Table of Contents 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178

Koert Gooijer

Quality of life and bleeding in Osteogenesis Imperfecta Koert Gooijer

Quality of life and bleeding in Osteogenesis Imperfecta Academic thesis, University of Amsterdam, Amsterdam, The Netherlands ISBN: 978-94-6506-029-3 Author: Koert Gooijer Cover design: Maaike Dias Krijtenburg Lay-out: Janneke Gooijer Printing: Ridderprint, the Netherlands Part of the research described in this thesis (Chapter 3) was supported by a grant from the Care 4 Brittle Bones foundation for the development of the mobile questionnaire application. Care 4 Brittle Bones had no involvement in the design of the study, collection, analysis and interpretation of the data or in writing the manuscript. Additional financial support for the printing of this thesis was kindly provided SBOH and by the department of Human Genetics, Amsterdam UMC. ©2024, Koert Gooijer. All rights reserved. No part of this thesis may be reproduced in any form or by any means without permission of the author.

Quality of life and bleeding in Osteogenesis Imperfecta ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. P.P.C.C. Verbeek ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op donderdag 13 juni 2024, te 13.00 uur door Koert Gooijer geboren te Zwolle

Promotiecommissie Promotores: prof. dr. M.M.A.M. Mannens AMC-UvA prof. dr. L. Henneman Vrije Universiteit Amsterdam Copromotoren: dr. A.A.M. Franken Isala dr. M.W. Elting VU Medisch Centrum Overige leden: prof. dr. M.M. van Haelst AMC-UvA prof. dr. E.M.A. Smets AMC-UvA prof. dr. P.H.L.T. Bisschop AMC-UvA prof. dr. M.C. Zillikens Erasmus Universiteit Rotterdam prof. dr. J.P. van den Bergh Universiteit Maastricht prof. dr. M.C. Cornel Vrije Universiteit Amsterdam Faculteit der Geneeskunde

Table of contents Chapter 1: General introduction Aim and outline of this thesis Part I Quality of life in Osteogenesis Imperfecta Chapter 2: A baseline measurement of Quality of life in 322 adults with Osteogenesis Imperfecta JBMR Plus 2020;4(12):e10416 Chapter 3: Fatigue in adults with Osteogenesis Imperfecta BMC Musculoskeletal Disorders 2020;21(1):6 PART II Bleeding and bruising in Osteogenesis Imperfecta Chapter 4: Bleeding and bruising in OI: ISTH Bleeding Assessment Tool and haemostasis laboratory assessment in 22 individuals British Journal of Haematology 2019;187(4):509-517 Chapter 5: Bleeding assessment in a large cohort of patients with Osteogenesis Imperfecta Accepted for publication Chapter 6: Bleeding and bruising in Osteogenesis Imperfecta: Laboratory assessment in extreme scorings with self bleeding assessment tool in 195 individuals with Osteogenesis Imperfecta Submitted Chapter 7: Discussion with future perspectives Chapter 8: Summary Chapter 9: Samenvatting Dankwoord Author affiliations Publications Curriculum vitae 9 18 27 29 61 75 77 97 115 131 153 159 166 170 172 174

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9 Chapter 1 General introduction

10 Introduction Osteogenesis Imperfecta (OI) is a rare congenital connective tissue disease with a prevalence of 6.5 per 100,000 live births 1,2. OI is often referred to as “brittle bone disease” because fragile bones and high fracture prevalence are one of its most prominent features. However, the features of OI are much broader as the underlying problem in most cases involves an abnormality in collagen type 1 production. Collagen type 1 is abundant in bones, teeth, ligaments and tendons, and to a lesser extent in sclera, blood vessels and internal organs 3. Therefore, abnormalities and symptoms can occur in all the above-mentioned tissues and organs in OI and can affect the quality of life of people with OI in different ways 4. This thesis addresses quality of life in OI and the bleeding tendency, one of the abnormalities that is often mentioned but scarcely investigated in OI. This introductory chapter provides background information on OI and is followed by a description of the aims and outline of the thesis. Osteogenesis Imperfecta Etiology of OI The biosynthesis of collagen is a complex process in which even minor disruptions lead to a number of serious diseases. Each protein must be properly folded and modified to become functional. Basic steps in the successful production and maturation of proteins are synthesis, posttranslational modifications, folding, quality control, and transport. The collagen type 1 molecule has a triple helix structure consisting of two α1 chains and one α2 chain. Of all OI patients, approximately 85-90% have an autosomal dominant pathogenic variant in either the COL1A1 or the COL1A2 gene, which encodes for the collagen type 1 α1 chain and collagen type 1 α2 chain, respectively 5. The cells that convert these mutations to proteins produce a mixture of normal and abnormal collagen 6. Recently, recessive, dominant, and X-linked variants in several genes have been shown to cause defects in proteins responsible for transcription, synthesis, and post-translational modification. In addition, chaperone proteins, retrograde transport, extracellular processing of procollagen for bone synthesis, transport of type 1 collagen, matrix mineralization, and osteoblast differentiation are affected by pathogenic gene variants. All these genetic defects may cause OI 3,7. The resulting phenotype can range from very mild to lethal, depending in part on which of the alpha strands is affected and the position and nature of the pathogenic variant (Table 1). Classification In addition to heterogeneity at the molecular level, OI is also a clinically heterogeneous disorder and several researchers have attempted to develop a useful, understandable, and comprehensive classification for it. The most widely used classification is the one developed by Sillence et al. 9 in 1979,

