The third-year results of denosumab sequential therapy trial: An extension of a randomized clinical trial.

Abstract

Background/purpose: Denosumab effectively increases bone mineral density (BMD) and reduces fracture risk in osteoporosis patients. Denosumab discontinuation is related with rebound bone loss and increased fracture risk. Zoledronate has been proposed as sequential therapy to mitigate this effect. We investigated the efficacy of an alternating regimen of denosumab and zoledronate on BMD and bone turnover markers (BTMs) over three years.

Methods: This one-year extension of a multicenter, open-label randomized controlled trial included postmenopausal women and men aged ≥50 who had been receiving biannual denosumab for at least two years but less than three years. In the original trial, participants were assigned to either a control group that received denosumab for two years or an intervention group that received zoledronate in the first year followed by a switch back to denosumab in the second year. In this extension study, both groups received denosumab in the third year.

Results: At 36 months, no statistically significant between-group differences in BMD changes were observed during the extension period. However, the intervention group exhibited lower levels of BTMs (CTX and P1NP), indicating a reduction in bone resorption activity. There was no significant difference in fracture rates between groups.

Conclusion: These findings suggest that an alternating regimen of denosumab and zoledronate may be a viable strategy for managing osteoporosis, effectively mitigating the rebound effect while maintaining BMD gains. The observed benefits of reduced BTMs in the intervention group highlight the long-lasting therapeutic effects of zoledronate. Further research is necessary to confirm these results and determine this approach's long-term safety and cost-effectiveness.

Trial registration: ClinicalTrials.gov NCT03868033; registered March 7, 2019.