increase in the mechanical strength of bones throughout their entire length. Telescoping rodding/nailing of long bones ensures prevention of deformity recurrence and decreases the frequency of fractures [10, 11, 14, 34]. The optimal moment for surgical correction is the age when the child is physiologically ready to stand and walk [8, 29, 30]. The common and recognized indications for surgical treatment in OI children are angular deformities of the lower extremities of over 20°, progressive deformities, repeated fractures, especially fractures over bowed bones, functional motor disorders caused by clinically significant torsion deformities, bone nonunion, varus deformity of the femoral neck associated with a reduced hip abduction, delay or even loss of standing and independent walking abilities due to frequent fractures even in case of minor deformities of the limbs, when an orthopedic treatment with orthoses is ineffective [4, 35–38]. The mostly accepted methods of deformity correction are realignment osteotomies of various types while the principal method of osteosynthesis is transphyseal telescopic intramedullary rigid or elastic rodding (a compound rod with two segments that telescope into each other) (Figure 2) [11, 12, 17, 19, 25, 26, 28]. They ensure constant reinforcement of the bone throughout the growth period because of the telescoping of its parts in opposite directions [25, 39]. Modern telescopic systems enable their extra-articular introduction and minimally invasive percutaneous osteotomies, preserve the periosteal blood supply, reduce the time of the operation, and also minimize the complications inherent in open surgical interventions. The Fassier-Duval rod [26, 39, 40], the Sheffield rod [41] and its modifications [42], the Santili telescopic intramedullary rod [43], and the Russian titanium telescopic rod [28, 44] have been used in surgical practice. Telescopic

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systems providing sliding of one part inside another have been currently the method of choice.

a

b

c

d

Figure 1. Fracture at site of bowed shaft, radiographs: a – standing AP radiographs of lower limb in 6 y.o. boy, note varus angulation at proximal femoral shaft; b – fracture of the right femur at the level of deformity apex; c – closed wedge osteotomy at fracture site and intramedullary telescopic rodding with titanium rod were performed, correction of varus and torsional deformity; d – 18 months later, note satisfactory bone remodeling, excellent alignment of femur, and telescoping of rod.

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Their use in children with severe and moderate-to severe OI results in an improvement in functional abilities, increased motor activity, a decrease in the number of reoperations and fractures [10, 30]. The minimally invasive surgery enables simultaneous bilateral femoral rodding in children with OI type III [10]. The sliding transphyseal flexible intramedullary nailing keeps its indications in selected cases in young preschool children under the age of 4-6 years old with severe forms of OI when the long bones and narrow medullary canal are not suitable for telescoping rods, in OI patients with low life expectancy and severe comorbidities, and for forearm deformities [25, 45-47]. In special cases of complete obliteration of the medullarhy canal a subperiosteal insertion at the shaft level of transphyseal elastic nails been indicated in complete obliteration of the medullary canal [48]. If there are indications, the reinforcement with elastic nails or Rush rods should be performed from the age of 2-3 years. Thus, the telescopic rodding is recommended (secondary with the replacement of the previously installed nails) as soon as the diameter of the bone and the transverse dimensions of the medullary canal allow this to be done technically [10, 17, 26, 30, 40]. The lengthening or gradual deformity correction can be done only in patients with OI of milder type (type I) or in combination with intramedullary osteoinductive osteosynthesis. A few cases present this possibility [49, 50]. Nowadays, the telescopic systems use in comparison with conventional intramedullary implants remains somewhat controversial. Telescopic systems are more difficult to use and much more expensive [51]. Besides, they have the risk of telescoping failure and growth cartilage lesion with loss of residual growth [8].

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b

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Figure 2. Telescopic rodding with titanium rod: a – radiograph before surgery on the left site; b – operation consisted of elastic nails removal, realignment osteotomy at distal shaft and telescopic rodding. Right femur was already operated on (see previous figure); at 18 months follow-up control, excellent alignment, telescoping of nails without rod parts migration.

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Complications and Repeated Interventions in Telescopic Nailing The family or caregivers should learn the information about all possible the risks associated with complications and re-interventions. The total reoperation rate, including rod exchange as the child grows and surgical management of complications is 14.3–53%; by using nontelescopic implants it is 58–87%, and up to 100% of cases in elastic nailing [8, 27, 40, 52, 53]. The Canadian team reported a 36.1% rate of reoperations over a follow-up period of more than 10 years, but the results were reported as a presentation, not publication in peer-reviewed journal [54]. The peer-reviewed literature reports that Fassier-Duval rod surgeryfree survival for the three-year period was 92.3% [30], 77% for BaileyDubow [55] and 92.9% for the Sheffiel telescopic Rod [56]. Azzam et al. reported Fassier-Duval rod replacement in 53% of cases within 52 months after surgery [52]. Cho et al. [57] for a modified Sheffield rod and Spahn et al. [30] for the Fassier-Duval rod show an 88% survival rate over a four-year period. For a five-year period, the telescopic rods did not required surgery in 63% for the femur and 64% for tibia according to Cox et al. [58]. Shin et al. used Dual Interlocking telescopic rod (D-ITR) and reported 75% survival rate for 5.3 years follow-up, which is the best result among all known telescopic rods [42]. On the other hand, the rate of revision surgery also depends on the severity of OI and it reaches 67.86% in OI type III and 31.82% in OI type IV [43]. Telescoping failures (2.1–40% of cases), intra-articular protrusion of the rod parts or their migration (2.1–12.7%), fractures and deformations of the rod (up to 6.9%), bone fractures over rod (up to 27%) are found, in general, in 35–40% of cases with the use of telescopic rods in patients with severe and moderate-to-severe OI (Figure 3) [11, 26]. The incidence of nonunion or delayed bone consolidation at the osteotomy level varies from 0 to 14.5% [26, 40]. Munns et al. observed delayed bone union in 103 cases out of 200 (51.5%) operated on with the Fassier-Duval rod.

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This complication was typical in patients with OI type IV after tibial osteotomy who received pamidronate [59].

a

b

c

d

Figure 3. Complications in telescopic rodding and its disadvantages: a – ankle joint protrusion; b – failure of telescoping; c – non-union resulted in breaking of steel rods; d – long-time lasting plaster cast immobilization without weight-bearing.

The eccentric position of the Fassier-Duval rod in the distal femoral epiphysis (technical errors) significantly increases the risks of nontelescoping, bending of the rod, loss of fixation in the epiphyses and the

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need for its replacement [60]. The publication about 13 patients who were treated with 66 Fassier-Duval rods and sustained 75 operations during a follow-up period of 8.9 years reports that the authors of this article encounted the following complications: loss of rod fixation in the distal epiphyses or greater trochanter (6 cases), failure of telescoping (7 cases), protrusion of the rod into the joint (12 cases), significant bending of the rod (6 cases) that required revision intervention. Using of only intramedullary implants requires from 4 to 8 weeks without weight-bearing in early postoperative period. This is an unfavorable condition as it leads to an additional decrease in bone density [25, 36, 61, 62]. Telescopic rods do not provide torsional and longitudinal stability of bone fragments. Secondary torsional deformity can result in a pronounced external rotation of the entire limb in case of external torsional displacement at femoral osteotomy site [36, 37, 63, 64]. An additional temporary reduced external fixation enables immediate axial loading on the operated limb in postoperative period and prevents any secondary torsion and longitudinal displacement of bone fragments [26, 28, 65]. In a series of 12 patients with a relatively short follow-up period of 1–3 years, the safety of the use of a limited (in time and volume) external osteosynthesis for patients with osteogenesis imperfecta was shown. There was not a single case of telescoping failure of the parts of the titanium rod or its deformities caused by alloy features [28]. Another way to prevent secondary torsional deformations is the combined use of telescopic rods and locking plates with unicortical screw fixation [66]. However, this method does not enable axial loading on the operated site (osteotomy level) of the bone. Furthermore, it requires a mandatory second operation to remove the plate after bone union [66]. Of course, this approach excludes the possibility of minimally invasive percutaneous osteotomies, which was an advantage of Fassier-Duval telescopic rod application [26, 39]. Preliminary results of the use of plate fixation in combination with telescopic or non-telescopic rods with follow up of 10 months revealed bone union occurred after an average of 8.8 weeks [67].

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There is a risk of epiphysiodesis as a complication of transphyseal implant position [8, 11, 17]. Currently, the magnitude of this risk has not been studied in clinical application. The use of steel implants limits or completely excludes the use of MRI in children with OI in situations if indicated [68–70]. The only publication based on a retrospective series of 10 cases (evidence level IV) demonstrates a possibility of performing MRI of no more than 1.5 T in patients with Fassier-Duval steel rods [71]. We emphasize limitation of this study due to a small sample, lack of data in performing MRI on more powerful systems (more than 1.5T) and, accordingly, the need to warn patients and their parents about the theoretical risk of migration of steel rods [71]. The use of titanium rods prevents problems with magnetic resonance imaging [44].

Orthopedic Interventions in Adults with OI Typical orthopedic problems in adults with osteogenesis imperfecta are pathological fractures, deformities, and early degenerative arthritis [72–74]. Conservative treatment is recommended for closed fractures without displacement [60]. Osteosynthesis should not be performed with plates or screws [72]. There is a high risk of nonunion or delayed consolidation by performing reconstructive surgery in adult patients [72, 73]. Using combined techniques in association with osteoinductive surface of intramedullary rods reduces the risk of nonunion [44]. Arthroplasty should be based on customized joint implants [8].

Orthopaedic Surgery and Bisphosphonate Therapy There is limited evidence of the effectiveness of bisphosphonates in reducing the incidence of long bone fractures in children in a controlled

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randomized trial [75]. Meta-analysis of the literature and two Cochrane reviews do not support a conclusion about the positive effect of bisphosphonates on the incidence of fractures in children with osteogenesis imperfecta [76–78]. Using bisphosphonates does not impair the healing of bone fractures [11, 78, 79]. There is a risk [80–82] of pathological fractures at zone of bowed bone with increased mineral density due to inhibition of bone remodeling associated with reduced elasticity of bone tissue as a result of excessive intake of bisphosphonates. The risk of delayed bone union after realignment procedure, performed not with a oscillate saw but with an osteotome can be reduced by taking a 4-month break in bisphosphonates intake (pamidronate) before surgery [59, 83]. The intake of bisphosphonates on bone tissue results in narrowing of the medullar canal and the bone cortex thickening that reduce the spongy bone amount and the intraoperative bleeding. On the other hand, bisphosphonates cause Inhibiting the farnesyl pyrophosphate synthase enzyme and reducing the prenylation of plasma proteins, including the methylene tetrahydrofolate reductase, that can lead to an alteration of the coagulation cascade [84]. It was reported that administration of pamidronate resulted in the absence of consolidation one year after the operation in 72% of cases. When pamidronate was changed to zoledronic acid in the therapeutic protocol, the infusion of which was started no earlier than 4 months after the operation, it reduced the incidence of nonunion to 42%. Moreover, the performance of osteotomy without oscillate saw but with an osteotome is also attributed to the factors that improve the conditions for bone union [59, 83].

CONCLUSION Orthopedic management for children and adults with severe and moderate-to-severe forms of osteogenesis imperfecta represents a part of

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multidisciplinary strategy that should also imply physical and pharmacological therapy. Surgical approaches use specialized implants, instrumentation, and methods of surgical intervention. A multidisciplinary team should consider the time for surgery and indications.

COMPLIANCE WITH ETHICAL STANDARDS Conflict of Interest: The authors declare that they have no conflict of interest. Ethical approval: This article does not contain any studies with human participants performed by any of the authors. Informed consent: Informed consent was obtained from all individual participants included in the study.

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In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 9

SLIDING TRANSPHYSEAL FLEXIBLE INTRAMEDULLARY NAILING IN CHILDREN WITH OSTEOGENESIS IMPERFECT Dmitry A. Popkov, MD, PhD, Eduard Mingazov, MD, PhD, Natalia Kononovich, VD, PhD and Arnold Popkov, MD Ilizarov National Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia

ABSTRACT Introduction Telescopic rods and sliding flexible intramedullary nailing (FIN) permit a long-lasting osteosynthesis and decrease complication rate in children with osteogenesis imperfecta (OI). The aim of this retrospective study was to assess the results of sliding FIN in deformity correction in children with severe types of OI. 

Corresponding Author’s Email: [email protected].

176 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al.

Materials and Methods We retrospectively reviewed 17 consecutive cases of types III and IV of OI. The mean follow-up was 1.9 years. In group I (9 patients, mean age – 5 years 2 months) the transphyseal FIN was performed using titanium nails. Sliding FIN was associated with Ilizarov frame in group II in 8 patients (mean age of 5 years 1 months).

Results All surgeries provided required deformity correction in early postoperative period. In group I, 9 children underwent 18 sliding flexible intramedullary nailing procedures. Nails were inserted simultaneously in femur and tibia of one side in 7 patients. In two cases, nailing was consecutively performed only for femurs. The contralateral leg was operated on average in 43.2÷7.3 days later. The overall reoperation rate was 100% (femur and tibia) throughout total FU. After the index surgery, the one-year survival rate, with nail revision as the endpoint, was 41%. In three years 28% of nails did not require their exchange, five-year survival rate was only 18.8%. For 7 segments, nails were exchanged for telescopic rods. Elastic nails were used for revision surgery in 19 segments. In group II, 15 sliding FIN procedures (28 segments) were performed in 8 children (the mean age of 5 years 1 month at the moment of nailing). The nails were simultaneously inserted in femur and tibia of one side in 6 patients. In two cases, nailing was consecutively performed only for femurs. After the first surgery on one leg, the contralateral limb was operated on in 31.3÷9.3 days on average. Simultaneously, the frame of the first operated leg was removed under the same general anesthesia. In group II, we performed implant revision after index surgery in 87.5% of cases throughout total FU. In the majority of cases, a revision was unscheduled: in 75% cases. After the index surgery, the one-year survival rate, with nail revision as the endpoint, was 71%. In three years, 64.3% of nails did not require their exchange, five-year survival rate was 32.1%. For 6 segments, nails were exchanged for telescopic rods. We used elastic nails for revision surgery in 13 segments.

Conclusion The sliding flexible intramedullary nailing keeps its indications in selected cases in young preschool children with severe forms of OI the

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long bones with narrow medullary canal, not suitable for telescoping rods, in OI patients under the age of 4-6 years old, low life expectancy and severe comorbidities as a salvage procedure. Short-time application of an external frame with FIN provides additional rotational and angular stability in early post-operative period that prevents secondary displacement of bone fragments and allows the early weight-bearing.

Keywords: osteogenesis imperfecta, sliding flexible intramedullary nailing

INTRODUCTION Osteogenesis imperfecta (OI) is a rare genetic disease with an incidence of 1 in 10.000 to 1 in 20.000 births [1-5]. The major orthopaedic features are bone fragility, osteopenia, progressive bone deformity and various degrees of short stature [1, 2]. Our multidisciplinary approach including medical treatment with bisphosphonates, orthopaedic treatment and rehabilitation for muscular strengthening and walking strategy, has as a goal amelioration of mobility, self-care, functional independence, and better quality of life [6, 7]. The goal of orthopaedic surgery implies the correction of long bone bowing, rotational malalignment, angular deformity and prevention or reduction of the fracture incidence [8-12]. Compared to conventional nailing, the telescopic rodding provides an advantage of a long-lasting osteosynthesis while a child is growing [1316]. The single-entry telescopic rod system, like the Fassier-Duval Telescopic System, is not available for widespread use in pediatric orthopaedic centres around the world. In such a situation, the sliding transphyseal FIN, named also Nancy sliding nailing, has to be used [1719]. Furthermore, the flexible intramedullary nailing (FIN) is indicated as a viable alternative in certain selected cases [20-22]. Using elastic intramedullary nails in OI, initially published by Metaizeau in 1987 [13] remains a solution for some authors [9, 18]. Persiani et al., [20] demonstrated advantages of sliding intramedullary

178 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. nailing for femur fractures. In patients under the age of 4, with narrow medullary canals, few rehabilitative prospectives or severe comorbidities. They considered elastic nailing as a less invasive approach compared to telescopic nail surgery. We have a series of 17 OI patients who had index surgery using FIN [21] between 2012 and 2015. They are being followed. The aim of this study was to assess the results of sliding FIN in deformity correction in children with severe and moderate-to-severe types of OI with 5.1 to 8 years follow-up.

MATERIALS AND METHODS Population For this study, we selected 17 patients with OI type 3 (6 cases) and 4 (11 cases), aged between 1 year 8 months and 12 years 9 months by index surgery, who underwent surgery for lower limb deformity with Flexible Intramedullary Nailing during the period from May 2012 to December 2015 and followed until Mars 2021. The mean follow-up was 6.1 years (range, 5.1-8.0 years). Approval from the Local Human Ethics Committee was obtained to conduct this study. Medical records and radiographs were reviewed. Data were collected prospectively throughout follow-up period. Telescopic rods were available in our institution since 2018. Previously, all patients had experienced multiple long bone fractures, bone deformity over 20° or torsional deformity, causing functional impairment. Before admission in our clinic, three patients underwent attempts of deformity correction with locked plates or nailing, but without positive results. Eight patients in this study received bisphosphonates (pamidronate or zolendronic acid) before the study. In all cases bisphosphonate therapy was arrested, at least, 3 months before surgery. In post-operative period, pamidronate therapy was started 4 to 6 months later in all children.

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Surgical Treatment Depending on the applied technique, we divided the patients into two groups. In group I (9 patients, 32 segments) the titanium transphyseal sliding bipolar FIN was performed (Figure 1). The moderately bent nails were inserted through epiphyseal or apophyseal areas, one proximally and another distally. The nails were advanced through the medullary canal without reaming. In deformity correction, the antegrade and retrograde nails were introduced until bowing level, then, the necessary osteotomies were performed (percutaneously or in open technique using oscillating power saw) and nails were advanced to the opposite metaphysis under visual and X-ray control. If necessary, at the bowing level in particular, where the obliteration of the medullary canal often manifested, we rearmed it in distal and proximal bone fragments. The curvatures of nails were reoriented in the opposite direction to the angular deformity. In a situation of a tiny external diameter of some part of diaphysis (internal diameter inferior to 3 mm), we inserted only one nail throughout medullary canal. The second nail was initially introduced through epiphysis but placed between periosteum and bone at the level of small diameter part of diaphysis. Then its leading end was again inserted into the bone in opposite metaphysis. We took care to limit surgical approaches and bone exposure to minimum to ensure the best possible biological environment for bone consolidation. At the final phase of the procedure, the trailing ends of nails were bent and anchored in the epiphysis. External immobilization was applied for 6 to 8 weeks with partial weight-bearing started 3-5 weeks after intramedullary nail placement. The surgery for the contralateral leg followed in 5 to 8 weeks. We associated the sliding FIN with Ilizarov frame in group II (Figure 2) in 8 patients (28 segments) aiming to achieve rotational and longitudinal stability and to provide early weight-bearing.

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a

b

c Figure 1. Radiographs of tibia with sliding FIN: a – before surgery; b – radiographs of lower limbs before treatment; c – at 18 months FU.

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c

d Figure 2. Combined technique (sliding FIN+Ilizarov frame), radiographs: a – before treatment; b – sliding FIN and external frame on right femur, preventive nailing of right tibia; c - sliding FIN and external frame on left femur, preventive nailing of the left tibia. Surgery was associated with frame removal on right site; d – at 14 months FU control.

