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.