title: Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial.
abstract: OBJECTIVE
  Patients with bone metastases have high rates of RANKL driven bone resorption and an increased risk of skeletal morbidity. Osteoclast mediated bone resorption can be assessed by measuring urine N-telopeptide and can be inhibited by denosumab, a fully human antibody against RANKL.
  
  
  METHODS
  Eligible patients (111) had bone metastases from prostate cancer, other solid tumors or multiple myeloma, 1 or more bone lesions and urine N-telopeptide greater than 50 nM bone collagen equivalents per mM creatinine (urine N-telopeptide greater than 50) despite the use of intravenous bisphosphonates. Patients were stratified by cancer type and screening urine N-telopeptide, and randomized to continue intravenous bisphosphonates every 4 weeks or receive 180 mg subcutaneous denosumab every 4 weeks or 180 mg every 12 weeks. The primary end point was the proportion of patients with urine N-telopeptide less than 50 at week 13. We report the efficacy results for the subset of patients with prostate cancer.
  
  
  RESULTS
  Patients with prostate cancer represented 45% (50 of 111) of the study population. At week 13, 22 of 32 (69%) patients in the denosumab arms had urine N-telopeptide less than 50 vs 3 of 16 (19%) in the intravenous bisphosphonates cohort. At week 25, 22 of 32 (69%) denosumab treated patients continued to have urine N-telopeptide less than 50 vs 5 of 16 (31%) treated with intravenous bisphosphonates. Grade 4, asymptomatic, reversible hypophosphatemia, possibly related to denosumab, was reported in 1 patient.
  
  
  CONCLUSIONS
  In patients with prostate cancer related bone metastases and increased urine N-telopeptide despite intravenous bisphosphonate treatment, denosumab normalized urine N-telopeptide levels more frequently than ongoing intravenous bisphosphonates.
authors.affiliation: Institut Gustave Roussy and University of Paris XI, Villejuif, France. fizazi@igr.fr
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.forename: Linda
authors.initials: L
authors.lastname: Bosserman
authors.forename: Guozhi
authors.initials: G
authors.lastname: Gao
authors.forename: Tomas
authors.initials: T
authors.lastname: Skacel
authors.forename: Richard
authors.initials: R
authors.lastname: Markus
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000556:secondary* / Q000652:urine*; D024042:Collagen Type I / Q000652:urine*; D000069448:Denosumab; D004164:Diphosphonates / Q000008:administration & dosage*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000652:urine*; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000652:urine*; D053245:RANK Ligand / 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