Differential efficacy of initial versus sequential combination of denosumab and teriparatide in osteoporosis at high fracture risk.

UNLABELLED: For patients already on denosumab, adding teriparatide is a suboptimal last resort: it offers limited spinal benefit but carries a significant risk of hip bone loss, mandating a site-specific risk-benefit assessment.

BACKGROUND

The management of patients with osteoporosis who exhibit a suboptimal response to denosumab remains clinically challenging. Adding teriparatide to established denosumab therapy is not well defined for high-risk patients in real-world settings.

OBJECTIVE

This study aimed to directly compare the 12-month effects on bone mineral density (BMD) and bone turnover markers between an "initial combination" versus "sequential combination" (adding teriparatide to ongoing denosumab) in a cohort of postmenopausal women at high fracture risk.

METHODS

In this 1-year retrospective cohort study, patients were assigned to one of two groups based on treatment history: the initial combination group (n = 54), in which teriparatide was initiated within 6 months of starting denosumab, and the sequential combination group (n = 25), in which teriparatide was added after more than 6 months of continuous denosumab monotherapy. The primary outcome was the percent change in lumbar spine (L1-L4) BMD.

RESULTS

The mean increase in lumbar spine BMD was significantly greater in the initial combination group (+13.4%; 95% CI 9.9 to 22.5%) compared with the sequential combination group (+8.3%; 95% CI 1.9 to 9.2%; P = 0.030). A critical divergence was observed at the total hip. The initial combination group showed an increase in BMD (+6.0%; 95% CI -0.5 to 12.2%), whereas the sequential combination group experienced a significant decrease (-5.1%; 95% CI -7.1 to -3.9%; P = 0.009). Bone turnover markers (P1NP and CTX) were markedly elevated in the sequential combination group compared to the initial combination group (both P < 0.01). These differential effects were consistent across subgroups, regardless of prior bisphosphonate use or the duration of denosumab pretreatment.

CONCLUSION

Initial combination is optimal, while if sequential combination is necessary, it requires caution and may be more suitable for patients with predominant vertebral risk, mandating a site-specific benefit-risk assessment.