Cardiovascular Safety of Denosumab Across Multiple Indications: A Systematic Review and Meta-Analysis of Randomized Trials

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 http://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).

Cardiovascular Safety of Antifracture Medications in Patients With Osteoporosis: A Narrative Review of Evidence From Randomized Studies

“…There was a doubling of risk when considering a five‐point MACE outcome (RR = 2.33; 95% CI, 1.19 to 4.56). ( 55 ) These findings mirror what was evidenced by the romosozumab trials—namely treatment arms experiencing elevated CV events in a BP‐controlled trial but not in a placebo‐controlled trial. This provides indirect evidence for cardioprotection by BPs.…”

“…For all serious CV events [186 (4.8%) vs. 178 (4.6%); RR= 1.04 (0.85 to 1.27)] and strokes [56 (1.4%) vs. 54 (1.4%); RR= 1.03 (0.71 to 1.49)] there was a balance in event rates; whilst there was a non-statistically significant reduced event rate in terms of coronary heart disease [47 (1.2%) vs. 39 (1.0%); RR= 0.87 (0.59 to 1.28)]. These data are supported by a series of metaanalyses (53)(54)(55) . Similar to the HORIZON sub-study on AAC, RANKL inhibition appeared to not change the fate of AAC progression in a sub-study of the FREEDOM trial (118/544 [22%] in denosumab versus 109/501 [22%] in placebo).…”

“…These data are supported by a series of meta‐analyses. ( 55–57 ) Similar to the HORIZON substudy on AAC, RANKL inhibition appeared to not change the fate of AAC progression in a substudy of the FREEDOM trial (118/544 [22%] in denosumab versus 109/501 [22%] in placebo). This finding was consistent across baseline AAC status (score ≤6 versus score >6) and, importantly, renal function (estimated glomerular filtration rate ≤45 versus >45).…”

Cardiovascular Safety of Denosumab Across Multiple Indications

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We have read with great interest the recently published work by Seeto and colleagues, (1) which comprehensively reviewed the currently available evidence to evaluate the cardiovascular safety of denosumab across multiple indications. This well-

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“…First, this systematic review and meta-analysis only included trials that enrolled more than 100 participants; therefore, 34 records and three full-text articles were excluded mainly because of inadequate population size. (1) We reviewed both the eligibility criteria of this study and the protocol registered with PROSPERO (CRD42019135414), and neither of them elaborated the reason for the exclusion. In general, clinical trials that randomize less than 100 participants are considered to have a relatively modest sample size, a scenario that, while not leading to a null finding, is more likely to result in overestimation of the treatment effect than studies with adequate sample size.…”