To improve median survival of patients with prostate cancer that has metastasized to bone, we need to better understand the early events of the metastatic process in skeleton and develop molecular tools capable of detecting the early tumor cell dissemination into bones (micrometastasis stage). However, the initial phase of tumor cell dissemination into the bone marrow is promptly followed by the migration of tumor cells into bone matrix, which is a crucial step that signals the transformation of micrometastasis to macrometastasis stage and clinically evident metastasis. The migration of cancer cells into bone matrix requires the activation of local bone resorption. Such an event contributes to tumor cell hiding/ escaping from high immunologic surveillance of bone marrow cells. Within bone matrix, tumor cells are establishing plethoric cell-cell interactions with bone marrow-residing cells, ensuring their survival and growth. Recently, RT-PCR detections of tumor marker transcripts, such as PSA and PSMA mRNA performed in RNA extracts of peripheral blood nucleated cells and bone marrow biopsy, have enabled the stratification of patients with clinically localized prostate cancer being of high risk for extraprostatic disease and bone involvement. Therefore, it is conceivable that bisphosphonate blockade of bone resorption can inhibit the migration of tumor cells into bone matrix during the early phase of disease dissemination into bone marrow (micrometastasis stage). Consequently, assessment of the efficacy and efficiency of bisphosphonates to arrest the evolution of bone lesions in this particular clinical setting of patients with clinically localized prostate cancer and positive molecular staging status (high risk for bone involvement) is warranted.