Bisphosphonates were introduced in the late 1990s to reduce the frequency of skeletal-related events(SREs)in patients with metastatic bone disease. In the 2010s, anti-RANKL antibodies were launched as another type of bone modifying agents(BMA). Both induce osteoclast apoptosis and have been used in Japan for solid tumors with bone metastases and multiple myeloma. In addition to osteoclasts, bone microenvironment includes a wide variety of cells such as osteoblasts, vascular endothelial cells, and immune cells, which spatiotemporally interact with cancer cells, resulting in the colonization of dissociated tumor cells(DTCs). Understanding the pathways and microenvironmental factors through which cancer evolves to promote bone colony formation will lead to better planning of the therapeutic strategies in individual cases and to further elucidation of molecular drivers.