Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: Systematic review and meta- analysis

Background: Osteoporosis and cardiovascular (CV) diseases are closely correlated. RANKL/RANK/OPG pathway and Wnt signalling pathway both implicated in the pathogenesis of osteoporosis and cardiovascular diseases. We aimed to investigate the effect of denosumab or romosozumab therapy on cardiovascular outcomes in patients with primary osteoporosis. Methods: PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2019. Randomized clinical trials evaluating the effect of denosumab or romosozumab versus active comparators or placebo for at least 6 months in patients with primary osteoporosis or osteopenia were included. Two investigators independently extracted data for study characteristics, outcomes of interest, and risk of bias in accordance with PRISMA guidelines. Results: 17 relevant studies (denosumab: n = 11, 13615 participants; romosozumab: n = 6, 12219 participants) were included. No associations between denosumab therapy and risk of a composite cardiovascular outcome (1.06 [95 % CI, 0.88-1.28], p = 0.54), three-point major adverse cardiovascular event (3P MACE, 1.01 [95 % CI, 0.83-1.23], p = 0.93), and four-point major adverse cardiovascular event (4P MACE, 0.99 [95 % CI, 0.83-1.18], p = 0.89) were identified. Romosozumab therapy did not increase the risk of composite cardiovascular outcome (1.26 [95 % CI, 0.95-1.68], p = 0.11), and 3P MACE (1.41 [95 % CI, 0.99-2.02], p = 0.06), while increased the risk of 4P MACE (1.39 [95 % CI, 1.01-1.90], p = 0.04) among elderly men and postmenopausal woman with osteoporosis over a period of 12-36 months. Denosumab or romosozumab did not increase or reduce specific cardiovascular outcomes, including CV death or death, myocardial infarction, stroke, atrial fibrillation, heart failure, aortic and intracranial aneurysm, aortic dissection, aortic valve disease and hypertension (all p > 0.05). Sensitivity analysis conducted by random effects model altered the result of 4 P MACE in romosozumab (1.36 [0.99-1.87], p = 0.06). No other significant difference was detected in the sensitivity analyses and subgroup analyses. Conclusions: Denosumab therapy was not associated with any risk of composite and specific cardiovascular outcomes among patients with primary osteoporosis than active comparators or placebo, while romosozumab therapy might increase the risk of 4 P MACE.