Denosumab Offers Relatively Lower Initial Protection Against Osteoporotic Vertebral Fractures in Treatment‐Naive Patients Compared With Zoledronate

We compared the initial efficacy of denosumab (Dmab) and zoledronate (ZOL) in treatment‐naive patients with osteoporosis. This cohort study, based on TriNetX data, evaluated the risks of fractures and mortality using Kaplan–Meier survival analyses, with hazard ratios (HRs) and 95% confidence intervals (CIs). Propensity‐score matching generated 10,811 well‐balanced patient pairs. Compared with initiation of annual ZOL, initiation of Dmab with the second dose administered within 7 months of the first injection (no or ≤ 1 month delay) was associated with higher risks of osteoporotic fractures (HR = 1.512, 95% CI = 1.277–1.790), vertebral fractures (HR = 1.609, 95% CI = 1.130–2.293), and lumbar fractures (HR = 2.225, 95% CI = 1.168–4.239). Fracture protection with Dmab declined markedly at 6–7 months but remained stable when two injections were administered within 6 months (no delay). Subgroup analyses showed higher risks of osteoporotic and vertebral fractures among Dmab users without diabetes, without prior steroid exposure, and with an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m 2 . Additionally, among patients with prior steroid exposure, Dmab users had a higher risk of osteoporotic fractures compared with ZOL users. In treatment‐naive patients with osteoporosis, Dmab provided less initial protection against osteoporotic and vertebral fractures than ZOL, and delayed dosing further increased fracture risk.