11 Chapter 1 OI Type Clinical features Mutated gene(s) Mode of inheritance* Pathway 1 Mild to moderate deformation, blue sclerae, normal stature COL1A1/2 AD Genes encoding (pro) collagen chain/fibril: start of pathway CREB3L1 AR ER stress response 2 Perinatal lethality COL1A1/2 See type 1 CREB3L1 See type 1 CRTAP Posttranslational modification KDELR2 Retrograde vesicle transport LEPREI Posttranslational modification PPIB Posttranslational modification 3 Progressively deforming with bowing, scoliosis and low bone density. Short stature and dentinogenesis imperfecta BMP1 AR Extracellular processing COL1A1/2 See type 1 CCDC134 AR Regulation of MAPK CREB3L1 See type 1 CRTAP Posttranslational modification IFITM5 Matrix mineralisation FAM46A Unknown FKBP10 Posttranslational modification KDELR2 See type 2 LEPREI See type 2 MBTPS2 XL ER stress response MESD AR WNT signaling pathway PLOD2 Posttranslational modification PPIB See type 2 SERPINF1 Matrix mineralisation SERPINH1 Posttranslational modification SP7 Bone cell diff. and sign TMEM38B Posttranslational modification/Ca2+ homeostasis WNT1 Bone cell diff. and sign 4 Mild to moderate deformation, white sclerae, variable fracture rate. COL1A1/2 See type 1 PLS3 XL Actin-bundling protein PPIB See type 2 SP7 See type 3 SPARC Extracellular matrix WNT1 See type 3 5 Mild deformation, calcification in interosseous membranes and hypercallus during fracture healing IFITM5 AD Matrix mineralisation NBAS AD Retrograde transport * Autosomal dominant (AD), autosomal recessive (AR) and recessive X-linked (XL) Table derived from van Dijk and Sillence , 2014 and Claeys et al. 2021 7,8. Table 1 Clinical features, mutated genes, and pathways of the different OI types

12 which describes four different types of OI based on clinical symptoms. In the last two decades, an attempt has been made to base the classification of OI more on its genetic causes rather than on clinical presentation 10–12. However, the genotype-phenotype relation is still insufficiently understood (Table 1). Therefore, this expanded classification with about 20 different types has not proven to be clinically useful, and clinicians and researchers have returned to the phenotyping according to Sillence et al., with the addition of one distinguishable clinical type 8. The phenotype of OI is thus clinically classified into five subtypes (Table 1) in which the severity ranges from barely detectable connective tissue abnormalities to lethality in the perinatal period 8. Type 1 is the relatively mildest and most common form of OI, with a birth prevalence of about 4 per 100,000 live births 8. OI type 1 is characterized by blue sclera, increased fracture frequency without extensive deformities, normal stature, sometimes hearing loss and sometimes dentinogenesis imperfecta. Type 2 is the most severe type and is characterized by such a lack of collagen in the bones that children die in utero during pregnancy, at birth or shortly after. This type is characterized by extensive fractures and bone deformity, micromelic bones and platyspondyly. Lethality occurs due to respiratory failure secondary to pulmonary hypoplasia as a consequence of a small thoracic cage caused by multiple rib fractures, as well as cerebral haemorrhage after vaginal delivery. In persons with type 3, there is small stature, frequent fractures with deformity of the limbs and vertebrae that increases over the years, sometimes causing respiratory insufficiency. Blue sclerae might be present or not, dentinogenesis imperfecta is usually evident. Type 4 is very similar to type 1, a difference being that there are no blue sclerae and some persons have a shorter stature. Type 5 is comparable to type 4, but persons with type 5 have a calcification of the interosseous membrane of the forearm, which restricts hand movements and can lead to secondary dislocation of the radial head. Very typically there is a greater chance of hypercalcification occurring after surgery or a fracture. Life expectancy for persons with all OI types other than type 2 is normal. In individuals with OI type 3, life expectancy may be shorter if there is severe kyphoscoliosis with restrictive pulmonary function 1,13–15. Based on the above-mentioned prevalence data, there are approximately more than 1,100 patients with OI in the Netherlands. Storoni et al. 2 estimated the total number of patients with OI to be 850. The Expertise Center for adults with OI in Isala in Zwolle, founded in 2008, now has a cohort with over 500 adult OI patients in care. Of these 500 patients, 67% have type 1 OI, 12% type 3 and 19% type 4. Of the cohort, 2% have type 5 or other rare (recessive inherited) variants 16.

