title: Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid.
abstract: BACKGROUND
  For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear.
  
  
  METHODS
  Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n = 578), hormone-refractory prostate cancer (HRPC; n = 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n = 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; > or =64 nmol/mmol creatinine).
  
  
  RESULTS
  After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N.
  
  
  CONCLUSIONS
  Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of skeletal complications and death.
authors.affiliation: Department of Hematology-Oncology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033, USA. alipton@psu.edu
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Richard
authors.initials: R
authors.lastname: Cook
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.forename: Patrick
authors.initials: P
authors.lastname: Garnero
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Janet E
authors.initials: JE
authors.lastname: Brown
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D015415:Biomarkers / Q000652:urine; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications / Q000401:mortality / Q000556:secondary* / Q000652:urine*; D001862:Bone Resorption / Q000150:complications*; D024042:Collagen Type I / Q000737:chemistry / Q000652:urine*; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000652:urine*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid