The effect of sequential antiresorptive therapy after denosumab discontinuation on fracture risk: a systematic review and meta-analysis

Abstract Background Discontinuation of denosumab (DMAb) causes a rapid rebound in bone turnover and increases the risk of multiple vertebral fractures. However, the optimal sequential antiresorptive strategy and its specific timing remain uncertain. Methods We systematically searched PubMed, Embase, Web of Science, and Cochrane Library through September 2025 for primary randomized controlled trials and cohort studies evaluating fracture outcomes after DMAb withdrawal. Pooled risk ratios (RRs) were calculated using a random-effects model, and subgroup analyses were performed according to sequential agent, timing of initiation, DMAb exposure duration, and study design. Results Nine studies involving 1886 patients met the inclusion criteria. Sequential antiresorptive therapy significantly reduced the risk of rebound-associated vertebral fractures compared with control or delayed treatment (pooled RR = 0.50; 95% CI: 0.34–0.75; I² = 20.2%). Early initiation (≤ 3 months after the last DMAb dose) suggested a trend toward greater benefit (RR = 0.32; 95% CI: 0.18–0.57), whereas delayed transition lost statistical significance (RR = 0.66; 95% CI: 0.38–1.14), although the test for subgroup interaction did not reach statistical significance ( p = 0.07). Intravenous zoledronic acid provided the most consistent protection, whereas oral alendronate demonstrated a trend toward fracture risk reduction that did not reach statistical significance. Conclusions Sequential bisphosphonate therapy, particularly potent agents such as intravenous zoledronic acid, with a suggested benefit when administered early (≤ 3 months) after DMAb cessation—substantially mitigates rebound-associated vertebral fracture risk. Proactive transition planning must be considered an integral component of denosumab therapy to preserve skeletal gains and prevent avoidable fractures. (PROSPERO registration Number: CRD420251166058)