Denosumab and Risk of Type 2 Diabetes Risk Among Patients With Osteoporosis

Objective: To compare the risk of new-onset type 2 diabetes mellitus (T2D) between intravenous (IV) bisphosphonates and denosumab among patients with osteoporosis. Methods: We conducted a retrospective cohort study using the TriNetX database from 2016 to 2024. Patients with osteoporosis initiating IV bisphosphonates (zoledronic acid or ibandronate) or denosumab were identified and assigned to respective cohorts. Propensity score matching (1:1) was applied to balance demographics, lifestyle factors, health care utilization, comorbidities, medications, and laboratory parameters. The primary outcome was incident T2D, defined by International Statistical Classification of Diseases, 10th Revision code E11 or the initiation of antidiabetic medications. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. Results: After matching, 20 735 patients remained in each cohort. Compared with denosumab, IV bisphosphonates were associated with a significantly lower risk of T2D at 1, 3, 5, and 7 years (HRs: 0.745 [95% CI 0.649-0.856], 0.806 [95% CI 0.731-0.890], 0.818 [95% CI 0.747-0.895], and 0.821 [95% CI 0.753-0.896], respectively; all P <.001). Subgroup analyses demonstrated consistent risk reduction among females (HR 0.739), individuals aged ≥65 years (HR 0.688), Whites (HR 0.799), and Black or African Americans (HR 0.608). Conclusions: Among patients with osteoporosis, IV bisphosphonates were associated with a lower risk of incident T2D compared with denosumab. These findings suggest potential metabolic benefits of IV bisphosphonates and support the need for prospective studies to validate these observations.