Teriparatide Plus Zoledronic Acid Does Not Reduce Fracture Risk in Adults with OI

Rethinking Fracture Prevention in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder of type I collagen synthesis that subjects patients to a lifetime of bone fragility and recurrent fractures, causing significant morbidity [1, 2, 3]. While bisphosphonates are widely used to improve bone mineral density (BMD), their efficacy in reducing fracture risk in adults with OI remains inconsistent [1, 4]. Teriparatide, a parathyroid hormone analogue that stimulates bone formation, has also been explored as a potential therapy [5, 6, 7]. A recent multicenter randomized trial, the TOPaZ study, directly addressed this therapeutic question by testing a sequential regimen of teriparatide followed by zoledronic acid. The findings revealed that despite significantly increasing BMD, this anabolic-first approach did not reduce the incidence of fractures compared with standard care, challenging the long-held assumption that density is the primary determinant of bone strength in this population [8].

Trial Design and Participant Characteristics

The TOPaZ study was a large, multicenter open-label, parallel-group, randomized clinical trial conducted between May 17, 2017, and March 21, 2025. By recruiting adults with a clinical diagnosis of osteogenesis imperfecta from 27 specialized referral centers, the study design aimed for broad applicability of its findings. Of the 350 individuals randomized, 176 were assigned to the teriparatide plus zoledronic acid group and 174 to standard care. After one withdrawal, 349 participants were included in the final analysis. The cohort had a mean age of 43.7 years, and 188 (53.9%) were female. Critically, most participants had type I osteogenesis imperfecta, the most common form, which is typically caused by pathogenic variants in type 1 collagen genes. This specific patient profile is essential for interpreting the trial's outcomes in the context of the most prevalent OI subtype.

Intervention and Outcome Measures

The active intervention consisted of a sequential therapy: 20 μg of teriparatide administered daily by subcutaneous injection for two years, followed by a single 5 mg infusion of zoledronic acid. The control group received standard care, which could include bisphosphonates or other bone-targeted medicines but expressly prohibited teriparatide or any other bone anabolic agents. This design created a clear comparison between an anabolic-first strategy and conventional management. The primary endpoint was the number of participants experiencing an incident fracture, confirmed by skeletal imaging and adjudicated by reviewers who were blinded to treatment allocation to prevent bias. Secondary endpoints included total fracture count, changes in BMD measured by dual x-ray absorptiometry, and shifts in biochemical markers of bone turnover. These markers included serum procollagen type 1 N-terminal propeptide, an indicator of bone formation, and C-terminal telopeptide of type 1 collagen, a marker of bone resorption.

Fracture Risk: No Significant Reduction

The study's primary outcome showed no statistically significant benefit for the sequential therapy in preventing fractures. In the teriparatide plus zoledronic acid group, 65 of 176 participants (36.9%) sustained an incident fracture, a rate nearly identical to the 63 of 173 participants (36.4%) in the standard care group. This translated to a negligible absolute risk reduction of –1.57% (95% CI, –9.90% to 5.89%). The hazard ratio further confirmed the lack of effect, at 0.97 (95% CI, 0.68 to 1.38). These results demonstrate that a two-year course of teriparatide followed by zoledronic acid did not confer a protective advantage against fractures over standard management. The authors suggest this finding points toward the central role of poor bone quality, a hallmark of OI's defective collagen matrix, as the dominant driver of fracture risk, which may not be overcome by simply increasing bone mass.

Bone Mineral Density and Quality of Life Improvements

Although the intervention failed to reduce fracture incidence, it did produce notable effects on secondary endpoints. Measurements from dual x-ray absorptiometry confirmed that lumbar spine and total hip BMD increased significantly more in the teriparatide plus zoledronic acid group than in the standard care group. This result highlights a critical dissociation: the therapy successfully increased bone mass but did not translate this gain into improved skeletal integrity. In addition to the BMD findings, several health-related quality-of-life measures favored the active treatment group, suggesting patients experienced a subjective benefit even in the absence of fracture reduction. Furthermore, the safety analysis was reassuring, as the incidence of adverse events was similar between the two groups, indicating the sequential regimen did not pose additional risks.

Clinical Implications: Beyond Bone Density

The central finding of this trial is that a potent anabolic-antiresorptive sequence of teriparatide and zoledronic acid did not reduce fracture risk in adults with osteogenesis imperfecta, despite successfully increasing BMD. This outcome has direct clinical relevance for physicians managing this condition, where fracture prevention is the paramount goal. The results strongly suggest that in adults with OI, fracture pathogenesis is driven more by inherently poor bone quality than by low bone density. Consequently, therapeutic strategies focused solely on increasing bone mass, as measured by standard densitometry, may be insufficient. This study underscores the need for future research to target the qualitative defects in the bone matrix itself. For practicing clinicians, these findings serve as a reminder that while improving BMD is a logical goal, it may not be an adequate surrogate for fracture reduction in patients with underlying collagen disorders.

References

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