Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta

Importance Osteogenesis imperfecta causes multiple fractures throughout life, causing substantial morbidity. Objective To determine whether the parathyroid hormone analogue teriparatide followed by zoledronic acid reduces the risk of fractures in adults with osteogenesis imperfecta. Design, Setting, and Participants Multicenter open-label, parallel-group, randomized clinical trial, conducted between May 17, 2017, and March 21, 2025, in adults attending one of 27 referral centers with a clinical diagnosis of osteogenesis imperfecta. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone turnover by serum procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type 1 collagen. Fractures were confirmed by skeletal imaging. Several measures of health–related quality of life were assessed. Interventions Those in the active group received 20 μg of teriparatide daily by subcutaneous injection for 2 years followed by an infusion of 5 mg of zoledronic acid. In the standard care group, bisphosphonates and other bone-targeted medicines could be used but teriparatide and other bone anabolic drugs were prohibited. Main outcomes and measures The primary end point was the number of participants with imaging-proven incident fractures adjudicated by reviewers blinded to treatment allocation. Secondary end points included the total number of fractures, changes in BMD, biochemical markers of bone turnover, and health–related quality of life. Results Of the 350 individuals randomized, 176 were allocated to receive teriparatide plus zoledronic acid, 174 to standard care, and 1 withdrew, leaving 349 evaluable participants. The mean age was 43.7 years (188 females [53.9%]). Most had type I osteogenesis imperfecta caused by pathogenic variants in the type 1 collagen genes. In the teriparatide plus zoledronic acid group 65 of 176 (36.9%) had incident fractures compared with 63 of 173 (36.4%) in the standard care group (absolute risk reduction, –1.57%; 95% CI, –9.90% to 5.89%; hazard ratio, 0.97; 95% CI, 0.68 to 1.38). Lumbar spine and total hip BMD increased significantly more with teriparatide plus zoledronic acid than standard care. Several quality-of-life measures favored teriparatide plus zoledronic acid. Adverse events were similar in both groups. Conclusions and Relevance This randomized clinical trial among adults with osteogenesis imperfecta found that teriparatide plus zoledronic acid did not reduce fracture risk compared with standard care despite significantly increasing BMD, suggesting the importance of reduced bone quality rather than low bone density in the pathogenesis of fracture. Trial Registration isrctn.org Identifier: ISRCTN15313991

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Journal
JAMA
Published
2026-05-14
DOI
https://doi.org/10.1001/jama.2026.6889
Primary Topic
Connective tissue disorders research
Type
article
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article

Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta

Holly A. Black, Wayne Lam, Christopher John Weir, Jonathan Tang et al.
JAMA
Connective tissue disorders research
article

Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta

Holly A. Black, Wayne Lam, Christopher John Weir, Jonathan Tang, Rosemary Hollick, Zoé Paskins, John R. Lindsay, Jannie Dahl Hald, Prashanth Patel, M. Cohen Solal, Deepa Narayanan, Kenneth Poole, Richard Keen, David Moore, Catriona Keerie, Jane Turton, Ellen Malcolm, Lorna Dewar, Johannes Feenstra, Matthew Roy, Tianyu Guo, Lynsey Milne, Elisabeth Marelise W. Eekhoff, Bente L. Langdahl, E M Curtis, Andrew D. Duckworth, Zaki Hassan-Smith, Rachel K. Crowley, Willem Lema, Philip Conaghan, Terry Aspray, Morag MacLean, Patricia Osborne, Nazim Ghouri, Osten Llungren, Anthony Woolf, Mashood Siddiqi, Eero Nevalainen, Jennifer S. Walsh, Christoper J Sutton, Robin Munro, Geeta Hampson, Stephen Tuck, Suzie Cro, Mike Stone, Navni S. Makaram, Stuart H. Ralston, Gregor Stenhouse, Nicholas C. Harvey, Muhammad Kassim Javaid, TOPaZ Investigators
article en

