Figure 3.

Schematic illustration of therapeutic agents used to treat bone metastasis. At the left side of the panel are the osteocytes and the right side are the breast cancer cells. These cells are subjected to the therapeutic treatment under the bone environment. The numbers indicate the steps of events that may happen during breast metastasis described in the review. ① Denosumab, a RANKL neutralizing antibody, binds RankL expressed by osteocytes and cancer cells, and inhibits the recruitment of monocytes and osteoclast differentiation. ② Bisphosphonates (BPs) inhibit osteoclast activity. Also, ③ BP increases osteocyte survival and induces opening of Cx43 hemichannels and the release of ATP. ④ eATP inhibits osteoclast activity. ⑤ eATP activates P2X receptor and reduces the proliferation, migration, and metastatic potential of cancer cells. The effects of the pharmacological agents reduce the activity of the vicious cycle.