13 Chapter 1 Diagnosis The diagnosis of OI can be made on the basis of clinical and radiographic findings 8. Fractures after mild trauma, bowing deformities of long bones, and growth deficiency are hallmark features. Specific skeletal features may include macrocephaly, flat midface and triangular facies, dentinogenesis imperfecta, chest wall deformities and scoliosis or kyphosis. Typical extra-skeletal features are blue sclerae, hearing loss and hypermobility (Table 2). Radiographic examination may reveal osteopenia, long-bone bowing and shortening, and vertebral fractures. The diagnosis of OI type 2 and the diagnosis of OI type 3 can be made prenatally based on ultrasound examination of the foetus because fractures typically occur prenatally in these types. The diagnoses of OI type 1, 4 and 5 are made postnatally on the basis of the clinical features and abnormalities on imaging examination 17. The most common differential diagnostic consideration is nonaccidental injury, frequently in cases of suspected OI type 1 or 4 18–20. The diagnosis can be confirmed through molecular DNA diagnostics. Treatment and management No successful cure is available for OI at this moment. Although novel approaches of gene therapy are being developed 45, treatment currently focuses on management of symptoms and preferentially takes place within a multidisciplinary team. Because symptoms can be diverse, treatment also has different angles. The most obvious treatment is orthopaedic treatment of fractures and deformities. In addition, pharmacological treatment of low bone density using antiresorptive drugs (bisphosphonates, denosumab) or anabolic drugs (teriparatide, antisclerostin antibodies) in combination with calcium and vitamin D suppletion can reduce fracture incidence and improve bone density. However, medical treatment does not address the defective collagen type 1, which leads not only to reduced bone quantity, but also to abnormal bone matrix and bone. Rehabilitation intervention (physiotherapy, occupational therapy, rehabilitation) is crucial to reduce fracture incidence and, more importantly, reduce the loss of function and improve quality of life. It is challenging for patients with brittle bones, weak muscles, and a cycle of frequent fractures followed by immobilization to maintain gross motor skills such as walking and to function independently 46. Most patients with OI can make independent transfers, have enough skills to live independently, are well educated and participate in social life. Because of additional complaints of hearing loss, diminished lung function due to scoliosis and rib cage deformities, cardiac manifestations of OI and dentinogenesis imperfecta, the ear, nose, and throat specialist, pulmonologist, cardiologist and dentist or oral surgeon are also often involved. A periodic visit to a centre of expertise is recommended to ensure adequate surveillance 47.

14 Table 2 Extra-skeletal features of the different OI types Features Pathway Prevalence Blue sclerae - Corneal thinning 21,22. - Decreased light scattering by the sclera 23. - Increased visibility of the underlying choroid and melanocytes beyond the scleral external surface 24. Common Glaucoma - Thinner cornea is a risk factor in glaucoma 25. Rare Dentinogenesis Imperfecta - Colour: Opalescent dentin, pigments and inclusion of remnants of blood vessels 26,27. - Fractures: scalloping interface between dentin and the enamel is absent 28, or dentin frailty 27. - Size and shape: defective type I collagen causes poor mineralization density and abnormal fibrillar structure 29. Common Cranial base anomalies: - Platybasia - Basilar impression - Basilar invagination - Deformation under the strain of the brain, differential growth deficiency and bending or fractures of the skeletal cranial structures 30. Common Bleeding tendency - Abnormal structure and function of the vessel wall, resulting in increased fragility and susceptibility to bleeding (Chapter 5). - Altered extracellular matrix in OI affects platelet function and activation, leading to impaired haemostasis 31-33. Common Skin - Thinness, fragility and translucency - Elastosis perforans serpiginosa - The dermis has a relative increase of argyrophil and elastic fibres and a deficiency of adult collagen 34,35. - Alteration in the elastic fibres 36,37. Rare Hearing loss - Among others: Ossicular chain problems 38. Common Cardiovascular disease - Collagen type 1 in myocardium and vessels 39. Unknown Pulmonary dysfunction - Chest wall abnormalities 40,41. - Pulmonary parenchymal abnormalities 41,42. Intermediate Muscle weakness, tendon and ligament laxity. - Muscle: Delayed motor milestones due to severely bowed legs or fractures 43. - Tendon and ligaments: unknown 44. Common Osteoarthritis and other joint problems - Secondary to musculoskeletal concerns 44. Common Short stature - Secondary to skeletal abnormalities 8. Common Quality of life in OI The World Health Organization (WHO) defines quality of life as an “individual’s perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, norms and concerns” 48. Health can have a major impact on quality of life because health is determined by the effect of illness and impairment on daily activities and behaviours, perceived health and functional status 49. Thus, quality of life has a broad scope and is influenced by several factors. OI primarily affects bone quality, but also potentially affects all other structures containing collagen type 1. Physically measurable factors such as fractures, decreased

15 Chapter 1 bone density, and scoliosis can affect quality of life, but the psychological burden of the disease such as fatigue, difficulty participating in daily life, mobility, self-care, independence, and pain can also affect the quality and are frequently reported 50,51. These factors can result in health impairment by limiting “normal” daytime activities. The lives of persons with OI are also regularly filled with hospital checkups, given that hospital checkups in these patients are on average 1.5-2.6 times more frequent than the Dutch average 2. People with OI sometimes describe their disease as a “full-time job”. The focus on preventing fractures in daily life sometimes limits activities, makes certain occupations impossible and makes certain homes unsuitable for living. These situational factors can also affect quality of life, in accordance with the WHO definition. Due to the huge impact of OI on life, it is important to determine how patients with OI experience their quality of life. There are many possible negative influencing factors, but the mindset of many people with OI also results in limitations being turned into opportunities 52. If the quality of life of people with OI is well known, the overall care in the multidisciplinary team for persons with OI can be focused on improving the worst perceived aspects. In addition, an individual patient with OI can be compared with other people with OI and more emphasis is placed on individual care needs. This underscores the importance of developing disease-specific patient-reported outcome measures (PROMs) in OI 53. In this way, value-driven care and shared decision-making develop the care that benefits people the most. Fatigue in OI One of the most frequently mentioned negative influencing factors on quality of life in clinical practice is fatigue. OI is a disease with a wide range of skeletal and extra-skeletal symptoms that can cause fatigue. Fatigue of itself has a major impact on both physical and psychological domains in healthy individuals. In the physical domain, for instance, pain and painkillers can promote fatigue 54,55 and lack of energy can lead to reduced enthusiasm and endurance to perform daily tasks. In the psychological domain, fatigue can reduce satisfaction and happiness, but can also have a negative impact on thinking skills, learning ability, memory, concentration and decision-making ability 56. The impairments on physical and psychological domains can contribute to a negative self-image or even a depression 57, and can affect social relationships and the dependence on others. OI is a disease which already has a wide range of skeletal and extra-skeletal symptoms that can cause restrictions on the physical domains and impairments on the psychological domain. For instance, brittle bones limit mobility and physical activities, and increase dependence on others 58. All the domains in which OI can cause impairment in itself and in which fatigue can cause additional impairment are at risk of reducing quality of life in OI.

