Bone, as well as the lung and liver, is among the sites of predilection for 
cancer metastasis. The bone stores large amounts of growth factors such as 
insulin-like growth factors and transforming growth factor-b, and provides 
fertile soil for metastatic cancer cells by continuously releasing these 
bone-stored growth factors, which are a consequence of osteoclastic bone 
resorption. Metastatic cancer cells in turn produce osteoclast-stimulating 
cytokines such as parathyroid hormone-related protein( PTH-rP), prostaglandin 
E2.(PGE2), and various interleukins(ILs). These cancer-produced 
osteoclast-stimulating cytokines bind to their cognitive receptors and promote 
the expression of ligands for the receptor activators of nuclear factor kB 
(RANKL)in osteoblasts. RANKL then binds to its receptor RANK, expressed in 
pre-osteoclasts, stimulates mature osteoclast formation, and subsequently, 
osteoclastic bone resorption. This vicious cycle between metastatic cancer cells 
and osteoclasts is critical to the development and progression of bone 
metastases. In addition, it is likely that metastatic cancer cells are 
influenced by bone environments(or niche)and acquire additional capacities such 
as an epithelial-mesenchymal transition(EMT), allowing them to be resistant to 
chemotherapy or apoptosis, to survive in a dormant state, or to aggressively 
spread to distant organs including lung and liver. Thus, the bone can serve as 
transit port. Disrupting this cycle by inhibiting osteoclastic bone resorption, 
antagonizing bone-derived growth factors, and neutralizing RANKL or PTH-rP, 
should be a promising therapeutic intervention for bone metastases. 
Bisphosphonates(BP)are specific inhibitors of osteoclasts, and have been shown 
to significantly reduce skeletal-related events(SRE)associated with bone 
metastasis. Denosumab is a neutralizing monoclonal antibody to RANKL and has 
recently been found to inhibit SRE more effectively than BP. Further 
understanding of the crosstalk communication between metastatic cancer cells and 
bone at the molecular level should lead us to design novel, more effective and 
specific treatments for cancer patients with bone metastases.