Osteogenesis imperfecta – A clinical update

    Osteogenesis Imperfecta-a clinical update Symeon Tournis, Anastasia D. Dede PII: DOI: Reference:

S0026-0495(17)30158-0 doi: 10.1016/j.metabol.2017.06.001 YMETA 53607

To appear in:

Metabolism

Received date: Revised date: Accepted date:

28 April 2017 30 May 2017 1 June 2017

Please cite this article as: Tournis Symeon, Dede Anastasia D., Osteogenesis Imperfecta-a clinical update, Metabolism (2017), doi: 10.1016/j.metabol.2017.06.001

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ACCEPTED MANUSCRIPT Osteogenesis Imperfecta-a clinical update

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Symeon Tournis MD, PhD1, Anastasia D. Dede MD1,2.

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1. Laboratory for Research of the Musculoskeletal System ‘Th. Garofalidis’, KAT Hospital, University of Athens, Athens, Greece.

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2. Department of Endocrinology and Diabetes, Chelsea and Westminster Hospital,

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London, UK

Correspondence: Symeon Tournis, MD, PhD, Laboratory for Research of the Musculoskeletal System ‘Th. Garofalidis’, KAT Hospital, University of Athens, 10 Athinas Str., Kifissia, PC: 14561 Athens, Greece. Tel: +302108018123, Fax:

Abstract: 219

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Tables:1

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Word count: 4979

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+302108018122, E-mail: [email protected]

Figures: 3

References: 112

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ACCEPTED MANUSCRIPT Abstract Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from

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defects associated with type 1 collagen. 85-90% of cases are inherited in an autosomal

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dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade,

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defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic

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clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) is the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI

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concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include

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denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-β inhibition. Gene targeting approaches are under

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evaluation. More research is needed to delineate the best therapeutic approach in this

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heterogeneous disease.

Keywords: collagen, bone fragility, bisphosphonates, blue sclerae, atypical fracture, zebra sign

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Abbreviation list:

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OI: osteogenesis imperfecta

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COL1A1: a1 chain of type 1 collagen COL1A2: a2 chain of type 1 collagen

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CNS: central nervous system aBMD: areal bone mineral density

BPs: bisphosphonates

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LS: lumbar spine

RANKL: receptor activator of the nuclear factor kappa-B ligand TGF: transforming growth factor

VF: vertebral fractures

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25(OH)D: 25 hydroxy vitamin D

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NVF: non-vertebral fractures

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APR: acute phase reaction

GFR: glomerular filtration rate

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ONJ: osteonecrosis of the jaw AFF: atypical femoral fractures P1NP: amino pro-peptide of type 1 collagen CTX: type 1 cross-linked C-telopeptide IU: international units WBV: whole body vibration

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ACCEPTED MANUSCRIPT 1. Introduction The term osteogenesis imperfecta (OI) was originally used to describe a group of connective tissue disorders characterized by bone fragility beginning from early

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childhood. It is considered a rare metabolic bone disorder estimated to affect about

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1/13,500-15,000 births [1,2]. The less severe forms, recognized later in life are not included in these estimations. Most of the patients present with the milder form of the

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disease [3]. The widely used and to a point, still valid, Silence classification [4] served clinicians and investigators for many years; it was based on the clinical phenotype, with type I being the less severe, type II lethal perinatally or shortly after

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birth, type III the most severe surviving form of OI leading to extreme morbidity, disability and mortality and type IV of intermediate severity. In the modern era of advanced genetic studies, the term osteogenesis imperfecta is used as an umbrella to include various quantitative and qualitative defects of type 1 collagen and noncollagenous matrix proteins, leading to decreased production and / or defective

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processing of type 1 collagen, eventually leading to impaired bone strength [5-7]. The number of involved genes is rapidly growing and includes not only COL1A1 and 2,

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but also a battery of genes encoding proteins involved in the proper folding of the triple helix of collagen. On clinical grounds, the diagnosis of OI is suspected in cases

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of bone fragility beginning in childhood associated with bone deformity [5]. There are several extra-skeletal manifestations such as bleu/gray sclera, dentinogenesis

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imperfecta, joint hypermobility, abnormal callus formation (type V), hearing impairment, cardiovascular and CNS complications, that need to be screened and managed. Given the inability to cure this chronic disease, it is of outmost importance to define the treatment goals at each age group, in order to prevent or ameliorate complications and prevent adverse effects associated with long-term drug treatment. Management is better served at referral centers, with a high degree of expertise in metabolic bone diseases. In the current narrative review, we will present contemporary data about the aetiology, clinical features, classification and management options for patients suffering from osteogenesis imperfecta. 2. Pathophysiology-genetics 2.1 Collagen synthesis 4

ACCEPTED MANUSCRIPT Type 1 collagen is the most abundant type of collagen in the bone matrix. It is composed by two a1 chains (encoded by COL1A1 gene) and one a2 chain (encoded by COL1A2 gene). It is initially produced in the endoplasmic reticulum (ER) as a

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precursor molecule, type 1 procollagen, which undergoes significant modifications.

