Denosumab withdrawal increases vertebral fracture and mortality risk compared with zoledronate

Objective: Rebound vertebral fractures (VFs) after denosumab (Dmab) withdrawal have been documented, highlighting the need for further research into this phenomenon and the importance of a well-planned strategy for discontinuing Dmab. Methods: From the TriNetX US network, we enrolled osteoporosis patients aged 50 years or older who had withdrawn from at least 2 doses of Dmab and compared them with a matched cohort who had received at least 1 dose of zoledronate (ZOL) before discontinuation. We analyzed hazard ratios (HRs) with 95% confidence intervals (CIs) and conducted Kaplan–Meier analyses, along with subgroup analyses, drug discontinuation modification, and sensitivity analyses. Results: After matching propensity scores (n = 10 422) between the 2 cohorts (Dmab: 11 104 and ZOL: 15 976), we found that the risks of VFs (HR = 1.479, 95% CI = 1.222-1.789) and its subcategories—thoracic (1.309, 1.023-1.674), lumbar (1.865, 1.425-2.440), and collapsed fractures (1.928, 1.462-2.542)—as well as all-cause mortality (1.588, 1.475-1.710), were significantly higher in the Dmab group compared with the ZOL group. Stratified analyses showed increased VF risks in Dmab patients who were female, aged 50-64, 65 years or older, and white, regardless of fracture history compared with those using ZOL. Conclusion: After adjusting for drug discontinuation, Dmab showed an increased risk of VFs within the first 2 years, contributing to an elevated overall mortality risk. Sensitivity analyses revealed consistent results across different regions.