Originally published as JCO Early Release 10.1200/JCO.2005.06.091 on June 27 2005

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Predictive Value of Bone Resorption and Formation Markers in Cancer Patients With Bone Metastases Receiving the Bisphosphonate Zoledronic Acid

From the Weston Park Hospital, Cancer Research Centre, Yorkshire Cancer Research Academic Unit of Clinical Oncology, Sheffield, United Kingdom; McMaster University, Juravinski Cancer Centre, Hamilton, Ontario; University of Waterloo, Department of Statistics and Actuarial Science, Waterloo, Ontario; Centre Hospitalier de l'Université de Montréal, Hôpital Notre-Dame, Montréal, Quebec, Canada; Milton S. Hershey Medical Center, Division of Oncology, Hershey, PA; Massachusetts General Hospital, Department of Hematology/Oncology, Boston, MA; Novartis Pharmaceuticals Corp, East Hanover, NJ

Address reprint requests to Robert E. Coleman, MD, Yorkshire Cancer Research Academic Unit of Clinical Oncology, Weston Park Hospital, Whitham Rd, Sheffield S10 2SJ, England, United Kingdom; e-mail: r.e.coleman{at}sheffield.ac.uk

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy.

PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients—1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non–small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high ( 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high ( 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates.

RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes.

CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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