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Osteogenesis imperfecta: diagnosis and treatment Telma Palomo a, Tatiane Vilac¸a a,b, and Marise Lazaretti-Castro a
Purpose of review Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. Recent findings Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. Summary Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice. Keywords bisphosphonate, bone fragility, collagen, fragility fractures, osteogenesis imperfecta
INTRODUCTION Osteogenesis imperfecta, also known as brittle bone disease, is a heritable disorder of the extracellular matrix [1 ]. This disorder manifests mainly as bone fragility, although other organs can be involved. Abnormalities of the teeth, known as dentinogenesis imperfecta, and soft tissues, such as discoloration of the sclera and joint hyperlaxity are often observed [2 ]. The new gene discoveries in the past years have contributed to better explanation of the pathophysiology of osteogenesis imperfecta, providing opportunities for the development of new therapies. In this review, we will outline the clinical and molecular diagnosis of osteogenesis imperfecta, mention the novel causative genes and review the treatment options. &
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EPIDEMIOLOGY AND PATHOPHYSIOLOGY Osteogenesis imperfecta affects approximately 1 in 10 000 to 20 000 births [3]. It is a genetically heterogeneous skeletal dysplasia with higher mortality than general population. In a recent cohort, people with osteogenesis imperfecta had higher risk of death from respiratory and gastrointestinal diseases
and trauma [4]. In addition to the low-bone mass achieved, patients with osteogenesis imperfecta experience age-associated bone loss, increasing even more the risk of fractures [5]. Women undergo perimenopause loss and the rate of fractures in postmenopausal women with osteogenesis imperfecta is twice as high as that of osteogenesis imperfecta in premenopausal women [6]. The predominant cause of osteogenesis imperfecta are mutations in the two genes that encode type I collagen [2 ,3]. The protein is a heterotrimer, containing two a1(I) and one a2(I) chains [7]. It is synthesised as a procollagen molecule, and undergoes multiple posttranslational modifications. Flanking propeptides are removed by specific proteases, then, the molecule spontaneously assembles &&
a Bone and Mineral Unit, Division of Endocrinology, Universidade Federal de Sa˜o Paulo, Brazil and bAcademic Unit of Bone Metabolism, University of Sheffield, Sheffield, United Kingdom
Correspondence to Telma Palomo, MD, PhD, Universidade Federal de Sa˜o Paulo (UNIFESP), Rua Botucatu 806, Vila Clementino, Sa˜o Paulo, SP, CEP 04023-062 Brazil. Tel: +55 11 55748432; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2017, 24:000–000 DOI:10.1097/MED.0000000000000367
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KEY POINTS Osteogenesis imperfecta is the most prevalent heritable bone fragility disorder in children. COL1A1 and COL1A2 are the most frequent causative mutations, but recently, mutations on 15 other genes have been identified, either with autosomal dominant or autosomal recessive inheritance. Intravenous bisphosphonate is the most used therapy for osteogenesis imperfecta and increases bone mass, has a marked effect on vertebra reshaping in growing children but little effect on the development of scoliosis. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. Novel promising osteogenesis imperfecta treatments in preclinical studies may provide a promising approach to treat patients with osteogenesis imperfecta.
types have been proposed based on genetic findings. The several mutations are listed in the OMIM Database. The new genetic discoveries provided a controversial classification, merging clinic and genetic findings. Each new gene affected, defined a new osteogenesis imperfecta type, beyond the Sillence original 4 types [8 ]. This system was criticised by clinicians and researchers [8 ,13 ]. The Nosology and Classification of Genetic Skeletal Disorders, published in 2015, adopted a phenotypic criterion to classify osteogenesis imperfecta types, limiting to five types (osteogenesis imperfecta types I–V) [2 ,13 ,14]. In our opinion, it is more useful to describe osteogenesis imperfecta types by stating the phenotypic severity and the involved gene, as proposed by Van Dijk et al. [2 ,7]. &&
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GENES ASSOCIATED WITH OSTEOGENESIS IMPERFECTA into fibrils in tissue, and is further stabilised by crosslinks. Mutations that affect the propeptide cleavage sites cause specific variants of osteogenesis imperfecta with unique phenotypes [7,8 ]. &&
CLASSIFICATION Osteogenesis imperfecta is a heterogeneous disease, and the severity ranges from subtle increase in fracture frequency to death in the perinatal period [9,10]. A classification based in the severity of bone fragility, according to clinical/radiological features, was proposed by Sillence et al. in 1979. He suggested four phenotypic categories: osteogenesis imperfecta type I, ‘nondeforming with blue sclera’; osteogenesis imperfecta type II, ‘perinatally lethal osteogenesis imperfecta’; osteogenesis imperfecta type III, ‘progressively deforming osteogenesis imperfecta’; and osteogenesis imperfecta type IV, ‘moderate severe osteogenesis imperfecta’ [9]. Additional osteogenesis imperfecta types (V and higher) were described, based on specific phenotypic characteristics and on the genetic findings. Osteogenesis imperfecta type V is characterised by moderate-to-severe bone fragility, and a calcified interosseous membrane at the forearm that can lead to secondary dislocation of the radial head. Osteogenesis imperfecta type V has an autosomal dominant pattern, and a hyperplastic callus can develop after fractures or surgical interventions [11]. Additional osteogenesis imperfecta types were described, such as osteogenesis imperfecta types VI and VII [10,12]. The discovery of multiple new genes spread out the field of osteogenesis imperfecta, and many additional osteogenesis imperfecta 2
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Almost all individuals with osteogenesis imperfecta type I and close to 80% of patients with moderateto-severe osteogenesis imperfecta types have an autosomal dominant form of osteogenesis imperfecta that is caused by heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2 [2 ]. Mutations can be inherited from an affected parent or arise de novo [15]. Although there is not a straight genotype–phenotype correspondence, mutations’ type and position influence the phenotype and there is a relation to some extent. The most frequent abnormality is a mutation in a glycine residue in one of the two collagen genes [10]. These mutations can be divided in two categories: quantitative defects and mutations that affect type I collagen structure. The first category results in haploinsuficiency of the gene, leading to the production of structurally normal collagen, however, in about half of the normal amount. This is the cause of osteogenesis imperfecta type I. In the second category, the mutations usually replace a glycine by another amino acid resulting in an abnormal collagen molecule [16,17 ]. Recessive mutations in genes that regulate posttranslational type I collagen processing, and genes that modulate osteoblast differentiation or bone mineralization cause about 10% of moderate-tosevere osteogenesis imperfecta cases. Collagen folding, secretion and processing might be affected. These noncollagen mutations usually cause moderate-to-severe osteogenesis imperfecta phenotype but mild phenotype similar to osteogenesis imperfecta type I has been described [2 ,3,18]. Table 1 and Fig. 1 summarises genetic findings and its mechanisms [2 ,8 ,18]. &&
