title: Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients with Advanced Cancer and Bone Metastases Treated with Bone Antiresorptive Agents.
abstract: OBJECTIVE
  Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment.
  
  
  METHODS
  This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs ≥ median versus < median based on month 3 assessments.
  
  
  RESULTS
  uNTx levels ≥ the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels ≥ median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels ≥ median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively).
  
  
  CONCLUSIONS
  BTM levels ≥ median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713-21. ©2016 AACR.
authors.affiliation: Division of Hematology/Oncology, Penn State Cancer Institute, Hershey, Pennsylvania. alipton@hmc.psu.edu.
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Department of Internal Medicine, Stony Brook Cancer Center, Stony Brook, New York, New York.
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.affiliation: Department of Medicine, Joan Karnell Cancer Center at Pennsylvania Hospital, Philadelphia, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Henry
authors.affiliation: Academic Unit of Clinical Oncology, Experimental Cancer Medicine Center, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Brown
authors.affiliation: Carolina Urologic Research Center, Myrtle Beach, South Carolina.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Shore
authors.affiliation: Department of Surgery, University of Montreal Hospital Centers, Montreal, Quebec, Canada.
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.affiliation: Department of Clinical Haematology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Global Biostatistical Sciences, Amgen Inc., Thousand Oaks, California.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Clinical Development, Amgen Inc., Thousand Oaks, California.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Warner
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects*; D024042:Collagen Type I / Q000378:metabolism; D000069448:Denosumab / Q000627:therapeutic use; D004164:Diphosphonates / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D051757:PAX5 Transcription Factor; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D000077211:Zoledronic Acid