16 Because each person with OI may have a different skeletal or extra-skeletal focus that causes fatigue, or in which fatigue may cause additional impairment, it is important to determine the extent of fatigue in OI compared to people without OI. Understanding the extent of fatigue in OI can be a valuable resource for quality of life interventions. Bleeding tendency In addition to clinically distinctive features, there are a number of complaints that are consistently mentioned by OI patients but are not clearly reflected in the literature. One notable complaint among these is frequent bruising. Frequent bruising can be a symptom of an underlying bleeding tendency 59. In well-known coagulation disorders, such as von Willebrand disease and haemophilia, an essential part of the coagulation cascade does not function properly 60 (Figure 1). Alongside the major known coagulation abnormalities, there is also a wide range of less obvious problems that can cause a mild bleeding tendency in both the coagulation cascade and the collagen in the vessel wall 61. Mild bleeding tendency is a well-known phenomenon in collagen disorders other than OI, such as Ehlers-Danlos. Bleeding tendency in Ehlers-Danlos is caused by a malfunction of fibrillin, which together with elastin forms an elastic fibre. These elastic fibres, together with other structures, form the basic meshwork for the connective tissue matrix 61. This connective tissue matrix has a direct interaction with coagulation factors and also provides strength to the capillary structure, protecting it from tearing during shearing forces. A similar mechanism could be underlying in OI. Diagnosing a mild bleeding tendency in OI can be a difficult task. In fact, bleeding problems occur frequently in the normal population without an increased bleeding tendency. Bleeding symptoms occur sequentially, sometimes with long intervals. Patients with a mild bleeding disorder may not consider the number of bleedings they experience as abnormal, as there is usually an inherited disorder at the basis of their disease. If several family members suffer from bleeding problems, it is less obvious that the bleedings are abnormal. In general practice, certain bleeding symptoms, such as heavy menstrual blood loss and epistaxis, are very common and are only recognized at a late stage as a manifestation of an underlying coagulation disorder. In coagulation disorders such as von Willebrand’s disease, the time lag to diagnosis is reported to be as long as 16 years 62. If a mild bleeding tendency is suspected, it remains extremely difficult to find an underlying explanation because not all the components of the complex coagulation cascade can be tested. This is why recent reviews emphasize the importance of a detailed bleeding history and family history 59,63. In OI, research into bleeding tendency began in the 1950s and was aimed at finding an explanation for the frequent bruising and significant bleeding tendency in OI as was reported in various case

17 Chapter 1 reports. So far, it has not yet yielded any clear answers. However, both case reports and complaints by OI patients on bleeding and bruising mentioned in clinical care are still relevant 64–69. The early detection of bleeding problems is very important because even mild bleeding tendencies can have an impact on operations, length of hospitalization, mortality, pregnancy, birth and miscarriages. Unexplained mild bleeding tendencies can also lead to anxiety. More clarity on the underlying cause of bleeding tendency would be crucial to providing more safety in the numerous operations and interventions that patients with OI undergo. Figure 1 Primary haemostasis Primary haemostasis involves two key processes: vasoconstriction and platelet adhesion to the injured vessel wall. (a) The plasma protein von-Willebrand-factor plays a vital role in capturing platelets from the rapidly flowing blood at the site of vessel wall damage. (b) Once adhered, platelets undergo activation and aggregation. (c) Concurrently, tissue factor present in the damaged vessel wall triggers secondary haemostasis. This leads to the activation of coagulation factors on the surface of the activated platelets, resulting in the generation of thrombin. (d) Ultimately, thrombin influences the formation of a fibrin network that reinforces the haemostatic plug and acts as a trap for erythrocytes, forming a blood clot. Following clot formation, the fibrinolytic system is responsible for breaking down the blood clot 70. d fibrin endothelial cell erythrocyte a b c direction of blood flow vascular wall lumen platelet von-Willebrand-factor thrombin ‘tissue factor’

18 Aim and outline of this thesis The aim of this thesis is to gain insights into quality of life issues and bleeding tendency in persons with Osteogenesis imperfecta (OI). To improve patient care and guidance and to increase the diagnostic capabilities, it is important to look at OI in a broader context than just a disease with bone fragility. Part I of this thesis focusses on the quality of life in people with OI. The following research questions were addressed: 1. What is the quality of life in people with OI compared to control populations? (Chapter 2) 2. What is the impact of fatigue on daily functioning in people with OI compared to control populations? (Chapter 3) In part II of this thesis the bleeding tendency in OI is investigated and the following research questions were formulated: 3. What is the prevalence of bleeding tendency in OI compared with a control population? (Chapter 5) 4. What are the clinical manifestations of bleeding tendency in OI? Is diagnostic testing for bleeding disorders indicated? (Chapter 4 and 6) 5. Which bleeding events are most clinically relevant in OI? What can be learned from therapeutic considerations in other mild bleeding disorders? (Chapter 5)

