Incidence and risk of denosumab-related hypocalcemia in cancer patients: a systematic review and pooled analysis of randomized controlled studies

Purpose: The aim of this study is to evaluate the frequency and relative risk of hypocalcemia in cancer patients receiving denosumab. Methods: We searched the PubMed (data from 1966 to October 2012), Embase (data from 1980 to October 2012) and Cochrane Library (up to October 2012) electronic databases for relevant randomized controlled trials (RCTs). Abstracts presented at conferences were also searched. Phase II and III trials of denosumab in patients with any type of cancer that reported occurrence of hypocalcemia were eligible. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity among included trials. Results: A total of 8990 patients with a variety of solid tumors from seven RCTs were included for the meta-analysis. The overall incidences of all-grade and high-grade hypocalcemia in cancer patients were 5.2% (95% confidence interval [CI]: 2.8-9.3%) and 2.0% (95% CI: 0.7-5.5%), respectively. The use of denosumab was associated with significantly increased risk of developing all-grade (RR 1.932, 95% CI: 1.590-2.347, p<0.001) and high-grade hypocalcemia (RR 4.027, 95% CI: 2.346-6.912, p<0.001) in comparison with controls. Conclusions: The use of denosumab is associated with a significantly increased risk of developing hypocalcemia (p<0.001). Physicians should be aware of this adverse effect and should monitor cancer patients receiving denosumab.