The cardiovascular safety of denosumab has not yet been evaluated in a systematic review. This systematic review and meta-analysis sought to quantify the number of randomized controlled trials (RCTs) of denosumab (against comparators) reporting cardiovascular adverse events (CAEs) and examine the balance of CAEs between treatment arms. MEDLINE, Embase and clinicaltrials.gov were searched from inception to 26 October 2019 for RCTs of denosumab versus comparators for any indication. Included trials were randomized, enrolled ≥100 participants and reported bone-related outcomes. Primary outcome for analysis was all CAEs; a composite endpoint representing summation of all CAEs as reported by included trials. Secondary outcomes included Major Adverse Cardiovascular Events (MACE). Data were pooled using a fixed effects model to determine relative risk (RR) and 95% confidence interval (95%CI). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 554 records screened, 49 were included, while 36 reported CAEs. Twenty-seven included trials (twelve eligible for meta-analysis) were conducted in 13,202 post-menopausal women. Compared with bisphosphonates, there was a 46% (95% CI: 1.05 to 2.02) increase in CAEs [85/2136 events in denosumab-treated vs. 58/2131 events in bisphosphonate-treated); seven trials]. There was a similar imbalance in a five-point (stroke, myocardial infarction, cardiovascular death, heart failure, atrial fibrillation) MACE endpoint [28/2053 vs. 12/2050; RR=2.33(1.19, 4.56)]. Compared with placebo-treated women, there was no imbalance in total CAEs [439/4725 events in denosumab vs. 399/4467 in placebo; RR=0.79 (0.41 to 1.52); seven trials]. No imbalance in total AEs [versus bisphosphonates: 0.98 (0.92 to 1.04); versus placebo: 0.99 (0.98 to 1.01)] occurred. Other indications showed no statistically significant results. The excess CAEs in post-menopausal women treated with denosumab compared with bisphosphonates, but not placebo, indirectly supports claims that bisphosphonates may suppress CAEs. Future trials should use standardized CAE reporting to better describe cardiovascular effects of bone active medications. (PROSPERO: CRD42019135414.).This article is protected by copyright. All rights reserved.