title: RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem?
abstract: OBJECTIVE
  The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162).
  
  
  METHODS
  The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation.
  
  
  RESULTS
  A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5).
  
  
  CONCLUSIONS
  Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.
authors.affiliation: Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. tim.van.den.wyngaert@skynet.be
authors.forename: Tim
authors.initials: T
authors.lastname: Van den Wyngaert
authors.forename: Kristien
authors.initials: K
authors.lastname: Wouters
authors.forename: Manon T
authors.initials: MT
authors.lastname: Huizing
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D017326:Clinical Trials, Phase III as Topic; D000069448:Denosumab; D005260:Female; D006801:Humans; D007568:Jaw / Q000473:pathology*; D008297:Male; D010020:Osteonecrosis / Q000139:chemically induced*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D000069448:Denosumab