title: Denosumab: mechanism of action and clinical outcomes.
abstract: OBJECTIVE
  To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments.
  
  
  METHODS
  Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches.
  
  
  RESULTS
  Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high-risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment.
  
  
  CONCLUSIONS
  Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first-line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options.
authors.affiliation: Departments of Medicine, Community Health Sciences and Oncology, University of Calgary, Calgary, AL, Canada. dahanley@ucalgary.ca
authors.forename: D A
authors.initials: DA
authors.lastname: Hanley
authors.forename: J D
authors.initials: JD
authors.lastname: Adachi
authors.forename: A
authors.initials: A
authors.lastname: Bell
authors.forename: V
authors.initials: V
authors.lastname: Brown
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016723:Bone Remodeling / Q000187:drug effects; D000069448:Denosumab; D004164:Diphosphonates / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D058866:Osteoporotic Fractures / Q000517:prevention & control; D017410:Practice Guidelines as Topic; D019379:Teriparatide / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019379:Teriparatide; D000069448:Denosumab