Figure 1.

Mechanisms of tumor‐induced bone destruction. Tumor cells secrete parathyroid hormone related protein (PTHrP), which signals through parathyroid hormone receptor type 1 (PTH1R) on the surface of osteoblasts to promote their activity and differentiation. Increased osteoblast activity results in increased secretion of the receptor activator of nuclear factor kappa‐B ligand (RANKL), which binds to RANK on pre‐osteoclasts to promote osteoclastogenesis and on mature osteoclasts to stimulate their activity. Increased number and activity of osteoclasts results in more bone resorption and release of growth factors from the bone matrix, including transforming growth factor β (TGF‐β), insulin‐like growth factor I and II (IGF‐I/II), platelet derived growth factor (PDGF), and bone morphogenetic proteins (BMPs). These growth factors normally function to couple osteoclast and osteoblast activity, but can also stimulate further tumor cell proliferation and PTHrP production by the tumor cells to feed this cycle of bone destruction