182 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. That approach implies Ilizarov frame application after nail insertion and wound closure, but the last step of the procedure was a final orientation of nail curvatures and slight nail impaction in metaphysis bone, application of moderate compression forces done in Ilizarov frame, trailing ends of nails bent and cut. The feature of frame assembly was the use of only two rings in tibia or short arc and 3/4 ring in femur placed at metaphysis levels and perpendicular to the anatomic axe of a segment. Usually, three elements for bone fixation were placed per ring or arc. In group II, we encouraged patients to walk with partial weight bearing since 5th-7th postoperative day. No manipulations like progressive deformity correction or external frame adjustment were performed after surgery. Frame removal was indicated and done while radiological signs of uninterrupted periosteal and endosteal callus were observed. All patients were advised to maintain an adequate calcium intake. After cast and frame removal, they underwent physiotherapy and kinesiotherapy, including exercises and design of special devices for transportation, walking and sitting. During post-operative period, we reviewed the patients every 6 months for clinical and radiological examinations. Anteroposterior radiographs of the lower extremities with the patella centered forward, and lateral radiographs of each segment with adjacent joints were taken. Torsional deformations were assessed by clinical and radiological examination in all patients. Criteria of assessment were: consolidation rate, number of intraoperative and postoperative complications (including nail migration, limited telescoping, joint intrusion, secondary deformities, deformity recurrence, delayed union) and their outcomes, reoperation rate and reference mechanical radiological angles. The nail revision and exchange for telescopic rod or regular rod (growth plates closure) was used as the endpoint for assessment of FIN survival. The statistical values described the mean and standard deviation. We compared the data by the Wilcoxon rank-sum test for independent

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samples. The test was two-tailed with a 0.05 level of significance. AtteStat 12.0.5 software was used for the statistical analyses.

RESULTS In group I, the 18 sliding flexible intramedullary nailing procedures were done in 9 children (mean age 5 years 2 months). The nails were simultaneously inserted in femur and tibia of one side in 7 patients, in two cases, we consecutively performed nailing only for femurs. The contralateral leg was operated on average in 43.2÷7.3 days later. Obvious bone callus formation ensuring weight-bearing (either active one with walker or passive standing) on operated leg was an obligatory condition for the opposite side operation. In group I, 9 patients developed complications after index surgery. Proximal nail migration occurred in 3 patients (5 segments – 3 femurs and 2 tibias). Early secondary torsional displacement resulted in malunion was observed in 4 cases (in 5 femurs and 4 tibias) after index surgery. Later, torsional deformities caused functional impairment of gait and compromised comfortable sitting position. Correction of torsional deformity was done in 3 patients simultaneously with realignment procedure for angular deformity developed in 9-28 months after the index surgery. Another patient had the problem of torsional deformity because of retroversion of femoral necks, it was fixed during surgical correction of coxa vara with Fassier technique (Figure 3). There was one case of non-union of proximal femur with angulation of over 25° that required resection of pseudarthrosis zone and exchange of nails. Five more patients (with age inferior to 10 y.o.) developed progressive angular deformity of femur and/or tibia due to nontelescoping on nails. In these cases, we changed the nails. Four patients experienced fractures over nails in situ without nail bending. Two more patients had fractures with angular deformities required surgery and nail change.

184 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. The non-telescoping of nails without secondary angular deformity was observed only in 8 segments. The risk of fractures or deformity at the level of bone without internal reinforcement was evaluated as high and additional transphyseal nails were inserted. In 4 cases, we scheduled a revisional surgery, related to the patient’s natural growth. There were no cases of infection in group I. In total, all patients had implant revision. The overall reoperation rate was 100% (femur and tibia) throughout total FU. After the index surgery, the one-year survival rate, with nail revision as the endpoint, was 41%. In three years 28% of nails did not require their exchange, five-year survival rate was only 18.8%. For 7 segments nails were exchanged for telescopic rods. Elastic nails were used for revision surgery in 19 segments. In group II, we performed 15 sliding FIN procedures (28 segments) in 8 children (the mean age of 5 years 1 month at the moment of nailing). The nails were simultaneously inserted in femur and tibia of one side in 6 patients. In two cases, nailing was consecutively performed only for femurs. After the first surgery on one leg, the contralateral limb was operated on in 31.3÷9.3 days on average. Simultaneously, the frame of the first operated leg was removed under the same general anesthesia. After the index surgery, the total number of complications in group II was significantly lower. We observed 9 complications in 6 patients. But only 6 cases required reintervention. Migration of external proximal and distal nail irritating soft tissues occurred in 2 patients (1 femur and 1 tibia) when the surgical revision (reinsertion or cut of the displaced nail) became necessary. One patient developed bilateral non-telescoping in femurs and bowing of both segments at the level of middle and distal metaphysis, in a zone without FIN. Later, this condition required the exchange of intramedullary nails. In three children younger than 10 y.o. non-telescoping of nails caused their migration into the medullary canal in 4 segments, but there was no secondary angular deformity. In those cases, additional transphyseal nails were inserted to prevent a secondary fracture or deformity at the level of newly formed bone. There were two fractures over FIN without displacement treated conservatively (Figure 4). We didn’t observe any case of infection in group II. There were no

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cases of external fixator-related complications because of a brief duration of external fixation with no fixator-related manipulation. There were no cases of delayed union or non-union in this group.

a

b Figure 3. (Continued)

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d Figure 3. Complications observed in the series: a – bilateral coxa vara and pseudarthrosis of femoral neck diagnosed in 2 years after index surgery; d - results of bilateral valgisation osteotomy and osteosynthesis; c – non-telescoping and fracture with angulation; d – nail migration.

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a

b Figure 4. Exchange nails for telescoping rod: a – in femur; b – in tibia.

We performed implant revision after index surgery in 87.5% of cases throughout total FU. In most of the cases, a revision was unscheduled in 75% cases. After the index surgery, the one-year survival rate, with nail revision as the endpoint, was 71%, in three years 64.3% of nails did not require their exchange, five-year survival rate was 32.1%. For 6

188 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. segments, nails were exchanged for telescopic rods. Elastic nails were used for revision surgery in 13 segments.

DISCUSSION The benefits of telescoping intramedullary rodding in fractures and deformity of long bones in children with OI are well known. These systems allow multilevel realignment, possibility to achieve walking with weight-bearing and, to prevent or decrease the rate of fractures and to improve self-care and mobility [9, 10, 13, 14]. A telescopic intramedullary rod is a well-known intramedullary device for OI management purposes [17]. The advantage of the Dual interlocking telescopic rod and Fassier-Duval rod over the Bailey-Dubow or sliding FIN is well-known [8-10, 23-26]. Implantation of telescopic rods is associated with fewer surgical scars, reduced blood loss, decreased time of operation. Thus, it allows to perform intervention on multiple bones during the same procedures. Nowadays, there are few indications for sliding flexible intramedullary nailing in OI children. In young preschool children with severe forms of OI, the long bones are narrow, and often not suitable for telescoping rods [20-22]. In such a situation, regular or elastic nailing can provide good middle-term results from the point of view of realignment and prevention of refracture [9, 27]. Persiani et al., [20] reported that the titanium elastic nail has indications in selected cases: in OI patients under the age of 4, with narrow medullary canals, low life expectancy and severe comorbidities. They consider the FIN as a less invasive approach compared to telescopic rodding, however, only temporarily. Langlais et al. suggest [22] the sliding elastic osteosynthesis in select cases where the absence of a medullary canal prevents the insertion of intramedullary rod or as a salvage procedure for children with severe OI under the age of 6 years old.

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Our technique with one transphyseal antegrade nail inserted through medullary canal and the second transphyseal retrograde nail placed subperiosteally providing telescopic effect is closed to ‘In-Out-In’ Kwires sliding technique described by Langlais et al. [22]. Finally, the sliding FIN becomes the only method to perform if no telescopic rod is approved by authorities. As for results and outcomes of our series, it is difficult to compare it with those of telescopic rods. The complication and reoperation rate in group I is evidently higher that in series based on experience with Fassier-Duval rod. But the number of surgeries per case is close to the results of series with sliding FIN reported by Boutaud et al., [18]. The major inconvenience of any telescopic system design is the lack of rotational stability [9, 25, 28] associated with insufficient longitudinal bone stability [22, 25]. Any telescoping system does not allow an immediate weight-bearing. Besides, the period of immobilization without charge must be short in patients with OI in order to prevent secondary bone mass reduction and disuse osteoporosis [15, 27]. In group II, the combined technique uniting sliding FIN and external fixation showed advantages in comparison to conventional sliding FIN in group I. Combination of external frame and intramedullary nails permitted to overcome inconveniencies of only sliding FIN. We did not observe any secondary torsional deformity in post-operative period. Combined technique enabled weight-bearing by 4th to 7th postoperative day. This approach represents an advantage compared to group I. Increased stability of bone fragments in immediate post-operative period and early full weight-bearing allowed to avoid delayed and non-union at all in group II. The total of complications was lower in children treated by combined technique. The idea of using an external frame as additional stabilization in treatment of orthopedic problems in metabolic bone disorders is not new [25, 30-32]. Birke et al., supposed the use of Ilizarov frame to be beneficial as additional stabilization in Fassier-Duval rodding in patients with severe underlying bone pathology [25]. Authors performed that combination in children with hypophosphatemic rickets and achieved

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190 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. good results. Kong et Sabharwal used FIN and monolateral external fixation in treatment of femoral shaft fractures in children with OI [31]. The external fixator provided angular and torsional stability at the fracture site and avoided inconveniencies of cast immobilization. Our own experience with Ilizarov frame and HA-coated FIN in surgical treatment of children with hypophosphatemic rickets was encouraging [30]. In literature, the use of sliding FIN in children with OI made the reoperation rate of 75% for 8 years’ follow-up [18]. But in the mentioned study, there were 6 patients with type I of OI and 8 patients with type III. Regarding complications, Boutaud et al. reports 25% rate of complication in use of elastic nailing but in series with 42.9% patients with Type I of OI. They report one case of pseudarthrosis (femur) for a series of 14 patients [18]. Munns et al. observed delayed bone healing after 103 of the 200 interventions [33]. And this complication was more frequent in patients receiving pamidronate, in children with OI type IV and in osteotomy of the tibia. Our previous study demonstrated that functional outcomes were favorable at 1-year and 2-year point time after surgery and close to results achieved with Fassier-Duval rod [8, 21]. Besides, we recognized that functional results were similar at sake of greater number of complications and higher reoperation rate. On the other hand, Ruck et al., [8] reported that obtained functional gains of rodding persist up to 4 years followed by decrease at the latest time point. In 2018, we proved that HA-coated nails can not be used in sliding intramedullary nailing in order to avoid their blocking and nontelescoping due osteoinductive features. We suggest nails with HAcoating in osteogenesis imperfecta patients older than 12 years old.

CONCLUSION Transphyseal sliding flexible intramedullary nailing allows to achieve a realignment of limb segments and outcomes similar to results

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of the telescopic rod application. But an important disadvantage of FIN is a greater number of complications that causes a higher reoperation rate. The sliding flexible intramedullary nailing keeps its indications in selected cases in young preschool children with severe forms of OI the long bones with narrow medullary canal, not suitable for telescoping rods, in OI patients under the age of 4-6 years old, low life expectancy and severe comorbidities as a salvage procedure. Application of the external frame with FIN for a short period provides additional rotational and angular stability in early post-operative period that prevents secondary displacement of bone fragments and allows the early weight-bearing.

COMPLIANCE WITH ETHICAL STANDARDS   

Conflict of Interest: The authors declare that they have no conflict of interest. Ethical approval: This chapter does not contain any studies with human participants performed by any of the authors. Informed consent: Informed consent was obtained from all individual participants included in the study.

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[2]

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Van Dijk, F. S., Sillence, D. O. (2014). Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am. J. Med. Genet. A., 164A(6):1470–1481. [4] Rauch, F., Glorieux, F. H. (2004). Osteogenesis imperfecta. Lancet, 363(9418):1377–1385. [5] Folkestad, L., Hald, J. D., Ersbøll, A. K., Gram, J., Hermann, A. P., Langdahl, B., Abrahamsen, B., Brixen, K. (2016). Fracture Rates and Fracture Sites in Patients with Osteogenesis Imperfecta - A Nationwide Register-Based Cohort Study. J. Bone Miner. Res., doi: 10.1002/jbmr.2920. [6] Montpetit, K., Palomo, T., Glorieux, F. H., Fassier, F., Rauch, F. (2015). Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity. Arch. Phys. Med. Rehabil., 96(10):1834-1839. [7] Aubry-Rozier, B., Unger, S., Bregou, A., Freymond Morisod, M., Vaswani, A., Scheider, P., Bonafé, L. (2015). News in osteogenesis imperfecta: from research to clinical management. Rev. Med. Suisse, 11(466):657-662. French. [8] Ruck, J., Dahan-Oliel, N., Montpetit, K., Rauch, F., Fassier, F. (2011). Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J. Child Orthop., 5(3):217-224. [9] Sterian, A., Balanescu, R., Barbilian, A., Ulici, A. (2015). Osteosynthesis in Osteogenesis Imperfecta, telescopic versus nontelescopic nailing. J. Med. Life, 8(4):563-565. [10] Zeitlin, L., Fassier, F., Glorieux, F.H. (2003). Modern approach to children with osteogenesis imperfecta. J. Pediatr. Orthop. B., 12(2):77–87. [11] Enright, W., Noonan, K. (2006). Bone plating in patients with type III osteogenesis imperfecta: results and complications. Iowa Orthop. J., 26:37-40. [12] Roberts, T. T., Cepela, D. J., Uhl, R. L., Lozman, J. (2016). Orthopaedic Considerations for the Adult with Osteogenesis Imperfecta. J. Am. Acad. Orthop. Surg., 24(5):298-308.

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[13] Metaizeau, J. P. (1987). Sliding centro-medullary nailing. Application to the treatment of severe forms of osteogenesis imperfecta. Chir. Pediatr., 28(4-5):240-243. French. [14] Violas, P., Mary, P. (2008). Imperfecta osteogenesis: interest of surgical treatment. Arch. Pediatr., 15(5):794-796. [15] Georgescu, I., Vlad, C., Gavriliu, T. Ş., Dan, S., Pârvan, A. A. (2013). Surgical treatment in Osteogenesis Imperfecta - 10 years experience. J. Med. Life, 15;6(2):205-213. [16] Cho, T. J., Choi, I. H., Chung, C. Y., Yoo, W. J., Lee, K. S., Lee, D. Y. (2007). Interlocking telescopic rod for patients with osteogenesis imperfecta. J. Bone Joint Surg. Am., 89(5):1028-1035. [17] Halloran, J., Fassier, F., Alam, N. (2010). Radiological assessment of Fassier–Duval tibial rodding in patients with Osteogenesis Imperfecta. In: Proceedings of the 29th Annual Meeting of the European Paediatric Orthopaedic Society (EPOS), Zagreb, Croatia. [18] Boutaud, B., Laville, J. M. (2004). Elastic sliding central medullary nailing with osteogenesis imperfecta. Fourteen cases at eight years follow-up. Rev. Chir. Orthop. Reparatrice Appar. Mot., 90(4):304311. French. [19] Lascombes, P. (2010). Flexible intramedullary nailing in children. Springer, Berlin/Heidenberg. [20] Persiani, P., Martini, L., Ranaldi, F. M., Zambrano, A., Celli, M., Celli, L., D’Eufemia, P., Villani, C. (2019). Elastic intramedullary nailing of the femur fracture in patients affected by osteogenesis imperfecta type 3: Indications, limits and pitfalls. Injury, Suppl 2:S52-S56. [21] Popkov, D., Popkov, A., Mingazov, E. (2019). Use of sliding transphyseal flexible intramedullary nailing in pediatric osteogenesis imperfecta patients. Acta Orthop. Belg., 85(1):1-11. [22] Langlais, T., Pannier, S., De Tienda, M., Dukan, R., Finidori, G., Glorion, C., Péjin, Z. (2021). ‘In-Out-In’ K-wires sliding in severe tibial deformities of osteogenesis imperfecta: a technical note. J. Pediatr. Orthop. B. 30(3):257-263.

194 Dmitry A. Popkov, Eduard Mingazov, Natalia Kononovich et al. [23] Shin, C. H., Lee, D. J., Yoo, W. J., Choi, I. H., Cho, T. J. (2018). Dual interlocking telescopic rod provides effective tibial stabilization in children with osteogenesis imperfect. Clin Orthop Relat Res., 476(11): 2238–2246. [24] [24] Cox, I., Al Mouazzen, L., Bleibleh, S., Moldovan, R., Bintcliffe, F., Bache, C.E., Thomas, S. (2020). Combined twocentre experience of single-entry telescopic rods identifies characteristic modes of failure. Bone Joint J. 102-B(8):1048-1055. [25] Birke, O., Davies, N., Latimer, M., Little, D. G., Bellemore, M. (2011). Experience with the Fassier-Duval telescopic rod: first 24 consecutive cases with a minimum of 1-year follow-up. J. Pediatr. Orthop., 31(4):458-464. [26] Anam, E. A., Rauch, F., Glorieux, F. H., Fassier, F., Hamdy, R. (2015). Osteotomy Healing in Children with Osteogenesis Imperfecta Receiving Bisphosphonate Treatment. J. Bone Miner. Res., 30(8):1362-1368. [27] Sinikumpu, J. J., Ojaniemi, M., Lehenkari, P., Serlo, W. (2015). Severe osteogenesis imperfecta Type-III and its challenging treatment in newborn and preschool children. A systematic review. Injury, 46(8):1440-1446. [28] Sterian, A., Balanescu, R., Barbilian, A., Tevanov, I., Carp, M., Nahoi, C., Barbu, M., Ulici, A. (2015). Early telescopic rod osteosynthesis for Osteogenesis Imperfecta patients. J. Med. Life, 8(4):544-547. [29] Abulsaad, M., Abdelrahman, A. (2009). Modified Sofield-Millar operation: less invasive surgery of lower limbs in osteogenesis imperfecta. Int. Orthop., 2009 Apr;33(2):527-532. [30] Popkov, A., Aranovich, A., Popkov, D. (2015). Results of deformity correction in children with X-linked hereditary hypophosphatemic rickets by external fixation or combined technique. Int. Orthop., 39(12):2423-2431. [31] Kong, H., Sabharwal, S. (2016). Fixator-augmented flexible intramedullary nailing for osteopenic femoral shaft fractures in children. J. Pediatr. Orthop. B., 25(1):11-16.

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[32] Saldanha, K. A., Saleh, M., Bell, M. J., Fernandes, J. A. (2004). Limb lengthening and correction of deformity in the lower limbs of children with osteogenesis imperfecta. J. Bone Joint. Surg. Br., 86(2):259-265. [33] Munns, C. F., Rauch, F., Zeitlin, L., Fassier, F., Glorieux, F. H. (2004). Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate. J. Bone Miner. Res., 19(11):1779-1786.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 10

SURGICAL CORRECTION OF LIMB DEFORMITIES IN CHILDREN WITH OSTEOGENESIS IMPERFECTA: EXPERIENCE OF TURNER CENTER Dmitry Buklaev, MD, PhD and Sergey Vissarionov, MD National Turner Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery, Saint-Petersburg, Russia

ABSTRACT This chapter is based on the analysis of our experience of observation and surgical treatment of children with osteogenesis imperfecta in the clinic of the H. Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery from 2010 to 2020.



Corresponding Author’s E-mail: [email protected].

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Dmitry Buklaev and Sergey Vissarionov

Material and Methods We have observed and treated 316 patients with osteogenesis imperfecta. 122 of them have undergone surgical treatment (231 interventions). Surgery was performed for long bone deformities, frequent fractures, pseudoarthrosis, foot deformities and discrepancy of the legs. The most common procedure was a multilevel osteotomy of long bones with intramedullary telescopic fixation. Intramedullary elastic transphyseal fixation was used less frequently. For planovalgus foot deformity subtalar arthroereisis was performed in cases of complaints associated with foot deformity. Operations for pseudoathrosis of long bones included resection of pseudoarthrosis and various types of fixation and bone plasty. The lengthening of the long bones of the lower extremities was carried out in two stages with the conversion of the external fixator to the internal one after the end of the distraction. Temporary hemiepiphysiodesis was used to correct deformities of the lower extremities in the area of the knee joints.

Results The duration of the survival of the result of surgery after the use of various intramedullary fixators during observation was evaluated, including a retrospective assessment of the use of plates. The analysis showed the advantages of intramedullary telescopic rods in comparison with other types of fixators, which was expressed in the duration of the preventive effect and the low number of revision interventions. The rate of survival of the result using telescopic rods depended on the patient’s age and reached 70-100%. The procedure of subtalar arthroereisis in all cases achieved elimination of complaints of pain and conflict with shoes. There were great difficulties, including failures in the treatment of pseudarthrosis, especially in the humerus. The probability of success in treating pseudoarthrosis of the long bones of the lower extremities was absolute, but in pseudoarthrosis of the humerus, success was achieved only with repeated interventions. The lengthening results were satisfactory in all 5 cases, but the condition for success was the correct selection of patients. The success rate of temporary epiphysiodesis was 100%, but the correct selection of patients is also of great importance here.

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Conclusion Deformities of the limbs in children with osteogenesis imperfecta are of great variety and require the use of various operations. Correct determination of indications and selection of patients allow achieving a high probability of success of surgical treatment. Patients need regular follow-up, as the presence of osteoporosis can lead to the need for revision interventions.

Keywords: osteogenesis imperfect, bone fragility, limb deformities, surgical treatment

INTRODUCTION Osteogenesis imperfecta is a group of genetic determined hereditary diseases of the connective tissue with the main manifestation in congenital osteoporosis, which leads to frequent bone fractures and the development of bone deformities [1]. The frequency of occurrence of osteogenesis imperfecta in the population, according to various publications, is 1/10000-1/20000. It is well known disease for doctors and ordinary people despite the rarity. The severity of clinical and radiological manifestations of OI varies from almost asymptomatic forms, in which the patients have normal lifestyle, has no complaints and sometimes they do not even know about the presence of the disease, to severe disabling and even lethal forms. Modern methods of diagnosis, treatment, and rehabilitation significantly improve the clinical and radiological picture in patients and their socialization. It’s important to apply a multidisciplinary approach in the treatment and rehabilitation of patients, not only because it’s a systemic disease and has skeletal and extra bone manifestations, but also because in cases where the complete elimination of any aspect of the disease is impossible, for example, achieving verticalization and independent walking, the efforts of specialists, patient and parents should be directed to the formation and improvement of other skills and abilities.

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Moreover, the mental development of children with osteogenesis imperfecta is not disturbed. In recent decades, due to the widespread use of bisphosphonates and telescopic intramedullary structures, a significant increase in the effectiveness of treatment of children with osteogenesis imperfecta has been observed. Due to the variety of clinical manifestations and deformities in patients with osteogenesis imperfecta, several types of surgeries were used in clinical practice. Surgical treatment is on the third position in importance after rehabilitation and drug treatment. The purpose of surgical treatment is to improve the quality of life by reducing the frequency of fractures, improving the function of the limbs, eliminating the complaints about pain. We follow the principles in our clinical practice: 1. Surgical treatment of osteogenesis imperfecta is indicated in the cases of insufficient effectiveness of conservative methods 2. Treating patient, not radiograms 3. Function of muscle is no less important than bone function 4. The indications for surgery are primarily the complaints and needs of the patient 5. It is not possible to achieve verticalization and functional independence in all patients Our experience in surgical treatment of patients with osteogenesis imperfecta allows us to distinguish such types of surgery: 1. Corrective osteotomies of long bones with extended fixation 2. Operations for the fusion of pseudoarthrosis 3. Correction of axial deformations due to temporary hemiepiphysiodesis 4. Lengthening of the low extremities 5. Correction of foot deformities

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Rehabilitation treatment after surgery is significant because ignoring it leads to a decrease in the patient’s functional capabilities despite a good local result of surgery.

MATERIAL AND METHODS We have observed and treated 316 patients with osteogenesis imperfecta. Surgical treatment has been carried out in 122 of them (231 operations). Patients demonstrated different kinds of deformities, the most common of which were varus and antecurvation of the femur. (Figure 1).

Figure 1. 3D CT of the pelvis and femurs of the OI patient’s.

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Various types of surgery are performed on patients with osteogenesis imperfecta. The main ones are extended telescopic fixing of long bones, operations for fusion of pseudarthrosis, correction of axial deformities by hemiepiphysiodesis, lengthening of the lower extremities, and correction of foot deformities. The types and number of operations are presented in table 1. The number of kinds of surgeries is shown in Table 1. The main type of the surgical treatment of children with osteogenesis imperfecta is the extended fixation of long bones with internal fixators. Currently, the gold standard is the intramedullary fixation of long bones with telescopic rods after corrective osteotomy or without it. We have performed 139 procedures of intramedullary telescopic rodding in 87 patients berween the ages of 19 months and 15 years. The distribution by segment and gender is presented in the Table 2. Table 1. Types and number of operations performed

Number of cases

Corrective osteotomies of long bones with extended fixation 102(203)

Operations for the fusion of pseudoarthrosis

Correction of axial deformations due to temporary hemiepiphysiodesis

Lengthening of limb bones

Correction of foot deformities

5(7)

4(4)

5(6)

6(11)

Table 2. The distribution of telescopic rodding by segment and gender

Male Female Total

Femur 36 (25%) 43 (31%) 79 (56%)

Tibia 29 (21%) 31 (22%) 60 (44%)

Total 65(46%) 74(53%) 139(100%)

Intramedullary telescopic rodding was used for correction of various deformities (Table 3).

Femur Tibia Total

31(22%) 6(4%) 37(26%)

Varus

Varus+ antecurvation 40(29%) 5(3%) 45(32%) 3(2%) 13(9%) 16(12%)

Valgus

Valgus+ antecurvation 2(1,5%) 33(24%) 35(25%) 4(3%) 3(2%) 4(3%)

No deformiries 2(1,5%) 0 0

recuvation

Table 3. The distribution of telescopic roding by segment and type of deformities

79(57%) 60(43%) 139(100%)

Total

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Formally, indications for this type of treatment are the presence of two or more fractures of one bone within 1 year and (or) a deformity of 30 or more degrees with the background of bisphosphonate therapy. This method of surgical treatment demonstrates high efficiency, preventing pathological fractures and deformities for a long time. In some cases, such treatment is an impetus to the activation of the patient and verticalization. Intramedullary telescopic rods provide long-term splinting of the growing bone due to the ability to lengthen as the bone grows, unlike other non-growing fixators, such as plates. They are characterized by t minimally invasive implantation and sufficient stability after implantation. In 121 surgeries we used FassierDuval rods, in 18 surgeries other kinds of telescopic rods were used. Telescopic intramedullary nail consists of two components, which are selected according to the diameter of the intramedullary canal, and the length of the components is adjusted during the operation. When performing these operations, it is necessary to take into account the presence of osteoporosis in children with osteogenesis imperfecta, which requires careful movements of the surgeon to avoid accidental penetration into the knee or ankle joints. It is possible with them to fix multilevel osteotomies in any part of the femur, tibia, humerus and ulna. The telescopic effect is achieved by blocking the threaded ends of the implant components in the bone epiphyses through the growth plates, by the longitudinal growth. In the postoperative period, plaster immobilization is required for 3-5 weeks. In case of rotational instability of fragments, a cast of the A-frame type is used. As the child grows and body weight increases, it may be necessary to replace the retainer with a similar of larger diameter. Also, in 3 patients, we used intramedullary telescopic rodding for a small deformity of the proximal femur where the Loozer area was in pain. We have experience with the use of intramedullary elastic fixation in 47 patients (64 operations). This method of extended fixation can be used in patients with osteogenesis imperfecta, including using in the

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transphyseal version as an alternative method in case of unavailability of intramedullary telescopic systems or for other reasons Correction of deformities of the upper extremities is relevant in case of impaired function. Surgical treatment of the upper extremities for cosmetic indications is impractical. Despite the fact that deformities of the upper extremities occur in most patients, functional impairment is observed in more than 8%. We performed surgical treatment of deformities of the bones of the upper extremities in only 5 patients because of the inconvenience of using the limb Pseudarthrosis of long bones with osteogenesis imperfecta is not a very common, but difficult problem. It leads to loss of function of the upper and lower extremities and is difficult to treat. We performed 7 operations in 5 patients for pseudarthrosis. Pseudarthrosis has been localized:   

Trochanteric area – 1 patient Femoral shaft – 2 patients Humerus - 2 patients

Resection of the pseudarthrosis area with various types of fixation was used:   

Bone plate – 2 patients (3 operations) Intramedullary rod 1 patient (1 operation) External fixation device for 2 patients (3 operations)

In all cases, bone grafting was used. In 4 patients with a light course of osteogenesis imperfecta having a valgus deformity at the level of the knee joint, temporary hemiepiphysiodesis was used for correction of deformities. The technique of surgery did not differ from the usual one. 3 patients underwent bilateral hemiepiphysiodesis of the tibia, 1 patient bilateral hemiepiphysiodesis of the femurs

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In 5 patients, who were able to walk well but had a significant difference in the length of the legs, the segments were lengthened. Two patients underwent tibia elongation, and two femur elongation, one sequential extension of the tibia and femur. In all cases, after the end of the distraction, the conversion of the external fixation to the internal one was performed taking into account osteoporosis. In all cases, the lengthening value in one stage was 4 cm. Flat feet in patients with osteogenesis imperfecta are a common condition. Most of them have no complaints. Nevertheless, some patients complain of pain when walking for a long time due to conflict with shoes. We observed 4 patients with osteogenesis imperfecta with distinct complaints of discomfort associated with flat feet. We also observed two patients who had congenital bilateral clubfoot as a concomitant disease. Four patients with flat feet underwent bilateral arthrodesis with a locking screw. Two patients with clubfoot underwent peritalar release.

RESULTS No matter how severe the long bone deformity in a patient with osteogenesis imperfecta is, a multilevel corrective fixated osteotomy with fixation is immediately beneficial, even if it requires some shortening of the bone (Figures 2, 3). But further success depends on many factors: 1. 2. 3. 4. 5. 6. 7.

The severity of osteoporosis, the development of the cortex Previous therapy Correct choice of fixation Correct implantation technique The degree of invasiveness required during the intervention Correctness of postoperative patient management Unforeseen circumstances

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Unfavorable characteristics of one or more of these factors increase the risk of failure and lead to revision interventions. In this regard, the true indicator for evaluation of the result of a multilevel osteotomy is the duration of the fixation effect, that is, the survival of the bone-fixator complex and the postponement of the revision procedure, or better, the absence of the need for this. This ensures an improvement in the quality of life and well-being of the patient. World experience in osteogenesis imperfecta surgery has shown that intramedullary fixation is an adequate fixation of osteotomy in childhood. Prior bisphosphonate therapy is also required. Our results support the thesis of the advantages of intramedullary telescopic fixation after multilevel osteotomies compared to plating and elastic fixation (Figure 4).

Figure 2. Intramedullary telescopic fixation after femur osteotomy.

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Figure 3. Intramedullary telescopic fixation after tibia osteotomy.

Figure 4. “Survival” of the results of the surgeries with different kinds of fixators in children with osteogenesis imperfecta for 3 years depending of age.

As can be seen from the diagram, the survival rate of telescopic fixation, although it depends on age, tends to be absolute.Thus, over 5 years of using telescopic fixation, out of 139 interventions, revision surgery was required only in 9 cases (7%).

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In some cases of elastic fixation, revision operations were not required for 5 years (Figure 5).

Figure 5. Five years follow up x-ray after femur osteotomies and elastic fixation.

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Figure 6. Corrective osteotomy of the humerus and intramedullary locking fixation.

Figure 7. Hemiepiphysiodesis of the proximal tibias.

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Figure 8. Lengthening of the femur and conversation of the fixators.

Figure 9. Bilateral arthrodesis of subtalar joints in patient with OI pre-op and after 1 year.

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Corrective osteotomy of the humerus was performed in 6 cases of dysfunction of the upper limb (Figure 6). All 4 cases of temporary hemiepiphysiodesis for hallux valgus were successful (Figure 7). Figure 8 shows the result of the lengthening of the femur with the replacement of the external fixator with internal ones. In 4 cases (100%) of subtalar arthroereisis, elimination of complaints was achieved. A case of the bilateral arthroeresis is shown in Figure 9.

DISCUSSION The world experience accumulated a lot of knowledge in the treatment of children with osteogenesis imperfect and it allows us to speak of certain standardization in this problem and the presence of mutual understanding among researchers. There is no doubt that for most patients there are indications for bisphosphonate therapy. This treatment is critical and allows many patients to make significant leaps towards relative well-being by reducing the number of fractures and the likelihood of the appearance and progression of limb and spinal deformities [2, 3]. In second place in terms of importance is rehabilitation, which gives the skills of physical independence and preserves muscle function [4]. Surgical treatment is in 3rd place in terms of demand and importance. Due to the variety of deformities, the correction of which surgical treatment is aimed at, patients with osteogenesis imperfecta undergo many different operations from tenotomy to total joint replacement [5]. The most common type of intervention is multilevel osteotomies of long bones with intramedullary fixation. Telescopic fixation is now the gold standard [6, 7]. At the same time, there are publications about complications when using telescopic rods. [8, 9]. Elastic fixation is also acceptable, mainly because of its affordability, low cost and flexibility in fracture management. Although, elastic

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fixation does not have the durability inherent in telescopic devices [1012]. Foot surgery in children with osteogenesis imperfecta is topical, mainly for flatfoot. The method of choice is arthroereisis. Temporary hemiepiphysiodesis is used to correct mild axial deformities [9].

Complications Among the patients treated with intramedullary telescopic rods, there were no infectious, inflammatory complications, and there were also no cases of non-fusion of fragments. Proximal migration of the femoral rod was observed in 4 cases, migration of the tibial rod into the knee joint cavity was observed in 3 cases. The migration of the femoral rod was not accompanied by the appearance of significant complaints, so the problem was eliminated during the next stages of surgery or left in the existing state. Migration of the tibial rod to the knee joint caused pain and flexion contracture and required revision surgery with reduction or replacement of the rod. In two cases, with an injury – a fracture of the lower leg, a deformation of the rod was observed. In such cases, revision was undertaken.

CONCLUSION A comparative analysis of the results of surgical treatment of telescopic intramedullary rodding was used to evaluate the duration of the beneficial effect, that is, the survival of the fixator-bone system. The comparison was carried out with the results of surgery with elastic nails and retrospective results of fixation with plates. The dependence on the type of fixator and the age at which the operation was performed was revealed. The longest time effect of the operation was observed when

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using intramedullary telescopic rods. The shortest duration is when using plates. In this regard, the generally accepted thesis is that the isolated use of plates for fixing long bones in children with osteogenesis imperfecta is contraindicated. The results of surgical treatment of pseudarthrosis of long bones with imperfect osteogenesis confirm the well-known of the difficulty of their treatment. Of 7 surgeries, only 5 were successful in 5 patients with pseudarthrosis. 2 cases of treatment of pseudarthrosis of the humerus were unsuccessful, despite repeated interventions and the use of various fixators. The use of temporary hemiepiphysiodesis for the correction of valgus deformity of the legs was successful in all cases of application. By the way, it should be noted that patients with osteogenesis imperfecta may have a limited growth potential, which may limit the use of this treatment method. Elongation of the lower limbs in patients with osteogenesis imperfecta is a difficult task due to osteoporosis, muscle weakness. Elongation can only be performed in patients who can walk independently, for whom the difference in the length of the legs is a clear inconvenience. If these conditions were met, the lengthening was successful in all 5 patients. All of them were replaced by an external retainer with an internal one. Correction of flat feet in children with osteogenesis imperfecta by arthroeresis showed high efficiency in the form of pain disappearance. In one case, due to migration and instability, the screw was removed 2 years after the operation. But the normal shape of the foot was preserved at the same time.

REFERENCES [1]

Marini, J. C., Forlino, A., Bächinger, H. P., Bishop, N. J., Byers, P. H., Paepe, A., Fassier, F., Fratzl-Zelman, N., Kozloff, K. M.,

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Krakow, D., Montpetit, K., Semler, O. (2017). Osteogenesis imperfecta. Nat. Rev. Dis. Primers., 3:17052. [2] Rauch, F., Lalic, L., Roughley, P., Glorieux, F. H. (2010). Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J. Bone Miner. Res., 25(6):1367-1374. [3] Rossi, V., Lee, B., Marom, R. (2019). Osteogenesis imperfecta: advancements in genetics and treatment. Curr. Opin. Pediatr., 31(6): 708-715. [4] Mueller, B., Engelbert, R., Baratta-Ziska, F., Bartels, B., Blanc, N., Brizola, E., Fraschini, P., Hill, C., Marr, C., Mills, L., Montpetit, K., Pacey, V., Molina, M.R., Schuuring, M., Verhille, C., de Vries, O., Yeung, E. H. K., Semler, O. (2018). Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J. Rare Dis., 13(1):158. [5] Kruse, R. W. (2020). Osteogenesis Imperfecta. A Case-Based Guide to Surgical Decision. Making and Care, Springer Nature, 291p. [6] Ruck, J., Dahan-Oliel, N., Montpetit, K., Rauch, F., Fassier, F. (2011). Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J. Child Orthop., 5(3):217-224. [7] Fassier, F. (2017). Fassier-Duval Telescopic System: How I Do It? J. Pediatr. Orthop., 37 Suppl 2:S48-S51. [8] Gamble, J. G., Strudwick, W. J., Rinsky, L. A., Bleck, E. E. (1988). Complications of intramedullary rods in osteogenesis imperfecta: Bailey-Dubow rods versus nonelongating rods. J. Pediatr. Orthop., (6):645-649. [9] Holmes, K., Gralla, J., Brazell, C., Carry, P., Tong, S., Miller, N. H., Georgopoulos, G. (2020). Fassier-Duval Rod Failure: Is It Related to Positioning in the Distal Epiphysis? J. Pediatr. Orthop., 40(8):448-452. [10] Imam, M. A., Negida, A. S., Elgebaly, A., Hussain, A. S., Ernstbrunner, L., Javed, S., Jacob, J., Churchill, M., Trikha, P.,

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Newman, K., Elliott, D., Khaleel, A. (2018) Titanium Elastic Nails Versus Spica Cast in Pediatric Femoral Shaft Fractures: A Systematic Review and Meta-analysis of 1012 Patients. Arch. Bone Jt. Surg., 6(3):176-188. [11] Burtsev, M. E., Frolov, A. V., Logvinov, A. N., et al., (2019). Current approach to diagnosis and treatment of children with osteogenesis imperfecta. Pediatric Traumatology, Orthopaedics and Reconstructive Surgery, 7(2):87-102. [12] Popkov, D. A., Kononovich, N. A., Mingazov, E. R., Shutov, R. B., Barbier, D. (2015). [Intramedullary Elastic Transphyseal Tibial Osteosynthesis and Its Effect on Segmental Growth]. Vestn Ross Akad Med Nauk., (4):441-449. Russian.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 11

USE OF TITANIUM TELESCOPIC RODS IN OSTEOGENESIS IMPERFECTA PATIENTS: COMBINED TECHNIQUE AND 3D GAIT ANALYSIS IN OI CHILDREN Dmitry A. Popkov1,, MD, PhD, Tamara Dolganova1, MD, PhD, Eduard Mingazov1, MD, PhD, Pierre Journeau2, MD, Dmitry Dolganov1, PhD, Nikita Gvozdev1, MD, PhD and Arnold Popkov1, MD 1

Ilizarov National Medical Center for Traumatology and Orthopaedics, Kurgan, Russian Federation 2 Service de Chirurgie Orthopédique et Traumatologique Pédiatrique, Hôpital d'enfant, CHU Nancy, Vandœuvre-lès-Nancy, France

ABSTRACT Introduction The main targets of orthopedic surgery in OI children are to maintain physical activity and self-care, to acquire and develop motor 

Corresponding Author’s E-mail: [email protected].

218 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. skills. It can be achieved by using a telescoping rodding that increases the mechanical strength of bones. The major limitation of any intramedullary telescopic system is rotational and longitudinal instability. The majority of telescopic rods are made of stainless steel that raises concerns for magnetic resonance imaging. This study aimed to examine the outcomes of deformity correction with a titanium telescopic rod or by combined technique uniting a titanium telescopic rod and reduced external fixation in children with OI types III or IV.

Material and Methods The study included 14 children with OI who underwent femoral deformity correction (22 segments) or tibial deformity correction (5 segments). The children ranged in age between 2 years 3 months and 13 years (mean: 8.4 ± 2.9 years) at the time of rodding. Parameters of surgery, clinical examination and radiological data, 3D gait analysis were assessed in the study with a follow up from 1.5 to 3 years.

Results Titanium telescopic rodding was applied alone for 4 segments. In 23 cases surgery consisted of combined technique. External fixation lasted 35.8 days in average. All patients, operated on with titanium rod and reduced external frame, were verticalized and encouraged for walking with axial loading on the operated limb since the first postoperative week. Neither loss of threaded fixation nor migration of the rod into the knee and ankle joints was observed in the follow-up. There were no secondary rotational or longitudinal bone displacements. Telescoping gain related to spontaneous growth assessed at one-year follow-up control was 13.7 mm in the tibia and 15.9 mm in the femur. We found no complications related to the external frame. Gait abnormalities in postoperative period were caused by bulk and weight of EF. These abnormalities were resolved by the one-year assessment.

Conclusion The combination of titanium telescopic rod with EF enables longitudinal and rotational stability of bone fragments over telescopic system. This technique provided ability for walking with weightbearing since an early postoperative period. Temporary gait changes

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were influenced by size of the external device. Titanium rods are not prone to failure of elongation.

Keywords: osteogenesis imperfecta, telescopic rod, gait analysis, Ilizarov

INTRODUCTION The bone fragility and refracture, osteopenia, progressive bone deformity and short stature are clinical manifestations representing involvement of the skeleton in OI children [1, 2]. Current surgical approaches for young patients with OI are based on telescopic rodding providing a long-lasting osteosynthesis while growth zones are still open [3-6]. The most often used systems are Fassier-Duval rod (Pega Medical, Laval, Quebec, Canada), Peditst telescopic rod (Peditst, Istanbul, Turkey), and dual interlocking telescopic rod (C&S Medical, Gyeonggi, Korea) allow correcting deformity, strengthening brittle bone and decreasing the complication and reoperation rate associated with regular nails/rods or sliding telescopic nailing [7-11]. However, the major limitation of any telescopic system is related to its inherent rotational and longitudinal instability [12-15]. Besides, in all telescopic systems the standing and walking with weight-bearing is delayed [16-18]. This inconvenience of the system raises concerns about secondary bone mass reduction, disuse osteoporosis and risks of fractures [4, 19-21]. Furthermore, stainless-steel telescopic constructs (e.g., Fassier-Duval rod) could cause difficulties in cases requiring MRI examination [22-25]. Since February, 2018, we have been using a titanium telescopic rod applied alone or in combination with external fixation (EF). In literature, the combination of telescopic intramedullary devices with an external fixator in patients with severe underlying bone pathology demonstrated advantages of stability and standing or/walking with weight-bearing [11, 15, 26, 27].

220 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. The objective of the current study was to examine the outcomes of deformity correction with titanium telescopic rod or by the combined technique in children with severe and moderate-to-severe types of OI. The report presents the authors’ experience with this device and analysis of advantages and complications.

MATERIAL AND METHODS This prospective study was approved by our institutional review board before data collection. Inclusion criteria were skeletally immature patients with severe and moderate-to severe OI according to Sillence classification [28] who underwent femoral or tibial deformity correction with at least one titanium telescopic rod (TTR) applied alone or associated with EF. All patients were treated at a single Institution. Surgical technique (Figures 1, 2). In all cases we implanted one TTR per surgery. Surgical steps included the removal of previous material if existed, that was followed by osteotomy (-ies) performed percutaneously or in an open technique. A guide wire was inserted through the greater trochanter or proximal tibial epiphysis.

a Figure 1. (Continued)

b

c

d

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f

g Figure 1. TTR applied alone or in combination with EF in a 4-y.o. boy with OI type IV, radiographs: a – full-size standing radiographs before surgery; b – fracture of right femur; c – combined technique with TTR and reduced EF; d – frame removal in 28 days, periosteal callus providing rotational and longitudinal stability in addition to TTR; e – at 6 month FU; f – corrective osteotomy at distal femoral shaft and telescopic rodding without EF; g – FU control in 28 months after right femur surgery and in 22 months after left femur surgery, rod elongation gain of 45 mm (right femur) and 32 mm (left femur). Note normal anatomical alignment of operated femurs.

Alternatively, the guide wire was placed through the osteotomy site or fracture. Then, the guide wire was replaced by a male rod. The male

222 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. rod was never screwed in first into distal epiphysis in order to avoid intraarticular protrusion [26].

a

b

c

d

Figure 2. TTR in combined technique used for alignment in severely deformed femur in a 9- y.o.-boy with OI type III, radiographs: a – before surgery; b – multiapical osteotomy, rodding followed by EF; c – bone union achieved in 28 days, frame removal under GA; d – in 28 months: alignment of left femur maintained, telescoping gain of 37 mm; alignment procedure for the right femur.

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The female rod was cut to size always intraoperatively and then inserted over the male rod. The female rod was always screwed first in the proximal tibial epiphysis/greater trochanter. At the last step of rodding, the male rod was screwed into distal epiphysis under x-ray control (C-arm) using T-handle. In all patients, the titanium alloy telescopic rod (Intramedullary Telescopic Rod, reg. certificate № RZN 2017/6876, dated 10.07.17., Designer: Metis Ltd, Tomsk, Russia) was used. The diameter of the female rod varied to find the best fit at the narrowest portion of the shaft. If applied, the external fixation using a reduced Ilizarov frame was done as the final step of the surgery.A proximal short arc with half-pins or half-wires and distal 2/3 ring with 3 wires were applied for the femur. In the tibia, two rings, each with 3 wires or half-pins, were used. Rings and the arc were connected in a definitive position by the end of surgery ensuring a rotational and longitudinal stability. Combined technique was used in elastic nails/regular rods replacement surgery for TTR, TTR associated with external fixator was used in cases of plate and/or rod removal and rotational and/or longitudinal instability of bone fragments revealed after osteotomy, multiple osteotomies, difficulty with plaster cast or split cast immobilization due to large shape of the segment. The TTR without EF was used in other situations (Figure 1). In the early postoperative period patients were encouraged for standing up and walking with weight bearing since the 3rd to 4th day using a walker or crutches (Figure 3). No manipulations or external frame adjustment took place after surgery. Frame removal was indicated and done when radiological signs of an uninterrupted periosteal and endosteal callus were observed. The following data were collected from all included patients (14 children): age at the index surgery, sex, Sillence classification type of OI, use of bisphosphonate treatment, dates of surgeries and frame removal, location of a rod implant, radiographs.

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a

b

d

c

e

Figure 3. Motor ability of patients with EF: a,b – reduced EF does not interfere with comfortable lying position; c – in stander with 45 degree inclination on the 3rd postoperative day; d – walking with walker; e – walking with aid of an adult.

Outcomes of surgical intervention were evaluated by: 1) external fixation period 2) reference radiological angles [29, 30] measured on the standard anteroposterior and lateral radiographs preoperatively, postoperatively, and at the latest follow-up control. Anatomical angles between the articular line and telescopic rod placed along the anatomical axis were measured postoperatively. That approach reflected orientation of an articular line with regards to the segment axis during residual growth or due to remodeling of pathological bone around the nail or nail lateral migration, 3) length of rod telescoping

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4) rod failure (staying out of the epiphysis, protruding out of the bone, failing to telescope) 5) other adverse effects and complications Each assessment, the children underwent a standardized clinical orthopedic examination. The range of internal and external rotation of the hips in the prone position was used to measure rotational malunion. Three-dimensional gait analysis was also carried out on subjects who were able for walking, with assistance if necessary (13 patients). Kinematic and kinetic variables were assessed on the 6th to 10th postoperative day only in children treated by combined technique and approximately in a year after frame removal. Six cameras (Qualisys Oqus system) and four AMTI force plates (Advanced Mechanical Technology Inc., Watertown, MA) were used to collect motion analysis data. In the Ilizarov Gait Analysis Laboratory the IOR model was used for markers [6, 31]. Temporospatial parameters, joint kinematics and kinetics were calculated for each patient. The gait parameters of the operated limb were compared with those of a limb without external fixator. We used AtteStat 12.0.5 software for the statistical analyses. The statistical values described the mean and standard deviations. Data were compared by using Wilcoxon signed–ranks test for matched pairs. The test was twotailed with a 0.05 level of significance. This research was approved by the Ilizarov Center Review Board. The study complies with the Declaration of Helsinki statement on medical protocol and ethics. Representatives of all patients enrolled in the study provided oral and written informed consent.

RESULTS The Sillence type III OI was diagnosed in three children, other 11 patients had type IV of OI. The children ranged in age between 2 years 3 months and 13 years, the mean age at surgery was 8.4 ± 2.9 years.

226 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. In 22 operations the TTR implantation was a non-emergency procedure. Urgent telescopic rodding was performed for five fractures of bowed femurs. In 9 cases (8 femurs and 1 tibia), the rodding was the primary surgical procedure. Rod insertion was associated with removal of previously inserted intramedullary material, locking plates or screws in 18 segments. Nine patients in this study were treated with bisphosphonates (pamidronate or zolendronic acid) as in standard practice before study. Bisphosphonates were continued or initiated in the middle postoperative period in all patients. All patients who underwent two or more surgeries were operated on consecutively. Two patients underwent three operations, rodding was done consecutively in 9 children. In ten patients, the telescopic rod insertion was done simultaneously with Ilizarov frame removal from the segment previously operated (Figure 2). In other cases of consecutive surgeries, an interval between operations varied from 2 to 6 months. In total, external fixation lasted 35.8 ± 11.7 days in average (range, 21 to 73 days). The mean external fixation time was 34.8 ± 9.8 days (range, 21 to 73 days) for the femur and 35.7 ± 7.8 days for the tibia (range, 29 to 46 days). All patients treated with combined technique were verticalized and encouraged for walking using crutches or walkers with a full axial loading on the operated limb since the 4th-7th postoperative day. A molded orthosis or plaster cast with free hip and ankle joints was applied for 3–4 weeks to all patients after frame removal. The patient continued walking with full weight-bearing with the orthosis on. In patients operated without EF, the walking weight-bearing was postponed for 4 to 12 weeks after surgery depending on radiographic condition of the periosteal callus. Radiological measurements of the operated femur and tibia are presented in Tables 1 and 2. We found no significant changes of radioanatomical angle values throughout the follow-up period (Figure 1 and 2). A slight decrease in mLPFA was not accompanied by hip abduction less than 40°. Increased values of mADTA were associated with normal

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ankle dorsiflexion, over 20° that excluded functional impairment due to reduced ROM. The mean rotational hip ROM remained well-balanced in one-year follow-up (42.7° for internal rotation and 53.7° for external rotation) reflecting avoidance of rotational malunion in all patients with a femoral TTR. In one femur we noticed a partial varus deformity recurrence at the osteotomy site due to insufficient diameter of a rod. Neither loss of threaded fixation in the distal femoral and tibial epiphyses and apophysis of the greater trochanter nor migration of the rod into the knee and ankle joints were observed in the patients except one case of proximal migration of the female part of TTR that required reinsertion into the greater trochanter (Figure 4). No secondary rotational or longitudinal bone displacement was noted in our series. During the follow-up, 2 patients required MRI for diagnostics of pituitary adenoma or basilar impression associated with neurologic disorders. The presence of titanium alloy telescopic rod did not interfere with magnetic resonance study. A telescoping gain related to spontaneous growth was assessed at the one-year follow-up control as 13.7 ± 3.1 mm in the tibia and 15.9 ± 2.3 mm in the femur. No growth disorders or disfunction of physis were found at the latest FU radiographs (Figure 2). Table 1. Radiological measurements of femoral reference angles (M±SD) Angle mLPFA;˚ aMPFA; ˚ mLDFA; ˚ aLDFA; ˚ PDFA; ˚

Preoperative 103.4±13.9 79.5±19.9 94.5±6.5 79.3±5.9 89.0±6.3

Postoperative 83.5±13.2 91.1±14.02 91.8±5.4 85.5±4.4 84.7±5.4

At 1.5-3 years FU 86.7±15.2 87.0±18.5 90.1±6.9 84.6±3.8 83.0±5.7

228 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. Table 2. Radiological measurements of tibial reference angles (M±SD) Angle mMPTA; ˚ aMPTA; ˚ mLDTA; ˚ aLDTA; ˚ mPPTA; ˚ mADTA; ˚

Preoperative 93.3±4.04 90.3±1.5 79.3±9.3 83.3±3.5 71.0±7.9 113.0±8.9

Postoperative (after frame removal) 91.0±2.0 89.0±3.6 83.7±7.6 82.3±7.5 81.0±3.6 100.3±2.9

In 12 months 90.2±2.7 90.2±3.4 82.1±6.4 83.1±6.2 83.0±3.2 103.1±5.2

There were no deep infection and neurologic complications including those, related to EF. In three cases, a superficial infection at proximal and distal pin sites required removal of a half-pin and a wire without compromising the result of treatment. Three patients fractured tibia or femur over telescopic rod without displacement of bone fragments. The fractures healed in plaster cast. Other adverse events included non-displaced fracture at the distal femoral metaphysis (n = 1) that occurred during positioning of the patient on the operating table. In one case preoperative planning omitted a procurvatum deformity at the distal third of femoral shaft. It caused modification of surgery while performing the operation. One patient sustained a fracture of the right femur with angulation and rod bending. But the threated ends of male and female parts remained in epiphysis as the rod was considered without loss of epiphyseal fixation. The fracture was managed by closed reduction with additional flexible intramedullary nailing but without rod replacement (Figure 4). Thus, we stated 100% rod survival for the FU of 1.5-3 years. Mean gait speed at the first study, with the external fixator (EF) in place, was 0.39 m/sec; this significantly increased to 0.73 m/sec at 1 year after frame removal (Table 3). Cadence and stride length were reduced when wearing the external fixator. The gait profile score revealed a progressive improvement of overall walking ability in children by 12 months after rodding. While EF wearing, the stride width increased significantly on the EF side. Regarding stance and swing time, there was significant decrease of stance time and increase of swing time on the

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operated side. Though situation improved by the time of 1 year followup.

a

b

Figure 4. Complications: a – proximal migration of female part and fracture of femur fracture; b – another case of fracture of femur and rod bending without loss of fixation in the greater trochanter and distal femoral epiphysis; reduction of fracture and flexible intramedullary nailing, and bone union in aligned position.

Sagittal kinematics was characterized by asymmetry between an external fixator side and contralateral extremity (Tables 4 and 5). There was significantly reduced ROM at all levels on the EF side. At the EF side, knee kinematics demonstrated full extension during the stance phase and significantly reduced peak flexion angle in the swing phase in comparison to contralateral limb. Ankle position at initial contact was usually planiflexion on both sides and was followed by reduced dorsiflexion through mid to terminal stance. Decreased ROM on the EF side in sagittal plane correlated with grossly reduced ankle plantarflexion moment, hip extension and flexion moment. Power generation on the EF side was significantly reduced at the ankle, knee and hip in comparison to kinetics of a limb without EF. These abnormalities are resolved by the one-year assessment.

230 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. Table 3. Temporospatial data; Mе (25%÷75%) Variable

Gait wearing external fixator

Gait speed; m/s Stride width; м Stride length; м Cadence; steps/s Gait Profile Score

0.39 (0.30÷0.52) 0.18 (0.17÷0.21) 0.60 (0.49÷0.69) 0.85 (0.77÷0.95) 16.0 (14.4÷16.3) Limb with External fixator 1.34 (1.26÷1.51) 61.2 (57.3÷61.8) 38.9 (38.0÷43.0) 32.6 (26.0÷41.8)

In one year after surgery 0.73 (0.42÷0.87)2 0.12 (0.09÷0.18)2 0.63 (0.47÷0.88) 0.96 (0.95÷0.98) 11.6 (9.5÷15.5) Both limbs 1.14 (0.85÷1.24) 64.9 (61.5÷71.9) 36.4 (28.5÷37.9) 31.9 (25.2÷43.3)

Contralateral limb Cycle time; s 1.33 (1.25÷1.53) Stance time; % 71.2 (66.2÷75.6)1 Swing time; % 28.7 (24.7÷32.7)1 Double support 33.4 (26.3÷41.8) time; % 1 Significant difference in comparison to value of contralateral leg by Wilcoxon signed-ranks test (р < 0.05). 2 Significant difference in comparison to value of first study (while Ilizarov frame) by Wilcoxon signed-ranks test (р < 0.05).

