title: Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies.
abstract: BACKGROUND
  Reports of serious joint adverse events (AEs) due to osteonecrosis were noted during randomized placebo-controlled clinical trials of monoclonal antibodies to nerve growth factor (NGF), including tanezumab and fulranumab.
  
  
  METHODS
  All available medical records from subjects with reported cases of osteonecrosis, as well as records of subjects who underwent joint replacement during these studies, were reviewed by an independent adjudication committee that was established by each company; the committees were different for each company and included distinct individual experts. Cases were categorized as having definite osteonecrosis, normal or rapid progression of osteoarthritis (OA), another diagnosis or unable to determine the underlying diagnosis.
  
  
  RESULTS
  The vast majority of investigator reported cases of osteonecrosis were adjudicated as either normal or rapid progression of OA. Indeed, the syndrome of rapid progression of OA associated with chondrolysis and bone destruction appears to be a safety signal that is associated with not only increasing doses of anti-NGF antibodies but also concomitant therapy with nonsteroidal anti-inflammatory drugs.
  
  
  CONCLUSIONS
  These results have implications for future clinical trials of anti-NGF agents in OA and other painful conditions.
authors.affiliation: Departments of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine and the Medical Care Clinical Center, VA Maryland Health Care System, Baltimore, MD, USA. Electronic address: mhochber@medicine.umaryland.edu.
authors.forename: M C
authors.initials: MC
authors.lastname: Hochberg
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D006801:Humans; D007592:Joint Diseases / Q000139:chemically induced*; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors*; D010020:Osteonecrosis / Q000139:chemically induced*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000592179:fulranumab; D020932:Nerve Growth Factor; C549319:tanezumab
keywords: Fulranumab; Monoclonal antibodies to nerve growth factor; Osteonecrosis; Rapidly progressive osteoarthritis; Tanezumab