The Effects of Bisphosphonates on the Bone Marrow Niche and Circulating and Disseminated Tumor Cells

Bone is a common site for metastases in patients with advanced breast or prostate cancer, with greater than 65% of patients developing bone metastases. This is hypothesized to be related to the bone marrow microenvironment providing a favorable niche for cancer cell survival and growth. Circulating tumor cells (CTCs) can colonize bone marrow niches to become disseminated tumor cells (DTCs). Survival of DTCs in the bone marrow is a function of the unique microenvironment and the ability of these cells to acquire an osteoblast-like phenotype through a process known as osteomimicry. Detecting CTCs in blood or DTCs in bone marrow has been shown to independently predict for disease progression and worse clinical outcomes in patients with breast or prostate cancer. Therapies that reduce levels of CTCs and DTCs may improve clinical outcomes in these patients. Bisphosphonates are bone-targeted agents used to reduce the rate of skeletal-related events in patients with bone metastases. Bisphosphonates such as zoledronic acid have demonstrated potential anticancer activity, and zoledronic acid was recently shown to reduce the persistence and prevalence of DTCs in patients with breast cancer. Research is ongoing to further define the role of bone-targeted therapies in the treatment of cancer.