Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials

Objectives: The aims of this meta-analysis were (i) to perform a systematic review of the relation between treatment with denosumab and the incidence of osteonecrosis of the jaw (ONJ) and (ii) to obtain information on dosage, first event apparition, and treatment approaches for patients with ONJ related to denosumab.

Materials and methods: A systematic review and meta-analysis of relevant literature was performed in the PubMed, MEDLINE, Embase, and Cochrane databases, identifying randomized clinical trials that evaluate the adverse effects of denosumab. The overall incidence rates and 95% confidence intervals (CI) for ONJ were calculated employing fixed- and random-effects models, according to the heterogeneity of the studies included.

Results: A total of 8963 patients with a variety of solid tumors reported in seven randomized controlled trials (RCTs) were included in the systematic analysis. The overall incidence of ONJ in patients with cancer receiving denosumab was 1.7% [95% CI: 0.9-3.1%]. The use of denosumab was associated with a significantly increased risk of ONJ in comparison with bisphosphonates (BPs)/placebo treatment (RR 1.61, 95% CI: 1.05-2.48, P = 0.029). Subgroup analysis based on controlled therapies demonstrated an increased risk of ONJ in denosumab therapy, when compared with BPs (RR 1.48, 95% CI: 0.96-2.29, P = 0.078) or placebo (RR 16.28, 95% CI: 1.68-158.05, P = 0.017). Similar results were observed for prostate cancer (RR 3.358, 95% CI: 1.573-7.166, P = 0.002).

Conclusions: Denosumab combined with risk factors such as dental extraction, poor oral hygiene, use of removable apparatus, and chemotherapy may favor the development of ONJ.