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Osteogenesis imperfecta: diagnosis and treatment Palomo et al. Table 1. Genes and clinical classification of osteogenesis imperfectaa Defective gene
Clinical OI typeb
Inheritance
Defective protein
Protein full name
COL1A1
I, II, III, IV
AD
COL1A1
Collagen type I alpha 1 chain
COL1A2
I, II, III, IV
AD
COL1A2
CRTAP
III, IV
AR
CRTAP
P3H1
III
AR
P3H1
Prolyl-3-hydroxlase 1
PPIB
III
AR
CypB
Cyclophyllin B
FKBP10
III, IV
AR
FKBP65
FK506 binding protein, 65 kDa
SERPINH1
III, IV
AR
HSP47
Heat-shock protein 47
PLOD2
III, IV
AR
LH2
BMP1
I, III, IV
AR
BMP1
Bone morphogenetic protein 1
SPARC
IV
AR
SPARC
Secreted protein, acidic, cysteine-rich
IV
AR
TMEM38B
III, IV
AR
SEC24D
TMEM38B SEC24D
Frequency
Defects in collagen synthesis and structure
85–90% of OI cases
Defects in collagen type I processing
10–15% of OI cases
Collagen type I alpha 2 chain Cartilage-associated protein
Lysyl hydroxylase 2
Transmembrane protein 38B SEC24D
P4HB
III
AR
PDI
Protein disulfide isomerase
IFITM5
V
AD
BRIL
Bone-restricted ifitm-like
III, IV
AR
PEDF
Pigment-epithelium derived factor
WNT1
IV
AR/AD
WNT1
SP7
III
AR
SP7
CREB3L1
II
AR
OASIS
SERPINF1
Mechanism
WNT1
Defects in bone mineralization
Defects in osteoblast development
Osterix; transcription factor Sp7 Old astrocyte specifically induced substance
All data of osteogenesis imperfecta (OI) mutations is from the OI Variant Database (https://oi.gene.le.ac.uk). AD, autosomal dominant pattern; AR, autosomal recessive pattern. && && a Adapted from Trejo et al. [2 ] and Forlino et al. [8 ]. b The 2015 Nosology and Classification of Genetic Skeletal Disorders has been followed.
DIAGNOSIS Osteogenesis imperfecta diagnosis is based on history, clinical examination, lumbar spine bone mineral density (BMD), bone biochemistry and radiographic findings (Fig. 2) [2 ]. The exclusion of metabolic causes of osteoporosis is important at baseline. The single most important clinical feature is bone fragility, that is common to all osteogenesis imperfecta types but other extra-skeletal features might be present. The most common features of each osteogenesis imperfecta type will be described according to the clinical classification proposed by Van Dijk and Sillence [7]. Osteogenesis imperfecta type I is associated with low-bone mass. Fractures are rare at birth, but there is an increase in the rate of long-bone fractures [19]. Blue or grey sclera and an increased risk of precocious hearing loss are common features. Deformities &&
of long bones or spine and dentinogenesis imperfecta are uncommon [7]. In osteogenesis imperfecta type II, the bones are extremely affected. Short and severely deformed long bones, and poor ossification of facial and skull bones are detected in 18–20 weeks’ foetal ultrasounds. Multiple rib fractures are observed in utero and perinatal lethality is almost a rule, with 90% of the affected babies dying by 4 weeks of age [7]. Osteogenesis imperfecta type III is characterised by severe bone fragility and progressive skeletal deformity. Generalised osteopenia and fractures are seen in radiographic studies at birth. Blue sclera and dentinogenesis imperfecta might be present, but the sclera tends to become less blue with ageing. Short stature is a rule and progressive kyphoscoliosis starts in childhood and progresses with growth. Hearing impairment might develop in adulthood [7].
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FIGURE 1. Genes and molecular mechanisms involved in osteogenesis imperfecta. (a) Abnormal structure in collagen a chains because of mutations in COL1A1 or COL1A2. (b) Procollagen posttranslational modification in the endoplasmic reticulum : trimeric complex (P3H1, prolyl-3-hydroxylase 1; CRTAP, cartilage-associated protein and CypB, cyclophillin B) for hydroxylation of the proline residues. (c) FKBP10 and HSP47 stabilize the triple helix and accelerate its folding. Lysyl hydroxylase 2 (LH2) hydroxylates collagen telopeptide lysines. After being secreted, the C-propeptides and N-propeptides are cleaved. BMP1 cleaves the procollagen C-propeptide. Adapted from Forlino et al. [8 ] and Marini et al. [18]. &&
Patients with osteogenesis imperfecta type IV have recurrent fractures and the deformity is variable. Most of them have normal sclera and hearing impairment is rare. Severity is also variable within families, with some individuals presenting mild osteogenesis imperfecta and others with more severe forms in the same family [7]. Finally, osteogenesis imperfecta type V is characterised by progressive calcification of the interosseous membrane and hyperplastic callus, as previously described. The bone fragility is moderate-to-severe and there is no blue sclera or dentinogenesis imperfecta [7]. The diagnosis of osteogenesis imperfecta can be difficult. Some primary skeletal disorders can be mixed up with osteogenesis imperfecta. The exclusion of idiopathic or juvenile osteoporosis might be a challenge [20 ]. Children with mild bone fragility and no extra-skeletal features of osteogenesis imperfecta, and children with fractures at birth may also demand careful assessment. Child abuse is a remarkable cause of fractures, and the highest incidence is &
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in the first year of life [10]. The most common signs are rib fractures, and classic metaphyseal lesions of the femur. The incidence of osteogenesis imperfecta in this context is between 2 and 5% [21]. These uncertain cases may still be caused by mutations in COL1A1 or COL1A2 [22,23]. Although the diagnosis is mainly based in clinical and radiological features, genetic tests may establish the exact cause of the disease and provide helpful information in unclear cases [20 ,24]. Molecular diagnosis also allows information about recurrent risk (dominant versus recessive osteogenesis imperfecta) and the identification of affected family members [2 ]. This could be interesting especially in very mild forms of osteogenesis imperfecta type I, wherever clinical signs can be very subtle. On the other hand, molecular diagnosis has low impact in the evaluation of suspected child abuse and in infants in whom careful examination has not shown clinical characteristics of osteogenesis imperfecta [21,25]. Currently, molecular diagnosis is performed by sequencing the DNA of target gene panels &
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FIGURE 2. Lateral lumbar spine and lower extremities radiographs of three patients with osteogenesis imperfecta type I (milder form), type III (most severe type of osteogenesis imperfecta) and type IV (intermediate in severity between types I and III). (A1 and A2) Spiral right femur healing fracture in a osteogenesis imperfecta type I patient without vertebral fractures. (B1 and B2) Osteogenesis imperfecta type III patient with severe vertebral compression fractures, protrusion of the acetabulum, fracture healing of the right femur and deformities in both femurs and tibias (small diameter and thin cortices). (C1 and C2) Full community ambulator osteogenesis imperfecta type IV patient with several vertebral compression fractures, bilateral femoral bowing and straight tibias. Vertebral fractures are indicated by asterisks.