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The procollagen chains are mostly modified immediately post-translation and before forming the trimeric chain and these changes are important to allow for proper fibril formation. A number of different proteins and genes are implicated in this process,

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and relevant genetic defects have been shown to cause an OI phenotype.

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2.2 Genetics

Around 90% of OI cases are caused by autosomal dominant mutations in the COL1A1 or COL1A2 genes. These genetic defects either reduce the amount of type 1 collagen (quantitative defects) and present with a milder phenotype, or affect its structure (qualitative defects) and present with a more severe phenotype. The rest of

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the cases are caused by genetic defects in genes involved in the post-translational modification and intracellular trafficking of type 1 collagen or genes associated with

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osteoblasts differentiation and function. Those generally result in a moderate to severe phenotype. Figure 1 depicts the formation of type 1 collagen and stages where several

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genes involved in the pathogenesis of OI are implicated. Haploinsufficiency of COL1A1 (quantitative defect) results in the mildest form of OI,

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while haploinsufficiency of COL1A2 results in normal phenotype. Homozygous null mutations of COL1A2 result in phenotypes of varying severity. The most frequent cause of OI resulting in a qualitative defect is induced by substitutions of glycine by different amino acids (each one resulting in different phenotype) in the helical domain of type 1 collagen. This disrupts the formation of the triple helix. Such mutations, when involving the a1 chains are associated with more severe phenotypes, whereas mutations in the a2 chains tend to be less severe [6]. Several genes that do not encode collagen have been implicated in the pathogenesis of OI. Recessive forms of OI have been described with mutations in genes involved in collagen processing, post-translational modification and crosslinking of type 1 collagen as well as in genes involved in osteoblast differentiation and function. Mutations in several genes including LEPRE1 [8], CRTAP [9,10], PPIB [11], BMP1 [12,13], SERPINH1, [14] SEC24D [15,16], CREB3L1 [17], PLOD2 [18,19], 5

ACCEPTED MANUSCRIPT FKBP10 [20-22], SERPINF1 [23,24], SP7 [25], WNT1 [26,27], TMEM38B [28,29] and IFITM5 [30,31] have all been described in OI. Autosomal dominant mutations of IFITM5 are responsible for a distinctive form of OI, type 5, with hypertrophic callus

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formation and calcification of the interosseous membranes. Details about these genes’

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products and function are summarized in table 1. Clinical presentation and classification

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3.1 Clinical Presentation

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The clinical spectrum of the disease is broad, ranging from the severe form which is lethal perinatally to a mild phenotype diagnosed later in life. The hallmark of the disease is bone fragility (brittle bones) with skeletal deformities and growth retardation but other features involving other tissues might also be prevalent. The severe forms can present as stillbirth or with several fractures and deformities soon after birth. In the mildest forms, fractures tend to decrease in number during

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adulthood but they can re-emerge postpartum or in menopause. Bone fragility in OI is complex and not entirely understood. Patients with OI tend to have low areal bone

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mineral density (aBMD), associated both with lower bone size and lower volumetric BMD [32]. Histomorphometry studies have indicated low cortical width and

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trabecular bone volume, which is the result of both lower trabecular number and trabecular thickness [33]. Increased cortical porosity has also been implicated [34].

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Bones in OI, however, appear hypermineralized with smaller but more abundant mineral crystals and this is associated with lower mechanical strength [35]. Skeletal deformities include bowing of long bones, kyphoscoliosis, acetabular protrusion and chest wall deformities such as pectus excavatum or carinatum, barrel chest [6]. Fractures involve vertebrae, ribs and upper and lower extremities and their rates vary significantly from less than one to several per year depending on the severity of the disease. Vertebral fractures are extremely common (figure 2), resulting in platyspondyly in the most severe cases, however, they can be present even in the mildest forms of the disease in up to 71% of cases [36]. Rib fractures are common in the most severe forms contributing to chest wall abnormalities. Long bone fractures are present in all types with varying rates. In children with the mildest forms an annual rate of 0.62 for long bone fractures has been reported and in most of the cases these involve the tibia or fibula [36]. The prevalence of fractures typically decreases 6

ACCEPTED MANUSCRIPT after adolescence in the mildest forms but can re-increase in postmenopausal women [37]. The presence of blue/gray sclerae is not uniform and might differ among patients even

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within the same kindred. It is a characteristic of OI type I, the mildest form, and the

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colour of the sclerae can either stay stable over the years or might become less dark over time [38]. Within the group of patients with blue sclerae, there is no correlation

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between the shade of blue and the presence of fractures, deformities or hearing impairment [38].