Abstract

Importance Osteogenesis imperfecta causes multiple fractures throughout life, causing substantial morbidity. Objective To determine whether the parathyroid hormone analogue teriparatide followed by zoledronic acid reduces the risk of fractures in adults with osteogenesis imperfecta. Design, Setting, and Participants Multicenter open-label, parallel-group, randomized clinical trial, conducted between May 17, 2017, and March 21, 2025, in adults attending one of 27 referral centers with a clinical diagnosis of osteogenesis imperfecta. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone turnover by serum procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type 1 collagen. Fractures were confirmed by skeletal imaging. Several measures of health–related quality of life were assessed. Interventions Those in the active group received 20 μg of teriparatide daily by subcutaneous injection for 2 years followed by an infusion of 5 mg of zoledronic acid. In the standard care group, bisphosphonates and other bone-targeted medicines could be used but teriparatide and other bone anabolic drugs were prohibited. Main outcomes and measures The primary end point was the number of participants with imaging-proven incident fractures adjudicated by reviewers blinded to treatment allocation. Secondary end points included the total number of fractures, changes in BMD, biochemical markers of bone turnover, and health–related quality of life. Results Of the 350 individuals randomized, 176 were allocated to receive teriparatide plus zoledronic acid, 174 to standard care, and 1 withdrew, leaving 349 evaluable participants. The mean age was 43.7 years (188 females [53.9%]). Most had type I osteogenesis imperfecta caused by pathogenic variants in the type 1 collagen genes. In the teriparatide plus zoledronic acid group 65 of 176 (36.9%) had incident fractures compared with 63 of 173 (36.4%) in the standard care group (absolute risk reduction, –1.57%; 95% CI, –9.90% to 5.89%; hazard ratio, 0.97; 95% CI, 0.68 to 1.38). Lumbar spine and total hip BMD increased significantly more with teriparatide plus zoledronic acid than standard care. Several quality-of-life measures favored teriparatide plus zoledronic acid. Adverse events were similar in both groups. Conclusions and Relevance This randomized clinical trial among adults with osteogenesis imperfecta found that teriparatide plus zoledronic acid did not reduce fracture risk compared with standard care despite significantly increasing BMD, suggesting the importance of reduced bone quality rather than low bone density in the pathogenesis of fracture. Trial Registration isrctn.org Identifier: ISRCTN15313991

JAMA
University College Dublin (IE), Belfast Health and Social Care Trust (GB), National Health Service Scotland (GB), NHS Lothian (GB), University of Liverpool (GB), Inserm (FR), Aston University (GB), Royal Free London NHS Foundation Trust (GB), University of Aberdeen (GB), Queen Elizabeth Hospital Birmingham (GB), Musgrave Park Hospital (GB), NHS Education for Scotland (GB), Hull University Teaching Hospitals NHS Trust (GB), Western General Hospital (GB), Nuffield Orthopaedic Centre (GB), Wishaw General Hospital (GB), Freeman Hospital (GB), Aarhus University Hospital (DK), University Hospitals of Leicester NHS Trust (GB), Cambridge University Hospitals NHS Foundation Trust (GB), Ninewells Hospital (GB), Edinburgh Cancer Research (GB), Royal Liverpool University Hospital (GB), Edinburgh Royal Infirmary (GB), Bristol Royal Infirmary (GB), University Hospital Southampton NHS Foundation Trust (GB), South Tees Hospitals NHS Foundation Trust (GB), University of Oxford (GB), St. Vincent's University Hospital (IE), NIHR Southampton Biomedical Research Centre (GB), Bioscar (FR), Royal National Orthopaedic Hospital NHS Trust (GB), St. Thomas Hospital (CA), Brittle Bone Society (GB), Isala (NL), University Hospital Llandough (GB), MRC Lifecourse Epidemiology Unit (GB), Information Today (United States) (US), Amsterdam University Medical Centers (NL), Queen Elizabeth University Hospital (GB), University of Southampton (GB), University College London (GB), Keele University (GB), University of Glasgow (GB), University of Amsterdam (NL), University of Sheffield (GB), University of Edinburgh (GB)
Openalex Percentile: Top 4%
Connective tissue disorders research
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