19 Chapter 1

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22 28. Levin LS, Brady JM, Melnick M. Scanning electron microscopy of teeth in dominant osteogenesis imperfecta: Support for genetic heterogeneity. Am J Med Genet 1980; 5. DOI:10.1002/ ajmg.1320050213. 29. Nanci A. Development, Structure, and Function. In: Ten Cate’ s Oral Histology , 9th edn. 2017. 30. Waltimo-Sirén J, Kolkka M, Pynnönen S, Kuurila K, Kaitila I, Kovero O. Craniofacial features in osteogenesis imperfecta: A cephalometric study. Am J Med Genet 2005; 133 A. DOI:10.1002/ ajmg.a.30523. 31. Evensen SA, Myhre L, Stormorken H. Haemostatic studies in osteogenesis imperfecta. Scand J Haematol 1984; 33: 177–9. 32. Hathaway WE, Solomons CC, Ott JE, Ott E. Platelet Function and Pyrophosphates in Osteogenesis Imperfecta. Blood 1972; 39. 33. Estes JW. Platelet size and function in the heritable disorders of connective tissue. Ann Intern Med 1968; 68: 1237–49. 34. Hansen B, Jemec GBE. The mechanical properties of skin in osteogenesis imperfecta. Arch Dermatol 2002; 138. DOI:10.1001/archderm.138.7.909. 35. Francis MJO, Williams KJ, Sykes BC, Smith R. The relative amounts of the collagen chains α1(I), α2 and α1(III) in the skin of 31 patients with osteogenesis imperfecta. Clin Sci 1981; 60. DOI:10.1042/cs0600617. 36. Mehta RK, Burrows NP, Rowland Payne CME, Mendelsohn SS, Pope FM, Rytina E. Elastosis perforans serpiginosa and associated disorders. Clin Exp Dermatol 2001; 26. DOI:10.1046/ j.1365-2230.2001.00882.x. 37. Pérez-Pérez L, Allegue F, Alfonsín N, Caeiro JL, Fabeiro JM, Zulaica A. An uncommon association: Elastosis perforans serpiginosa and osteogenesis imperfecta. Journal of the European Academy of Dermatology and Venereology 2009; 23. DOI:10.1111/j.1468-3083.2008.02751.x. 38. Pillion JP, Vernick D, Shapiro J. Hearing Loss in Osteogenesis Imperfecta: Characteristics and Treatment Considerations. Genet Res Int 2011; 2011. DOI:10.4061/2011/983942. 39. Ashournia H, Johansen FT, Folkestad L, Diederichsen ACP, Brixen K. Heart disease in patients with osteogenesis imperfecta - A systematic review. Int J Cardiol 2015; 196: 149–57. 40. LoMauro A, Pochintesta S, Romei M, et al. Rib cage deformities alter respiratory muscle action and chest wall function in patients with severe Osteogenesis imperfecta. PLoS One 2012; 7. DOI:10.1371/journal.pone.0035965. 41. Gochuico BR, Hossain M, Talvacchio SK, et al. Pulmonary function and structure abnormalities in children and young adults with osteogenesis imperfecta point to intrinsic and extrinsic lung abnormalities. J Med Genet 2023; published online May 16. DOI:10.1136/jmg-2022-109009.

23 Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter 1 2 3 4 5 6 7 8 9 10 11 42. Widmann RF, Bitan FD, Laplaza FJ, Burke SW, DiMaio MF, Schneider R. Spinal deformity, pulmonary compromise, and quality of life in osteogenesis imperfecta. Spine (Phila Pa 1976) 1999; 24: 1673–8. 43. Engelbert RH, Gulmans VA, Uiterwaal CS, Helders PJ. Osteogenesis imperfecta in childhood: Perceived competence in relation to impairment and disability. Arch Phys Med Rehabil 2001; 82. DOI:10.1053/apmr.2001.23889. 44. McKiernan FE. Musculoskeletal manifestations of mild osteogenesis imperfecta in the adult. Osteoporosis International 2005; 16: 1698–702. 45. Schindeler A, Lee LR, O’Donohue AK, Ginn SL, Munns CF. Curative Cell and Gene Therapy for Osteogenesis Imperfecta. Journal of Bone and Mineral Research 2022; 37. DOI:10.1002/ jbmr.4549. 46. Montpetit K, Palomo T, Glorieux FH, Fassier F, Rauch F. Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity. Arch Phys Med Rehabil 2015; 96. DOI:10.1016/j.apmr.2015.06.006. 47. Lafage-Proust MH, Courtois I. The management of osteogenesis imperfecta in adults: state of the art. Joint Bone Spine 2019. DOI:10.1016/j.jbspin.2019.02.001. 48. World Health Organization. WHOQOL-HIV Instrument Users Manual. SubStance 2002; : 1–13. 49. WHOQOL Group, Szabo S, Orley J, Saxena S. WHOQOL User Manual PROGRAMME ON MENTAL HEALTH. Geneve, 1997. 50. Hill, Hammond J, Sharmin M, et al. Living with osteogenesis imperfecta: A qualitative study exploring experiences and psychosocial impact from the perspective of patients, parents and professionals. Disabil Health J 2022; 15. DOI:10.1016/j.dhjo.2021.101168. 51. Vartiainen P, Heiskanen T, Sintonen H, Roine RP, Kalso E. Health-related quality of life and burden of disease in chronic pain measured with the 15D instrument. Pain 2016; 157. DOI:10.1097/j.pain.0000000000000641. 52. Wekre LL, Frøslie KF, Haugen L, Falch JA. A population-based study of demographical variables and ability to perform activities of daily living in adults with osteogenesis imperfecta. Disabil Rehabil 2010; 32. DOI:10.3109/09638280903204690. 53. Nijhuis W, Franken A, Ayers K, et al. A standard set of outcome measures for the comprehensive assessment of osteogenesis imperfecta. Orphanet J Rare Dis 2021; 16. DOI:10.1186/ s13023-021-01682-y. 54. Conrad R, Geiser F, Mücke M. Pain and fatigue-a systematic review. Z Psychosom Med Psychother 2018; 64. DOI:10.13109/zptm.2018.64.4.365.

