title: Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Department of Pharmacological Research in Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain.
authors: Ana
authors: A
authors: Boquete-Castro
authors: Department of Pharmacological Research in Dentistry, Periodontology and Implant Dentistry, Special Care in Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain.
authors: Gerardo
authors: G
authors: Gómez-Moreno
authors: Department of Implant Dentistry, Implant Dentistry and Biomaterials, School of Medicine and Dentistry, University of Murcia, Murcia, Spain.
authors: José Luis
authors: http://orcid.org/0000-0002-9860-5416
authors: JL
authors: Calvo-Guirado
authors: Department of Pharmacological Research in Dentistry, Periodontology and Implant Dentistry, Faculty of Dentistry, University of Granada, Granada, Spain.
authors: Antonio
authors: A
authors: Aguilar-Salvatierra
authors: School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA.
authors: Rafael Arcesio
authors: http://orcid.org/0000-0003-1721-0509
authors: RA
authors: Delgado-Ruiz
mesh_terms: D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000209:etiology*; D050071:Bone Density Conservation Agents / Q000009:adverse effects*; D000069448:Denosumab / Q000009:adverse effects*; D006801:Humans; D012307:Risk Factors
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab
keywords: adverse effects; antiresorptive drug-related ONJ; denosumab; osteonecrosis of the jaws