ORF43-02 - Cardiovascular Safety of Romosozumab Versus Alendronate in Postmenopausal Women with Severe Osteoporosis

Background: Romosozumab is a highly effective therapy for severe osteoporosis, but its cardiovascular safety remains debated. While the ARCH trial reported an imbalance in major adverse cardiovascular events against romosozumab, the FRAME trial showed no cardiovascular signals. To address this uncertainty, we compared the 12-month real-world cardiovascular outcomes among postmenopausal women with severe osteoporosis initiating romosozumab versus alendronate.

Methods: Using the TriNetX US Collaborative Network, we identified women ≥55 years with severe osteoporosis who initiated romosozumab or alendronate. Severe osteoporosis was defined by the presence of a pathological fracture, including hip or lumbar vertebral fracture, within 2 years prior to initiation of romosozumab or alendronate. The index date was defined as the date of treatment initiation. Patients with acute coronary syndrome (ACS), coronary revascularization, ischemic stroke, or intracerebral hemorrhage within 12 months before the index date were excluded from both cohorts. Cohorts were propensity-score matched on age, race, BMI, baseline cardiovascular risk factors, and use of statin, antiplatelet, and anticoagulant therapies, and were followed for 12 months. Outcomes included myocardial infarction (MI), ACS (MI and unstable angina), and ischemic stroke. In secondary event-naïve analyses, we further excluded patients with any prior history of the evaluated outcome. Outcomes were evaluated using Cox proportional hazards models.

Results: After matching, 6,419 patients remained in each group with well-balanced baseline characteristics and equal median follow-up of 365 days. 12-month MI risk (1.14% vs 1.53%; HR 0.79; 95% CI 0.58–1.07; p=0.13) and ACS risk (1.29% vs 1.71%; HR 0.80; 95% CI 0.60–1.07; p=0.13) were comparable. However, ischemic stroke risk was significantly lower among patients treated with romosozumab (1.09% vs 1.62%; HR 0.71; 95% CI 0.53–0.97; p=0.03). In event-naïve analyses, acute MI (0.95% vs 1.36%; HR 0.74; 95% CI 0.53–1.03; p=0.07), ACS (1.05% vs 1.46%; HR 0.76; 95% CI 0.55–1.05; p=0.09), and ischemic stroke (0.98% vs 1.33%; HR 0.78; 95% CI 0.56–1.09; p=0.14) did not reach statistical significance.

Conclusion: In this propensity-matched real-world cohort of postmenopausal women with severe osteoporosis, romosozumab was not associated with higher 12-month risks of major cardiovascular events, including MI, ACS, or ischemic stroke, compared with alendronate. A lower rate of ischemic stroke was observed in the primary analysis, while analyses excluding patients with prior events showed directionally similar but non-significant trends. Overall, these findings suggest no increase in short-term cardiovascular risk with romosozumab compared to alendronate. Findings should be interpreted in light of the observational design and the potential for residual confounding.