24 Chapter 55. Cortés RM, Pastor JFS, Dolz VM. Chronic pain in adults with osteogenesis imperfecta and its relationship to appraisal, coping, and quality of life: A cross-sectional study. Medicine (United States) 2022; 101. DOI:10.1097/MD.0000000000030256. 56. Campbell RD, Bagshaw M. Human Performance and Limitations in Aviation. 2002 DOI:10.1002/9780470774472. 57. Giallo R, Gartland D, Woolhouse H, Brown S. “I didn’t know it was possible to feel that tired”: exploring the complex bidirectional associations between maternal depressive symptoms and fatigue in a prospective pregnancy cohort study. Arch Womens Ment Health 2016; 19. DOI:10.1007/s00737-014-0494-8. 58. Dogba MJ, Bedos C, Durigova M, et al. The impact of severe osteogenesis imperfecta on the lives of young patients and their parents - a qualitative analysis. BMC Pediatr 2013; 13. DOI:10.1186/1471-2431-13-153. 59. Boender J, Kruip MJHA, Leebeek FWG. A diagnostic approach to mild bleeding disorders. Journal of Thrombosis and Haemostasis 2016; 14: 1507–16. 60. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67. DOI:10.1146/annurev.biochem.67.1.395. 61. Malfait F, Paepe A De. Bleeding in the heritable connective tissue disorders: Mechanisms, diagnosis and treatment. Blood Rev 2009; 23. DOI:10.1016/j.blre.2009.06.001. 62. Kirtava A, Crudder S, Dilley A, Lally C, Evatt B. Trends in clinical management of women with von Willebrand disease: A survey of 75 women enrolled in Haemophilia Treatment Centres in the United States. Haemophilia 2004; 10. DOI:10.1046/j.1351-8216.2003.00832.x. 63. Moenen FCJI, Nelemans PJ, Schols SEM, Schouten HC, Henskens YMC, Beckers EAM. The diagnostic accuracy of bleeding assessment tools for the identification of patients with mild bleeding disorders: A systematic review. Haemophilia. 2018; 24. DOI:10.1111/hae.13486. 64. Mayer SA, Rubin BS, Starman BJ, Byers PH. Spontaneous multivessel cervical artery dissection in a patient with a substitution of alanine for glycine (G13A) in the α1(I) chain of type I collagen. Neurology 1996; 47: 552–6. 65. Edge G, Okafor B, Fennelly ME, Ransford AO. An unusual manifestation of bleeding diathesis in a patient with osteogenesis imperfecta. Eur J Anaesthesiol 1997; 14: 215–9. 66. Kastrup M, von Heymann C, Hotz H, et al. Recombinant factor VIIa after aortic valve replacement in a patient with osteogenesis imperfecta. Ann Thorac Surg 2002; 74: 910–2. 67. Mondal RK, Mann U, Sharma M, Mondal RK, Mann U, Sharma M. Osteogenesis imperfecta with bleeding diathesis. Indian J Pediatr 2003; 70: 95–6. 68. Faqeih E, Roughley P, Glorieux FH, Rauch F. Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2. Am J Med Genet A 2009; 149A: 461–5.

25 Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter 1 2 3 4 5 6 7 8 9 10 11 69. Paterson CR, Monk EA. Temporary brittle bone disease: association with intracranial bleeding. Journal of Pediatric Endocrinology and Metabolism 2013; 26: 417–26. 70. van Vulpen LFD, Wichers IM, Urbanus RT, van Galen KPM. [Diagnostics on suspicion of a bleeding disorder]. Ned Tijdschr Geneeskd 2020; 164.

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27 Part I Quality of life in Osteogenesis Imperfecta

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29 Chapter 2 A baseline measurement of quality of life in 322 adults with osteogenesis imperfecta Journal of Bone and Mineral Research Plus 2020;4(12):e10416 Koert Gooijer, Arjan G.J. Harsevoort, Fleur S. van Dijk, Hendrikje (Rik) Withaar, Guus J.M. Janus, and Anton A.M. Franken

30 Abstract Osteogenesis imperfecta (OI) is characterized by bone fragility and secondary features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity, and short stature. It was thought that health-related quality of life (QoL) in patients with OI mainly depends on the severity of the skeletal deformities. However, it has become clear that additional factors can affect the QoL in all patients with OI. In this study, we compare dimensions of QoL in adults with OI with a control population. The SF-36 questionnaire was distributed among 330 adult patients with different OI types. Results were compared with two control populations from the Netherlands. Age-matched comparisons were made with one of the two control populations. The results were summarized in eight domains: general and mental health, physical and social function, bodily pain, vitality, and physical and emotional role. General health and physical function in all types of OI are low compared with controls, except patients with OI type 4 aged 55+ years. Bodily pain in patients with OI appeared significantly worse than in the control population. There was no significant difference between OI types regarding pain and vitality. Vitality was only in the OI type 1 group significantly lower compared with controls. Patients with OI type 1 had a significantly reduced mental health. Social functioning appeared most effective in type 3 around 20 years of age. QoL in adult patients with OI should be an important outcome measure in every OI clinic, but the amount of baseline data on this subject is sparse. This baseline measurement study is the largest study to date investigating QoL in adult patients with OI. The mean scores indicate that people with OI generally have a significantly lower QoL than the control population. Further qualitative evaluation of QoL and its influences is important for future management.