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Teeth are commonly involved in OI. Dentinogenesis imperfecta is a genetic disorder in the formation of dentin and can be seen ether in the context of OI or can be isolated. The teeth exhibit discoloration and translucency and can be worn off prematurely. The roots are short and constricted and dentine is hypertrophic with complete destruction of the pulp. The phenotype can vary even within the same

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patient, with some teeth appearing normal and others being overtly affected [39]. There is no association between the discoloration and the type of OI or the

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histological examination and the type of OI and both the deciduous and permanent teeth can be affected event though the former tend to be affected more frequently

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[40]. Notably, more than 80% of patients with OI can present with involvement of their primary dentition [41].

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Hearing impairment is quite common in OI, with a prevalence ranging from 39% to 57.9% in audiometric studies [42,43]. Its prevalence increases with age, it usually presents between the second and fourth decade of life, it is progressive and is usually of mixed type, even though conductive hearing loss is more common in younger patients [44]. Interestingly, self-reported hearing impairment is far less common [42], while there is no clear association with other clinical features and there is significant variability within families [44]. This calls for regular audiometric evaluation in all patients with OI, which should start in childhood as a small proportion of patients will develop hearing impairment early. Joint hypermobility is also a common feature and can be found in up to 66%-70% of patients with OI [45,46]. It can be present in all types of OI irrespective of the severity of the phenotype [46]. Moreover, up to 56% of patients report a history of joint dislocation and up to 39% a history of tendon rupture [45]. Joint hypermobility, 7

ACCEPTED MANUSCRIPT however, can decrease over time along with the joints’ range of motion and this is thought to be the effect of progressive stiffening associated with aging or with the mechanical effects of skeletal deformities and fractures [47].

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Involvement of the craniocervical junction in OI is a serious complication with

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potentially life-threatening implications. The deformity can be divided into 3 different subtypes, which are radiologically distinct: basilar invagination, basilar impression

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and platybasia. 22%-37% of OI patients, depending on population and thresholds used for diagnosis, present a form of craniofacial junction anomaly and the most common is platybasia, which is, however, usually asymptomatic [48,49]. The prevalence is

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higher in the more severe forms of OI [48,49]. Basilar invagination and basilar impression can present at any age after 2 years and platybasia from birth, but deformities can also occur during follow-up [49]. The presence of dentinogenesis imperfecta, lower height Z-score and lower lumbar spine (LS) aBMD are predictors for skull base anomalies, however, there is no correlation with age, gender, sclerae

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hue or history of bisphosphonates use [48]. It has been suggested that bisphosphonates may slow its development [50], but data are extremely limited and

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based on retrospective studies subject to bias. Relevant neurological symptoms are headaches on movement, coughing or sneezing, trigeminal neuralgia, imbalance, legs

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or arms weakness, and clinical signs can precede symptoms, while hydrocephalus can also occur, albeit rarely [51]. Guidance on screening and follow-up varies, from

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assessment at age 5 and then every 2-3 years onwards [51], to baseline evaluation before school age and then adjustment of follow-up based on the initial evaluation [49].

Young patients with OI type I have lower muscle mass and lower muscle strength compared to matched controls [52]. Total muscle strength is even lower in the more severe phenotypes and is generally strongly associated with the level of ambulation [47,53]. The combination of fractures, deformities and low muscle strength leads to significant functional impairment with reduced ambulation [53]. Cardiovascular disease is more common in patients with OI, presenting mostly as valvular disease, atrial fibrillation and heart failure [54]. The higher prevalence of valvular disease seems to be consistent among the studies and more severe OI phenotypes confer a higher risk for cardiovascular abnormalities [55]. Notably, type 1 8

ACCEPTED MANUSCRIPT collagen is abundant in the cardiovascular connective tissue in the heart valves, aortic wall and the heart chambers. OI affects mortality even in its milder forms. Patients with a more severe phenotype

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(excluding patients with the perinatally lethal form) have a very low life expectancy

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with a mean age of death at 6.2 years [56]. When the less severe forms are included, the median age of survival is 72.4 years for males and 77.4 years for females and is

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significantly reduced comparing to the general population [57]. The most common cause of death is respiratory tract infections [56,57]. Those are exacerbated by the presence of skeletal deformities such as severe scoliosis and chest wall deformities.

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Other causes are gastrointestinal diseases and trauma [57]. 3.2 Classification

The initial classification by Sillence in 1979 was based on clinical presentation and pattern of inheritance defining 4 distinct types [4]; type I, or the non-deforming type,

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autosomal dominant with mild presentation and blue sclerae, type II, the most severe form which is lethal perinatally and with autosomal recessive inheritance, type III, a

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severe form with progressive deformity and autosomal recessive inheritance pattern and type IV with moderate severity, normal sclerae and autosomal dominant

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inheritance pattern.

