Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta: A Randomized Clinical Trial

# Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta: A Randomized Clinical Trial *Published: 2026 May 14* print. Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta: A Randomized Clinical Trial. Hald JD(1)(2), Weir CJ(3), Keerie C(3), Dewar L(3), MacLean M(3), Milne L(3), Keen R(4), Walsh JS(5), Poole KES(6), Langdahl BL(1), Lindsay JR(7), Ghouri N(8)(9), Hollick R(10), Aspray T(11), Crowley RK(12)(13), Cohen-Solal M(14), Hassan-Smith Z(15), Tuck S(16), Curtis EM(17)(18), Harvey NC(17)(18), Eekhoff EMW(19), Feenstra J(20), Hampson G(21), Stone M(22), Turton J(22), Patel P(23), Siddiqi M(24), Munro R(25), Roy M(26), Paskins Z(27), Narayanan D(28), Malcolm E(29), Javaid MK(30), Osborne P(31), Tang JCY(32)(33), Lam W(34), Moore D(34), Black HA(34), Duckworth AD(35)(36), Makaram NS(35), Guo T(37), Stenhouse G(37), Ralston SH(33)(38); TOPaZ Investigators. Collaborators: Conaghan P, Llungren O, Sutton CJ, Nevalainen E, Woolf A, Cro S, Lema W. Author information: (1)Endocrinology, Aarhus University Hospital, Aarhus, Denmark. (2)Centre for Rare Disorders, Aarhus University Hospital, Aarhus, Denmark. (3)Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom. (4)Metabolic Bone Clinic, Royal National Orthopaedic Hospital NHS Trust, London, United Kingdom. (5)Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom. (6)Cambridge University Hospitals NHS Trust, Addenbrookes Hospital, Cambridge, United Kingdom. (7)Belfast Health and Social Care Trust, Royal Victoria Hospital, and Musgrave Park Hospital, Belfast, United Kingdom. (8)Queen Elizabeth University Hospital, Endocrinology, Glasgow, United Kingdom. (9)University of Glasgow, Glasgow, United Kingdom. (10)Aberdeen Centre for Arthritis and Musculoskeletal Health (Epidemiology), University of Aberdeen, Aberdeen, United Kingdom. (11)University of Newcastle, Bone Clinic- Freeman Hospital, Newcastle, United Kingdom. (12)Department of Endocrinology, St Vincent's University Hospital, Dublin, Ireland. (13)Rare Disease Clinical Trial Network, University College Dublin, Dublin, Republic of Ireland. (14)Department of Rheumatology, Inserm U1132 Bioscar, Paris, France. (15)Aston Medical School, Aston University, Birmingham and Queen Elizabeth Hospital, Department of Endocrinology, Birmingham, United Kingdom. (16)South Tees Hospitals NHS Foundation Trust, Rheumatology, Middlesborough, United Kingdom. (17)MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, United Kingdom. (18)NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. (19)Amsterdam University Medical Centre, Endocrinology, Amsterdam, Netherlands. (20)Isala Hospital Zwolle, Expert Centre for Osteogenesis Imperfecta in Adults, Zwolle, Netherlands. (21)Guys & St Thomas NHS Trust, Metabolic Bone Clinic, London, United Kingdom. (22)University Hospital Llandough, Metabolic Bone Clinic, Cardiff, United Kingdom. (23)University Hospitals of Leicester NHS Trust, Chemical Pathology and Metabolic Disease, Leicester, United Kingdom. (24)University Hospitals of Liverpool Group, Liverpool, United Kingdom. (25)University Hospital Wishaw, Wishaw, United Kingdom. (26)University Hospitals Bristol NHS Trust, Bristol Royal Infirmary, Bristol, United Kingdom. (27)Keele University, School of Medicine, Keele, United Kingdom. (28)The Centre for Metabolic Bone Disease, Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom. (29)Ninewells Hospital and Medical School, Department of Medicine, Dundee, United Kingdom. (30)Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. (31)Brittle Bone Society, Chief Executive Office, Dundee, United Kingdom. (32)Royal Free London NHS Foundation Trust London, United Kingdom. (33)Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom. (34)South East Scotland NHS Genetics Service, Edinburgh, United Kingdom. (35)Department of Orthopaedic Surgery, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, United Kingdom. (36)Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom. (37)Department of Radiology, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, United Kingdom. (38)Department of Rheumatology, Western General Hospital, NHS Lothian, Edinburgh, United Kingdom. Comment in doi: 10.1001/jama.2026.6971. ## 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. DOI: 10.1001/jama.2026.6889 PMCID: PMC13177192 DOI: 10.1001/jama.2026.6971