Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study

doi:10.1016/S0140-6736(04)16101-1

The Lancet

Volume 363, Issue 9419, 1 May 2004, Pages 1427-1431

https://doi.org/10.1016/S0140-6736(04)16101-1 Get rights and content

Summary

Background

Non-randomised studies have suggested beneficial effects of bisphosphonates in osteogenesis imperfecta. We assessed the effects of oral olpadronate in children with this disorder in a randomised double-blind placebo-controlled trial.

Methods

34 children recruited from the Dutch national centre for osteogenesis imperfecta were randomly assigned olpadronate (10 mg/m² daily; n=16) or placebo (n=18) for 2 years. All children also received calcium and vitamin D supplements. Primary endpoints were incident fractures of long bones and changes in bone mineral content (BMC), bone mineral density (BMD), and functional outcome. Anthropometry, vertebral height, and urinary markers of bone resorption were also studied. Analyses were by intention to treat.

Findings

Fracture follow-up was complete for all the children, including two who withdrew from the study (one from each group). Olpadronate treatment was associated with a 31% reduction in relative risk of fracture of long bones (hazard ratio 0·69 [95% CI 0·52–0·91], p=0·01). The olpadronate group showed significantly greater increases than the placebo group in spinal BMC (difference between groups 2·24 g/year [0·20–4·29], p=0·03) and spinal BMD (difference between groups 0·054 g/cm² per year [0·012–0·096], p=0·01). There were no detectable effects on functional outcome, anthropometrics, or vertebral height and no differences between the groups in changes in urinary markers of bone resorption.

Interpretation

Oral treatment with olpadronate at a daily dose of 10 mg/m² results in a reduction of fracture risk of long bones in children with osteogenesis imperfecta. However, the issue of whether bisphosphonates will alter the natural course of osteogenesis imperfecta remains unresolved, and further studies are needed.

Introduction

Bisphosphonates are effective in the clinical management of osteoporosis by suppressing osteoclast-mediated bone resorption and decreasing bone turnover.¹ Osteogenesis imperfecta is caused by a defect in collagen I synthesis and shows highly variable clinical expression.² Osteoporosis is one of the common consequences of this “brittle bone disease” and is frequently used as a reason to give bisphosphonates to patients with severe expression of the disease. Improved dual X-ray absorptiometry (DXA) outcomes with bisphosphonates have been reported in some uncontrolled studies, and several have also found lower fracture rates.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 As a consequence of these reports, many children with osteogenesis imperfecta are now receiving bisphosphonates. However, owing to the small number of patients available for clinical trials and the variability of fracture incidence per child per year, the efficacy of any medical treatment of osteogenesis imperfecta is difficult to prove.

The first descriptions of beneficial skeletal effects in children with osteogenesis imperfecta were reported with the use of oral administration of pamidronate.14, 15 The encouraging results with this nitrogen-containing bisphosphonate were later confirmed with cyclical intravenously administrated pamidronate in larger groups of children.5, 6, 7, 8, 9, 10, 11, 12, 13 Meanwhile, more potent nitrogen-containing bisphosphonates have been developed with the potential for effective and safe oral use. There have been previous reports on long-term use of oral pamidronate or olpadronate in children with severe osteoporosis, some of them with osteogenesis imperfecta.3, 4 The bioequivalence of pamidronate doses of 150–300 mg and olpadronate doses of 10 mg has been validated in vitro and in vivo.¹

This study was undertaken at the Dutch national centre for children with osteogenesis imperfecta. We carried out a double-blind randomised placebo-controlled single-centre trial for 2 years to assess the effects of daily olpadronate (10 mg/m²) on incident fractures, DXA outcomes, and functional outcome in children with osteogenesis imperfecta. Vertebral fractures were not assessed because many microfractures and small collapses of vertebral bodies remain undiscovered, so the counting of vertebral fractures is unreliable. Estimates of olpadronate's effects on the spine were made by use of comparisons of seated height and anterior, mid, and posterior heights of vertebrae L1-L4 as measured on standardised radiographs. Concomitant changes in anthropometry and urinary markers of bone resorption were also compared. All patients included were seen regularly in the outpatient multidisciplinary unit for children with osteogenesis imperfecta.