The recent evolution in genetics initially called for a classification based on the

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specific genetic defect responsible for the disease, with new mutations being discovered constantly. This, however, would cause confusion and inability to correlate a specific genetic defect with the clinical presentation and severity as there is significant overlap. Thus, on the 2015 revision for the classification of genetic skeletal disorders [58], the authors, acknowledging the genetic complexity of OI and the broad phenotypic variation arising from a single loci mutation, suggested that the initial clinical classification by Sillence should be preserved for the classification of the severity of the disease, as it is freed from any direct molecular association. Types are now characterized by arabic rather than latin numerals, but types 1-4 correlate to the previous I-IV classification by Sillence. Type 5 was added as it has distinct radiographical features from all the other types. Table 1 illustrates this new classification along with the several genetic alterations associated with each clinical phenotype. 9

ACCEPTED MANUSCRIPT 3. Management 4.1 General principles

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Treatment goals in patients with OI include reduction of fracture incidence,

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management of bone pain, improvement of mobility, growth and independent leaving, detection and management of extraskeletal manifestations, and avoidance of short and long-term adverse effects of drug treatment. Measures to improve bone health include

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nutrition, physical activity, and treatment of the underlying condition and associated comorbidities. Currently bisphosphonates (BPs) represent the main pharmacological

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intervention in both paediatric and adult patients with OI. There are also preclinical and a small number of clinical studies in adult patients with OI concerning denosumab, a monoclonal antibody targeting RANKL. Regarding anabolic therapy, teriparatide, currently the only available anabolic agent, has shown promising results in adult patients with OI type I. Finally, preclinical studies indicate that inhibition of

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TGF-beta signaling and also sclerostin inhibition might have a role in the management of bone fragility in OI. Apart from pharmacological interventions, a

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multidisciplinary approach that includes experienced orthopedic surgeons, specialists in pediatric dental care, physiotherapists and occupational therapists is of outmost

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importance for delivering the best of care.

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4.2 Calcium and vitamin D Although adequate calcium intake and vitamin D are considered of major importance in patients with metabolic bone disease, there are limited data from randomized trials about the optimal dose and target levels for both calcium and vitamin D in patients with OI. Cross-sectional studies indicate that 25(OH)D levels are positively associated with LS aBMD in patients with OI [59], while combined calcium and vitamin D supplementation is associated with fracture prevention in adults with osteoporosis [60]. Moreover, it is accepted that BPs might be less effective or even result in adverse effects in cases of inadequate calcium intake and or vitamin D deficiency [61,62]. A recent randomized trial in children and adolescents with OI tested two daily doses of vitamin D3 (400 IU vs. 2000 IU) for one year, with LS aBMD z-score as an endpoint [63]. Although the high dose vitamin D group attained higher levels of 25(OH)D, there were no significant between group differences in

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ACCEPTED MANUSCRIPT terms of BMD. However, subgroup analysis indicated that in patients with 25(OH)D levels below 20 ng/ml, high dose vitamin D was associated with marginally better BMD response. Thus, it seems that, at least in short term, patients with low 25(OH)D

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levels might benefit from higher doses. In general, guidelines advocate that daily

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calcium and vitamin D intake up to 1300 mg and 600-800IU per day respectively is sufficient, at least in most cases. Given the significant inter-individual variability in attained 25(OH)D levels following vitamin D supplementation, the safety of the

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higher doses (up to 2000IU or more), the possible positive effects in muscle function and the limited data in OI, it is sensible to target for 25(OH) D levels up to 30 ng/ml

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using higher doses on a case by case basis. 4.3 Physical activity

Resistance exercise has an anabolic effect on the skeleton, especially in the prepubertal period [64]. However, the effect and the safety of exercise programs in

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patients with OI, children or adults, with varying degrees of disability, has not been tested. Modified exercise programs, minimizing risk of falls and preferring no contact

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or limited contact sports rather than collision or contact ones should be encouraged. In cases of physical impairment, individualized training programs, including whole body

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vibration training, concomitant physiotherapy, resistance training and treadmill training have been shown to improve motor function and BMD [64,65]. However, a recent short-term randomized controlled pilot trial in 24 children with OI type 1 and 4

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reported no effect of whole body vibration (WBV) training on bone density, geometry, muscle function, mobility and balance, although total lean mass increased more in the intervention group. These results indicate reduced biomechanical responsiveness of the bone-muscle unit in patients with OI and cast doubt on the effectiveness of WBV training in children with OI [66]. 4.4 Bone specific agents 4.4.1 Indications for treatment Indications for treatment in patients with OI depend on the clinical phenotype and the growth potential, given that there are no data from “primary prevention” controlled trials suggesting that mild OI cases would benefit from treatment with BPs. Generally, in childhood osteoporosis the presence of either vertebral fractures (VF), independent 11

ACCEPTED MANUSCRIPT of LS BMD z-score, or at least 2 or 3 low trauma long bone fractures by the age of 10yrs or 18yrs, respectively and LS BMD z-score ≤ -2, especially in cases with heritable forms, might be considered as indications for therapy [64]. In clinical

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practice experts advocate therapy in moderate and severe cases of OI. Mild cases of

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OI are followed up to screen for complications that would prompt treatment [5]. Concerning adults with OI, most experts would agree that fragility fractures (either VF or long bone fractures) represent an absolute indication for intervention. We also

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suggest that a BMD T-score ≤-2.5 in postmenopausal women or males over 50 years

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might be considered as a relative indication for treatment.

