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 m2. 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.