Cardiovascular safety of romosozumab versus denosumab for osteoporosis treatment: a multinational real-world data analysis

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Background: Romosozumab and denosumab are two highly effective, widely used osteoporosis treatments. There has been no study directly comparing the effectiveness of romosozumab and denosumab in a clinical setting using large-scale, real-world data. Objectives: To evaluate the association between romosozumab and cardiovascular outcomes compared to denosumab in patients with osteoporosis. Design: Retrospective propensity score-matched cohort study. Methods: Using the TriNetX global health research network, we identified 59,058 patients aged 60 years or older with osteoporosis who initiated romosozumab ( n = 5200) or denosumab ( n = 53,858) between January 2019 and December 2024. After 1:1 propensity score matching, 2 balanced cohorts of 5192 patients each were obtained. Cardiovascular outcomes, including three-point major adverse cardiac events (3P-MACE ), 4P-MACE, 5P-MACE, individual MACE components, and other cardiovascular diseases (CVDs), were assessed across three follow-up periods: short-term (1 year), mid-term (3 years), and long-term (5 years). Primary analyses were conducted among patients without a prior cardiovascular history, and sensitivity analyses were performed among those with a prior cardiovascular history. Results: Among patients without a prior cardiovascular history, romosozumab was associated with significantly lower risks of 3P-MACE at 3-year (hazard ratio (HR) 0.645, 95% confidence interval (CI) 0.438–0.950, p = 0.023) and 5-year follow-up (HR 0.755, 95% CI 0.512–0.873, p = 0.028), and lower mortality at 3-year (HR 0.554, 95% CI 0.316–0.972, p = 0.038) and 5-year follow-up (HR 0.533, 95% CI 0.312–0.913, p = 0.028). No significant differences were observed at 1-year follow-up. In contrast, among patients with a prior cardiovascular history, romosozumab was associated with significantly higher risks of 4P-MACE, 5P-MACE, stroke, mortality, and chronic ischemic heart disease across all three follow-up time horizons. Conclusion: Romosozumab was associated with lower risks of 3P-MACE and mortality compared to denosumab among patients without a prior cardiovascular history at mid-term and long-term follow-up. In contrast, romosozumab was associated with consistently higher cardiovascular risks in patients with preexisting CVD. These findings highlight the importance of careful cardiovascular risk assessment prior to initiating romosozumab, particularly in patients with preexisting CVD. The 3P-MACE finding in patients without prior cardiovascular history is the primary confirmatory result; all other outcomes should be considered exploratory and hypothesis-generating.

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