4.4.2 Bisphosphonates

BPs are the most widely used drugs for the management of postmenopausal, male and glucocorticoid-induced osteoporosis. BPs’ bind to hydroxyapatite, are taken up by

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osteoclasts where they exert their antiresorptive action. BPs decrease bone remodeling, increase mineralization and increase BMD. Several randomized

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controlled trials established their antifracture efficacy at all sites, at least concerning the most widely used alendronate, risedronate and zoledronic acid. Oral BPs have

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extremely low bioavailability and only about 1% of the administered oral dose is absorbed by the gastrointestinal tract. Due to their prolonged “burial” to bones, BPs

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have a terminal half-life up to ten years [67]. BPs have been extensively used in children with OI. Both oral (alendronate, risedronate) and intravenous BPs (pamidronate, zoledronate, neridronate) improve aBMD almost at all sites, especially at the spine. However, data from randomized placebo controlled trials concerning antifracture efficacy, pain relief and mobility are still lacking and are unlikely to be acquired. Indeed, recent reviews concerning the effect of BPs in patients OI did not find consistent reduction in fracture rate and improvement of clinical status [68-70]. These data highlight the heterogeneity of the disease, and the fact that existing trials are of short duration and underpowered for these endpoints. Decision to start and continue treatment is based on the presence of vertebral compression fractures and/or long bone fractures, the growth potential, while adjustments of the dose or infusion intervals of iv zoledronate, the most widely used, 12

ACCEPTED MANUSCRIPT due to its higher efficacy and ease of administration as compared to pamidronate, are mainly guided by the clinical response and the LS aBMD z-score. The most commonly used dose of zoledronate is 0.1 mg/kg, divided in two yearly infusions,

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apart from the first dose (0.0125 mg/kg), which for safety reasons, is much lower. If

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the patient is still growing and hasn’t reached a z-score > -2.0, the same therapeutic regimen is followed. If the patient has reached a z-score > -2.0, then the dose is reduced to half, until completion of growth. If the z-score is >0.0 and the patient is

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still growing then the infusion is given on a yearly basis [5]. The reason for continued treatment until completion of growth lies on the fact that interruption of treatment

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results in areas of reduced aBMD adjacent to previously treated areas of higher BMD at the metaphysis, creating stress risers and leading to increased fracture incidence at these sites [71,72]. Furthermore, vertebral body reshaping depends on the growth potential and this is clearly facilitated by iv BP therapy (zoledronate and pamidronate) [73,74], an effect that is not seen with oral BPs [75,76]. Concerning scoliosis, most

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studies indicate that BPs might slow the progression of scoliosis, assessed by Cobb angle changes, only in severe cases, but unfortunately the prevalence of scoliosis at

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maturity was independent of BP exposure or age of starting treatment in cases with OI type I or IV [77]. Regarding non-vertebral fractures (NVF), most studies reported a

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favorable but nonsignificant effect, with the exception of a single study by Bishop et al in OI using risedronate for one year in which a significant benefit was observed [75]. This fact is in accordance with the general modest effect of most antiresorptive

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therapies in NVF risk reduction and highlights the inability of current therapies to correct the altered bone geometry, the material defects and preexisting deformities. Concerning the effect of BPs in adults with OI there are limited data from case series or non-randomized trials that tested the effect of various BPs on aBMD. All studies were underpowered for fracture reduction. Almost all studies reported beneficial effect on LS aBMD (increase up to 13.9%), with less marked effects at the total hip (increase up to 4.3%) [78]. 4.4.2.1 Adverse effects of BPs One of the most common short-term adverse effect of BPs is the “acute phase reaction” (APR), that comprises of fever, back and bone pain, malaise, nausea and vomiting, that usually begins within 24h following the first dose and does not usually 13

ACCEPTED MANUSCRIPT recur in subsequent administration [5,64]. Hypocalcemia may occur following iv BPs, but can be prevented by ensuring adequate 25(OH)D levels prior to infusion and calcium supplementation for at least a week after the infusion. Some authors support

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calcitriol administration (0.05 mcg/kg/day) the night prior to infusion [79]. A recent

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retrospective study addressing adverse events following zoledronate infusion in children and adolescence with various metabolic bone diseases reported that hypophosphatemia was the most common side effect (25.2%), followed by APR

