Cardiovascular Effects of Denosumab and Romosozumab in Osteoporosis

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In a meta-analysis, researchers aimed to explore the association between denosumab and romosozumab and cardiovascular risk in patients with primary osteoporosis.

Treatment with denosumab is not associated with composite or specific cardiovascular risk, whereas romosozumab may be slightly associated with an increased risk for 4-point major adverse cardiovascular events (MACE) in some patients with osteoporosis, according to study results published in Bone. However, romosozumab was not linked to other cardiovascular outcomes.

Recent studies have reported an association between osteoporosis and vascular calcification and cardiovascular disease, with the suggested pathogenesis involving receptor activator of nuclear factor-κB (RANKL)/osteoprotegerin pathway and Wnt signaling.

In a meta-analysis, researchers sought to explore the association between denosumab and romosozumab and cardiovascular risk in patients with primary osteoporosis. Several composite cardiovascular endpoints were investigated, including 3-point MACE (cardiovascular death, myocardial infarction, and stroke), 4-point MACE (3-point MACE plus heart failure), and composite cardiovascular outcome (including stroke, atrial fibrillation, heart failure, and coronary heart disease).

The researchers completed a comprehensive search in PubMed, Cochrane Library, and EMBASE and focused on randomized controlled trials that included patients with primary osteoporosis or osteopenia, compared placebo with other anti-osteoporosis drugs over a follow-up of ≥6 months, and included data on cardiovascular events. Ultimately, the meta-analysis included 17 trials, with 11 studies (13,615 participants) that examined denosumab and 6 studies (12,219 participants) that examined romosozumab.

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Treatment with denosumab was not associated with the specific or composite cardiovascular outcomes examined by the researchers. The absolute risk for the composite cardiovascular outcome was 3.25% in denosumab-treated patients compared with 3.01% in control patients. In a similar fashion, there was no association between treatment with denosumab and risk for 3-point or 4-point MACE.

Romosozumab did not increase or reduce risk for composite cardiovascular outcome (risk ratio [RR], 1.26; 95% CI, 0.95-1.68; P =.11) or 3-point MACE (RR, 1.41; 95% CI, 0.99-2.02; P =.06), but did increase risk for 4-point MACE (RR, 1.39; 95% CI, 1.01-1.90; P =.04) among older men and postmenopausal woman with osteoporosis over a period of 12 to 36 months. However, sensitivity analysis conducted using random effects model showed romosozumab did not increase the risk for 4-point MACE (RR, 1.36; 95% CI, 0.99-1.87; P =.06).

The researchers acknowledged several study limitations, including difficulties retrieving data on cardiovascular events from the trials, missing data on cardiovascular death, and lack of data on baseline cardiovascular risk factors.

“Further studies with longer term follow-up and specific attention to a variety of cardiovascular events may enhance our understanding of denosumab or romosozumab therapy,” concluded the researchers.

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Lv F, Cai X, Yang W, et al. Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: systematic review and meta- analysis. Bone. 2020;130:155121.