Bone Turnover Markers As Predictive Tools For Skeletal Complications In Men With Metastatic Prostate Cancer Treated With Zoledronic Acid

Bisphosphonates such as zoledronic acid (ZA) are used to prevent skeletal complications from prostate cancer (CaP) metastatic to bone. Bone scintigraphy is used to diagnose bone metastasis and to monitor response to therapy. Bone turnover markers measured in serum and urine are proposed to predict which patients with bone metastasis are at risk of skeletal complications. A report in the online version of The Prostate from Dr. Michael Lein and a group of German investigators suggest that bone turnover markers are useful.

Data and serum specimens were taken from a prospective, single-arm study of ZA in bisphosphonate naïve men with CaP bone metastases. ZA was given every 4 weeks over a 15-month schedule, along with oral calcium supplements and a daily multivitamin. The study cohort was 308 patients at 38 German study centers. Blood sampling occurred prior to the start of ZA and every 12 weeks thereafter. The bone markers evaluated were total alkaline phosphatase (tALP), bone-specific alkaline phosphatase (bALP), amino-terminal pro-collagen propeptides of type I collagen (PINP), as well as the bone resorption markers cross-linked N-terminal (NTx) and cross-linked C-terminal (CTx) telopeptides of type-I collagen, and C-terminal telopeptides of type-I collagen (ICTP).

In this analysis the clinical data of 117 ZA treated patients classified into 56 with and 61 without skeletal related events (SREs) were compared. Patients with an SRE had significantly higher baseline values than patients without an SRE. All bone markers correlated among each other and with PSA. All the bone markers except ICTP significantly decreased from baseline at 12 weeks after initiation of ZA. The largest decline was for CTx (up to 30% of baseline value). Except for NTx (which showed an inverse relationship), the non-SRE group showed a significantly greater extent of decreased values. In addition, the bone marker concentrations in the SRE group further increased, indicating the occurrence of a SRE. In a Cox regression model using all variables, plus chemotherapy and analgesic use, the only variable that predicted for an earlier occurrence of an SRE was chemotherapy before study entry. NTx was the single bone marker that remained in the predictive model, predicting 68% of patients with an SRE during the study. PINP and ICTP had the highest values in ROC analysis and the diagnostic sensitivity and specificity for all five post-treatment time points amounted to 81% and 48% for PINP and 80% and 38% for ICTP. Thus, percentage changes for PINP and ICTP over the treatment period were most indicative for SREs.

Lein M, Miller K, Wirth M, Weißbach L, May C, Schmidt K, Haus U, Schrader M, Jung K
Prostate. 2009 Jan 13. Epub ahead of print.
doi:10.1002/pros.20917