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(19.1) and hypocalcemia (16.4%) [79]. One subject with concomitant seizure disorder experienced seizures, an event that is also reported in adults. Renal impairment

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(estimated GFR < 35 ml/min) is an absolute contraindication for BPs use. Care must be taken for correct evaluation of renal function in cases where serum creatinine is not a reliable marker (e.g. low muscle mass) [5,64]. Concerning osteonecrosis of the jaw (ONJ), a recent review of 5 studies in children and adolescents with OI (n=439) who received iv BPs (mean duration of BPs use: 4.6-6.8 yrs) and had regular dental

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examinations did not identify any case of ONJ [80]. Moreover, a recent study [81] that assessed dental development (developmental stage of the permanent teeth,

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resorption of the deciduous teeth, and number of the erupted permanent teeth) in children with OI reported that children treated with BPs displayed age-appropriate

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dental development, while OI per se was associated with accelerated dental development as assessed in BPs-naïve cases. However, it is sensible to complete any invasive dental interventions prior to BPs administration whenever this is possible

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[82]. Regarding the process of fracture healing, in general BPs do not seem to have a significant adverse effect [83]. However, a recent study reported significant delay in osteotomy healing following corrective surgery [84]. Delaying BPs infusion for 4 months following osteotomy and using an osteotome instead of a power saw, resulted in significant reduction in the incidence of delayed healing. The most feared complication of long term BPs treatment is atypical femoral fractures (AFF) [85]. In the last five years, a number of case reports of AFF in adult patients with OI treated with BPs have been published [86-89]. Following these reports Hegazy A [90], et al reported six cases of subtrochanteric fractures with features of AFF in children with OI over preexisting intramedullary rods treated with pamidronate; Vasanwala RF et al [91] reported one case of recurrent bilateral proximal femur fracture fulfilling the criteria of AFFs in a teenager with OI type IV on continuous pamidronate therapy. A recent detailed retrospective analysis by 14

ACCEPTED MANUSCRIPT Vuorimies I et al [92] of 127 femoral fractures in 24 children with OI (11 type I, 6 type II, 7 type IV) did not find any association with either BP exposure (naïve vs. ongoing vs. previous) nor with BP cumulative dose. Rather the authors concluded that

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the most severe types of OI (III and IV) were associated with distal location and

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transverse configuration of the femoral fractures. Although the pathogenesis of AFF and the connection with BP exposure is still debated, bone material [93] and geometrical properties in OI in conjunction with the known effects of BP justify

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concern about the benefit of continuing high dose BPs therapy in teenagers with OI. Clearly, more research is needed to clarify whether BP related AFF is an issue in

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children with OI as well as the optimal treatment regimens. 4.4.3 Denosumab

Denosumab, a monoclonal antibody targeting RANKL, is approved in the dose of 60 mg subcutaneously (sbc) every six months for the treatment of postmenopausal

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osteoporosis and male osteoporosis. A number of studies evaluated the effect of denosumab in patients with OI caused by a mutation in SERPINF1 [94,95],

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characterized by a poor response to BSP and in patients with OI I/IV (n=8) and OI III (n=2) [96]. The dose used was 1 mg/kg sbc every 3 months. All studies reported

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significant increase in aBMD and no significant adverse effects of treatment in a twoyear period. All cases were pretreated with BPs, thus the rebound increase in bone remodeling was not reported. Given that BPs naïve patients might suffer multiple

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vertebral fractures following denosumab discontinuation, care must be taken to prevent this rare complication [97]. 4.4.4 Anabolic therapy Teriparatide is currently the only approved anabolic therapy for the management of postmenopausal, male and glucocorticoid induced osteoporosis. Teriparatide increases bone remodeling, bone formation over resorption, and reduces vertebral and nonvertebral fracture risk. Its use is contraindicated in subjects with open epiphysis. An open label study in 13 postmenopausal women with OI type 1, previously treated with neridronate, reported significant increase in LS BMD following teriparatide treatment for 18 months [98]. A recent randomized placebo-controlled trial in 78 adults with OI reported significant increase in aBMD and vertebral vBMD and strength with

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ACCEPTED MANUSCRIPT teriparatide for 18 months in Type I cases, while there was no beneficial effect in the severe type III/IV cases [99]. Sclerostin inhibition might be another option in the management of bone fragility in

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OI. The recently published FRAME study showed that administration of

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romosozumab (a monoclonal antibody that binds sclerostin), for one year, reduced the incidence of vertebral and clinical osteoporotic fractures in postmenopausal women

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with osteoporosis [100]. Studies in mouse models with OI reported promising results in mild forms [101-106]. A recent randomized phase 2a trial [107] evaluated the effect of BPS804, a neutralizing, anti-sclerostin, fully human IgG2λ monoclonal

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antibody in 14 adults with OI (BPS804 n=9, controls n=5). The authors reported significant increase in markers of bone formation (P1NP 84%) and decrease in markers of bone resorption (CTX 44%) at 43 days following three iv escalating doses of BPS804, while LS aBMD increased significantly by 4% at day 141. These encouraging results should prompt for a large phase 3 clinical trial, however, Novartis

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has stopped the development of BPS804 [108].

