title: Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.
abstract: OBJECTIVE
  Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy.
  
  
  METHODS
  Eligible patients had histologically confirmed malignancy, > or = 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks.
  
  
  RESULTS
  Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P < .001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P = .01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups.
  
  
  CONCLUSIONS
  Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.
authors.affiliation: Department of Medicine, Institut Gustave Roussy, University of Paris XI, Villejuif, France. fizazi@igr.fr
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Body
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rahim
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.forename: Guozhi
authors.initials: G
authors.lastname: Gao
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Winnie
authors.initials: W
authors.lastname: Sohn
authors.forename: Susie
authors.initials: S
authors.lastname: Jun
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications / Q000556:secondary*; D001862:Bone Resorption / Q000139:chemically induced / Q000517:prevention & control*; D001943:Breast Neoplasms / Q000473:pathology; D024042:Collagen Type I / Q000652:urine; D000069448:Denosumab; D004164:Diphosphonates / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology; D010455:Peptides / Q000652:urine; D011471:Prostatic Neoplasms / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D010455:Peptides; D053245:RANK Ligand; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab