Teriparatide Plus Zoledronic Acid Does Not Lower Fracture Risk in Osteogenesis Imperfecta, Study Finds
Denmark: A large randomized clinical trial published in JAMA has found that a treatment strategy combining teriparatide followed by zoledronic acid does not reduce fracture risk in adults with osteogenesis imperfecta, despite significantly improving bone mineral density (BMD).
Osteogenesis imperfecta is a genetic disorder characterized by fragile bones and recurrent fractures throughout life, leading to considerable morbidity. While therapies that increase bone density have been widely used, their effectiveness in preventing fractures in this population has remained uncertain. To explore this, researchers led by Jannie Dahl Hald from Aarhus University Hospital conducted a multicenter, open-label randomized trial across 27 referral centers.
The study enrolled 350 adults diagnosed with osteogenesis imperfecta, of whom 349 were included in the final analysis. Participants were randomly assigned to receive either daily teriparatide injections for two years followed by a single infusion of zoledronic acid, or standard care, which included bisphosphonates and other bone-targeted therapies but excluded anabolic agents such as teriparatide. The average participant age was 43.7 years, and most had type I osteogenesis imperfecta linked to mutations in type 1 collagen genes.
The trial revealed the following findings:
- The primary outcome was imaging-confirmed new fractures, with no significant difference between groups.
- Incident fractures occurred in 36.9% of the combination therapy group versus 36.4% in the standard care group.
- No statistically significant reduction in fracture risk was observed with teriparatide followed by zoledronic acid.
- Total fracture counts also showed no advantage of the intervention over standard care.
- The combination therapy resulted in significant increases in bone mineral density at the lumbar spine and total hip.
- Despite improved bone density, fracture rates were not reduced, indicating limited impact on skeletal fragility.
- The findings suggest that bone quality may play a more critical role than bone density in fracture risk.
- Patient-reported quality of life showed some improvement with the combination therapy.
- Interpretation of quality-of-life outcomes is limited due to the open-label study design.
- The safety profile was similar in both groups, with no major differences in adverse events.
The investigators noted several limitations. Fewer fractures than expected may have reduced the ability to detect treatment effects. Fall frequency was not assessed and could have influenced outcomes. Additionally, prior bisphosphonate use in many participants may limit the applicability of the findings to treatment-naïve patients.
Overall, the study highlights the need to rethink current therapeutic approaches for osteogenesis imperfecta. While pharmacological strategies that enhance bone density show measurable biological effects, they may not adequately reduce fracture risk. The authors emphasize the importance of developing treatments that target bone quality and structural integrity to more effectively manage this complex condition.
Reference:
Hald JD, Weir CJ, Keerie C, et al. Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta: A Randomized Clinical Trial. JAMA. Published online May 14, 2026. doi:10.1001/jama.2026.6889
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