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4.4.5 Other Potential therapies

In mouse models with OI, increased TGF-β signaling has been shown to be

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implicated in OI phenotype, while inhibiting TGF-β improved bone mass and strength. A phase 1 study will test the safety of fresolimumab, a high-affinity

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neutralizing antibody that targets all 3 TGF-β isoforms, in adults with moderate-tosevere OI [109]. Combination therapy with antiresorptive and anabolic agents is another potential option for the management of bone fragility in patients with OI [110]. Studies in postmenopausal women have shown favorable results in terms of BMD with the combination of teriparatide with zolendronate [111] or denosumab [112]. Other interventions such as bone-marrow transplantation and gene therapy are under evaluation for the management of the severe forms of OI [110]. 4. Conclusion Existing therapeutic interventions in OI, as in several inherited bone diseases, are not curative. Current treatment with BPs improves aBMD, facilitates vertebral reshaping, reduces fractures and improves mobility and independent leaving. However, longterm BPs therapy did not result in substantial reduction of long bone fracture 16

ACCEPTED MANUSCRIPT incidence, while there are issues regarding long-term safety at all age groups. Other available antiresorptive therapies share the same issues, while current anabolic therapies or combination therapies are reserved only for adults and for a limited time

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frame. Although in recent years there has been substantial progress in the

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understanding of the pathophysiology of OI, current pharmacological interventions do not really improve the fundamental defect of OI, namely abnormal type 1 collagen production or processing. More research is need to delineate the best therapeutic

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approach in this heterogenous disease and to develop gene targeting approaches for

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the severe forms [5,91,109].

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Declaration of interest: S. Tournis and A.D. Dede declare they have no conflicts of interest

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ACCEPTED MANUSCRIPT Figure legends Figure 1. Production of type 1 collagen and sites where several genes implicated in the pathogenesis of OI are involved.

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A1 and a2 chains are encoded by COL1A1 and COL1A2 respectively. The three chains start folding from the carboxyterminal site to form a heterotrimer. Several mutations in the COL1A1 and COL1A2 (most commonly substitutions of glycine with other amino acids) interfere with the ability of the chains to properly fold into a trimer. Cartilage-associated protein, prolyl 3-hydroxylase 1 and cyclophilin B form a complex that hydroxylates proline in a1 and a2 chains, a step crucial for proper folding. Heat shock protein 47 (encoded by SERPINH1) binds to the triple helix, contributing to its stabilization and transfer to Golgi apparatus. The triple helix (procollagen) is secreted in the extracellular matrix where C and N-propeptides are cleaved by specific proteases. After this process, the helices assemble into fibrils, which are stabilized by crosslinking. Fibrils then assemble further to form collagen fibers. Proper crosslinking is important for normal mineralization.

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ER: endoplasmic reticulum, C: carboxyterminal, N: aminoterminal, OH: hydroxylation

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Figure 2. Multiple vertebral fractures in a 6-year old female patient with OI type 3.

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At presentation, the patient had blue sclerae and severe dentinogenesis imperfecta. There was a history of fractures perinatally. She is treated with zoledronic acid infusions every 6 months. (Courtesy of Dr Artemis Doulgeraki)

Figure 3. Zebra stripe sign. Multiple zebra lines in a 14-year old female patient with OI type 1. The patient received zoledronic acid infusions every 6 months for 5 years and has discontinued. Zebra lines are common in children with OI and they are the effect of cyclical administration of bisphosphonates before epiphyseal closure. Each sclerotic band corresponds to an infusion cycle. (Courtesy of Dr Artemis Doulgeraki)

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ACCEPTED MANUSCRIPT A single recurrent mutation in the 50-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet 91:343–348

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[89] Manolopoulos KN, West A, Gittoes N. The paradox of preventionbilateral atypical subtrochanteric fractures due to bisphosphonates in osteogenesis imperfecta. J Clin Endocrinol Metab. 2013 Mar;98(3):871-2.

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[91] Vasanwala RF, Sanghrajka A, Bishop NJ, Högler W. Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating? J Bone Miner Res. 2016 31(7):144954.

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[92] Vuorimies I, Mäyränpää MK, Valta H, Kröger H, Toiviainen-Salo S, Mäkitie O. Bisphosphonate Treatment and the Characteristics of Femoral Fractures in Children with Osteogenesis Imperfecta. J Clin Endocrinol Metab. 2017; in press. doi: 10.1210/jc.2016-3745.

