Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review

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Abstract

Background/Aims: To systematically assess contemporary knowledge regarding the effectiveness and safety of bisphosphonates (BPs) in children with osteogenesis imperfecta (OI). Methods: PubMed/MEDLINE, Embase, and Cochrane were searched for eligible articles up to June 2014. Studies eligible for inclusion were (randomized) controlled trials assessing the effects of BPs in children with OI. Methodological quality was assessed independently by 4 reviewers using the Cochrane Collaboration's tool for risk of bias. Results: Ten studies (519 children) were included. Four studies (40%) showed a low risk of bias. All studies investigating lumbar spine areal bone mineral density indicated a significant increase as a result of BP treatment. Most studies observed a significant decrease in fracture incidence. The most frequently reported adverse events were gastrointestinal complaints, fever, and muscle soreness. A significant decrease in (bone) pain due to BP treatment was observed in more than half of the studies. Most studies measuring urinary markers of bone resorption reported a significant decrease. The majority of studies with intravenous treatment showed a significant increase in lumbar projection area, whereas studies with oral treatment did not. Conclusions: Treatment with oral or intravenous BPs in children with OI results in an increase in bone mineral density and seems to be safe and well tolerated.

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Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

F Glorieux, N. Bishop, H Plotkin … (1998)

Severe osteogenesis imperfecta is a disorder characterized by osteopenia, frequent fractures, progressive deformity, loss of mobility, and chronic bone pain. There is no effective therapy for the disorder. We assessed the effects of treatment with a bisphosphonate on bone resorption. In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta, we administered pamidronate intravenously (mean [+/-SD] dose, 6.8+/-1.1 mg per kilogram of body weight per year) at 4-to-6-month intervals for 1.3 to 5.0 years. Clinical status, biochemical characteristics reflecting bone turnover, the bone mineral density of the lumbar spine, and radiologic changes were assessed regularly during treatment. Administration of pamidronate resulted in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide. There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density, and the deviation of bone mineral density from normal, as indicated by the z score, improved from -5.3+/-1.2 to -3.4+/-1.5. The cortical width of the metacarpals increased by 27+/-20.2 percent per year. The increases in the size of the vertebral bodies suggested that new bone had formed. The mean incidence of radiologically confirmed fractures decreased by 1.7 per year (P<0.001). Treatment with pamidronate did not alter the rate of fracture healing, the growth rate, or the appearance of the growth plates. Mobility and ambulation improved in 16 children and remained unchanged in the other 14. All the children reported substantial relief of chronic pain and fatigue. In children with severe osteogenesis imperfecta, cyclic administration of intravenous pamidronate improved clinical outcomes, reduced bone resorption, and increased bone density.

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Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

Thomas Hangartner, C P Burren, Oliver Semler … (2013)

Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. Alliance for Better Bone Health (Warner Chilcott and Sanofi). Copyright © 2013 Elsevier Ltd. All rights reserved.

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Bisphosphonate-induced osteopetrosis.

Deborah Wenkert, Michael Whyte, Wilson Clements … (2003)

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Journal ID (publisher-id): HRP

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2015

Publication date (Print): August 2015

Publication date (Electronic): 23 May 2015

Volume: 84

Issue: 1

Pages: 26-42

Affiliations

^aChild Development & Exercise Center and Departments of ^bPediatrics and ^cOrthopedics, Wilhelmina Children's Hospital, and ^dClinical Health Sciences, University Medical Center Utrecht, Utrecht, ^eDepartment of Epidemiology, School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, and ^fPediatric Endocrinology Subdivision, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Author notes

*Marco van Brussel, MSc, PhD, Child Development & Exercise Center, Wilhelmina Children's Hospital, University Medical Center Utrecht, KB.02.056.0, PO Box 85090, NL-3508 AB Utrecht (The Netherlands), E-Mail m.vanbrussel@umcutrecht.nl

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Bart C. Bongers https://orcid.org/0000-0002-1948-9788

Article

Publisher ID: 381713 Other ID: Horm Res Paediatr 2015;84:26-42

DOI: 10.1159/000381713

PubMed ID: 26021524

SO-VID: c18b2bb3-347e-47d7-bddc-3076b9a09d7e

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 03 February 2015

Date accepted : 12 March 2015

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Figures: 1, Tables: 2, References: 51, Pages: 17

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Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review

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Karger: Endocrinology

Most cited references 43

Cyclic administration of pamidronate in children with severe osteogenesis imperfecta.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial.

Bisphosphonate-induced osteopetrosis.

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