title: Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review.
abstract: OBJECTIVE
  Denosumab (an anti RANKL antibody) is known to be associated with an increased risk for osteonecrosis of the jaw (ONJ). Due to the variety of clinical presentation, many ONJ definitions are used. Evaluation of ONJ's frequency during phase III randomized controlled trials (RCTs) is crucial to assess benefit-risk ratio. We verified that phase III RCTs involving denosumab reported the definition of ONJ used.
  
  
  METHODS
  We systematically searched in Central, Medline, Cochrane, and Scopus, until 31 August 2015. We included original phase III RCTs, involving denosumab. Post hoc analysis and trial extension were excluded. Articles that did not mention ONJ in their methods or results were excluded. The primary outcome was the prevalence of a complete definition of ONJ. When no definition was provided, ONJ adjudication process was analyzed.
  
  
  RESULTS
  Of 313 articles found, 13 RCTs were included. A definition of ONJ was detailed in two RCTs (15%). For the remaining 11 RCTs, adjudication process was mentioned for nine. In those processes, "blinded," "expert," and "independent" were the most used words.
  
  
  CONCLUSIONS
  Most of the published phase III RCTs involving denosumab did not specify the definition of ONJ used to adjudicate events in the study. Instead of definition, non-scientific and non-reproducible expressions were used. Because the chosen definition could impact the ONJ estimated frequency, it should be mandatory to give the precise definition used in each RCT publication involving denosumab.
authors.affiliation: Regional Center for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, Avenue du Général Koenig, 51100, Reims, France. pdeboissieu@chu-reims.fr.|Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France. pdeboissieu@chu-reims.fr.
authors.forename: Paul
authors.initials: P
authors.lastname: de Boissieu
authors.affiliation: Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France.|Department of Research and Innovation, Reims University Hospital, Reims, France.
authors.forename: L
authors.initials: L
authors.lastname: Kanagaratnam
authors.affiliation: Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France.|Department of Geriatrics and Internal Medicine, Reims University Hospital, Reims, France.
authors.forename: R
authors.initials: R
authors.lastname: Mahmoudi
authors.affiliation: Regional Center for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, Avenue du Général Koenig, 51100, Reims, France.
authors.forename: A
authors.initials: A
authors.lastname: Morel
authors.affiliation: Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France.|Department of Research and Innovation, Reims University Hospital, Reims, France.
authors.forename: M
authors.initials: M
authors.lastname: Dramé
authors.affiliation: Regional Center for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, Avenue du Général Koenig, 51100, Reims, France.|Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France.
authors.forename: T
authors.initials: T
authors.lastname: Trenque
mesh_terms: D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D000069448:Denosumab / Q000627:therapeutic use*; D006801:Humans; D007571:Jaw Diseases / Q000188:drug therapy*; D010020:Osteonecrosis / Q000188:drug therapy*
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab
keywords: Denosumab; Osteonecrosis of the jaw; Pharmacovigilance; Safety