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[93] Bishop N. Bone Material Properties in Osteogenesis Imperfecta. J Bone Mineral Research, 2016;31: 699–708

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[94] Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E (2012) First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact 12:183–188 [95] Hoyer-Kuhn H, Netzer C, Koerber F, Schoenau E, Semler O (2014) Two years’ experience with denosumab for children with osteogenesis imperfecta type VI. Orphanet J Rare Dis 9:145 [96] Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, Hero B, Schoenau E, Semler O (2016) Safety and efficacy of denosumab in children with osteogenesis imperfecta—a first prospective trial. J Musculoskelet Neuronal Interact 16:24–32. [97] Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases. J Bone Miner Res. 2017 doi: 10.1002/jbmr.3110.

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ACCEPTED MANUSCRIPT [98] Gatti D, Rossini M, Viapiana O, Povino MR, Liuzza S, Fracassi E, Idolazzi L, Adami S. Teriparatide treatment in adult patients with osteogenesis imperfecta type I. Calcif Tissue Int. 2013; 93(5):448-52.

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[100] Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, Hofbauer LC, Lau E, Lewiecki EM, Miyauchi A, Zerbini CA, Milmont CE, Chen L, Maddox J, Meisner PD, Libanati C, Grauer A. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016 Oct 20;375(16):1532-1543. Epub 2016 Sep 18. [101] Sinder BP, Eddy MM, Ominsky MS, Caird MS, Marini JC, Kozloff KM. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta.J Bone Miner Res. 2013 Jan;28(1):73-80.

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[102] Jacobsen CM, Barber LA, Ayturk UM, Roberts HJ, Deal LE, Schwartz MA, Weis M, Eyre D, Zurakowski D, Robling AG, Warman ML.Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J Bone Miner Res. 2014 Oct;29(10):2297-306

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ACCEPTED MANUSCRIPT [108] Makras P, Delaroudis S, Anastasilakis AD. Novel therapies for osteoporosis. Metabolism. 2015 Oct;64(10):1199-214. doi: 10.1016/j.metabol.2015.07.011.

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Figure 1

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Figure 2

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Figure 3

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ACCEPTED MANUSCRIPT Table 1. Classification of OI LOCUS OR GENE COL1A1

Type 1

AD COL1A2 COL1A1 COL1A2

Type 2

AD, AR

CRTAP

a1 chain of type 1 collagen a2 chain of type 1 collagen a1 chain of type 1 collagen a2 chain of type 1 collagen cartilageassociated protein prolyl 3hydroxylase 1 cyclophilin B a1 chain of type 1 collagen a2 chain of type 1 collagen cartilageassociated protein prolyl 3hydroxylase 1 cyclophilin B

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Perinatal lethal form

PROTEIN FUNCTION

PROTEIN

T

PATTERN OF INHERITANCE

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Nondeforming form

TYPE

SC

NAME

LEPRE1 PPIB

COL1A1

AC

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ED

COL1A2

Progressively deforming form

Type 3

AD, AR

CRTAP LEPRE1 PPIB SERPINH1

heat-shock protein 47

BMP1

bone morphogenetic protein 1

FKBP10 PLOD2 SERPINF1

peptidyl prolyl isomerase FKBP65 lysyl hydroxylase 2 pigment epitheliumderived factor

SP7

osterix

WNT1

wingless family member 1

TMEM38B

trimeric intracellular

Hydroxylation of proline in the a1 and a2 chains

Hydroxylation of proline in the a1 and a2 chains Assembly and stability of the triple helix of collagen Cleavage of the collagen Cterminal domain of procollagen Crosslinking of collagen chains

Bone mineralization Osteoblast differentiation Osteoblast differentiation and function Intracellular calcium release 33

ACCEPTED MANUSCRIPT cation channel subtype B cAMP response element-binding protein 3-like 1

SEC24D

proteincomponent of the COPII complex

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a1 chain of type 1 collagen

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COL1A1

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CREB3L1

Regulation of the expression of COL1A1 Regulation of the secretion of matrix proteins Export of procollagen from the endoplasmic reticulum

COL1A2

Type 4

AD, AR

AC

CE

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Moderate form

ED

CRTAP PPIB

FKBP10

SERPINF1

a2 chain of type 1 collagen cartilageassociated protein cyclophilin B peptidyl prolyl isomerase FKBP65 pigment epitheliumderived factor

WNT1

wingless family member 1

SP7

osterix

Hydroxylation of proline in the a1 and a2 chains Crosslinking of collagen chains Bone mineralization Osteoblast differentiation and function Osteoblast differentiation

With calcification of the interosseous Type bone-restricted Bone AD IFITM5 membranes 5 ifitm-like protein mineralization and/or hypertrophic callus OI: osteogenesis imperfecta, AD: autosomal dominant, AR: autosomal recessive.

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