title: Skeletal-related events and clinical outcomes in patients with bone metastases and normal levels of osteolysis: exploratory analyses.
abstract: OBJECTIVE
  High levels of bone resorption markers (e.g. N-telopeptide of type I collagen; NTX) have been correlated with increased risks of skeletal-related events and death in patients with bone metastases from solid tumours. However, the disease course has not been well characterised in patients with bone metastases but normal NTX levels. Therefore, the aim of this study was to evaluate the patterns of skeletal morbidity in patients with normal NTX levels.
  
  
  METHODS
  Exploratory analyses were carried out on patients with bone metastases from breast cancer, castration-resistant prostate cancer, non-small cell lung cancer or other solid tumours treated with zoledronic acid (ZOL) in phase III trials. The effects of covariates on the relative risk of death were estimated using the Cox proportional hazard model. The prognostic values of covariates were compared between patients with normal (<64 nmol/mmol creatinine) versus elevated (≥64 nmol/mmol creatinine) NTX levels.
  
  
  RESULTS
  Among patients with normal baseline NTX (n = 501), less than 10% developed elevated NTX levels before a skeletal-related event or death during ZOL treatment over 12 months. The prognostic factors identified in these analyses were mostly similar across NTX groups. However, some indicators of aggressive disease (e.g. visceral/cerebral metastases from breast cancer) were associated with poor clinical outcomes only in the normal NTX group.
  
  
  CONCLUSIONS
  Skeletal-related events were generally not preceded or followed by transition to elevated NTX in patients treated with ZOL. Elevated baseline NTX and aggressive extraskeletal disease were independently associated with reduced survival.
authors.affiliation: Penn State Cancer Center, Milton S. Hershey Medical Center, Pennsylvania State University, Division of Hematology/Oncology, Hershey, PA 17033, USA. alipton@hmc.psu.edu
authors.forename: A
authors.initials: A
authors.lastname: Lipton
authors.forename: R
authors.initials: R
authors.lastname: Cook
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.forename: J J
authors.initials: JJ
authors.lastname: Body
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Coleman
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D024042:Collagen Type I / Q000378:metabolism*; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010014:Osteolysis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D014408:Biomarkers, Tumor; 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