On the EF side, transverse plane kinematics was variable. In general, hip rotation was always external associated with foot progression angle slightly externally rotated as well. These changes in transverse plane reflected gait adaptation to bulk and weight of Ilizarov frame and joint stiffness in sagittal plane. Table 4. Kinematics and kinetics of ankle; Mе (25%÷75%) Variable

Ankle Initial Contact; Ankle ROM in Stance; Ankle ROM in Swing; Timing of Max in Stance; % Foot progression angle; ° Ankle plantarflexion moment; N*m/kg Ankle Power; W/k

Gait with external fixator Limb with external fixator -1.2 (-4.6÷3.9) 19.3 (17.2÷26.4) 9.0 (4.8÷14.0) 52.0 (46.0÷59.0) -16.3 (-39.9÷-11.7) 0.16 (0.13÷0.3)

Contralateral limb

At one year after surgery Both limbs

-1.7 (-6.4÷4.0) 18.0 (16.4÷20.4) 16.6 (9.6÷20.2) 54.0 (49.0÷55.0) -14.4 (-24.1÷-1.9) 0.32 (0.22÷0.56)

1.0 (0.22÷2.1) 22.2 (17.3÷27.3) 16.4 (14.9÷18.2) 55.0 (45.5÷56.7) -5.5 (-18.4 ÷ 6.9) 0.33 (0.2÷0.66)

0.26 (0.11÷0.56)

0.51 (0.32÷1.35)

0.88 (0.53÷1.59)

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DISCUSSION Improvement of mobility, self-care, functional skills and functional independence are the main goals ensuring better quality of life for children with OI [1, 32]. Currently, there is no pathogenic treatment of the condition and OI patients have to rely on a long-term multidisciplinary approach including bisphosphonate therapy, orthopedic treatment, and physical providing satisfactory outcomes [16, 32, 33]. The telescopic rods have their limits and complications including telescoping failure, rotational and longitudinal instability, delayed weight-bearing, rod part migration, joint intrusion etc. A review article on OI [34] indicates to the use of telescopic rods versus regular rods or elastic nails as being controversial with technically demanding technique and high costs of telescopic systems [35]. The reoperation rate with telescoping rods is reported to be close to 50% compared with 58–87% with regular rods [36]. Avoidance of the operated limb during walking may adversely impact joint and muscle conditioning, as well as delay bone union due to a lack of axial loading [37]. Use of telescopic rods suggests a 3-to-8week period without weight-bearing. Weight-bearing is authorized by the end of this period, only with the locked KAFO (it means without active motions in standing position) and on a tilt table [16, 18]. Only on condition of radiological evidence of bone callus formation the weightbearing with aid of orthoses may be authorized [17, 18]. This aspect is unfavorable for the osteoporotic bone as it results in secondary bone mass reduction and disuse osteoporosis [7, 38]. Furthermore, telescopic rods are prone to secondary torsion displacement at osteotomy site or postoperative loss of torsional correction [7, 26, 39]. Combination of telescopic rods and small locking plates with unicortical screw fixation is supposed to prevent secondary torsional deformations [14]. However, this approach method does not ensure early axial loading on the operated site of the bone and requires a mandatory second operation to remove the plate [12, 13]. Unfortunately,

232 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. additional plate fixation depreciates advantages of minimally invasive percutaneous osteotomies [12, 13]. Table 5. Knee and Hip kinematics and kinetics; Mе (25%÷75%) Variable

Gait with external fixator Limb with external fixator 5.6 (-2.0÷10.4)

Contralateral limb

In one year after surgery Both limbs

Knee Initial Contact 11.3 (5.9÷17.3) 11.7 (2.1÷20.2) angle; ° Knee ROM; ° 18.0 (13.8÷26.7) 46.7 (37.5÷51.5)1 52.3(45.7÷62.4) Knee extension moment; 0.05 (0.03÷0.06) 0.10 (0.05÷0.12) 0.17(0.11÷0.35) N*m/kg Knee flexion moment; -0.07(-0.07÷-0.08) -0.12(-0.25÷-0.07) -0.07(-0.21÷-0.02) N*m/kg Knee Power; W/kg 0.19 (0.13÷0.42) 0.53 (0.48÷0.72)1 0.87 (0.58÷1.44)2 Hip initial contact angle; 36.3 (28.1÷46.9) 44.3 (31.9÷49.5) 32.0 (23.8÷36.8) ° Hip ROM in sagittal 18.2 (14.0÷26.1) 37.8 (32.7÷43.0)1 35.2 (27.4÷43.0)2 plane; ° Hip Rotation; ° -21.3 (-26.6÷-4.8) -18.5 (-34.3÷3.7) -1.1 (-24.3÷6.0) Hip abduction; ° 11.7 (9.4 ÷ 14.2) 4.3 (0 ÷ 14.8)1 8.1 (4.5 ÷ 11.0) Hip ROM in coronal 11.7 (9.4 ÷ 14.2) 13.8 (12.9 ÷ 19.0) 13.1 (9.4 ÷ 19.3) plane; ° Hip extensor moment; 0.18 (0.09÷ 0.24) 0.43 (0.33÷ 0.56)1 0.47 (0.27÷0.67) N*m/kg Hip flexion moment; -0.13(-0.14÷-0.12) -0.18(-0.26÷-0.17)1 -0.26 (-0.34÷-0.22) N*m/kg Hip Power; W/kg 0.3 (0.16÷0.37) 0.7 (0.64÷0.95)1 1.12 (0.96÷1.73) Pelvic Tilt; ° 25.1 (20.8÷29.7) 13.0 (11.1÷15.6) 1 Significant difference in comparison to value of contralateral leg by Wilcoxon signed-ranks test (р < 0,05). 2 Significant difference in comparison to value of first study (while Ilizarov frame) by Wilcoxon signed-ranks test (р < 0.05).

The peer-reviewed literature reports that surgery-free survival for the three-year period for Fassier-Duval rod was 92.3% [40], 77% for BaileyDubow [41] and 92.9% for the Sheffiel telescopic Rod [42]. Azzam et al. reported the Fassier-Duval rod replacement in 53% of cases within 52 months after surgery [43]. Cho et al. [3] for a modified Sheffield rod and Spahn et al. [40] for the Fassier-Duval rod indicate an 88% survival rate

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over a four-year period. For a five-year period, the telescopic rods did not require surgery in 63% of cases for the femur and 64% for the tibia according to Cox et al. [44]. Shin et al. used the Dual Interlocking telescopic rod (D-ITR) and reported a 75% survival rate for the 5.3-year follow-up, which is the best result among all the reported telescopic rods [9]. One limitation of our study is a relatively short FU varying from 1.5 to 3 years. As reported by Shin [9], repositioning of any part of the rod, removal of an interlocking pin, or rod bending should not be considered an endpoint in rod survival assessment as telescopic rod remained in the bone without loss of locking in epiphyses. In our series the rod survival is 100% but it was not a surgery-free period. There were two unscheduled surgical procedures caused by fracture, rod bending, and proximal migration of the female part. On the other hand, we found no rod telescoping failure. Two more advantages of the titanium rod are worth of mentioning. The titanium alloy of the rod did not affect neuroimaging studies with MRI in two our patients. The cost of TTR is quite low. Regarding assessment of the gait in postoperative period, there are few published studies reporting a quantitative influence of bulk and weight of external fixator on gait abnormalities in patients wearing an external fixator and after frame removal [45-47]. Gait abnormalities magnify when the frame is attached to an injured leg. Wong et al. [45] reported that patients in EF group kept the knee joint close to full extension throughout stance and swing, absence of push-off, reduced ankle moment and power in order to reduce pain. Gait abnormalities included significant hip abduction and marked lateral trunk shift over injured leg reflecting antalgic gait strategy as well. Gait abnormalities disappear soon after frame removal. In another group managed by the hip spica cast children demonstrated the gait characterized by quadriceps weakness caused by disuse muscle atrophy. Our study of the gait demonstrated OI patients walking and\or standing with aid in the early postoperative period with weight-bearing. Besides, the gait can be assessed quantitatively. The revealed gait abnormalities were caused by bulk and weight of EF: external hip

234 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. rotation, slight external angle of foot progression, increased stride width and an increased hip abduction angle. Reduced knee and ankle ROM was associated with significantly decreased ankle and hip kinetics in comparison to the EF-free limb. In our study a plantarflexed ankle position at the initial contact was never followed by excessive dorsiflexion in stance as it was reported by Wong et al. [45]. The gait analysis in a year showed those abnormalities significantly improved. The limitation of the study is related to a relatively small sample size of the cohort and FU limited to 3 years. Further observation can reveal obstacles and problems related to a long-term patient growth.

CONCLUSION The combination of TTR with a reduced external fixation is reliable advantage in reconstructive orthopaedic surgery for OI children. Limited in time and reduced in bulk external fixation allows overcoming inconveniencies of telescopic intramedullary system related to longitudinal and rotational instability. The titanium alloy telescopic rod is not prone to limited telescoping and deformity relapse. Children demonstrated walking abilities with weight-bearing since the early postoperative period because of external fixation. We find that our rigorous indications for the combined technique are justified. The use TTR alone is reserved for the primary surgery with a one-level osteotomy without a severe deformity and on condition of reliable rotational stability of bone fragments assessed by surgeon intraoperatively.

COMPLIANCE WITH ETHICAL STANDARDS  

Conflict of Interest: The authors declare that they have no conflict of interest. Ethical approval: This chapter does not contain any studies with human participants performed by any of the authors.

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Informed consent: Informed consent was obtained from all individual participants included in the study.

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[37] Goodship, A. E., Kenwright, J. (1985). The influence of induced micromovement upon the healing of experimental tibial fractures. J Bone Joint Surg Br., 67(4):650-655. [38] Binder, H. (1995). Rehabilitation of infants with osteogenesis imperfecta. Connect Tissue Res., 31(4):S37-39. [39] Larson, T., Brighton, B., Esposito, P. (2010). High reoperation rate and failed expansion in lower extremity expandable rods in osteogenesis imperfecta. Proceedings of the Annual Meeting of the Pediatric Orthopaedic Society of North America (POSNA), Waikoloa, Hawaii. [40] Spahn, K. M., Mickel, T., Carry, P. M., Brazell, C. J., Whalen, K., Georgopoulos, G., Miller, N. H. (2019). Fassier-Duval Rods are Associated With Superior Probability of Survival Compared With Static Implants in a Cohort of Children With Osteogenesis Imperfecta Deformities. J Pediatr Orthop., 39(5):e392-e396. [41] Marafioti, R. L., Westin, G. W. (1977). Elongating intramedullary rods in the treatment of osteogenesis imperfecta. J Bone Joint Surg Am., 59:467-472. [42] El-Adl, G., Khalil, M. A., Enan, A., et al. (2009). Telescoping versus nontelescoping rods in the treatment of osteogenesis imperfecta. Acta Orthop Belg., 75:200-208. [43] Azzam, K. A., Rush, E. T., Burke, B. R., Nabower, A. M., Esposito, P. W. (2018). Mid-term Results of Femoral and Tibial Osteotomies and Fassier-Duval Nailing in Children With Osteogenesis Imperfecta. J Pediatr Orthop., 38(6):331-336. [44] Cox, I., Al Mouazzen, L., Bleibleh, S., Moldovan, R., Bintcliffe, F., Bache, C. E., Thomas, S. (2020). Combined two-centre experience of single-entry telescopic rods identifies characteristic modes of failure. Bone Joint J., 102-B(8):1048-1055. [45] Wong, J., Boyd, R., Keenan, N. W., Baker, R., Selber, P., Wright, J. G., Nattrass, G. R., Graham, H. K. (2004). Gait patterns after fracture of the femoral shaft in children, managed by external fixation or early hip spica cast. J Pediatr Orthop., 24(5):463-471.

240 Dmitry A. Popkov, Tamara Dolganova, Eduard Mingazov et al. [46] Layton, R. B., Stewart, T. D., Harwood, P., Messenger, N. (2018). Biomechanical analysis of walking gait when simulating the use of an Ilizarov external fixator. Proc Inst Mech Eng H., 232(6):628636. [47] Besch, L., Radke, B., Mueller, M., Daniels-Wredenhagen, M., Varoga, D., Hilgert, R. E., Mathiak, G., Oehlert, K., Seekamp, A. (2008). Dynamic and functional gait analysis of severely displaced intra-articular calcaneus fractures treated with a hinged external fixator or internal stabilization. J Foot Ankle Surg., 47(1):19-25.

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ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 12

SPINAL PATHOLOGY IN CHILDREN AND ADULTS WITH OSTEOGENESIS IMPERFECTA Sergey Ryabykh1, MD, PhD, Elena Schurova1, MD, Polina Ochirova1,, MD, PhD, Olga Sergeenko1, MD, PhD, Tatiana Ryabykh1, MD and Oleg Chelpachenko2, MD, PhD 1

National Ilizarov Medical Research Centre for Traumatology and Ortopaedics, Kurgan, Russia 2 National Medical Research Center for Children’s Health, Moscow, Russia

ABSTRACT This chapter describes etiology, epidemiology and types of spinal pathology in osteogenesis imperfecta (OI). In addition you can find some points regarding conservative treatment and prevention of OIdepended spinal problems.

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Corresponding Author’s E-mail: [email protected].

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Keywords: osteogenesis imperfecta, spine, basilar invagination, spinal deformity, scoliosis, braces therapy, osteoporosis

INTRODUCTION Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue disorders that mainly affects bones, but also have extra-skeletal manifestations (blue sclerae, dentinogenesis imperfecta, hearing loss, muscle weakness, cardiovascular and pulmonary complications) [1, 2]. It is characterized by bone fragility, causing a significant morbidity due to pain, immobility, skeletal deformities and growth deficiency [2]. Inheritance can be autosomal recessive (most common), dominant and Xlinked. The pathogenesis of OI is based on defects of type I collagen synthesis, post-translational modification and processing, bone mineralization and osteoblast differentiation [1, 3]. The most famous genes for OI are COL1A1 or COL1A2, this mutations cause up to 8090% of pathology [3]. However, currently, new OI-causing genes and novel pathogenic variants identify increasingly [2]. Sillence et al., proposed the clinical classification of OI in 1979, in which they singled out four subgroups [4]. Now this classification has undergone many modifications, it has been expanded and currently includes more than 15 types of the disease [2]. Some relationship between genotype and phenotype in patients with OI has been revealed [5], but in general, the genotype is an unreliable predictor. The incidence of OI is 5-7 in 100 000 live births [6, 7]. With the accumulation of cases and the development of medicine, more and more light is shed on the etiology, pathogenesis, treatment and prognosis of the disease, but there is no specific therapy at that moment [1, 8]. Spinal pathology in OI is represented by scoliosis and kyphoscoliosis, abnormalities of the craniovertebral junction (basilar invagination, inclination and platybasia), instability and fractures of the cervical spine, and lumbosacral spondylolysis and spondylolisthesis [9, 10].

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The causes of various spinal pathologies in patients with OI are softening of bones, osteoporosis, vertebral compression fractures [9, 11, 12], ligamentous and joint laxity [13], muscle weakness, lower limbs deformities causes the pelvis misalignment, pathology of the spinal cord and brainstem on the background of basilar invagination (syringomyelia, myelopathy, medullar compression). The presence of spinal pathology in patients with OI worsens the outcome of the disease [24]. There are the following main types of spinal pathology in OI patients: 1. 2. 3. 4.

CVJ malformations (basilar invagination, inclination and platybasia) Scoliosis and kyphoscoliosis Pathologic vertebral fracture Lumbosacral spondylolysis and spondylolisthesis.

OI-RELATED CVJ MALFORMATIONS: TERMINOLOGY, EPIDEMIOLOGY, RADIOLOGIC SIGNS AND SYMPTOMS Basilar invagination (primary) is the process of axial odontoid migration into the foramen magnum. Basilar impression (secondary/acquired) is similar condition, associated with softening of the bone and secondary settling [14]. These terms are often used interchangeably due to symptoms and treatment similarity. For the chapter purposes, both basilar impression and invagination will be referred to as BI. CVJ pathology is described in most types of OI (I, II, III, IV) [15]. Anomalies of CVJ were found in 30-40% of patients, most of them are combined with platybasia [15-17]. The severity of clinical manifestation of OI correlates with the frequency of skull base abnormalities occurrence. The more severe course of OI is one of the signs of possible BI in patient [18].

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Recognized radiological criteria for BI are: the position of the odontoid process more than 5 mm above Chamberlain’s line and/or more than 7 mm above McGregor’s line and/or above McRae’s line [19]. A radiological criterion for platybasia is a base of skull angle over 143º (Figure 1) [20]. Clinical manifestations of CVJ anomaly usually occurs due to compression of the brainstem, spinal cord and cranial nerves. It may manifest itself as a spastic tetraparesis, bulbar syndrome, nystagmus, headaches, ataxia, facial numbness, cerebrospinal fluid flow restriction and hydrocephalus [16, 21]. In the case of brainstem compression and CVJ instability there is a risk of sudden paralysis and even death [22, 23]. To prevent all these complications, CVJ pathology screening and early treatment are necessary in all OI patients. OI-related CVJ abnormalities usually manifested at the age 11-15 years [23], nevertheless, there are some reports in younger patients [23]. For this reason, MRI for all patients older than 5 years (even asymptomatic) may be useful option, also lateral skull radiographs for screening purposes is a simple, low cost and low screening radiation method [23].

Figure 1. MRI of CVJ of 13 years old girl with BI and OI, T2-weighted scans. Tip of the dens above McRae line (1 mm), above Chamberlain line (11 mm) and above McGregor line (13 mm).

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SCOLIOSIS AND KYPHOSCOLIOSIS: EPIDEMIOLOGY, NATURE COURSE, RADIOLOGIC SIGNS AND SYMPTOMS The incidence of spinal deformities in patients with OI ranges from 39% to 88%, depending on the OI type [24]. The occurrence of spinal deformity is more typical for patients with I, III and IV types of OI [9]. Slight deformity more often appears in type I (100°Cobb) [9]. The incidence of scoliosis lower in OI type I (39%), and higher in severe OI types (III and IV types - 68% and 54%, respectively) [9]. Thoracic and pelvic distortions and active progression of deformity are typical for scoliosis and kyphoscoliosis more than 50°Cobb (Figure 2, 3). Spine deformities in patients with OI are rarely found until the age of 6 years (with the exception of OI type III), but as the child grows, the probability of scoliosis increases from 26% to 82% [25]. Spinal deformity can also increase after the end of puberty, which is quite rare [26].

Figure 2. Anteroposterior and lateral X-ray of the spine of 14-year-old girl with kyphoscoliosis and OI type IV. The white line shows the high diaphragm position.

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Figure 3. Anteroposterior and lateral X-ray of the spine of the 16-year-old patient with kyphoscoliosis and OI type V. The black field shows the reduced right half of the chest cavity.

Predictors of spinal deformity progression in OI patients are the curve angle over 50°Cobb, the presence of 6 or more biconcave vertebrae, the absence of bisphosphonate therapy, osteopenia, and the severity of skeletal disorders [9, 27-29]. A positive correlation was detected between scoliosis origin and CVJ abnormalities [30]. Multiple vertebral compression fractures and loss of vertebral height lead to thoracic hyperkyphosis (firstly in upper part of thoracic spine) and sagittal trunk imbalance (global sagittal balance of the trunk displaced anteriorly) [30]. Spine deformity is often combined with reduced chest volume [24]. Respiratory failure is the cause of death in 82% of OI type III and 39% in types I and IV [12, 30-32]. In kyphoscoliosis over 60° Cobb vital capacity fell to an average of 40%, contributing to respiratory insufficiency, atelectasis and pneumonia [26]. The pulmonary anomaly (e.g., lung hypoplasia) can be a component of some OI types, therefore even patients without scoliosis show progressive restrictive pulmonary disease, supporting a primary cardiopulmonary effect of abnormal collagen [2, 33-36]. Probably, an additional factor in the vital capacity decrease may be a high level of the diaphragm in OI.

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PATHOLOGIC VERTEBRAL FRACTURE Patients with OI have a predisposition to vertebrae compression fractures and vertebral body biconcave deformity because of increased bone fragility, decreased bone mass, and increased ligamentous laxity (Figure 4) [37]. Multiply vertebral fractures are associated with scoliosis and low height [38]. Some sources indicate that up to 70% of patients with OI develop vertebral fractures [38]. Thoracic vertebrae fractures are most common, and the second most common are lumbar fractures, cervical fractures are rare [37, 38]. In addition, there are isolated observations of odontoid fractures and atlanto-axial rotatory fixation in OI [39, 40].

Figure 4. Anteroposterior and lateral X-ray of the spine of 9-year-old girl with compression fracture of the Th5 vertebral body and OI type I. The black line shows vertebrae compressive fractures and vertebral body biconcave deformity.

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LUMBOSACRAL SPONDYLOLYSIS AND SPONDYLOLISTHESIS Spondylolysis and spondylolisthesis in OI are most often described for the L5-S1 segment. Their occurrence ranges from 5% to 11% [40, 41]. Presumably, the development of spondylolysis and spondylolisthesis is based on mechanical loads on the osteopenic vertebra that can cause bone remodeling and the pedicle elongation, hyperlordosis, sagittal balance violations, started during childhood [29, 43, 44]. The elongation of the vertebral pedicle was found in 40% of patients with OI [42].

