Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.
BACKGROUND
Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid.


METHODS
Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided.


RESULTS
In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels.


CONCLUSIONS
Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.
Brown
Janet E
JE
Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, England, United Kingdom.
Cook
Richard J
RJ
Major
Pierre
P
Lipton
Allan
A
Saad
Fred
F
Smith
Matthew
M
Lee
Ker-Ai
KA
Zheng
Ming
M
Hei
Yong-Jiang
YJ
Coleman
Robert E
RE
D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001859:Bone Neoplasms / Q000175:diagnosis* / Q000517:prevention & control / Q000556:secondary*; D001861:Bone Regeneration; D002289:Carcinoma, Non-Small-Cell Lung / Q000556:secondary; D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D003094:Collagen / Q000652:urine*; D024042:Collagen Type I; D004164:Diphosphonates / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000473:pathology; D010455:Peptides / Q000652:urine*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000473:pathology*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D000077211:Zoledronic Acid; D003094:Collagen; D000469:Alkaline Phosphatase