(‘next-generation sequencing’) [26,27]. The evaluation of this known disease-causing genes identifies mutations in 97% of individuals with a clinical diagnosis of ‘typical osteogenesis imperfecta’ [14].
also to address reduced mobility, long-bone deformities and scoliosis [2 ,28]. In severe forms of osteogenesis imperfecta, intramedullary rodding surgery may be required for straightening bowed femurs and tibias [29 ,30]. Multiple fractures may result in deformities and repeated periods of immobilization, which may compromise the functional status and mobility. In this scenario, a multidisciplinary approach is the best option and physical rehabilitation plays an important role in improving individual’s function and promoting independence [28,30]. For many years, intravenous bisphosphonate therapy has been the most widely used approach to treat bone fragility in children with osteogenesis imperfecta. In a systematic review, all the randomised &&
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TREATMENT The therapeutic approach to osteogenesis imperfecta patients will vary with age, severity of the disease and functional status. Individuals with mild disease may require subtle restrictions, such as avoiding contact sports, and orthopaedic therapy is reserved to the management of fractures [2 ]. Conversely, moderate-to-severe osteogenesis imperfecta patients demand rehabilitation and orthopaedic interventions not only in acute fractures, but &&
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studies that evaluated areal BMD reported an increase with bisphosphonates [31–34], and some studies reported a decrease in the incidence of fractures [33]. However, two recent meta-analyses that assessed the effects of bisphosphonates on fracture in osteogenesis imperfecta reported different findings: Hald et al. [31] observed inconclusive results, whereas Shi et al. [34] reported a decrease in the risk of fractures in children, but not in adults. Studies to better define the role of bisphosphonates in fracture prevention in this population are needed, however, a long randomised controlled trial is unlikely to take place [2 ]. Bisphosphonates have a remarkable effect on vertebra during growth and can induce reshaping in vertebral compression fractures in growing children with osteogenesis imperfecta [1 ]. It is important to highlight that vertebral reshaping is associated with growth. Reshaping will depend on the amount of growth in use of bisphosphonates. In addition to the striking outcome in vertebra compression fractures, the effect of this therapy is small on the scoliosis development [1 ,2 ]. The effects of bisphosphonates are also less pronounced in long bones. Although bisphosphonates decrease longbone fracture, the rates are still very high in children with osteogenesis imperfecta. This finding is probably associated with abnormal bone geometry (small bone cross-section area) and deformities [1 ]. Multiple different protocols have been proposed for bisphosphonate use [17 ]. Table 2 summarises the most widely used [1 ,2 ,10]. Other modified protocols have been proposed, such as by Palomo et al. [37] that showed the safety of pamidronate in a shorter single infusion over a 2-h period what could be suitable for countries with reduced number of hospital beds. Although intravenous bisphosphonates have shown positive results, the same was not observed with oral bisphosphonates [2 ]. Two large randomised placebo-controlled trials on oral alendronate (n ¼ 139) and risedronate (n ¼ 147) did not observe &&
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improvements on vertebral fractures [38,39]. Possibly because the observation periods were not long enough to show vertebral reshape. Oral alendronate did not decrease fracture incidence in children with moderate and severe osteogenesis imperfecta [38]. Nevertheless, oral risedronate showed a significant reduction in the risk of clinical fracture in children with osteogenesis imperfecta [39]. Although some studies reported positive results with the use of oral bisphosphonate, there is better evidence on the benefit of intravenous bisphosphonate and this should be the treatment of choice. The benefits of bisphosphonates in adults is less clear. Two randomised controlled trials and few observational nonrandomised studies have shown an increase in BMD but few evidence to support a positive effect in fracture risk [40]. Many of these studies showed increase in lumbar spine areal bone mineral density (LS-aBMD) with less effective benefits on the total hip [41]. Recently, Viapiana et al. [42] showed a positive effect of neridronate on BMD and bone turnover markers in adults with osteogenesis imperfecta, albeit there was no significant effect on the risk of fracture. The bisphosphonate therapy is considered as well tolerated. Intravenous bisphosphonates can lead to a decrease in serum calcium immediately after infusion, however, this decrease is transient in calcium and vitamin D-replete patients [10,35]. The main adverse effect is reported in the first infusion: an influenza-like syndrome, characterised by fever, muscle pain and vomiting. This reaction should be treated with standard antipyretics and often does not recur [10]. Osteonecrosis of the jaw is an adverse effect associated with high doses of bisphosphonates, and has never been reported in osteogenesis imperfecta [2 ,43]. Atypical femoral fractures are subtrochanteric or diaphyseal fractures described in postmenopausal women associated with long-term use of bisphosphonates [44]. Although considered atypical in this female population, transverse &&
Table 2. Most widely used intravenous bisphosphonates protocol Dose according to age Less than 2 years
2–3 years
More than 3 years
Pamidronate on 3 successive days (maximum dose 60 mg/day)
0.5 mg/kg every 2 months
0.75 mg/kg every 3 months
1.0 mg/kg every 4 months
Zoledronate (single infusion)
Only in studies
Bisphosphonate (IV)
0.05 mg/kg every 6 months
The first exposure to intravenous bisphosphonate occurs at a lower dose to minimize adverse events (in particular, the acute phase reaction and hypocalcaemia) [10,35]. The initial annual dose (’full-dose’) of pamidronate is 9 mg/kg of body weight and of zoledronic acid is 0.1 mg/kg of body weight. These annual doses of both bisphosphonates should be reduced to half of the ‘full-dose’ schedules whenever the lumbar spine areal bone mineral density (BMD) z-score exceeded 2 & [1 ]. Bisphosphonate infusions were discontinued once longitudinal growth ceased [36].