Section snippets

Participants

Medical histories of children with skeletal dysplasias were extracted from a database kept by the Department of Paediatric Orthopaedic Surgery, Wilhelmina Children's Hospital of the University Medical Centre Utrecht, the Netherlands. This was the only database we could use for retrieval and selection of patients, since all members of the Dutch osteogenesis imperfecta association are referred to the Wilhelmina Children's Hospital and the vast majority of children with osteogenesis imperfecta in

Methods

Primary endpoints were incident non-vertebral fractures, changes in DXA outcomes, and functional outcome. Secondary endpoints were changes in anthropometric measurements, vertebral height (L1-L4) on plain radiographs of the spine, and urinary markers of bone resorption. New fractures were radiologically confirmed non-vertebral fractures. Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L1-L4) and of the os calcis were measured before randomisation, after 1 year,

Drug tolerability and adherence

Before the study, children and parents were informed about the occasional occurrence of gastrointestinal sideeffects reported with the use of any bisphosphonate (regurgitation, heartburn, and upper-abdominal discomfort). They were specifically instructed to report any such side-effect immediately. Furthermore, each participant kept a study diary to register all side-effects and days on which study medication was forgotten. The parents were asked to return all bottles for tablet counting. All

Statistical analysis

Mean values and SDs were calculated for continuous baseline characteristics and proportions for categorical characteristics, separately for each study group. Differences in annual changes in outcome variables between the olpadronate and placebo groups were tested by random-effects repeated-measures analysis (SAS, Proc Mixed, version 8.2). The effect of olpadronate on (recurrent) fracture risk was analysed by use of a generalised Cox's proportional-hazards model with a robust method for

Discussion

To date, intravenous cyclical pamidronate is the most frequently reported bisphosphonate regimen for children with osteogenesis imperfecta.5, 6, 7, 8, 9, 10, 11, 12, 13 In accordance with the general effort to achieve more convenient treatment regimens, we decided to investigate continuous administration of an oral bisphosphonate. Olpadronate, like alendronate and risedronate, is one of the more potent nitrogen-containing bisphosphonates, and the efficacy of the drug was investigated on the

