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Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized
Alexander H Seeto1, Bo Abrahamsen2,3,4, Peter R Ebeling5,6
1School of Medicine, Griffith University, Gold Coast, Australia.
Insights
This review found denosumab increased cardiovascular adverse events (CAEs) compared to bisphosphonates in postmenopausal women, but not placebo. Standardized reporting is needed for bone medications’ cardiovascular effects.
Area of Science:
- Bone and Mineral Research
- Cardiovascular Safety
- Pharmacovigilance
Background:
- Cardiovascular safety of denosumab requires systematic evaluation.
- Previous studies lack comprehensive analysis of cardiovascular adverse events (CAEs) with denosumab.
- Understanding denosumab's cardiovascular risk profile is crucial for patient management.
Purpose of the Study:
- To systematically review and quantify randomized controlled trials (RCTs) reporting CAEs for denosumab.
- To examine the balance of CAEs between denosumab treatment arms and comparators.
- To assess the cardiovascular safety of denosumab in various indications.
Main Methods:
- Systematic review and meta-analysis of RCTs from MEDLINE, Embase, and clinicaltrials.gov.
- Included trials involved denosumab versus comparators, ≥100 participants, and reported bone outcomes.
- Primary outcome: all CAEs; Secondary outcome: major adverse cardiovascular events (MACE). Data pooled using fixed-effects model.
Main Results:
- In postmenopausal women, denosumab showed a 46% increase in CAEs versus bisphosphonates (RR 1.52 [1.05 to 2.02]).
- A similar imbalance in MACE was observed with denosumab compared to bisphosphonates (RR 2.33 [1.19 to 4.56]).
- No significant imbalance in CAEs was found when comparing denosumab to placebo (RR 0.79 [0.41 to 1.52]).
Conclusions:
- Denosumab is associated with increased CAEs compared to bisphosphonates in postmenopausal women, suggesting bisphosphonates may suppress CAEs.
- No increased cardiovascular risk was observed with denosumab versus placebo.
- Standardized reporting of CAEs in future trials is recommended for better characterization of cardiovascular effects of bone-active medications.
Abstract:
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 October 26, 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 (12 eligible for meta-analysis) were conducted in 13,202 postmenopausal women. Compared with bisphosphonates, there was a 46% (95% CI 1.05 to 2.02) increase in CAEs (85/2136 events in denosumab-treated versus 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 versus 12/2050; RR = 2.33 [1.19 to 4.56]). Compared with placebo-treated women, there was no imbalance in total CAEs (439/4725 events in denosumab versus 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 postmenopausal 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.) © 2020 American Society for Bone and Mineral Research (ASBMR).
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