CONSERVATIVE TREATMENT AND PREVENTION OF SPINAL PATHOLOGY IN PATIENTS WITH OI General goals of treatment in OI include decreasing fracture incidence, improving pain, promoting growth, mobility and functional independence. As was noted earlier, the width of the restrictions depends on the severity of the disease. The multidisciplinary team for the management of OI consists of physiotherapist, medical genetics, orthopedic surgeon and other subspecialties based on the symptoms and complications [2]. Conservative management focused on muscle strength and joint range of motion, the degree of activity. Outpatient treatment includes occupational therapy, physiotherapy, walking aids or wheelchair (if needed), orthosis (mainly ankle foot orthoses), drugs that are used to treat osteoporosis (bisphosphonates) [45]. Growth hormone can increase linear growth rate with a mild improvement in cancellous bone density in OI patients, but there is no convincing evidence for it effectiveness and it is not in standard clinical use [2]. Bisphosphonates and their analogues are widely used to treat patients with OI and show some effectiveness in preventing of the spinal deformity progression and vertebrae compression, but it does not prevent

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deformity [45]. The new bone, which is formed by bisphosphonates, still defective, but the hypothesis behind the treatment, is that an increased volume of bone would be beneficial to bone strength [46]. Scoliosis in OI is not amenable to bracing and bracing may cause rib deformity in such cases [26]. Moreover, thoracic deformity, ribs fragility, cardiovascular and pulmonary complications can limit transfer of corrective forces from the brace to the spine [10]. Nevertheless, some authors advocate the combination of bisphosphonate therapy and bracing, which may have some effect on children under 6 years old [26].

CONCLUSION Spinal pathology in OI is represented by scoliosis and kyphoscoliosis, abnormalities of the CVJ, vertebral fractures, spondylolysis and spondylolisthesis. The severity of spinal pathology varies depending on the type of OI. Screening for the spinal pathology is required in all patients with OI. Bisphosphonates are widely used to treat patients with OI, from an early age. This group of medicines shows some efficiency in preventing spinal deformity progression and vertebrae compression, but it does not prevent spinal deformity.

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El-Gazzar, A., & Högler, W. (2021). Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis. International Journal of Molecular Sciences, 22(2), 625. Rossi, V., Lee, B., & Marom, R. (2019). Osteogenesis imperfectaadvancements in genetics and treatment. Current opinion in pediatrics, 31(6), 708. Jovanovic, M., Guterman-Ram, G., Marini, J. C. (2021). Osteogenesis Imperfecta: Mechanisms and signaling pathways

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connecting classical and rare OI types. Endocr Rev., May 19:bnab017. [4] Sillence, D., Senn, A., & Danks, D. M. (1979). Genetic heterogeneity in osteogenesis imperfecta. Journal of medical genetics, 16(2), 101-116. [5] Smith, R. (1994). Osteogenesis imperfecta: from phenotype to genotype and back again. International journal of experimental pathology, 75(4), 233. [6] Van Dijk, F. S., Pals, G., Van Rijn, R. R., Nikkels, P. G. J., & Cobben, J. M. (2010). Classification of osteogenesis imperfecta revisited. European journal of medical genetics, 53(1), 1-5. [7] Lindahl, K., Åström, E., Rubin, C. J., Grigelioniene, G., Malmgren, B., Ljunggren, Ö., & Kindmark, A. (2015). Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta. European Journal of Human Genetics, 23(8), 1042-1050. [8] Trejo, P., & Rauch, F. (2016). Osteogenesis imperfecta in children and adolescents - new developments in diagnosis and treatment. Osteoporosis International, 27(12), 3427-3437. [9] Wallace, M. J., Kruse, R. W., & Shah, S. A. (2017). The spine in patients with osteogenesis imperfecta. JAAOS-Journal of the American Academy of Orthopaedic Surgeons, 25(2), 100-109. [10] Castelein, R. M., Hasler, C., Helenius, I., Ovadia, D., Yazici, M., & EPOS Spine Study Group. (2019). Complex spine deformities in young patients with severe osteogenesis imperfecta: current concepts review. Journal of children’s orthopaedics, 13(1), 22-32. [11] Watanabe, G., Kawaguchi, S., Matsuyama, T., & Yamashita, T. (2007). Correlation of scoliotic curvature with Z-score bone mineral density and body mass index in patients with osteogenesis imperfecta. Spine, 32(17), E488-E494. [12] Ishikawa, S., Kumar, S. J., Takahashi, H. E., & Homma, M. (1996). Vertebral body shape as a predictor of spinal deformity in osteogenesis imperfecta. JBJS, 78(2), 212-219.

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[13] Engelbert, R. H., Uiterwaal, C. S., van der Hulst, A., Witjes, B., Helders, P. J., & Pruijs, H. E. (2003). Scoliosis in children with osteogenesis imperfecta: influence of severity of disease and age of reaching motor milestones. European Spine Journal, 12(2), 130134. [14] Kovero, O., Pynnönen, S., Kuurila-Svahn, K., Kaitila, I., & Waltimo-Sirén, J. (2006). Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers. Journal of neurosurgery, 105(3), 361-370. [15] Arponen, H., Mäkitie, O., Haukka, J., Ranta, H., Ekholm, M., Mäyränpää, M. K., ... & Waltimo‐Sirén, J. (2012). Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta. Journal of Bone and Mineral Research, 27(5), 1142-1149. [16] Oppenheim, W. L. (1995). The spine in osteogenesis imperfecta: a review of treatment. Connective tissue research, 31(sup4), s59-s63. [17] Sillence, D. O. (1994). Craniocervical abnormalities in osteogenesis imperfecta: genetic and molecular correlation. Pediatric radiology, 24(6), 427-430. [18] Cheung, M. S., Arponen, H., Roughley, P., Azouz, M. E., Glorieux, F. H., Waltimo‐Sirén, J., & Rauch, F. (2011). Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. Journal of Bone and Mineral Research, 26(2), 405413. [19] Cronin, C. G., Lohan, D. G., Mhuircheartigh, J. N., Meehan, C. P., Murphy, J., & Roche, C. (2009). CT evaluation of Chamberlain’s, McGregor’s, and McRae’s skull-base lines. Clinical radiology, 64(1), 64-69. [20] Koenigsberg, R. A., Vakil, N., Hong, T. A., Htaik, T., Faerber, E., Maiorano, T., ... & Gonzales, C. (2005). Evaluation of platybasia with MR imaging. American journal of neuroradiology, 26(1), 8992. [21] Khandanpour, N., Connolly, D. J., Raghavan, A., Griffiths, P. D., & Hoggard, N. (2012). Craniospinal abnormalities and neurologic

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Sergey Ryabykh, Elena Schurova, Polina Ochirova et al. complications of osteogenesis imperfecta: imaging overview. Radiographics, 32(7), 2101-2112. McAllion, S. J., & Paterson, C. R. (1996). Causes of death in osteogenesis imperfecta. Journal of clinical pathology, 49(8), 627630. Ríos-Rodenas, M., De Nova, J., Gutiérrez-Díez, M. P., Feijóo, G., Mourelle, M. R., Garcilazo, M., & Ortega-Aranegui, R. (2015). A cephalometric method to diagnosis the craniovertebral junction abnormalities in osteogenesis imperfecta patients. Journal of clinical and experimental dentistry, 7(1), e153. Widmann, R. F., Bitan, F. D., Laplaza, F. J., Burke, S. W., DiMaio, M. F., & Schneider, R. (1999). Spinal deformity, pulmonary compromise, and quality of life in osteogenesis imperfecta. Spine, 24(16), 1673. Benson, D. R., Donaldson, D. H., & Millar, E. A. (1978). The spine in osteogenesis imperfecta. The Journal of bone and joint surgery. American volume, 60(7), 925-929. Anissipour, A. K., Hammerberg, K. W., Caudill, A., Kostiuk, T., Tarima, S., Zhao, H. S., ... & Smith, P. A. (2014). Behavior of scoliosis during growth in children with osteogenesis imperfecta. The Journal of bone and joint surgery. American volume, 96(3), 237. Watanabe, G., Kawaguchi, S., Matsuyama, T., & Yamashita, T. (2007). Correlation of scoliotic curvature with Z-score bone mineral density and body mass index in patients with osteogenesis imperfecta. Spine, 32(17), E488-E494. Arponen, H., Mäkitie, O., & Waltimo-Sirén, J. (2014). Association between joint hypermobility, scoliosis, and cranial base anomalies in paediatric Osteogenesis imperfecta patients: a retrospective cross-sectional study. BMC musculoskeletal disorders, 15(1), 1-6. Liu, G., Chen, J., Zhou, Y., Zuo, Y., Liu, S., Chen, W., Wu, Z., Wu, N. (2017). The genetic implication of scoliosis in osteogenesis imperfecta: a review. J Spine Surg., 3(4):666-678.

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[30] Abelin, K., Vialle, R., Lenoir, T., Thévenin-Lemoine, C., Damsin, J. P., & Forin, V. (2008). The sagittal balance of the spine in children and adolescents with osteogenesis imperfecta. European Spine Journal, 17(12), 1697-1704. [31] Moorefield Jr, W. G., Miller, G. R. (1980). Aftermath of osteogenesis imperfecta: the disease in adulthood. The Journal of bone and joint surgery. American volume, 62(1), 113-119. [32] McAllion, S. J., & Paterson, C. R. (1996). Causes of death in osteogenesis imperfecta. Journal of clinical pathology, 49(8), 627630. [33] Himakhun, W., Rojnueangnit, K., & Prachukthum, S. (2012). Perinatal lethal osteogenesis imperfecta in a Thai newborn: the autopsy and histopathogical findings. J Med Assoc Thai, 95(Suppl 1), S190-194. [34] Shapiro, J. R., Burn, V. E., Chipman, S. D., Jacobs, J. B., Schloo, B., Reid, L., ... & Louis, F. (1989). Case report: Pulmonary hypoplasia and osteogenesis imperfecta type II with defective synthesis of alpha I (1) procollagen. Bone, 10(3), 165-171. [35] Thiele, F., Cohrs, C. M., Flor, A., Lisse, T. S., Przemeck, G. K., Horsch, M., ... & Hrabé de Angelis, M. (2012). Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms. Human molecular genetics, 21(16), 3535-3545. [36] Leng, L. Z., Shajari, M., & Härtl, R. (2010). Management of acute cervical compression fractures in two patients with osteogenesis imperfecta. Spine, 35(22), E1248-E1252. [37] Sepulveda, A. M., Terrazas, C. V., Saez, J., & Reyes, M. L. (2017). Vertebral fractures in children with type I osteogenesis imperfecta. Rev Chil Pediatr, 88(3), 348-353. [38] Meyer, S., Villarreal, M., & Ziv, I. (1986). A three-level fracture of the axis in a patient with osteogenesis imperfecta: a case report. Spine, 11(5), 505-506.

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[39] Rao, S., Patel, A., Schildhauer, T. (1993). Osteogenesis imperfecta as a differential diagnosis of pathologic burst fractures of the spine. A case report. Clin Orthop Relat Res. 1993 Apr;(289):113-117. [40] Verra, W. C., Pruijs, H. J., Beek, E. J., & Castelein, R. M. (2009). Prevalence of vertebral pars defects (spondylolysis) in a population with osteogenesis imperfecta. Spine, 34(13): 1399-1401. [41] Hatz, D., Esposito, P. W., Schroeder, B., Burke, B., Lutz, R., & Hasley, B. P. (2011). The incidence of spondylolysis and spondylolisthesis in children with osteogenesis imperfecta. Journal of Pediatric Orthopaedics, 31(6): 655-660. [42] Ivo, R., Fuerderer, S., & Eysel, P. (2007). Spondylolisthesis caused by extreme pedicle elongation in osteogenesis imperfecta. European Spine Journal, 16(10): 1636-1640. [43] Rauch, F. (2006). Material matters: a mechanostat-based perspective on bone development in osteogenesis imperfecta and hypophosphatemic rickets. J Musculoskelet Neuronal Interact. 6(2):142-146. [44] Ralston, S. H., Gaston, M. S. (2020). Management of Osteogenesis Imperfecta. Front Endocrinol (Lausanne), 10:924. [45] Dwan, K., Phillipi, C. A., Steiner, R. D., Basel, D. (2016). Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev., 10(10):CD005088. [46] Forlino, A., Marini, J. C. (2016). Osteogenesis imperfecta. The Lancet, 387(10028), 1657-1671.

In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 13

SURGICAL CORRECTION OF SPINAL PATHOLOGY IN PATIENTS WITH OSTEOGENESIS IMPERFECTA Sergey Ryabykh, MD, PhD, Elena Schurova, MD, Polina Ochirova, MD, PhD, Olga Sergeenko, MD, PhD and Dmitry Savin, MD, PhD National Ilizarov Medical Research Centre for Traumatology and Orthopaedics, Kurgan, Russia

ABSTRACT In this chapter we discussed the indications, main surgical techniques and complications of surgical correction of different spinal pathology in OI patients.

Keywords: osteogenesis imperfecta, spine, craniocervical junction, spinal deformity, scoliosis, spinal fusion, basilar invagination

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Corresponding Author’s E-mail: [email protected].

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INTRODUCTION Most of scientific work devoted to the correction of kyphoscoliosis in osteogenesis imperfecta (OI) recommends spinal fusion to correct spine deformity and prevent its progression. However, due to the poor quality of the bone tissue and the rigidity of the deformity, it is often impossible to achieve a satisfactory scoliosis correction (Figure 1). impossible to achieve a satisfactory scoliosis correction (Figure 1).

103°

Figure 1. Anteroposterior X-ray ofX-ray the spine 16-year-old patient with scoliosis Figure 1. Anteroposterior of theof spine of 16-year-old patient with scoliosis and and OI type III. OI type III.

Children with OI should be observed at least once a year for clinical signs of spinal deformity [1]. Indications for surgical correction of scoliosis in IO [2]:   

the deformity angle >50° Cobb deformity angle progression >4° Cobb per year inefficiency of conservative therapy

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The criteria for the effectiveness of surgical treatment is the correction of spinal deformity, a decrease in the rate of scoliosis progression, stability of the neurological status and vital capacity of lung, improvement of the quality of life and pain relief. For patients who have suffered instrumental fixation of the spine the additional efficiency criterion is the stable position of the metal structure, the integrity of the implant and bone fusion [2, 3].

SURGICAL CORRECTION OF SPINAL DEFORMITIES IN OI The most effective correction of spinal deformity in OI achieved by applying pedicle screw fixation systems. Pedicle screws (PS) provide rigid fixation, three-column control of the spine and equable distribution of efforts along the spine [4]. It is optimal to use the maximum possible points of fixation (Figure 2) [5, 6]. High strength titanium constructions with maximum possible screws and rod diameters with cross-links preferred for applying [7]. Additional laminar hooks in a “claw” configuration, wire or laminar tapes can help to correct deformity and reduce stress on screws, especially in the deformity apex [8]. Hooks, wire and tapes also possible to introduce when morphological vertebrae changes prevent the pedicle screw installation [7]. Pelvic fixation is recommended in cases of pelvis misalignment >10° [4, 6, 7, 9]. In cases of rigid spinal deformity multi-level osteotomy Schwab I-II would allow to achieve a more effective scoliosis correction. Schwab IIIVI osteotomy increases the risk of non-union, hardware instability and intraoperative complications [9]. Spine osteotomy can be performed by bone knife, nippers, curettes and drill. Rod rotation and soft segmental distraction and compression are performed to achieve deformity correction. Overcorrection of thoracic hyperkyphosis should be avoided, it is better to prefer mild correction.

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Figure 2. Anteroposterior and lateral X-ray of the spine of 16-year-old patient with scoliosis and OI type III.

Growth friendly spinal implants for early onset spinal deformities is recommended to use to children with open growth zones and scoliosis >50° Cobb [10-12]. The frequency of complications associated with growth-friendly implants in OI patients is comparable with others [1315]. Staged distractions are usually performed once every 6 months [13]. An alternative to classic growing rod are magnetically controlled growing rods [16]. Their disadvantages are high cost and unreliability [17]. Thoracic insufficiency syndrome in OI patient is the indication for the costo-vertebral or costo-pelvic growth devises usage [14]. Preoperative halo-gravity traction (HGT) can be useful to prepare the patient for spinal deformity surgery in scoliosis >70°Cobb (Figure 3) [3, 7, 18]. Halo traction can help avoid aggressive osteotomy (Schwab III-

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VI) and allow to achieve satisfactory correction in some patients with OI [1]. nts with OI [1].

70°

Figure 3. Anteroposterior X-ray of the spine with halo-gravity traction of 16-year-old patient with Figure 3. Anteroposterior X-ray of the spine with halo-gravity traction of 16-year-old scoliosis and OI typescoliosis III. patient with and OI type III.

Pamidronate should be canceled for the fourth month after spinal surgery, since it can affect the quality of the fusion. In four month X-ray or CT will help to identify early sign of fusion and pamidronate can be resumed [1, 3, 19]. An additional way to improve the reliability of instrumental fixation and fusion is to use fenestrated pedicle screws and high viscosity bone cement (polymethylmetacrylate, PMMA) [4, 6]. This method can be used along the entire length or only at the cranial and caudal screws [7]. Biomechanical studies have shown a 110-190% increase in pedicle screw pull-out force when using PMMA [20] and 77% increase when using

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calcium phosphate cement (CPC) [21]. The disadvantages of this technique are the lack of data on the safety of using PMMA in pediatric patients, as well as possible difficulties during revision surgery [4].

SURGICAL CORRECTION OF CVJ PATHOLOGY IN OI Indications for surgical treatment are symptomatic variants of basilar invagination (BI) and presence of vertebrogenic myelopathy signs in MRI [22-24]. The most common treatment option is posterior decompression and reduction with occipitospondylodesis, preoperative and/or intaroperative halo traction [1, 2, 25-29]. Screw construction preferable to wire, hooks and tapes. Occipital plating with occipital ridge screws creates a secure fixation point and a lever for BI reduction. Anterior CVJ approaches, including anterior endoscopic odontoidectomy, are also effective methods [1, 2, 25]. Additional bone grafting (rib, iliac crest, allograft) is used to reduce the risk of non-union, besides bisphosphonates are canceled for the four month after surgery [19, 26, 28, 29].

SURGICAL TREATMENT OF SPONDYLOLISTHESIS IN OI Standard methods of treatment, such as pedicle fixation and interbody fusion, are used in cases of spondylolisthesis [2, 3]. The approach and method of interbody fusion, as well as the instrumentation zone, are determined by the surgeon. As a rule, the following methods are used: posterior lumbar interbody fusion, transforaminal lumbar interbody fusion and anterior lumbar interbody fusion with posterior pedicle screws. In the postoperative period, rehabilitation treatment and verticalization should be applied as early as possible.

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CONCLUSION The main problems in the correction of spinal deformity in patients with IO are poor bone quality and deformity stiffness. Modern fixation by pedicle screw systems provides rigid fixation and 3D-control of the spine. Preoperative bisphosphonates treatment improves the stability of the implant, if necessary augmentation is possible. Halo gravity traction has advantages in the preoperative period. Treatment of the CVJ pathology usually includes occipitospondylodesis, reduction of BI and neural decompression. Standard methods and treatment options for isthmic spondylolisthesis are used in OI patients: segmental pedicle fixation and interbody fusion. A multidisciplinary approach and a combination of pharmacological treatment, surgical and rehabilitation therapy significantly improve the functional outcomes of treatment in OI patients.