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diaphyseal femoral fractures were already common in osteogenesis imperfecta, even before the use of bisphosphonates [29 ]. These fractures have been associated with the severity of osteogenesis imperfecta, but not with bisphosphonate use. Therefore, in osteogenesis imperfecta these fractures cannot be considered ‘atypical’ and more studies are needed to assess the association with bisphosphonates [29 ,44]. The bisphosphonate-therapy benefits for patients with osteogenesis imperfecta are clearly established, but other treatment options would be desirable. Denosumab is an antiresorptive therapy currently approved for postmenopausal osteoporosis treatment. The use of denosumab has been reported in children with osteogenesis imperfecta caused by SERPINF1 and COL1A1 and COL1A2 mutations and resulted in a decrease in bone turnover markers and in an increase in areal BMD [45,46]. Differently from bisphosphonates, which has a long half-life in bone, the effect of denosumab is limited to a few months, which seemed to be interesting in some cases. However, there is a potential rebound effect described after interruption of treatment, leading to hypercalcemia, which cannot be neglected [46,47]. Nevertheless, this was not observed in the study of children with osteogenesis imperfecta treated with denosumab who had been previously treated with bisphosphonates [46]. More studies about the efficacy and, especially, safety of denosumab in osteogenesis imperfecta patients are required. Anabolic therapies seem attractive in osteogenesis imperfecta setting. A randomised controlled trial on teriparatide in adults with osteogenesis imperfecta showed an increase in BMD in the milder form of osteogenesis imperfecta (type I), but no benefit in more severe forms of the disease [48]. Antisclerostin antibodies decrease the inhibitory effect of sclerostin, which results in an increase in BMD. Effects were promising in osteogenesis imperfecta mouse models and preliminary results in adults with moderate osteogenesis imperfecta were positive [49]. However, long-term phase 3 studies are required to evaluate efficacy and safety in this population. &
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CONCLUSION The diagnosis and treatment of patients with osteogenesis imperfecta have advanced recently. It is clear that current medical treatment (intravenous bisphosphonate) have a beneficial effect on bone density, fracture rates and in the reshape of vertebras after compression fractures. A multidisciplinary approach has been improving patient care,
producing remarkable gains in functionality and mobility. The safety and efficacy of new antiresorptive and anabolic treatments need to be established along with new approaches in children with osteogenesis imperfecta. The aim is to reduce the disease burden carried by children and adults with osteogenesis imperfecta. An individualised mutationspecific approach is a visionary target for the future. Acknowledgements We thank Frank Rauch, from the Shriners Hospital for Children in Montreal, Canada, for helpful suggestions. Financial support and sponsorship T.V. is funded by Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Brazil. Conflicts of interest There are no conflicts of interest.
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Parathyroids, bone and mineral metabolism 14. Bardai G, Moffatt P, Glorieux FH, et al. DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos int 2016; 27:3607–3613. 15. Cohen JS. Patterns of inheritance in osteogenesis imperfecta. In: Shapiro JR, Byers PH, Glorieux FH, Sponseller PD, editors. Osteogenesis imperfecta: a translational approach to brittle bone disease, 1st ed New York: Elsevier; 2013. p. 99. 16. Ben Amor IM, Glorieux FH, Rauch F. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos 2011; 2011:9. 17. Besio R, Forlino A. Treatment options for osteogenesis imperfecta. Expert & Opin Orphan Drugs 2015; 3:165–181. Review on current and novel therapies (gene and cell-based therapy) for murine models and osteogenesis imperfecta patients. 18. Marini JC, Blissett AR; New genes in bone development. What’s new in osteogenesis imperfecta. J Clin Endocrinol Metab 2013; 98:3095–3103. 19. Ben Amor IM, Roughley P, Glorieux FH, et al. Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res 2013; 28:2001–2007. 20. Bardai G, Ward LM, Trejo P, et al. Molecular diagnosis in children with & fractures but no extraskeletal signs of osteogenesis imperfecta. Osteoporos Int 2017; 28:2095–2101. Twenty-eight percentage of individuals with a significant fracture history but without extra-skeletal manifestations of osteogenesis imperfecta had mutations in COL1A1 or COL1A2, LRP5, BMP1, and PLS3. 21. Zarate YA, Clingenpeel R, Sellars EA, et al. Col1a1 and col1a2 sequencing results in cohort of patients undergoing evaluation for potential child abuse. Am J Med Genet A 2016; 170:1858–1862. 22. Rauch F, Lalic L, Roughley P, et al. Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I. Eur J Hum Genet 2010; 18:642–647. 23. Lindahl K, Astrom E, Rubin CJ, et al. Genetic epidemiology, prevalence, and genotype-phenotype correlations in the swedish population with osteogenesis imperfecta. Eur J Hum Genet 2015; 23:1042–1050. 24. Shapiro JR, Sponsellor PD. Osteogenesis imperfecta: questions and answers. Curr Opin Pediatr 2009; 21:709–716. 25. Pepin MG, Byers PH. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases. Am J Med Genet C Semin Med Genet 2015; 169:307–313. 26. Sule G, Campeau PM, Zhang VW, et al. Next-generation sequencing for disorders of low and high bone mineral density. Osteoporos Int 2013; 24:2253–2259. 27. Rauch F, Lalic L, Glorieux FH, et al. Targeted sequencing of a pediatric metabolic bone gene panel using a desktop semiconductor next-generation sequencer. Calcif Tissue Int 2014; 95:323–331. 28. Montpetit K, Palomo T, Glorieux FH, et al. Multidisciplinary treatment of severe osteogenesis imperfecta - functional outcomes at skeletal maturity. Arch Phys Med Rehabil 2015; 96:1834–1839. 29. Trejo P, Fassier F, Glorieux FH, et al. Diaphyseal femur fractures in osteogen& esis imperfecta: characteristics and relationship with bisphosphonate treatment. J Bone Miner Res 2017; 32:1034–1039. A retrospective study that analyzed 166 femur fractures in 119 osteogenesis imperfecta children who had not undergone intramedullary rodding procedures. These fractures have been associated with the severity of osteogenesis imperfecta, but not with the use of bisphosphonates. 30. Azzam KA, Rush ET, Burke BR, et al. Mid-term results of femoral and tibial osteotomies and fassier-duval nailing in children with osteogenesis imperfecta. J Pediatr Orthop 2016. [Epub ahead of print]
