The bone microenvironment. (A) The bone microenvironment under conditions of normal bone remodeling; (B) and in the presence of osteolytic bone metastases. (A) The bone remodeling unit consists of osteoblasts, which produce osteoid, bone matrix, and osteoclasts, which degrade mineralized bone. Osteoblasts derive from mesenchymal stem cells in the marrow under control of Runx2, a key osteoblastic transcription factor. Osteoclasts derive from mononuclear myeloid precursors that fuse to form pre-osteoclasts. Under the influence of macrophage colony-stimulating factor (M-CSF) and RANKL (receptor activator for NFκB ligand) produced by osteoblasts and other cells in the microenvironment, pre-osteoclasts differentiate into multinuclear, activated osteoclasts that adhere to the bone and begin matrix degradation. Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor to RANKL. The ratio of RANKL to OPG determines the extent of the osteoclast activity and bone degradation. Other cells of the osteoblastic lineage include bone lining cells and osteocytes. (B) Metastatic breast cancer cells in the bone microenvironment secrete parathyroid hormone-related protein (PTHrP), cytokines and growth factors that negatively impact osteoblast function. RANKL and other pro-osteoclastogenic cytokines are increased with a concomitant reduction in OPG, resulting in more osteoclast formation and bone degradation. Osteoblast differentiation is suppressed; new osteoid production is no longer able to keep pace with bone resorption. Current therapeutic targets are indicated in green. Bisphosphonates binding to hydroxyapatite are ingested by osteoclasts and cause their apoptosis. These drugs may also cause cancer cell death; however, they may also negatively affect osteoblasts. Denosumab is an antibody directed to RANKL that prevents osteoclast differentiation. Teriparatide is a recombinant peptide of parathyroid hormone that stimulates osteoblast activity and bone formation. In addition, pre-clinical trials with agents that target cathepsin K, certain matrix metalloproteinases (MMPs), and transforming growth factor (TGF)-β are underway. IGF, insulin-like growth factor; MCP-1, monocyte chemotactic protein-1; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.