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Shah SA, Wallace MJ: Osteogenesis Imperfecta in the Spine. In: Osteogenesis Imperfecta. edn.: Springer; 2020: 221-230. Wallace MJ, Kruse RW, Shah SA: The Spine in Patients with Osteogenesis Imperfecta. The Journal of the American Academy of Orthopaedic Surgeons 2017, 25(2):100-109. Kruse RW: Osteogenesis Imperfecta: A Case-Based Guide to Surgical Decision-Making and Care: Springer Nature; 2020. Yilmaz G, Hwang S, Oto M, Kruse R, Rogers KJ, Bober MB, Cahill PJ, Shah SA: Surgical treatment of scoliosis in osteogenesis imperfecta with cement-augmented pedicle screw instrumentation. Journal of Spinal Disorders & Techniques 2014, 27(3):174-180. Rao S, Patel A, Schildhauer T: Osteogenesis imperfecta as a differential diagnosis of pathologic burst fractures of the spine. A

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case report. Clinical Orthopaedics and Related Research 1993(289):113-117. [6] O’Donnell C, Bloch N, Michael N, Erickson M, Garg S: Management of Scoliosis in Children with Osteogenesis Imperfecta. JBJS Reviews 2017, 5(7):e8. [7] Castelein RM, Hasler C, Helenius I, Ovadia D, Yazici M: Complex spine deformities in young patients with severe osteogenesis imperfecta: current concepts review. Journal of Children’s Orthopaedics 2019, 13(1):22-32. [8] Wilke HJ, Kaiser D, Volkheimer D, Hackenbroch C, Püschel K, Rauschmann M: A pedicle screw system and a lamina hook system provide similar primary and long-term stability: a biomechanical in vitro study with quasi-static and dynamic loading conditions. European Spine Journal: Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2016, 25(9):2919-2928. [9] Piantoni L, Noel MA, Francheri Wilson IA, Tello CA, Galaretto E, Remondino RG, Bersusky ES: Surgical Treatment With Pedicle Screws of Scoliosis Associated With Osteogenesis Imperfecta in Children. Spine Deformity 2017, 5(5):360-365. [10] Gardner A, Sahota J, Dong H, Saraff V, Högler W, Shaw NJ: The use of magnetically controlled growing rods in paediatric Osteogenesis Imperfecta with early onset, progressive scoliosis. Journal of Surgical Case Reports 2018, 2018(3):rjy043. [11] Ono Y, Miyakoshi N, Hongo M, Kasukawa Y, Misawa A, Ishikawa Y, Kudo D, Shimada Y: Growing Rod Surgery for Early-Onset Scoliosis in an Osteogenesis Imperfecta Patient. World Neurosurgery 2020, 144:178-183. [12] Karlin LI, McClung A, Johnston CE, Samdani A, Hresko MT, Perez-Grueso FJ, Troy M: The growth-friendly surgical treatment of scoliosis in children with osteogenesis imperfecta using distraction-based instrumentation. Spine Deformity 2021, 9(1):263274.

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[13] Skaggs DL, Akbarnia BA, Flynn JM, Myung KS, Sponseller PD, Vitale MG: A classification of growth friendly spine implants. Journal of Pediatric Orthopedics 2014, 34(3):260-274. [14] Campbell RM, Jr., Smith MD: Thoracic insufficiency syndrome and exotic scoliosis. The Journal of Bone and Joint Surgery American volume 2007, 89 Suppl 1:108-122. [15] Wijdicks SPJ, Tromp IN, Yazici M, Kempen DHR, Castelein RM, Kruyt MC: A comparison of growth among growth-friendly systems for scoliosis: a systematic review. The Spine Journal: Official Journal of the North American Spine Society 2019, 19(5):789-799. [16] Figueiredo N, Kananeh SF, Siqueira HH, Figueiredo RC, Al Sebai MW: The use of magnetically controlled growing rod device for pediatric scoliosis. Neurosciences (Riyadh, Saudi Arabia) 2016, 21(1):17-25. [17] Teoh KH, Winson DM, James SH, Jones A, Howes J, Davies PR, Ahuja S: Do magnetic growing rods have lower complication rates compared with conventional growing rods? The Spine Journal: Official Journal of the North American Spine Society 2016, 16(4 Suppl):S40-44. [18] Janus GJ, Finidori G, Engelbert RH, Pouliquen M, Pruijs JE: Operative treatment of severe scoliosis in osteogenesis imperfecta: results of 20 patients after halo traction and posterior spondylodesis with instrumentation. European Spine Journal: Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2000, 9(6):486-491. [19] Wallace MJ, Kruse RW, Shah SA: The spine in patients with osteogenesis imperfecta. JAAOS-Journal of the American Academy of Orthopaedic Surgeons 2017, 25(2):100-109. [20] Frankel BM, D’Agostino S, Wang C: A biomechanical cadaveric analysis of polymethylmethacrylate-augmented pedicle screw fixation. Journal of Neurosurgery Spine 2007, 7(1):47-53.

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[21] Masaki T, Sasao Y, Miura T, Torii Y, Kojima A, Aoki H, Beppu M: An experimental study on initial fixation strength in transpedicular screwing augmented with calcium phosphate cement. Spine 2009, 34(20):E724-728. [22] Cheung MS, Arponen H, Roughley P, Azouz ME, Glorieux FH, Waltimo-Sirén J, Rauch F: Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research 2011, 26(2):405413. [23] Arponen H, Mäkitie O, Haukka J, Ranta H, Ekholm M, Mäyränpää MK, Kaitila I, Waltimo-Sirén J: Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta. Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research 2012, 27(5):1142-1149. [24] Khandanpour N, Connolly DJ, Raghavan A, Griffiths PD, Hoggard N: Craniospinal abnormalities and neurologic complications of osteogenesis imperfecta: imaging overview. Radiographics: A Review Publication of the Radiological Society of North America, Inc. 2012, 32(7):2101-2112. [25] Ibrahim AG, Crockard HA: Basilar impression and osteogenesis imperfecta: a 21-year retrospective review of outcomes in 20 patients. Journal of Neurosurgery Spine 2007, 7(6):594-600. [26] Pakkasjärvi N, Mattila M, Remes V, Helenius I: Upper cervical spine fusion in children with skeletal dysplasia. Scandinavian Journal of Surgery: SJS: Official Organ for the Finnish Surgical Society and the Scandinavian Surgical Society 2013, 102(3):189196. [27] Lastikka M, Aarnio J, Helenius I: Instrumented cervical spinal fusions in children: indications and outcomes. Journal of Children’s Orthopaedics 2017, 11(6):419-427.

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In: Osteogenesis Imperfecta Editors: Dmitry A. Popkov et al.

ISBN: 978-1-68507-499-9 © 2022 Nova Science Publishers, Inc.

Chapter 14

QUALITY OF LIFE AND OUTCOMES OF RECONSTRUCTIVE SURGERY IN CHILDREN WITH OSTEOGENESIS IMPERFECTA Dmitry A. Popkov1,, MD, PhD, Eduard Mingazov1, MD, PhD, Fedor Hoffman1, MD, Anatoly Korkin1, MD, PhD, Nikita Gvozdev1, MD, PhD and Siniša Ducic2, MD 1

Ilizarov National Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia 2 Children’s University Hospital, Belgrade, Serbia

ABSTRACT Introduction The multidisciplinary approach in Osteogenesis Imperfecta (OI) treatment including medical treatment with bisphosphonates, orthopedic treatment and rehabilitation for muscular strengthening and walking strategy has as a goal amelioration of mobility, self-care, functional  Corresponding Author’s E-mail: [email protected].

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Dmitry A. Popkov, Eduard Mingazov, Fedor Hoffman et al. independence and better quality of life. The purpose of this descriptive study was to assess Quality of Life (QoL) and ambulation skills of children with OI in 18-24 months after surgery of lower limbs for comparison with preoperative measures.

Material and Methods We measured children’s Health-Related Quality of Life and ambulation skills using the generic Pediatric Quality of Life Inventory questionnaire (PedsQL) and Gillette Functional Assessment Questionnaire Ambulation Scale (FAQ). Assessment was performed in 24 children with type III and IV of OI preoperatively and in 2 years after index surgery.

Results and Discussion Preoperatively, children reported significantly low quality of life scores for all domains related to severity of the condition and associated orthopedic complications in comparison to scores of healthy peers. Realignment surgery using long-lasting intramedullary devices in combination with physical therapy and bisphosphonates allowed to improve Quality of Life total score as well as physical and psychosocial functioning score at 2 years follow up control in our study. Children reported decrease of pain syndrome, improvement in self-care, mobility and independence in daily life. Decrease of missing of school and/or social activities due to disease or hospital visiting were found as well. The findings of our study correlate to the results of Rodriguez Celin et al. (2020) and Ruck et al. (2011) who reported that expanding intramedullary rodding resulted in benefits in ambulation, function, self-care, and mobility for children with OI.

Conclusion Our children OI cohort reported significantly decreased psychosocial and physical QoL across multiple domains. HRQoL was significantly impaired in OI patients, and patients with more severe OI had poorer HRQoL scores. Psychosocial functioning was less impaired than physical health. Most individuals with moderate and severe types of OI undergone nailing or rodding procedures have improved mobility outcomes, psychosocial and physical functioning. We emphasize that a measurable assessment of outcomes should include not only objective

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clinical evaluation but patient-reported outcomes measurements for feedback basis in justification of evidence-based care modifications and control of treatment results.

Keywords: health-related quality of life, Osteogenesis imperfecta, PedsQL 4.0, walking ability

INTRODUCTION Osteogenesis imperfecta (OI) is a group of genetic disorders with wide phenotypic and molecular heterogeneity. The major orthopedic features are bone fragility, osteopenia, progressive bone deformity and varying degree of short stature [1, 2]. It is a rare genetic disease with an incidence of 1 in 10.000 to 1 in 20.000 births [1, 3, 4]. The multidisciplinary approach including medical treatment with bisphosphonates, orthopedic treatment and rehabilitation for muscular strengthening and walking strategy has as a goal amelioration of mobility, self-care, functional independence and better quality of life (QoL) [5-8]. The goal of orthopedic surgery implies the correction of long bone bowing, rotational malalignment, angular deformity and prevention or reduction of the fracture incidence [9-12]. OI may also result in problems of social interaction: too much attention, the wrong kinds of attention, or social exclusion [13, 14]. The health related QoL in individuals with OI is a growing concern of medical research [6, 8, 15-17]. Recently published best practice guidelines for OI surgical management [18] encourage the use of specific measures including the Pediatric Quality of Life Inventory (PEDS-QL) QoL to assess postoperative result for children with OI. The purpose of this descriptive study was to assess QoL and ambulation skills of children with OI in 18-24 months after surgery of lower limbs for comparison with preoperative measures.

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MATERIAL AND METHODS For the purpose of this study, we selected 24 patients with OI type III (6 cases) and type IV (18 cases) according to Sillence modified classification [19] aged between 5 years 1 month and 12 years 9 months by index surgery, who were surgically treated for lower limb deformity with Flexible Intramedullary Nailing or Telescopic rodding during the period from May 2012 to April 2019 and followed until May 2021. The mean follow-up was 4.4 years (range, 2.1-9.0 years). Approval from the Local Human Ethics Committee was obtained to conduct this study. Data were collected prospectively throughout follow-up period. Telescopic rodding and sliding elastic transphyseal nailing were applied in 11 patients. Combined technique associating telescopic device (rod or flexible intramedullary nails) was used in 13 children. The time gap between surgeries for contralateral lower limbs varied between 25 days to 6 months. During post-operative period, the patients were reviewed every 6 months for clinical and radiological examinations. We measured children’s Health-Related Quality of Life using the generic Pediatric Quality of Life Inventory questionnaire (PedsQL4.0™) [20, 21]. The PedsQL is a generic health related QoL measure consisting of 4 core scales, physical function, emotional function, social function and school function which are intended for use in healthy and patient populations. Self-report versions of the PedsQL are available for ages 57, 8-12, 13-17. The PedsQL is responsive to clinical improvement across the physical and psychosocial scores as well as the total score [22]. Preoperatively and in 18-24 months after index surgery respondents were asked to recall the last month and indicate how frequently they have experienced specific phenomena. The Psychosocial Health Summary Score was assessed as a Sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales. The rate of Physical Health Summary Score corresponded to Physical Functioning Scale Score in our study. Assessment of ambulation skills were performed using the Gillette Functional Assessment Questionnaire Ambulation Scale (FAQ) [23]. The

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FAQ score comprises a 10-point patient-reported scale where each point on the scale indicates a functional level. A score of 1 is the least functional score and corresponds to “Cannot take any steps at all” whereas the top score of 10 corresponds to “Walks, runs, and climbs on level and uneven terrain without any difficulty.” The subjects were scored before index surgery in our institution and in 1,5-2 years postoperatively. We assessed results separately in two groups of patients - children with severe type III of OI (group I) and children with moderate-to-severe type of OI (type IV). Mean total health-related QoL scores of 2 years follow up were compared to preoperative values. Twenty-one children started or continued bisphosphonate therapy with a delay of 4 moths at least after surgery (on condition of good callous formation evident on radiographs). Statistical analysis was conducted with AtteStat 12.0.5 software, Russia. Means, SDs, and ranges were used to describe continuous variables. The PedsQL scores were compared by using the Wilcoxon rank-sum two-tailed test for independent samples with a 0.05 level of significance.

RESULTS AND DISCUSSION Table 1 represents measurements of Physical Health Summary Score and Psychosocial Health Summary Score. In the sample, children with OI reported significantly low quality of life scores for all domains related to severity of the condition and associated orthopedic complications. Participant’s mean total scores and physical function scores were significantly lower than Huang and colleagues’ mean scores for Healthy Children [24]. Patients of both groups had total PedsQL scores psychosocial and physical function scores more than two standard deviations below healthy reference population norms [20, 25].

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Score Physical Health Summary Score Psychosocial Health Summary Score Total *

Type III OI children Before In 2 years FU surgery 54.6 ± 6.4 61.2 ± 8.1*

Type IV OI children Before In 2 years FU surgery 59.5 ± 6.2 67.5 ± 13.8*

68.3 ± 5.9

72.8 ± 11.8*

69.0 ± 11.4

78.1 ± 12.6*

59.1 ± 5.6

69.3 ± 9.2*

64.8 ± 8.1

72.3 ± 13.2*

significant difference with preoperative score (р ˂ 0.05; Wilcoxon test).

Many studies focus only on physical factors such as functionality, walking ability, self-care, bone pain [26, 27] without measuring QoL except the article of Song y et al. [12] and Vanz et al. [28]. Song Y et al. [12] in a detailed investigations (PedsQL) about the quality of life in a large sample of patients with OI demonstrated that osteogenesis imperfecta significantly impaired the quality of life in children, and moderate/severe OI patients had worse QoL scores than patients with mild OI. In this study, the HRQoL scores of OI patients were 50.0, 69.7, and 64.8 in physical functioning, psychosocial health and total score, respectively, in type III of OI. In moderate-to-severe type IV, the mean scores were 58.5, 75.1, and 71.0 in physical functioning, psychosocial health and total score, respectively. The findings of our study correlate to these results. The study of Vanz et al. [28] revealed differences in physical functioning in relation to OI severity and mobility using PedsQL as assessment tool, emphasizing the importance of the clinical management of these patients with the aim of functional improvement. Realignment surgery using long-lasting intramedullary devices in combination with physical therapy and bisphosphonates allowed to improve Quality of Life total score as well as physical and psychosocial functioning score at 2 years follow up control in our study. Children reported decrease of pain syndrome, improvement in self-care, mobility and independence in daily life. Decrease of missing of school and/or

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social activities due to disease or hospital visiting were found as well. Children described improvement in social involvement and lower level of sadness. They became less afraid. There was no significant difference regarding other domains of Peds-QL assessment tool. In literature, few information is known about functional outcomes following rodding procedures in OI [29]. In the study of Rodriguez Celin et al. [10], the Type-III OI rodded group showed better results in most mobility outcomes than the non-rodded group. But this benefit of a surgical procedure was not observed in Type-IV subjects. In agreement with this, some other studies described the benefits of rodding/nailing regarding mobility and physical functioning [29, 30]. In agreement with Rodriguez Celin et al. and Ruck et al. [10, 29] we found that expanding intramedullary rodding resulted in benefits in ambulation, function, selfcare, and mobility for children with OI. Bisphosphonate treatment represents a basic medical therapy in severe types of OI. Use of bisphosphonates benefits mobility, muscle force, and well-being [31-33]. However, in the study of Rodriguez Celin et al., no correlation between the use of bisphosphonates and mobility outcomes in the rodded children was found [10]. In our study majority of patients received bisphosphonates in long-term follow-up but all the children reported improvement in functional abilities and QoL. Mobility/Walking ability changes are represented in the Table 2. According to the received values of the Gillette FAQ there were no improvement of functional motor abilities in 1 case of type III OI (4.2%), advancement by one level in 2 children with type III OI and in 2 patients with type IV OI (16.7%), advancement by two levels and more was observed in 19 patients (79.1%). At admittance, there was no patient walking without manual guarding for safety or manual contact. Their preoperative ambulation status was not functional representing “some stepping on his/her own with the help of another person. Does not walk on a routine basis” [23]. In agreement with Ruck, we found that in majority of type-IV subjects, the mean FAQ was close to level 6 (the first of five community ambulation levels of the walking scale) after surgery. In 2 years follow-up, four patients (66%)

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with type III of OI were able to walk but required either manual contact to walk on even surface or an assistance device like a walker. They were able to walk some feet outside the home, but usually used a wheelchair for community distances. One child with type III OI walked freely on even surface but with crutches. In group of type IV OI, 12 children ambulated independently (85.7%). Two children used crutches but required standby guarding of one person for safety. In total, 13 children became independent at home, and 8 patients walked outside without assistance of a person. Table 2. Ambulation skills (FAQ) Group Type III OI (number of cases) Type IV OI (number of cases)

Before surgery; level I II III IV 5 1 -

At 2yrs FU control; level I III IV V 1 2 2 1

VI -

VII -

2

-

5

3

4

6

2

a Figure 1. (Continued)

-

2

4

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b

c Figure 1. Outcomes in long-term FU period: a - type IV boy participates in social activities without fear nor pain, ambulation skills of level 7 FAQ; b - a girl with type III OI uses bicycle and does not experience pain, level 5 of FAQ; c - a girl with type III OI has no more physical discomfort for social functioning with level 4 of FAQ achieved with surgery.

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CONCLUSION Osteogenesis imperfecta is a disease with many different causes and clinical presentations. Indications for orthopedic surgery are often justified and surgical treatment is required in order to improve the patients’ growth development and quality of life. Our children OI cohort reported significantly decreased psychosocial and physical QoL across multiple domains. HRQoL was significantly impaired in OI patients, and patients with more severe OI had poorer HRQoL scores. Psychosocial functioning was less impaired than physical health. This study demonstrated that most individuals with moderate and severe types of OI undergone nailing or rodding procedures have improved mobility outcomes, psychosocial and physical functioning. Osteogenesis imperfecta patients require an interdisciplinary and tailored treatment that involves both medical and surgical components. The association of medical treatment and surgical correction of long bone deformity in children with OI followed by a rehabilitation and a social support represents a “gold” standard in management of OI. Thus, a measurable assessment of outcomes should include not only objective clinical evaluation but patient-reported outcomes measurements for feedback basis in justification of evidence-based care modifications and control of treatment results. Although summary scores are no substitute for the detailed anatomical and functional analysis of treatment results, this work has shown that the PedsQL provides a simple and low-cost technique for the assessment of outcomes in OI children.

COMPLIANCE WITH ETHICAL STANDARDS  

Conflict of Interest: The authors declare that they have no conflict of interest. Ethical approval: This chapter does not contain any studies with human participants performed by any of the authors.

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Informed consent: Informed consent was obtained from all individual participants included in the study.

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CONCLUSION Osteogenesis imperfecta has been a topic of considerable interest for more than four decades among geneticists, pediatricians, orthopedists, physical therapists, and neurosurgeons. OI should be recognized as one of the most studied skeletal systemic dysplasias. Considering the recent improvement of technology, diagnostic and therapeutic strategies for OI might evolve in the future. This is reflected in the diagnosis and genetic verification of new types of pathology, in the innovations of drug treatment with the development of drugs and pathogenetic therapy schemes, in the selection of criteria for X-ray and MRI assessment of limb deformity and spine pathology, in the evolution of technologies for reinforcing long bones and hybridization of surgical approaches for limb reconstruction, in the selection of methods for correcting the axis of the spine and restoring its support function, which are impossible without improving the schemes of anesthetic management and assessing the risks of complications. Finally, comprehensive treatment must include individualized rehabilitation. The authors of this book deliberately went beyond the treatment of fractures and orthopedic issues of OI. The key thread that unites the chapters is the multidisciplinary approach for the diagnostic and management of OI.