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31. Hald JD, Evangelou E, Langdahl BL, et al. Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials. J Bone Miner Res 2015; 30:929–933. 32. Dwan K, Phillipi CA, Steiner RD, et al. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev 2014; 7:Cd005088. 33. Rijks EB, Bongers BC, Vlemmix MJ, et al. Efficacy and safety of bisphosphonate therapy in children with osteogenesis imperfecta: a systematic review. Horm Res Paediatr 2015; 84:26–42. 34. Shi CG, Zhang Y, Yuan W. Efficacy of bisphosphonates on bone mineral density and fracture rate in patients with osteogenesis imperfecta: a systematic review and meta-analysis. Am J Ther 2016; 23:e894–e904. 35. Munns CF, Rajab MH, Hong J, et al. Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone 2007; 41:366–370. 36. Rauch F, Munns C, Land C, et al. Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab 2006; 91:1268–1274. 37. Palomo T, Andrade MC, Peters BS, et al. Evaluation of a modified pamidronate protocol for the treatment of osteogenesis imperfecta. Calcif Tissue Int 2016; 98:42–48. 38. Ward LM, Rauch F, Whyte MP, et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab 2011; 96:355–364. 39. Bishop N, Adami S, Ahmed SF, et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382:1424–1432. 40. Shapiro JR, Thompson CB, Wu Y, et al. Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta. Calcif Tissue Int 2010; 87:120–129. 41. Lindahl K, Langdahl B, Ljunggren O, et al. Treatment of osteogenesis imperfecta in adults. Eur J Endocrinol 2014; 171:R79–R90. 42. Viapiana O, Idolazzi L, Fassio A, et al. Long-term effects of neridronate in adults with osteogenesis imperfecta: an observational three-year italian study. Calcif Tissue Int 2017; 100:341–347. 43. Hennedige AA, Jayasinghe J, Khajeh J, et al. Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta. J Oral Maxillofac Res 2013; 4:e1. 44. Vuorimies I, Mayranpaa MK, Valta H, et al. Bisphosphonate treatment and the characteristics of femoral fractures in children with osteogenesis imperfecta. J Clin Endocrinol Metab 2017; 102:1333–1339. 45. Hoyer-Kuhn H, Netzer C, Koerber F, et al. Two years inverted question mark experience with denosumab for children with osteogenesis imperfecta type vi. Orphanet J Rare Dis 2014; 9:145. 46. Hoyer-Kuhn H, Franklin J, Allo G, et al. Safety and efficacy of denosumab in children with osteogenesis imperfecta - a first prospective trial. J Musculoskelet Neuronal Interact 2016; 16:24–32. 47. Setsu N, Kobayashi E, Asano N, et al. Severe hypercalcemia following denosumab treatment in a juvenile patient. J Bone Miner Metab 2016; 34:118–122. 48. Orwoll ES, Shapiro J, Veith S, et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest 2014; 124: 491 – 498. 49. Glorieux FH, Devogelaer JP, Durigova M, et al. Bps804 antisclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res 2017; 32:1496–1504.
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REVIEW URRENT C OPINION
Osteogenesis imperfecta: diagnosis and treatment Telma Palomo a, Tatiane Vilac¸a a,b, and Marise Lazaretti-Castro a
Purpose of review Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults. Recent findings Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation. Summary Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice. Keywords bisphosphonate, bone fragility, collagen, fragility fractures, osteogenesis imperfecta
INTRODUCTION Osteogenesis imperfecta, also known as brittle bone disease, is a heritable disorder of the extracellular matrix [1 ]. This disorder manifests mainly as bone fragility, although other organs can be involved. Abnormalities of the teeth, known as dentinogenesis imperfecta, and soft tissues, such as discoloration of the sclera and joint hyperlaxity are often observed [2 ]. The new gene discoveries in the past years have contributed to better explanation of the pathophysiology of osteogenesis imperfecta, providing opportunities for the development of new therapies. In this review, we will outline the clinical and molecular diagnosis of osteogenesis imperfecta, mention the novel causative genes and review the treatment options. &
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EPIDEMIOLOGY AND PATHOPHYSIOLOGY Osteogenesis imperfecta affects approximately 1 in 10 000 to 20 000 births [3]. It is a genetically heterogeneous skeletal dysplasia with higher mortality than general population. In a recent cohort, people with osteogenesis imperfecta had higher risk of death from respiratory and gastrointestinal diseases
and trauma [4]. In addition to the low-bone mass achieved, patients with osteogenesis imperfecta experience age-associated bone loss, increasing even more the risk of fractures [5]. Women undergo perimenopause loss and the rate of fractures in postmenopausal women with osteogenesis imperfecta is twice as high as that of osteogenesis imperfecta in premenopausal women [6]. The predominant cause of osteogenesis imperfecta are mutations in the two genes that encode type I collagen [2 ,3]. The protein is a heterotrimer, containing two a1(I) and one a2(I) chains [7]. It is synthesised as a procollagen molecule, and undergoes multiple posttranslational modifications. Flanking propeptides are removed by specific proteases, then, the molecule spontaneously assembles &&
a Bone and Mineral Unit, Division of Endocrinology, Universidade Federal de Sa˜o Paulo, Brazil and bAcademic Unit of Bone Metabolism, University of Sheffield, Sheffield, United Kingdom
Correspondence to Telma Palomo, MD, PhD, Universidade Federal de Sa˜o Paulo (UNIFESP), Rua Botucatu 806, Vila Clementino, Sa˜o Paulo, SP, CEP 04023-062 Brazil. Tel: +55 11 55748432; e-mail: [email protected] Curr Opin Endocrinol Diabetes Obes 2017, 24:000–000 DOI:10.1097/MED.0000000000000367
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KEY POINTS Osteogenesis imperfecta is the most prevalent heritable bone fragility disorder in children. COL1A1 and COL1A2 are the most frequent causative mutations, but recently, mutations on 15 other genes have been identified, either with autosomal dominant or autosomal recessive inheritance. Intravenous bisphosphonate is the most used therapy for osteogenesis imperfecta and increases bone mass, has a marked effect on vertebra reshaping in growing children but little effect on the development of scoliosis. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. Novel promising osteogenesis imperfecta treatments in preclinical studies may provide a promising approach to treat patients with osteogenesis imperfecta.
