Association between Denosumab and Risk of Cardiovascular Events in Patient with Osteoporosis: A Target Trial Emulation Study with Clone-Censor-Weight Approach

Background: Observational studies have indicated that denosumab is associated with a higher risk compared to bisphosphonates. However, this observed higher risk may not necessarily implicate denosumab in increased risk, as bisphosphonates may be associated with reduced cardiovascular risk.

Objectives: To evaluate the association between the risk of cardiovascular events and denosumab use in patients with osteoporosis.

Methods: We emulated a pragmatic, open-label clinical trial using data from the National Health Insurance Database between 2009-2020. The study included patients newly received denosumab for osteoporosis (with a one-year washout period). We applied the clone-censor-weight approach with a 225-day grace period to determine group assignment. The denosumab group was defined as those receiving at least two doses of denosumab within the grace period; otherwise, patients were defined as the control group. We cloned each patient and assigned them to the other group. The outcomes were macrovascular events (coronary artery disease, stroke, and peripheral vascular disease), microvascular events (retinopathy, neuropathy, and nephropathy), and all-cause mortality. Patients were followed up for 1 year or until occurrence of the outcomes or death. We utilized the Cox model to generate hazard ratios to compare the risk of outcome events between the denosumab group and control group. We used a non-parametric bootstrap method of 100 samples to yield 95% confidence intervals. The inverse probability of censoring weights was used to address artificial censoring.

Results: A total of 35,159 patients with denosumab were included, with a mean age of 76.6 (SD: 8.4), and 86.4% were females. Compared to the control group, the denosumab group was not associated with an increased risk of macrovascular (HR=1.00; 95% CI, 0.97-1.03) and microvascular events (HR=1.02; 95% CI, 0.97-1.07), but was associated with a reduced risk of all-cause mortality (HR=0.80; 95% CI, 0.78-0.85).

Conclusions: Our results suggested that denosumab was not associated with an increased risk of cardiovascular events. The study provided evidence that concerns over cardiovascular events may not be necessary for those receiving denosumab for osteoporosis.