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Dmitry A. Popkov and Sergey Ryabykh

The authors hope that the book will be a useful reference for a wide range of specialists, and the feedback from readers will help to improve it in the future. Separately, we ask you not to ignore the disadvantages and limitations of the book and provide recommendations for improving it ... after all, this is only its first generation!

ABOUT THE EDITORS Dmitry A. Popkov, Professor, is the Head of Clinic of Neuroorthopedics and Systemic diseases, National Ilizarov Medical Research Center for Traumatology and Orthopedics, Kurgan, Russia. E-mail: [email protected]

Sergey Ryabykh, Doctor of Medical Sciences, is the Deputy Director for projects, education and communication, Moscow, Russia. E-mail: [email protected]

INDEX A

B

acid, 45, 46, 47, 48, 142, 164, 178, 226 adolescents, 41, 58, 107, 215, 250, 253, 280 adults, xiii, 30, 41, 49, 58, 95, 100, 104, 106, 127, 128, 130, 132, 151, 152, 163, 164, 173, 278 age, x, 37, 42, 45, 46, 48, 50, 52, 76, 93, 96, 104, 105, 130, 140, 141, 154, 155, 156, 158, 176, 177, 178, 183, 184, 188, 191, 198, 208, 213, 218, 223, 225, 244, 245, 249, 251 angulation, 155, 157, 183, 186, 228 assessment, x, 20, 37, 53, 126, 131, 166, 170, 182, 192, 193, 198, 218, 225, 229, 233, 268, 272, 273, 276, 277, 279, 283 assistive technology, 109, 110, 115, 116, 121, 122 asymptomatic, 199, 244 autosomal dominant, 1, 3, 10, 31, 32, 33, 34, 61, 62, 70 autosomal recessive, 3, 14, 24, 27, 31, 33, 34, 35, 55, 62, 73, 74, 80, 85, 86, 242

basilar invagination, 38, 172, 237, 242, 243, 255, 260 behavioral disorders, 126, 139 bending, 161, 183, 228, 229, 233 bilateral, 41, 127, 158, 184, 186, 205, 206, 212 biochemistry, 65 biosynthesis, 6, 10, 73, 77, 78 births, 5, 92, 177, 242, 269 bisphosphonate treatment, 30, 39, 57, 58, 59, 223 blood, 34, 42, 51, 126, 128, 131, 138, 142, 144, 145, 146, 156, 188 blood plasma, 126, 131 blood pressure, 145 blood supply, 156 blood transfusion, 138, 142, 144, 145 body mass index, 250, 252 bone cells, 72 bone form, 7, 8, 9, 17, 18, 19, 20, 26, 32, 48, 49, 53, 71, 77, 78, 87

288

Index

bone fragility, ix, 1, 2, 3, 21, 26, 31, 33, 35, 61, 62, 65, 84, 87, 177, 199, 219, 242, 247, 249, 269 bone growth, 78, 172 bone marrow, 49, 59 bone marrow transplant, 59 bone mass, 1, 2, 9, 12, 16, 17, 19, 96, 139, 189, 219, 231, 247 bone resorption, 9, 11, 16, 17, 45 braces therapy, 242 brain, 34, 38, 39, 55, 146 breathing, 37, 38, 92, 97, 102, 129, 142

C calcium, 7, 8, 42, 51, 72, 182, 260, 264 capillary, 138, 142, 144, 146 cardiopulmonary dysfunction, 30, 54, 253 cardiovascular disease, 128 cardiovascular system, 36, 37, 52, 62 cerebral palsy, 42, 138, 140, 141, 142, 143, 144, 145, 146, 149, 150 cerebrospinal fluid, 38, 150, 244 childhood, 41, 61, 74, 98, 131, 138, 171, 207, 248 classification, v, ix, 1, 2, 3, 4, 6, 20, 29, 30, 31, 62, 63, 64, 65, 66, 67, 68, 77, 80, 82, 83, 91, 97, 100, 140, 152, 153, 154, 165, 166, 220, 223, 242, 250, 263, 270, 279 clinical application, 163 clinical diagnosis, 20, 53, 74, 88, 166, 192, 277 clinical examination, 218 clinical presentation, 64, 79, 153, 276 clinical symptoms, 4, 11, 18, 38, 94 clinical trials, 48, 53 collagen, ix, 2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 22, 23, 24, 30, 31, 37, 40, 43, 52, 63, 65, 67, 70, 71, 72, 73, 75, 77, 78, 79, 80, 81, 82, 84, 85, 92, 126, 127, 242, 246

communication, 99, 103, 105 community, 111, 137, 139, 151, 273 comorbidity background, 126, 127 compression, x, 33, 34, 35, 50, 127, 146, 182, 243, 244, 246, 247, 248, 249, 253, 257 compression fracture, 33, 34, 35, 50, 243, 246, 247, 253 conflict, 165, 191, 198, 206, 234, 276 conflict of interest, 165, 191, 234, 276 connective tissue, 6, 10, 30, 52, 84, 92, 125, 126, 199, 242 consent, 165, 191, 235, 277 consolidation, 160, 163, 164, 179, 182 control group, 138, 140, 141, 145 controversial, 62, 130, 158, 231 correlation, 22, 79, 80, 88, 89, 132, 251, 273 craniocervical junction, 132, 137, 139, 251, 255, 264, 265 cross-sectional study, 252, 280

D data analysis, 140, 146 data collection, 220 database, 3, 4, 32, 37, 74, 80 defects, 1, 4, 9, 12, 15, 22, 42, 63, 77, 79, 242, 254 deficiency, 14, 17, 19, 23, 25, 73, 84, 92, 242 deformation, 31, 33, 34, 35, 39, 74, 97, 213 differential diagnosis, 254, 261 diseases, ix, 20, 30, 52, 53, 64, 66, 68, 76, 98, 105, 127, 199, 285 disorder, 1, 23, 62, 66, 74, 84, 127 displacement, 129, 162, 163, 177, 183, 184, 191, 227, 228, 231 distribution, 27, 76, 79, 143, 202, 203, 257 drug discovery, 20 drug treatment, 200, 283

Index drugs, 46, 48, 248, 283 dysplasia, 1, 13, 22, 83, 127, 264

E elongation, 206, 219, 221, 248, 254 encoding, 9, 13, 18, 24, 30, 43, 70, 73, 76, 126 environment, 93, 97, 98, 101, 102, 105, 106, 122, 179 epiphyses, 35, 161, 204, 227, 233 epiphysis, 161, 179, 220, 225, 228, 229 evidence, 74, 127, 130, 163, 231, 248, 269, 276 exercise, 95, 101, 102, 103, 108 external fixation, 162, 168, 185, 189, 190, 194, 206, 218, 219, 223, 224, 226, 234, 235, 239, 278 extracellular matrix, 11, 77, 84

F families, x, xiii, 19, 74, 80, 83, 85, 86, 89, 94, 133, 148 femur, 49, 117, 134, 135, 147, 149, 157, 159, 160, 167, 169, 170, 176, 178, 181, 182, 183, 184, 187, 190, 193, 201, 204, 206, 207, 209, 211, 212, 218, 221, 222, 223, 226, 227, 228, 229, 233, 236, 238 fixation, 161, 162, 172, 182, 198, 200, 202, 204, 205, 206, 207, 208, 209, 210, 212, 213, 218, 226, 227, 228, 229, 231, 234, 236, 247, 257, 259, 260, 261, 263, 264 fragility, ix, 1, 2, 3, 26, 31, 33, 35, 50, 61, 62, 63, 64, 65, 84, 87, 177, 199, 219, 242, 247, 249, 269 fragments, 155, 162, 177, 179, 189, 191, 204, 213, 218, 223, 228, 234 fusion, 200, 202, 213, 257, 259, 260, 261, 264, 265

289 G

gait analysis, 217, 218, 219, 225, 234, 238, 240 general anesthesia, 129, 130, 131, 150, 176, 184 genes, 2, 4, 5, 9, 11, 13, 16, 17, 18, 20, 22, 30, 31, 32, 43, 53, 63, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 80, 81, 126, 153, 242 genetic defect, 10, 66 genetic disease, 62, 177, 269 genetic disorders, 61, 269 genetic heterogeneity, ix, xi, 1, 2, 3, 9, 20, 70, 81, 92, 149, 165, 238, 250 genetic information, 67 genetics, ix, 3, 9, 62, 64, 77, 82, 89, 215, 248, 249, 250, 253 genotype, 11, 22, 79, 88, 132, 215, 242, 250 growth, x, 6, 14, 18, 31, 35, 50, 51, 59, 61, 95, 105, 107, 132, 134, 147, 156, 158, 182, 184, 204, 214, 218, 219, 224, 227, 234, 242, 248, 251, 252, 258, 262, 263, 264, 276 growth factor, 14, 51 growth hormone, 51 growth rate, 50, 248

H healing, 118, 164, 171, 190, 195, 236, 239 health, 21, 95, 96, 97, 269, 270, 271, 272, 279, 280 health-related quality of life, 269, 278, 280 hearing impairment, 2, 26, 41 hearing loss, 32, 41, 56, 61, 63, 76, 127, 242 heterogeneity, ix, xi, 1, 2, 9, 20, 62, 68, 70, 76, 81, 92, 149, 165, 238, 250, 269 hip abduction, 156, 226, 233, 234

290

Index

hip surgery, 138, 146 homeostasis, 7, 18, 19, 26, 87 human, 48, 49, 54, 74, 85, 165, 191, 234, 253, 276 hydrocephalus, 4, 38, 127, 137, 138, 139, 140, 141, 146, 172, 237, 244 hypoplasia, 33, 34, 36, 39, 40, 246, 253

I identical twins, 135 identification, 81, 153 iliac crest, 260 Ilizarov, 29, 125, 137, 140, 175, 176, 179, 181, 182, 189, 219, 223, 225, 226, 230, 232, 240, 241, 255, 285 immobilization, 155, 161, 179, 189, 190, 204, 223 implants, 152, 155, 158, 160, 162, 163, 165, 258, 263 incidence, 9, 15, 39, 43, 62, 75, 126, 127, 130, 136, 148, 160, 163, 164, 177, 242, 245, 248, 254, 269 independence, 92, 105, 106, 109, 110, 177, 200, 212, 231, 248, 268, 269, 272 inheritance, 3, 31, 35, 62, 64, 66, 70, 73, 74, 80, 153 interdisciplinary approach, 91, 115 intervention, 95, 96, 98, 99, 104, 105, 106, 156, 162, 188, 206, 212 intracranial pressure, 137, 139, 146, 149, 150 issues, x, 30, 98, 131, 283

J joints, 64, 96, 105, 121, 154, 182, 198, 204, 211, 218, 226, 227 justification, 269, 276

K kinetics, 225, 229, 230, 232, 234 kyphosis, 32, 33, 42, 237

L learning, 101, 105 life expectancy, 158, 177, 188, 191 limb deformities, vi, 36, 39, 197, 199 limb orthopedic surgery, 152 local anesthetic, 129, 139, 146 low-density lipoprotein, 8, 14 lumbar puncture, 149 lumbar spine, 47 lung function, 37, 38

M magnetic resonance imaging, 150, 163, 172, 218 majority, 38, 94, 104, 176, 218, 273 materials, 80, 98, 111, 112, 118, 119, 120, 121 measurements, 45, 226, 227, 228, 271 mechanical properties, 155 mechanical stress, 79 mechanical ventilation, 38, 139, 140, 141 medical, 62, 92, 97, 110, 116, 122, 132, 137, 139, 149, 151, 152, 177, 225, 238, 248, 250, 267, 269, 273, 276 mesenchymal stem cells, 18, 20, 52, 59 migration, 159, 160, 163, 172, 182, 183, 184, 186, 213, 214, 218, 224, 227, 229, 231, 233, 243 mineralization, 2, 6, 9, 17, 18, 19, 20, 30, 31, 32, 33, 34, 35, 41, 50, 63, 70, 71, 73, 242 modifications, 10, 12, 15, 73, 156, 242, 269, 276

Index molecular genetic research, 62 motor skills, x, 93, 101, 102, 156, 218 multiple fractures, 2, 4, 32, 33, 34, 35, 50, 64, 74 muscle strength, 94, 95, 102, 106, 154, 248

N narcotic analgesics, 142, 145 neuroimaging, 233 neurologic complications, 55, 228, 252, 264 neuropathy, 127 neurosurgery, 251 next generation, 88 nonsense mutation, 74 normal distribution, 143 null hypothesis, 140, 143, 147 nutritional status, 107, 133, 146 nystagmus, 38, 244

O obstructive sleep apnea, 38 occupational therapy, 248 open angle glaucoma, 56 operations, 154, 162, 199, 201, 202, 204, 205, 209, 212, 226 orthotics, vi, 109, 110, 116 osteoporosis, 4, 19, 21, 26, 36, 46, 48, 58, 69, 78, 83, 86, 87, 94, 139, 155, 189, 199, 204, 206, 214, 219, 231, 242, 243, 248, 249, 250 osteotomy, 157, 159, 160, 162, 164, 171, 186, 190, 195, 198, 202, 206, 207, 208, 210, 212, 220, 221, 222, 223, 227, 231, 234, 236, 257, 258

291 P

pain, x, 39, 76, 94, 97, 105, 125, 126, 128, 130, 131, 138, 139, 142, 147, 150, 198, 200, 204, 206, 213, 214, 233, 242, 248, 257, 268, 272, 275 pathogenesis, 5, 9, 20, 30, 31, 63, 64, 67, 69, 75, 81, 242 pathology, 30, 37, 38, 40, 41, 52, 54, 76, 92, 126, 127, 128, 131, 138, 139, 140, 141, 189, 219, 241, 242, 243, 244, 249, 250, 252, 253, 255, 261, 283 pathophysiological, 1 pathophysiology, 2, 5, 22, 108 PedsQL 4.0, 269, 280 perioperative pain therapy, 126 phenotype, xi, 4, 11, 14, 15, 16, 17, 19, 22, 35, 52, 55, 56, 65, 66, 68, 73, 76, 77, 79, 81, 88, 89, 132, 215, 242, 250 phenotypes, ix, 3, 4, 14, 67, 80 physical activity, x, 94, 95, 99, 104, 106, 111, 113, 125, 154, 156, 217, 277 physical exercise, 94, 101, 106 physical health, 268, 276 physical inactivity, 128 physical therapist, 97, 98, 283 physical therapy, vi, 91, 93, 94, 95, 96, 97, 98, 104, 106, 122, 152, 154, 268, 272 population, 5, 21, 75, 76, 79, 88, 89, 96, 152, 199, 250, 254, 271, 279 preschool children, 158, 167, 176, 188, 191, 194, 237 prevention, x, 102, 156, 173, 177, 188, 241, 269 probability, 129, 145, 146, 147, 198, 199, 245 prolonged epidural analgesia, 137, 138, 139, 140, 142, 146, 147 proteins, 7, 8, 9, 12, 15, 16, 17, 19, 27, 31, 67, 70, 73, 74, 77 pulmonary hypertension, 32, 37

292

Index

pyrophosphate, 45, 164

Q quality of life, x, 37, 41, 91, 92, 93, 97, 125, 131, 139, 177, 200, 207, 231, 238, 252, 257, 268, 269, 271, 272, 276, 277, 278, 279, 280, 281 questionnaire, 133, 268, 270, 279

R rehabilitation, 91, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 104, 107, 108, 109, 115, 177, 199, 200, 212, 215, 260, 261, 267, 269, 276, 283 rehabilitation program, 109, 115 risk, 40, 46, 49, 51, 93, 102, 118, 126, 128, 129, 130, 136, 137, 139, 140, 141, 158, 163, 164, 167, 172, 174, 184, 207, 244, 257, 260 risk assessment, 126, 167 risk factors, 174 Russia, ix, 29, 42, 61, 62, 76, 91, 98, 109, 125, 137, 151, 175, 197, 223, 241, 255, 267, 271, 285

S safety, 50, 105, 115, 130, 135, 138, 139, 146, 162, 260, 273 sclera, 3, 31, 32, 33, 34, 35, 40, 42, 64, 65, 68, 92 scoliosis, 32, 35, 37, 42, 54, 75, 76, 129, 130, 133, 147, 148, 242, 243, 245, 246, 247, 249, 251, 252, 255, 256, 257, 258, 259, 261, 262, 263 sequencing, 44, 67, 74, 75, 76, 78, 79, 81, 85, 88 signaling pathway, 17, 49, 77, 78, 249

signs, 38, 41, 42, 49, 154, 182, 223, 243, 256, 260 sliding flexible intramedullary nailing, 175, 176, 177, 183, 188, 190, 191 somatic issues, v, 29, 30 specialists, 92, 94, 97, 98, 99, 100, 104, 105, 199, 284 spinal deformity, 36, 242, 245, 246, 248, 249, 250, 252, 255, 256, 257, 258, 261, 262, 263, 265 spinal fusion, 255, 256, 264 spine, x, 32, 33, 34, 35, 37, 47, 95, 127, 129, 132, 133, 139, 149, 172, 242, 245, 246, 247, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 261, 262, 263, 264, 265, 283 spondylolisthesis, 242, 243, 248, 249, 254, 260, 261 stress, 16, 25, 73, 85, 155, 257 structure, 4, 11, 30, 37, 52, 61, 62, 63, 70, 94, 97, 100, 118, 120, 138, 257 surgical intervention, x, 38, 48, 74, 138, 141, 156, 165, 224 surgical technique, 152, 169, 255 surgical treatment, x, 52, 105, 126, 139, 154, 155, 156, 167, 168, 171, 179, 190, 193, 197, 198, 199, 200, 201, 202, 204, 205, 212, 213, 214, 235, 257, 260, 261, 262, 276 survival, 160, 176, 182, 184, 187, 198, 207, 208, 213, 228, 232, 233 survival rate, 160, 176, 184, 187, 208, 232 syndrome, 4, 13, 14, 15, 22, 34, 35, 37, 38, 39, 64, 85, 133, 139, 148, 244, 258, 263, 268, 272 synthesis, 12, 14, 30, 43, 52, 63, 67, 77, 242, 253

T teeth, 35, 92, 127, 129, 133

Index telescopic rods, vii, x, 152, 160, 162, 168, 171, 175, 176, 178, 184, 188, 189, 194, 198, 202, 204, 212, 213, 214, 217, 218, 231, 233, 235, 239, 278 therapy, 30, 37, 44, 45, 46, 47, 48, 50, 52, 53, 58, 59, 81, 93, 94, 96, 104, 106, 122, 125, 126, 130, 131, 142, 144, 146, 152, 165, 173, 178, 204, 206, 207, 212, 231, 242, 246, 249, 254, 256, 261, 271, 273, 281, 283 therapy bisphosphonate treatment, 30 tibia, 160, 167, 170, 176, 180, 181, 182, 183, 184, 187, 190, 204, 205, 206, 208, 218, 223, 226, 227, 228, 233, 238 tissue, 9, 19, 31, 45, 46, 51, 52, 61, 62, 70, 71, 73, 92, 155, 164, 251, 256 titanium, x, 126, 132, 139, 140, 147, 156, 157, 159, 162, 163, 168, 170, 176, 179,

293 188, 218, 219, 220, 223, 227, 233, 234, 235, 257, 278

V vertebrae, 32, 33, 50, 129, 134, 246, 247, 248, 249, 257

W walking ability, 228, 269, 272, 273 weakness, 35, 38, 39, 94, 154, 214, 233, 242, 243

Y young adults, 36