Evolving role of bone biomarkers in castration-resistant prostate cancer

Abstract

The preferential metastasis of prostate cancer cells to bone disrupts the process of bone remodeling and results in lesions that cause significant pain and patient morbidity. Although prostate-specific antigen (PSA) is an established biomarker in prostate cancer, it provides only limited information relating to bone metastases and the treatment of metastatic bone disease with bisphosphonates or novel noncytotoxic targeted or biological agents that may provide clinical benefits without affecting PSA levels. As bone metastases develop, factors derived from bone metabolism are released into blood and urine, including N- and C-terminal peptide fragments of type 1 collagen and bone-specific alkaline phosphatase, which represent potentially useful biomarkers for monitoring metastatic bone disease. A number of clinical trials have investigated these bone biomarkers with respect to their diagnostic, prognostic, and predictive values. Results suggest that higher levels of bone biomarkers are associated with an increased risk of skeletal-related events and/or death. As a result of these findings, bone biomarkers are now being increasingly used as study end points, particularly in studies investigating novel agents with putative bone effects. Data from prospective clinical trials are needed to validate the use of bone biomarkers and to confirm that marker levels provide additional information beyond traditional methods of response evaluation for patients with metastatic prostate cancer.

Figure 1

The vicious cycle of bone metastases (reproduced and adapted from Guise et al. [121], with permission from the American Association for Cancer Research). The production of cytokines and growth factors by tumor cells, particularly parathyroid hormone-related peptide (PTH-rP), stimulates osteoblasts to produce RANKL, a key mediator of osteoclastogenesis that is inhibited by OPG. In turn, osteoclast-mediated bone resorption releases growth factors, such as transforming growth factor β, platelet-derived growth factor (PDGF), and insulin-like growth factors (IGFs), which promote tumor growth [9,10]. Osteoblast and osteoclast activity results in the release of proteins, protein fragments, or mineral components directly involved in bone structure or metabolism into the blood and urine. Biomarkers of bone formation include BAP, PICP/PINP, and OC. Biomarkers of bone resorption include CTX/NTX, PYD, and DPD; ICTP; BSP; and TRACP5b.

Figure 2

Modulation of NTX in patients with metastatic CRPC after treatment with novel therapies. (A) Percentage change in uNTX during weeks 1 to 25 in patients treated with denosumab or zoledronic acid, demonstrating rapid denosumab-induced suppression of bone resorption (reprinted from Fizazi et al. [97], Copyright 2009, with permission from Elsevier). (B) Waterfall plot of maximal percentage change in uNTX from baseline in patients treated with 70 or 100mg of dasatinib twice daily. Of 41 patients, 33 (80%) had a decrease in uNTX while on study (reproduced and adapted from Yu et al. [90], with permission from the American Association for Cancer Research). (C) Percentage change in uNTX during weeks 1 to 12 in patients treated with atrasentan or atrasentan plus zoledronic acid. Mean serum NTX increased by 32.4% ± 14.5% with atrasentan and decreased by 34.4% ± 6.9% in the combination group (P < .001; reproduced and adapted from Michaelson et al. [87], with permission from John Wiley and Sons).