types have been proposed based on genetic findings. The several mutations are listed in the OMIM Database. The new genetic discoveries provided a controversial classification, merging clinic and genetic findings. Each new gene affected, defined a new osteogenesis imperfecta type, beyond the Sillence original 4 types [8 ]. This system was criticised by clinicians and researchers [8 ,13 ]. The Nosology and Classification of Genetic Skeletal Disorders, published in 2015, adopted a phenotypic criterion to classify osteogenesis imperfecta types, limiting to five types (osteogenesis imperfecta types I–V) [2 ,13 ,14]. In our opinion, it is more useful to describe osteogenesis imperfecta types by stating the phenotypic severity and the involved gene, as proposed by Van Dijk et al. [2 ,7]. &&
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GENES ASSOCIATED WITH OSTEOGENESIS IMPERFECTA into fibrils in tissue, and is further stabilised by crosslinks. Mutations that affect the propeptide cleavage sites cause specific variants of osteogenesis imperfecta with unique phenotypes [7,8 ]. &&
CLASSIFICATION Osteogenesis imperfecta is a heterogeneous disease, and the severity ranges from subtle increase in fracture frequency to death in the perinatal period [9,10]. A classification based in the severity of bone fragility, according to clinical/radiological features, was proposed by Sillence et al. in 1979. He suggested four phenotypic categories: osteogenesis imperfecta type I, ‘nondeforming with blue sclera’; osteogenesis imperfecta type II, ‘perinatally lethal osteogenesis imperfecta’; osteogenesis imperfecta type III, ‘progressively deforming osteogenesis imperfecta’; and osteogenesis imperfecta type IV, ‘moderate severe osteogenesis imperfecta’ [9]. Additional osteogenesis imperfecta types (V and higher) were described, based on specific phenotypic characteristics and on the genetic findings. Osteogenesis imperfecta type V is characterised by moderate-to-severe bone fragility, and a calcified interosseous membrane at the forearm that can lead to secondary dislocation of the radial head. Osteogenesis imperfecta type V has an autosomal dominant pattern, and a hyperplastic callus can develop after fractures or surgical interventions [11]. Additional osteogenesis imperfecta types were described, such as osteogenesis imperfecta types VI and VII [10,12]. The discovery of multiple new genes spread out the field of osteogenesis imperfecta, and many additional osteogenesis imperfecta 2
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Almost all individuals with osteogenesis imperfecta type I and close to 80% of patients with moderateto-severe osteogenesis imperfecta types have an autosomal dominant form of osteogenesis imperfecta that is caused by heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2 [2 ]. Mutations can be inherited from an affected parent or arise de novo [15]. Although there is not a straight genotype–phenotype correspondence, mutations’ type and position influence the phenotype and there is a relation to some extent. The most frequent abnormality is a mutation in a glycine residue in one of the two collagen genes [10]. These mutations can be divided in two categories: quantitative defects and mutations that affect type I collagen structure. The first category results in haploinsuficiency of the gene, leading to the production of structurally normal collagen, however, in about half of the normal amount. This is the cause of osteogenesis imperfecta type I. In the second category, the mutations usually replace a glycine by another amino acid resulting in an abnormal collagen molecule [16,17 ]. Recessive mutations in genes that regulate posttranslational type I collagen processing, and genes that modulate osteoblast differentiation or bone mineralization cause about 10% of moderate-tosevere osteogenesis imperfecta cases. Collagen folding, secretion and processing might be affected. These noncollagen mutations usually cause moderate-to-severe osteogenesis imperfecta phenotype but mild phenotype similar to osteogenesis imperfecta type I has been described [2 ,3,18]. Table 1 and Fig. 1 summarises genetic findings and its mechanisms [2 ,8 ,18]. &&
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Osteogenesis imperfecta: diagnosis and treatment Palomo et al. Table 1. Genes and clinical classification of osteogenesis imperfectaa Defective gene
Clinical OI typeb
Inheritance
Defective protein
Protein full name
COL1A1
I, II, III, IV
AD
COL1A1
Collagen type I alpha 1 chain
COL1A2
I, II, III, IV
AD
COL1A2
CRTAP
III, IV
AR
CRTAP
P3H1
III
AR
P3H1
Prolyl-3-hydroxlase 1
PPIB
III
AR
CypB
Cyclophyllin B
FKBP10
III, IV
AR
FKBP65
FK506 binding protein, 65 kDa
SERPINH1
III, IV
AR
HSP47
Heat-shock protein 47
PLOD2
III, IV
AR
LH2
BMP1
I, III, IV
AR
BMP1
Bone morphogenetic protein 1
SPARC
IV
AR
SPARC
Secreted protein, acidic, cysteine-rich
IV
AR
TMEM38B
III, IV
AR
SEC24D
TMEM38B SEC24D
Frequency
Defects in collagen synthesis and structure
85–90% of OI cases
Defects in collagen type I processing
10–15% of OI cases
Collagen type I alpha 2 chain Cartilage-associated protein
Lysyl hydroxylase 2
Transmembrane protein 38B SEC24D
P4HB
III
AR
PDI
Protein disulfide isomerase
IFITM5
V
AD
BRIL
Bone-restricted ifitm-like
III, IV
AR
PEDF
Pigment-epithelium derived factor
WNT1
IV
AR/AD
WNT1
SP7
III
AR
SP7
CREB3L1
II
AR
OASIS
SERPINF1
Mechanism
WNT1
Defects in bone mineralization
Defects in osteoblast development
Osterix; transcription factor Sp7 Old astrocyte specifically induced substance
All data of osteogenesis imperfecta (OI) mutations is from the OI Variant Database (https://oi.gene.le.ac.uk). AD, autosomal dominant pattern; AR, autosomal recessive pattern. && && a Adapted from Trejo et al. [2 ] and Forlino et al. [8 ]. b The 2015 Nosology and Classification of Genetic Skeletal Disorders has been followed.
DIAGNOSIS Osteogenesis imperfecta diagnosis is based on history, clinical examination, lumbar spine bone mineral density (BMD), bone biochemistry and radiographic findings (Fig. 2) [2 ]. The exclusion of metabolic causes of osteoporosis is important at baseline. The single most important clinical feature is bone fragility, that is common to all osteogenesis imperfecta types but other extra-skeletal features might be present. The most common features of each osteogenesis imperfecta type will be described according to the clinical classification proposed by Van Dijk and Sillence [7]. Osteogenesis imperfecta type I is associated with low-bone mass. Fractures are rare at birth, but there is an increase in the rate of long-bone fractures [19]. Blue or grey sclera and an increased risk of precocious hearing loss are common features. Deformities &&
of long bones or spine and dentinogenesis imperfecta are uncommon [7]. In osteogenesis imperfecta type II, the bones are extremely affected. Short and severely deformed long bones, and poor ossification of facial and skull bones are detected in 18–20 weeks’ foetal ultrasounds. Multiple rib fractures are observed in utero and perinatal lethality is almost a rule, with 90% of the affected babies dying by 4 weeks of age [7]. Osteogenesis imperfecta type III is characterised by severe bone fragility and progressive skeletal deformity. Generalised osteopenia and fractures are seen in radiographic studies at birth. Blue sclera and dentinogenesis imperfecta might be present, but the sclera tends to become less blue with ageing. Short stature is a rule and progressive kyphoscoliosis starts in childhood and progresses with growth. Hearing impairment might develop in adulthood [7].