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It may be that the action of bisphosphonates to increase bone mass primarily by increasing cortical thickness, retaining newly formed trabecular bone and reducing cortical porosity (all demonstrated on transiliac bone biopsies) [116] is insufficient to offset the microarchitectural degradation and altered material properties seen to a greater or lesser extent in all affected individuals. This might be reflected in the more statistically significant results obtained in the oral treatment studies which largely focused on more mildly affected children [105,114]; the study of oral alendronate did not show a fracture difference in the moderately and severely-affected cohort studied [113] and neither was a difference seen in the dose-ranging study of risedronate in children with type III/IV disease [112]. In clinical practice in children, intravenous therapy is given as a first line approach (see below) with oral therapy usually given only in very mild cases, or when the clinical situation has been stable for some time.
Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility.
The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive.
New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone – for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation – both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.
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The numbers of participants with OI required to detect different effect sizes in PODCI scores are listed in Table 3. To date, there exist no disease-specific PROMs to assess disease burden and functional outcomes in OI, and thus various PROMs including Pediatric Evaluation of Disability Inventory, WeeFIMTM, Pediatric Quality of Life InventoryTM, Patient-Reported Outcome Measurement Information Systems (PROMIS)®, and PODCI have been used in the clinical and clinical investigational settings.20,32-38 These PROMs assess different but overlapping domains of functionality and quality of life and previously, our group has reported that there is some degree of correlation between measures assessed by different PROMs like PROMIS® and PODCI in OI.20
Patient-reported outcome measures (PROMs) are increasingly recognized as valuable endpoints in clinical trials. The Pediatric Outcomes Data Collection Instrument (PODCI) is a PROM utilized in children with musculoskeletal disorders. We evaluated the validity and reliability of PODCI in children with osteogenesis imperfecta (OI).
Physical functioning and psychological well-being were assessed using PODCI in a large cohort of children enrolled in a multicenter study conducted by the Brittle Bone Disorders Consortium. Physical function scores were correlated with a validated, observer-rated scale, Brief Assessment of Motor Function (BAMF), and with psychological well-being scores. We calculated sample sizes required to detect clinically meaningful differences in physical function.
Four hundred seventeen children with OI types I, III, and IV were enrolled. Physical function scores in OI type III were significantly lower than those in OI types I and IV. There were no significant differences in psychological well-being. PODCI physical function scores showed moderate-to-strong correlation with BAMF. The Global Functioning Scale, a composite of physical function, did not consistently correlate with psychological well-being.
PODCI can be a reliable measure of physical functioning in children with OI and offers valuable information about patient-reported health status and new ways to examine the utility of interventions in this population.
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There has been a growing interest in pediatric and adolescent bone health over the past two decades. There is increasing recognition that the adolescent years are critical ones for bone accrual as peak bone mass is achieved during young adulthood. Gains in bone density and strength from the adolescent period ultimately influence the risk of fracture and osteoporosis throughout the life span. This chapter discusses the mechanisms by which genetic and acquired disorders of childhood can compromise the development of bone density and strength and reviews the current approach to diagnosis, treatment, and prevention of bone and mineral disorders in children and adolescents.
Effects of zoledronic acid on vertebral shape of children and adolescents with osteogenesis imperfecta
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We also observed that the compressed vertebrae of OI children could be reshaped during ibandronate treatment [34]. Although oral BPs also could inhibit bone resorption, increase BMD and reduce fracture incidence in children and adolescents with OI [35], it seemed to have a limited effect on vertebral shape [36–38]. We also found the height-Z score was considerably increased in VCF group after ZOL treatment, indicating catch-growth.
Vertebral compression fracture (VCF) is a common and severe complication of osteogenesis imperfecta (OI). We prospectively observe the changes of vertebral shape during zoledronic acid (ZOL) treatment and assess influence factors of VCF in OI children. 32 children with VCF and 10 children without VCF (NVCF) were included and given ZOL treatment for 2 years, who were matched in age and gender. Control group included 17 treatment naïve OI patients with VCF who were matched in age, gender and clinical severity to 17 patients in VCF group received ZOL treatment for 1 year (as ZOL treated group). We performed quantitative vertebral morphometry and calculated concavity index (mh/ph), height-length ratio (ah/LL, mh/LL, ph/LL) and projection area (PA) of vertebrae from T4 to L4 before and after treatment. At baseline, patients in VCF group had significantly lower PA, mh/ph, ah/LL, mh/LL and ph/LL than patients in NVCF group (P < 0.01). PA, mh/ph, ah/LL, mh/ LL and ph/LL of patients with VCF were raised by (35.2 ± 19.5)%, (22.9 ± 15.1)%, (19.6 ± 13.9)%, (33.6 ± 25.5)%, and (8.1 ± 8.8)% (P < 0.01) after 1-year treatment of ZOL, and were increased by (71.8 ± 28.2)%, (42.8 ± 21.8)%, (35.1 ± 20.6)%, (65.4 ± 43.2)%, and (12.5 ± 11.4)% after 2-year treatment of ZOL (P < 0.01). Compared to control group, mh/ph, ah/LL and mh/LL were significantly higher (P < 0.01) in ZOL treated group. LS-BMD and its increase were positively correlated to vertebral height and PA at baseline and the improvement of vertebral height and PA after ZOL treatment, respectively. In conclusion, the compressive vertebrae of OI children could be effectively reshaped during ZOL treatment. Low LS-BMD was an independent risk factor for VCF and its increase was positively correlated to the improvement in vertebral shape after ZOL treatment.
Mobility in osteogenesis imperfecta: a multicenter North American study
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Land et al. reported that cyclical pamidronate treatment improves mobility, ambulation level, and muscle force in children with moderate to severe OI32 while Seikaly reported improvements in well-being scores and self-care abilities but no change in mobility in patients treated with alendronate.33 Other reports found no changes in mobility or functional outcomes using oral34-36 or intravenous bisphosphonates.37 In agreement with these studies, our results showed no significant relationship between years on bisphosphonate treatment and mobility outcomes.
Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes.
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Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV).
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ArticlesSkeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Methods

Drug tolerability and adherence

Statistical analysis

Discussion

J Pediatr

J Pediatr

Arch Phys Med Rehabil

Arch Phys Med Rehabil

Lancet

Bisphosphonates: pharmacology and use in the treatment of osteoporosis

Osteogenesis imperfecta

Treatment of osteogenesis imperfecta with the bisphosphonate olpadronate (dimethylaminohydroxypropydilene bisphosphonate)

Eur J Pediatr

Long-term effects of bisphosphonates on the growing skeleton

Medicine

Cyclic administration of pamidronate in children with severe osteogenesis imperfecta

N Engl J Med

Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age

J Clin Endocrinol Metab

Efficacy of low dose schedule pamidronate infusion in children with osteogenesis imperfecta

J Pediatr Endocrinol Metab

Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta

Eur J Pediatr

Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta

Arch Dis Child

Pamidronate treatment of osteogenesis imperfecta: lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and treatment response

J Pediatr Endocrinol Metab

Articles
Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study