Cardiovascular safety of denosumab across multiple indications:​ a systematic review and meta‐analysis of randomized trials

Seeto, Alexander H.<sup>1</sup>; Abrahamsen, Bo<sup>2,3,4</sup>; Ebeling, Peter R.<sup>5,6</sup>; Rodríguez, Alexander J.<sup>2,5,7</sup>

Affiliations

¹School of Medicine, Griffith University, Gold Coast, Australia

²OPEN-Odense Patient Data Explorative Network, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

³Musculoskeletal Pharmaco- and Device Epidemiology, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatologyand Musculoskeletal Sciences, University of Oxford, Oxford, UK

⁴Department of Medicine, HolbaekHospital, Holbaek, Denmark

⁵Bone and Muscle Health Research Group, Department of Medicine, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Monash Medical Centre, Clayton, Australia

⁶Australian Institute for Musculoskeletal Science, St Albans, Australia

⁷Disorders of Mineralisation Research Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia

Abstract and keywords

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.)

Keywords: ANTIRESORPTIVES; CANCER; CLINICAL TRIALS; MENOPAUSE; OSTEOPOROSIS

Links

DOI: 10.1002/jbmr.4157

PubMed: 32780899

WoS: 000571168400001

History

Received: 2020-05-1

Revised: 2020-07-20

Accepted: 2020-08-2

Online: 2020-09-19

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Cited By (1)

Year	Entry
2023	Seeto AH, Tadrous M, Gebre AK, Lewis JR, Fink HA, Ebeling PR, Rodríguez AJ. Evidence for the cardiovascular effects of osteoporosis treatments in randomized trials of post-menopausal women: a systematic review and Bayesian network meta-analysis. Bone. February 2023;167:116610.