Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

Cancer. 2008 Jul 1;113(1):193-201. doi: 10.1002/cncr.23529.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / urine
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Neoplasms / complications
  • Bone Neoplasms / mortality
  • Bone Neoplasms / secondary*
  • Bone Neoplasms / urine*
  • Bone Resorption / complications*
  • Collagen Type I / chemistry
  • Collagen Type I / urine*
  • Diphosphonates / therapeutic use*
  • Female
  • Humans
  • Imidazoles / therapeutic use*
  • Male
  • Middle Aged
  • Peptides / urine*
  • Retrospective Studies
  • Survival Analysis
  • Treatment Outcome
  • Zoledronic Acid


  • Biomarkers
  • Bone Density Conservation Agents
  • Collagen Type I
  • Diphosphonates
  • Imidazoles
  • Peptides
  • collagen type I trimeric cross-linked peptide
  • Zoledronic Acid