31 Chapter 2 Introduction Osteogenesis imperfecta (OI) is an inherited connective tissue disorder primarily characterized by susceptibility to fractures. The prevalence of OI has been reported to be 6 to 7 individuals per 100,000 population 1. OI is a clinically and genetic heterogeneous disorder. Clinically, OI is classified in five types (OI types 1 to 5) 2. According to the clinical severity and characteristics, OI is further classified into five subtypes: nondeforming OI with blue sclerae (type 1), perinatally lethal OI (type 2), progressively deforming OI (type 3), common variable OI (type 4), and finally OI with calcification in the interosseous membranes (type 5) 2. Patients can have blue sclerae, dentinogenesis imperfecta, hearing loss, joint hypermobility, and short stature as secondary features 3. Symptoms such as hearing loss, physical restrictions caused by pain, bone deformation as a result of (recurrent) fractures can increase in severity with age and can affect the health-related quality of life (QoL) in patients with OI. No cure for OI exists; treatment focuses on management of symptoms. Orthopedic and fracture treatment, physical therapy, special dental care, treatment for hearing loss, and medical treatment for low BMD are common therapies. However, there has been less attention paid to the psychosocial impact of living with OI in adults. Today, it is commonly recognized that measuring the QoL in people with OI can provide new information to improve treatment and subsequently the QoL of patients. Here, we report on the QoL of 322 patients with a diagnosis of OI type 1, 3, and 4 in the Netherlands compared with the general Dutch population. We suspected that the QoL in patients with OI would be decreased compared with controls. To measure the QoL in a patient cohort with OI, we decided to use the validated self-reported health assessment tool, the SF-36 questionnaire 5,6, which is frequently used in international studies. The SF-36 measures QoL across eight different subscales. We compared the SF-36 subscales against the different OI-type groups and with the QoL data of two Dutch control groups, including different age categories. Patients and Methods Study design and population A cross-sectional cohort study was undertaken in the National Expert Center for Adults with Osteogenesis Imperfecta, Isala Hospital, Zwolle, the Netherlands. In this center, patients with a clinical and usually confirmed molecular diagnosis of OI are assessed by the multidisciplinary OI team.

32 The SF-36 questionnaire 4 was provided during the first appointment. All new adult patients who attended the center from December 2007 until November 2018 were selected. Exclusion criteria were age <18 years and unavailability to fill in the questionnaire. Informed consent was obtained from each participant, and the Medical Ethics Committee of the Isala Hospital, Zwolle, the Netherlands, approved the study protocol and provided a non-WMO (Medical Research Involving Human Subjects Act) waiver. Evaluation of quality of life in patients with OI QoL was assessed using the validated self-reported health assessment tool, the SF-36 questionnaire 5,6, which is composed of 36 questions in eight different domains that examine aspects of physical and mental health in a 4-week timeframe. The SF-36 questionnaire is used in multiple countries to measure QoL in patients; it has been extensively tested for reliability and validity 6–10. The four main physical domains are physical function, role limitations caused by physical health problems, bodily pain, and general health perceptions. The four main mental domains are vitality, social function, role limitations based on emotional problems, and general mental health. Each domain score is linearly converted to a 0 to 100 scale. A higher score is correlated with better mental and physical health. The physical and mental domains can be summarized in two broad scores: the physical component summary and the mental component summary. These summary scores reflect self-assessed physical and mental activity. All patients with different types of OI were divided in age categories to compare QoL in patients with OI. Control groups The control values are based on two different studies. The first control was the result of a municipal screening that was carried out in 1992 by the University of Groningen, the Netherlands. It concerned a group of 1063 adults, randomly selected from the civil register of Township Emmen. The data of this control group were available according to different age ranges 11. For the general comparison, a national randomly selected control group without age range (n = 1742) was used. Data from these individuals were generated from a study conducting a nationwide, population-based health status survey for the purpose of generating normative data for a study of patients with congenital heart defects 5. The SF-36 questionnaire results of both control groups are presented in Figure 1.

33 Chapter 2 Converted Domainscore 0-100 8 Different SF-36 domains Physic function Role, physical Role, emotional Mental health Vitality General Health Social function Pain 76 83 57 18 64 77 76 60 83 82 77 77 75 74 75 79 71 71 62 60 62 62 68 64 66 69 59 56 58 55 50 77 77 76 76 76 85 84 53 48 0 10 20 30 40 50 60 70 80 90 100 Emmen n = 1036 National n = 1742 OI type4 OI type 1 OI type 3 Figure 1 Visualization of the eight different SF-36 questionnaire domains, divided per osteogenesis imperfecta type and control group

34 Data and statistical analysis In Table 1, the data of both control groups 5,11 have been combined and compared with the recruited patients with OI. Only the first control group11 was used for the data presented in the Supplementary Appendix. For each age category, a comparison was made with the age-matched control patients to test if the null-hypothesis (no differences between OI and controls) could be rejected. Then, the OI types were reciprocally compared. To calculate a Δ score, the score of the youngest patient group was subtracted from the eldest patient group. As the oldest OI type 3 group consisted only of three individuals, the Δ score was not calculated. Given that the questionnaire score cannot be reliably estimated for participants with extreme scores, floor and ceiling effects were examined (Table 1). Variables were tested for normal distribution with the Kolmogorov–Smirnov test, Shapiro–Wilk test, and q-q plots. Means and SDs were given for normally distributed continuous variables. Non-normally distributed continuous variables were presented as median, interquartile range (IQR). Differences in means comparing patients with OI with the controls were in normally distributed data tested using the summary independent sample t tests and in not normally distributed data tested with the one-sample Wilcoxon signed-rank test. Comparisons between OI types of different ages were done using ANOVA in normally distributed data, and with independent-samples Kruskal-Wallis tests with Dunn’s comparison for post hoc testing in not normally distributed data. A two-sided p value of 0.05 was considered significant. Significance values for comparison between OI types have been adjusted by the Bonferroni correction for multiple testing. Significance values for comparing patients with OI with controls are presented with three decimals for adequate interpretation. Analyses were performed using SPSS 25 (SPSS, Inc., Chicago, IL, USA) for Windows. We did not assess separately modifiers of QoL such as fracture history, scoliosis, and pulmonary function. Results Clinical characteristics A total of 372 patients with OI were identified for participation in the current study. Fifty patients were excluded as their SF-36 questionnaires were unavailable. Therefore, 322 patients were available for analysis.

