Potent bisphosphonate therapy for preventing fractures after denosumab discontinuation in osteoporosis

Background: Denosumab cessation causes rebound bone turnover, fast bone loss, and an elevated risk of vertebral fractures. Pooled data about the fracture prevention efficacy of potent bisphosphonates (BPs) as sequential therapy have been lacking to counteract this risk. Methods: This systematic review and meta-analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. PubMed, Scopus, the Cochrane Library, and ClinicalTrials.gov were searched from the beginning through May 1, 2026. Included studies comprised adults with osteoporosis or low bone mass who discontinued denosumab and subsequently received potent BP therapy, defined as alendronate or zoledronic acid, compared with no subsequent antiresorptive therapy or a selective estrogen receptor modulator (SERM). Random-effects meta-analyses were performed using the Mantel–Haenszel method to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Prespecified subgroup analyses were conducted based on comparator type. The Grading of Recommendations Assessment, Development and Evaluation assessment method was applied to assess the certainty of the evidence. Results: Six studies were included; 683 participants contributed to the primary incident vertebral fracture analysis. Potent BP therapy was linked to a considerable reduction in incident vertebral fractures (RR = 0.29; 95% CI: 0.14–0.59; 71% relative risk reduction), multiple vertebral fractures (RR = 0.08; 95% CI: 0.01–0.43; 92% relative risk reduction), and clinical vertebral fractures (RR = 0.18; 95% CI: 0.07–0.49; 82% relative risk reduction). The protective effect was driven mainly by comparisons with no subsequent therapy, while comparisons with SERM therapy were limited and not statistically significant. There was no statistically significant reduction in any fracture (RR = 0.35; 95% CI: 0.10–1.24) or non-vertebral fracture (RR = 0.43; 95% CI: 0.07–2.64). Overall certainty of evidence was low to very low, mainly due to the observational nature of most included studies and imprecision in several outcomes. Conclusion: Potent BP therapy was related to decreased vertebral fracture risk after denosumab termination, particularly when compared with no subsequent therapy. Evidence versus SERM comparators was limited and inconclusive. The results are in agreement with the present clinical guideline recommendations for sequential BP use after the discontinuation of denosumab, but further high-quality randomized trials are required to prove this.