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FIGURE 1. Genes and molecular mechanisms involved in osteogenesis imperfecta. (a) Abnormal structure in collagen a chains because of mutations in COL1A1 or COL1A2. (b) Procollagen posttranslational modification in the endoplasmic reticulum : trimeric complex (P3H1, prolyl-3-hydroxylase 1; CRTAP, cartilage-associated protein and CypB, cyclophillin B) for hydroxylation of the proline residues. (c) FKBP10 and HSP47 stabilize the triple helix and accelerate its folding. Lysyl hydroxylase 2 (LH2) hydroxylates collagen telopeptide lysines. After being secreted, the C-propeptides and N-propeptides are cleaved. BMP1 cleaves the procollagen C-propeptide. Adapted from Forlino et al. [8 ] and Marini et al. [18]. &&
Patients with osteogenesis imperfecta type IV have recurrent fractures and the deformity is variable. Most of them have normal sclera and hearing impairment is rare. Severity is also variable within families, with some individuals presenting mild osteogenesis imperfecta and others with more severe forms in the same family [7]. Finally, osteogenesis imperfecta type V is characterised by progressive calcification of the interosseous membrane and hyperplastic callus, as previously described. The bone fragility is moderate-to-severe and there is no blue sclera or dentinogenesis imperfecta [7]. The diagnosis of osteogenesis imperfecta can be difficult. Some primary skeletal disorders can be mixed up with osteogenesis imperfecta. The exclusion of idiopathic or juvenile osteoporosis might be a challenge [20 ]. Children with mild bone fragility and no extra-skeletal features of osteogenesis imperfecta, and children with fractures at birth may also demand careful assessment. Child abuse is a remarkable cause of fractures, and the highest incidence is &
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in the first year of life [10]. The most common signs are rib fractures, and classic metaphyseal lesions of the femur. The incidence of osteogenesis imperfecta in this context is between 2 and 5% [21]. These uncertain cases may still be caused by mutations in COL1A1 or COL1A2 [22,23]. Although the diagnosis is mainly based in clinical and radiological features, genetic tests may establish the exact cause of the disease and provide helpful information in unclear cases [20 ,24]. Molecular diagnosis also allows information about recurrent risk (dominant versus recessive osteogenesis imperfecta) and the identification of affected family members [2 ]. This could be interesting especially in very mild forms of osteogenesis imperfecta type I, wherever clinical signs can be very subtle. On the other hand, molecular diagnosis has low impact in the evaluation of suspected child abuse and in infants in whom careful examination has not shown clinical characteristics of osteogenesis imperfecta [21,25]. Currently, molecular diagnosis is performed by sequencing the DNA of target gene panels &
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FIGURE 2. Lateral lumbar spine and lower extremities radiographs of three patients with osteogenesis imperfecta type I (milder form), type III (most severe type of osteogenesis imperfecta) and type IV (intermediate in severity between types I and III). (A1 and A2) Spiral right femur healing fracture in a osteogenesis imperfecta type I patient without vertebral fractures. (B1 and B2) Osteogenesis imperfecta type III patient with severe vertebral compression fractures, protrusion of the acetabulum, fracture healing of the right femur and deformities in both femurs and tibias (small diameter and thin cortices). (C1 and C2) Full community ambulator osteogenesis imperfecta type IV patient with several vertebral compression fractures, bilateral femoral bowing and straight tibias. Vertebral fractures are indicated by asterisks.
(‘next-generation sequencing’) [26,27]. The evaluation of this known disease-causing genes identifies mutations in 97% of individuals with a clinical diagnosis of ‘typical osteogenesis imperfecta’ [14].
also to address reduced mobility, long-bone deformities and scoliosis [2 ,28]. In severe forms of osteogenesis imperfecta, intramedullary rodding surgery may be required for straightening bowed femurs and tibias [29 ,30]. Multiple fractures may result in deformities and repeated periods of immobilization, which may compromise the functional status and mobility. In this scenario, a multidisciplinary approach is the best option and physical rehabilitation plays an important role in improving individual’s function and promoting independence [28,30]. For many years, intravenous bisphosphonate therapy has been the most widely used approach to treat bone fragility in children with osteogenesis imperfecta. In a systematic review, all the randomised &&
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TREATMENT The therapeutic approach to osteogenesis imperfecta patients will vary with age, severity of the disease and functional status. Individuals with mild disease may require subtle restrictions, such as avoiding contact sports, and orthopaedic therapy is reserved to the management of fractures [2 ]. Conversely, moderate-to-severe osteogenesis imperfecta patients demand rehabilitation and orthopaedic interventions not only in acute fractures, but &&
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studies that evaluated areal BMD reported an increase with bisphosphonates [31–34], and some studies reported a decrease in the incidence of fractures [33]. However, two recent meta-analyses that assessed the effects of bisphosphonates on fracture in osteogenesis imperfecta reported different findings: Hald et al. [31] observed inconclusive results, whereas Shi et al. [34] reported a decrease in the risk of fractures in children, but not in adults. Studies to better define the role of bisphosphonates in fracture prevention in this population are needed, however, a long randomised controlled trial is unlikely to take place [2 ]. Bisphosphonates have a remarkable effect on vertebra during growth and can induce reshaping in vertebral compression fractures in growing children with osteogenesis imperfecta [1 ]. It is important to highlight that vertebral reshaping is associated with growth. Reshaping will depend on the amount of growth in use of bisphosphonates. In addition to the striking outcome in vertebra compression fractures, the effect of this therapy is small on the scoliosis development [1 ,2 ]. The effects of bisphosphonates are also less pronounced in long bones. Although bisphosphonates decrease longbone fracture, the rates are still very high in children with osteogenesis imperfecta. This finding is probably associated with abnormal bone geometry (small bone cross-section area) and deformities [1 ]. Multiple different protocols have been proposed for bisphosphonate use [17 ]. Table 2 summarises the most widely used [1 ,2 ,10]. Other modified protocols have been proposed, such as by Palomo et al. [37] that showed the safety of pamidronate in a shorter single infusion over a 2-h period what could be suitable for countries with reduced number of hospital beds. Although intravenous bisphosphonates have shown positive results, the same was not observed with oral bisphosphonates [2 ]. Two large randomised placebo-controlled trials on oral alendronate (n ¼ 139) and risedronate (n ¼ 147) did not observe &&
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improvements on vertebral fractures [38,39]. Possibly because the observation periods were not long enough to show vertebral reshape. Oral alendronate did not decrease fracture incidence in children with moderate and severe osteogenesis imperfecta [38]. Nevertheless, oral risedronate showed a significant reduction in the risk of clinical fracture in children with osteogenesis imperfecta [39]. Although some studies reported positive results with the use of oral bisphosphonate, there is better evidence on the benefit of intravenous bisphosphonate and this should be the treatment of choice. The benefits of bisphosphonates in adults is less clear. Two randomised controlled trials and few observational nonrandomised studies have shown an increase in BMD but few evidence to support a positive effect in fracture risk [40]. Many of these studies showed increase in lumbar spine areal bone mineral density (LS-aBMD) with less effective benefits on the total hip [41]. Recently, Viapiana et al. [42] showed a positive effect of neridronate on BMD and bone turnover markers in adults with osteogenesis imperfecta, albeit there was no significant effect on the risk of fracture. The bisphosphonate therapy is considered as well tolerated. Intravenous bisphosphonates can lead to a decrease in serum calcium immediately after infusion, however, this decrease is transient in calcium and vitamin D-replete patients [10,35]. The main adverse effect is reported in the first infusion: an influenza-like syndrome, characterised by fever, muscle pain and vomiting. This reaction should be treated with standard antipyretics and often does not recur [10]. Osteonecrosis of the jaw is an adverse effect associated with high doses of bisphosphonates, and has never been reported in osteogenesis imperfecta [2 ,43]. Atypical femoral fractures are subtrochanteric or diaphyseal fractures described in postmenopausal women associated with long-term use of bisphosphonates [44]. Although considered atypical in this female population, transverse &&
Table 2. Most widely used intravenous bisphosphonates protocol Dose according to age Less than 2 years
2–3 years
More than 3 years
Pamidronate on 3 successive days (maximum dose 60 mg/day)
0.5 mg/kg every 2 months
0.75 mg/kg every 3 months
1.0 mg/kg every 4 months
Zoledronate (single infusion)
Only in studies
Bisphosphonate (IV)
0.05 mg/kg every 6 months
The first exposure to intravenous bisphosphonate occurs at a lower dose to minimize adverse events (in particular, the acute phase reaction and hypocalcaemia) [10,35]. The initial annual dose (’full-dose’) of pamidronate is 9 mg/kg of body weight and of zoledronic acid is 0.1 mg/kg of body weight. These annual doses of both bisphosphonates should be reduced to half of the ‘full-dose’ schedules whenever the lumbar spine areal bone mineral density (BMD) z-score exceeded 2 & [1 ]. Bisphosphonate infusions were discontinued once longitudinal growth ceased [36].
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diaphyseal femoral fractures were already common in osteogenesis imperfecta, even before the use of bisphosphonates [29 ]. These fractures have been associated with the severity of osteogenesis imperfecta, but not with bisphosphonate use. Therefore, in osteogenesis imperfecta these fractures cannot be considered ‘atypical’ and more studies are needed to assess the association with bisphosphonates [29 ,44]. The bisphosphonate-therapy benefits for patients with osteogenesis imperfecta are clearly established, but other treatment options would be desirable. Denosumab is an antiresorptive therapy currently approved for postmenopausal osteoporosis treatment. The use of denosumab has been reported in children with osteogenesis imperfecta caused by SERPINF1 and COL1A1 and COL1A2 mutations and resulted in a decrease in bone turnover markers and in an increase in areal BMD [45,46]. Differently from bisphosphonates, which has a long half-life in bone, the effect of denosumab is limited to a few months, which seemed to be interesting in some cases. However, there is a potential rebound effect described after interruption of treatment, leading to hypercalcemia, which cannot be neglected [46,47]. Nevertheless, this was not observed in the study of children with osteogenesis imperfecta treated with denosumab who had been previously treated with bisphosphonates [46]. More studies about the efficacy and, especially, safety of denosumab in osteogenesis imperfecta patients are required. Anabolic therapies seem attractive in osteogenesis imperfecta setting. A randomised controlled trial on teriparatide in adults with osteogenesis imperfecta showed an increase in BMD in the milder form of osteogenesis imperfecta (type I), but no benefit in more severe forms of the disease [48]. Antisclerostin antibodies decrease the inhibitory effect of sclerostin, which results in an increase in BMD. Effects were promising in osteogenesis imperfecta mouse models and preliminary results in adults with moderate osteogenesis imperfecta were positive [49]. However, long-term phase 3 studies are required to evaluate efficacy and safety in this population. &
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CONCLUSION The diagnosis and treatment of patients with osteogenesis imperfecta have advanced recently. It is clear that current medical treatment (intravenous bisphosphonate) have a beneficial effect on bone density, fracture rates and in the reshape of vertebras after compression fractures. A multidisciplinary approach has been improving patient care,
producing remarkable gains in functionality and mobility. The safety and efficacy of new antiresorptive and anabolic treatments need to be established along with new approaches in children with osteogenesis imperfecta. The aim is to reduce the disease burden carried by children and adults with osteogenesis imperfecta. An individualised mutationspecific approach is a visionary target for the future. Acknowledgements We thank Frank Rauch, from the Shriners Hospital for Children in Montreal, Canada, for helpful suggestions. Financial support and sponsorship T.V. is funded by Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq), Brazil. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Palomo T, Fassier F, Ouellet J, et al. Intravenous bisphosphonate therapy of & young children with osteogenesis imperfecta: skeletal findings during follow up throughout the growing years. J Bone Miner Res 2015; 30:2150–2157. Retrospective study showing long-term outcomes (median treatment, 14.8 years) on bisphosphonate therapy in children with osteogenesis imperfecta. 2. Trejo P, Rauch F. Osteogenesis imperfecta in children and adolescents&& new developments in diagnosis and treatment. Osteoporos Int 2016; 27:3427–3437. Detailed review on recent updates in diagnosis and treatment of osteogenesis imperfecta. 3. Lim J, Grafe I, Alexander S, et al. Genetic causes and mechanisms of osteogenesis imperfecta. Bone 2017; 102:40–49. 4. Folkestad L, Hald JD, Canudas-Romo V, et al. Mortality and causes of death in patients with osteogenesis imperfecta: a register-based nationwide cohort study. J Bone Miner Res 2016; 31:2159–2166. 5. Bishop NJ, Walsh JS. Osteogenesis imperfecta in adults. J Clin Invest 2014; 124:476–477. 6. Folkestad L, Hald JD, Ersboll AK, et al. Fracture rates and fracture sites in patients with osteogenesis imperfecta: a nationwide register-based cohort study. J Bone Miner Res 2017; 32:125–134. 7. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 2014; 164A:1470–1481. 8. Forlino A, Marini JC. Osteogenesis imperfecta. Lancet 2016; 387: && 1657–1671. Review addressing pathophysiology, clinical and genetic osteogenesis imperfecta classification and manegement. 9. Van Dijk FS, Byers PH, Dalgleish R, et al. Emqn best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur J Hum Genet 2012; 20:11–19. 10. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004; 363:1377–1385. 11. Glorieux FH, Rauch F, Plotkin H, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000; 15:1650–1658. 12. Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type Vi: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002; 17:30–38. 13. Bonafe L, Cormier-Daire V, Hall C, et al. Nosology and classification of & genetic skeletal disorders: 2015 revision. Am j med genet A 2015; 167a:2869–2892. The nosology helps to describe genotype–phenotype correlations combining clinical observations and genetic results. The panel maintain the five phenotype-based classification.
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