35 Chapter 2 Physical domains OI (all types) (n = 322) P Value Type 1 (n = 220) P Value OI type 3 (n = 40) P Value OI type 4 (n = 62) P Value General population (n = 1063 + 1742) PF 57 ± 31.3 .000 63.6 ± 28.6 .000 18.4 ± 21.8 .000 57.2 ± 28.4 .000 79.4 ± 22.8 RP 50 (0; 100) .000 50 (0; 100) .000 50 (0; 100) .000 75 (0; 100) .012 76.5 ± 36.3 BP 60.4 ± 27.2 .000 59.4 ± 27.8 .000 60.4 ± 25.5 .000 64 ± 26 .000 77.14 ± 24.4 GH 54.8 ± 20.7 .000 54.6 ± 20.4 .000 50.4 ± 23.9 .000 58.2 ± 19.3 .000 69.42 ± 21.14 PCSS 39.6 ± 11.6 .000 40.6 ± 11.8 .000 31.8 ± 9.2 .000 41 ± 10.4 .000 50 ± 10 Mental Domains Vitality 58 ± 20.6 .000 56.1 ± 20.5 .000 61.7 ± 20.6 .081 62.2 ± 20.4 .043 67.53 ± 19.9 SF 75 (50; 100) .000 75 (50; 100) .000 62.5(37.5;87.5) .000 75 (62.5; 100) .066 84 ± 22.3 RE 100 (66; 100) .018 100 (66; 100) .064 100 (66; 100) .438 100 (66; 100) .210 82.57 ± 33.3 MH 74.2 ± 18 .012 73.6 ± 18 .009 75.3 ± 18.9 .618 75.6 ± 17.7 .600 76.8 ± 17.56 MCSS 49.7 ± 11.2 .615 48.7 ± 10.9 .087 53.2 ± 11.2 .078 51 ± 11.6 .492 50 ± 10 Data shown as mean ± SD or median (interquartile range) as appropriate. p Values are osteogenesis imperfecta vs general population (summary independent t test or one-sample Wilcoxon signed-rank test). Values indicating floor (≥15% with a score of 0) and ceiling (≥15% with a score of 100) effects are in bold face. BP = Bodily pain; GH = general health; MCSS = mental component summary score; MH = mental health; PCSS = physical component summary score; PF = physical functioning; RE = role functioning emotional; RP = role functioning physical; SF = social functioning. Table 1 SF-36 scores in OI types and in the general population Osteogenesis Imperfecta type

36 A total of 190 (59%) of the 322 patients with OI in our cohort were women; 132 (41%) were men. The mean and median age of participants with OI at the first visit were, respectively, 38 and 35.5 years (interquartile range (IQR) 27 years). Skewness and kurtosis were, respectively, 0.343 and −1.119, confirming a normal distribution with a small overrepresentation of the middle group 12. There were 220 (66.7%) subjects who had a diagnosis of OI type 1, 40 (12.1%) were diagnosed with OI type 3, and 61 patients (18.5%) had OI type 4. Scores of all patients with OI across eight different SF-36 subscales Figure 1 shows the results of the eight different SF-36 subscales of the three OI types in comparison with two control groups in the Netherlands 5,11. Individuals with OI type 1, 3 and 4 had a significantly lower mean physical function score compared with the control groups (Table 1) 5,11. A significant difference between patients with OI and controls applied to all the subscales except for vitality in OI type 3, role limitations caused by emotional problems in OI types 3 and 4, and mental health in OI types 3 and 4 (Table 1). Comparison of SF-36 subscale scores in different age categories A complete overview of the results is available in the Supplementary Table S2. The comparisons have been made with the first control group 11 because in this control group participants were divided in age categories, suitable for making agematched comparisons. Physical functioning Physical function in the overall OI cohort was significantly lower compared with controls 5,11 in all different age categories, except for patients with OI type 4 and aged >55 years (Table 1 and Supplementary Table S2) 11. Individuals with OI type 3 had the lowest score on physical function, (Table 1), whereas individuals with OI type 1 in the age group 18 to 24 years had the highest score on physical function. The physical function of OI type 3 was significantly lower than OI type 1 and 4 in all age categories except when compared with OI type 4 in the age group 35 to 54 years (Supplementary Table S2). The physical function of individuals with OI types 1 and 4 in the different age categories were not significantly different from each other, except in the age category 18 to 24 years (Supplementary Table S2). In the control group 11, physical function declined during at least 30 years with 27.9 points (Δ; see Patients and Method section). The OI type 1 group followed that trend (Δ −21.72, p < 0.05), whereas patients with OI type 4 showed a climbing trend (Δ +18.7, p = 0.106), implying that several individ-

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