Pharmacologic management after denosumab discontinuation in osteoporosis: A systematic review and meta-analysis
Rathapoom Suwanaratana, Attaporn Lawanprasert, Nuttawut ChanalithichaiBackground
Denosumab discontinuation is associated with rebound bone turnover, rapid bone mineral density (BMD) loss, and increased vertebral fracture risk. Although subsequent antiresorptive therapy is recommended, the comparative effectiveness of post-denosumab strategies remains uncertain.
Objectives
To evaluate management strategies after denosumab discontinuation in adults treated for osteoporosis or low bone mass, with emphasis on vertebral fracture risk, BMD response, and bone turnover marker (BTM) patterns.
Design
Systematic review and meta-analysis.
Data Sources and Methods
PubMed/MEDLINE, Scopus, and the Cochrane Library/CENTRAL were searched through May 24, 2026. Eligible reports evaluated adults who discontinued, delayed, or transitioned from denosumab and reported fracture, BMD, or BTM outcomes after management. Comparative vertebral fracture data were pooled using random-effects risk ratios. Lumbar spine BMD change after zoledronate follow-on therapy was synthesized using supportive single-arm random-effects meta-analysis. Heterogeneous comparative BMD and BTM outcomes were summarized narratively.
Results
Twenty-two reports representing 19 studies or cohorts were included. Three comparative reports contributed to the vertebral fracture meta-analysis. More potent bisphosphonate follow-on therapy was associated with a lower vertebral fracture risk than no treatment or less potent antiresorptive therapy (pooled risk ratio 0.25, 95% CI 0.11 to 0.60; I 2 = 0%). In the strict single-arm zoledronate synthesis, the supportive pooled estimate of residual lumbar spine BMD change was −1.86% (95% CI −4.63 to 0.91; I 2 = 89.7%). Comparative BMD evidence generally suggested greater preservation with alendronate or zoledronate than with no treatment or other less potent antiresorptive strategies. BTM evidence showed heterogeneous post-transition turnover patterns, with persistent CTX elevation associated with residual BMD loss in some studies. However, marker-guided retreatment was not shown to improve clinical outcomes.
Conclusion
Very low-certainty evidence supports planned antiresorptive therapy after denosumab discontinuation rather than passive cessation. The available evidence does not establish a preferred agent or regimen, and optimal timing, dosing, and retreatment strategies remain uncertain.