title: Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association?
abstract: Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.
  
  
  BACKGROUND
  Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk.
  
  
  METHODS
  FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, "Infections and Infestations," was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored.
  
  
  RESULTS
  Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab.
  
  
  CONCLUSIONS
  Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.
authors: Bone Health and Osteoporosis Center, College of Medicine, University of Cincinnati, 222 Piedmont Avenue, Suite 6300, Cincinnati, OH 45219, USA. nelson.watts@uc.edu
authors: N B
authors: NB
authors: Watts
authors: C
authors: C
authors: Roux
authors: J F
authors: JF
authors: Modlin
authors: J P
authors: JP
authors: Brown
authors: A
authors: A
authors: Daniels
authors: S
authors: S
authors: Jackson
authors: S
authors: S
authors: Smith
authors: D J
authors: DJ
authors: Zack
authors: L
authors: L
authors: Zhou
authors: A
authors: A
authors: Grauer
authors: S
authors: S
authors: Ferrari
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000069448:Denosumab; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004696:Endocarditis / Q000139:chemically induced / Q000150:complications; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000150:complications; D006801:Humans; D008875:Middle Aged; D009894:Opportunistic Infections / Q000150:complications / Q000209:etiology*; D015663:Osteoporosis, Postmenopausal / Q000150:complications / Q000188:drug therapy*; D058866:Osteoporotic Fractures / Q000517:prevention & control; D010031:Otitis / Q000139:chemically induced / Q000150:complications; D010919:Placebos; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D012874:Skin Diseases, Infectious / Q000139:chemically induced / Q000150:complications; D014552:Urinary Tract Infections / Q000139:chemically induced / Q000150:complications
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D010919:Placebos; D053245:RANK Ligand; D000069448:Denosumab