Is denosumab associated with an increased risk for infection in patients with low bone mineral density? A systematic review and meta-analysis of randomized controlled trials.

Aim Denosumab increases bone mineral density through inhibition of the receptor activator of nuclear factor κ-Β ligand (RANKL). RANKL has known immunomodulatory effect. The largest study to date that reviewed denosumab efficacy in osteoporosis demonstrated an increased incidence of serious adverse events of infection (SAEI). We aimed to further evaluate risk of infection and SAEI in denosumab-treated patients. Method PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomized controlled trials. Studies comparing denosumab 60 mg every 6 months with placebo or bisphosphonate for treatment of low bone mineral density were included. Trials were excluded for use of denosumab in cancer patients treated for skeletal-related events, immunosuppressed patient populations, or for comparison to teriparatide. Risk ratios (RR) with a 95% confidence interval (CI) were pooled using a fixed effects model, or a random effects model if heterogeneity occurred. Results Twenty-four randomized controlled trials (20 470 patients) were analyzed. An increased incidence of any infection (RR 1.11; 95% CI 1.02-1.20; P = 0.02) was observed in denosumab-treated patients compared with bisphosphonates, but not when compared with placebo. In contrast, a higher incidence of SAEI (RR 1.21; 95% CI 1.03-1.43; P = 0.02) was seen with denosumab when compared with placebo, but not compared with bisphosphonates. Conclusion Denosumab-treated patients with low bone mineral density have slightly increased incidence of SAEI compared with placebo, but not when compared with bisphosphonates. Application of these results requires consideration of the entire body of data available regarding denosumab safety.