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Methods: From the TriNetX US network, we enrolled osteoporosis patients aged 50 years or older who had withdrawn from at least two doses of Dmab and compared them with a matched cohort who had received at least one dose of zoledronate (ZOL) before discontinuation. We analyzed hazard ratios (HR) with 95% confidence intervals (CI) 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 two 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 two years, contributing to an elevated overall mortality risk. Sensitivity analyses revealed consistent results across different regions.