Osteoarthritis risk associated with denosumab in adults with osteoporosis: A target trial emulation

Denosumab, a well-established osteoporosis treatment, has demonstrated potential bone- and cartilage-protective effects in preclinical and early trials. However, it remains unclear whether these promising findings extend to osteoarthritis prevention in weight-bearing joints and broader real-world osteoporotic populations. We compared osteoarthritis incidence between denosumab and oral bisphosphonates in adults aged 50 years or older with osteoporosis using a sequential nested target trial emulation with propensity score matching based on longitudinal health insurance claims data from Japan collected between 2015 and 2024. Two target comparisons were conducted: one compared new users of denosumab with new users of oral bisphosphonates, and the other compared patients who switched from oral bisphosphonates to denosumab with those who continued oral bisphosphonates. The primary outcome was osteoarthritis incidence. Secondary outcomes included joint-specific osteoarthritis (knee, hip, and hand) over 3 years. The absolute risk reduction (ARR) and relative risk (RR) at 3 years were estimated using a Kaplan-Meier estimator in both the per-protocol and intention-to-treat analyses. In the per-protocol analyses, the ARR for incident osteoarthritis was 2.0% (95% confidence interval [CI], 1.1%-3.2%) in the new-user comparison, with an RR of 0.83 (95% CI, 0.73-0.91), and 0.9% (95% CI, -0.2% to 2.8%) in the switch-continue comparison, with an RR of 0.92 (95% CI, 0.76-1.02). In the intention-to-treat analyses, the corresponding ARR was 1.9% (95% CI, 1.3%-3.3%) in the new-user comparison, with an RR of 0.84 (95% CI, 0.73-0.89), and 1.2% (95% CI, -0.2% to 2.7%) in the switch-continue comparison, with an RR of 0.89 (95% CI, 0.77-1.02). Denosumab initiation was associated with a modestly lower risk of incident osteoarthritis than oral bisphosphonate initiation, although the association was weaker in the switch-continue comparison.