Figure 2.

Nitrogen-containing bisphosphonates anti-osteoclastic and anti-tumor molecular mechanism of action. A. BPs localize with a very high affinity to skeletal areas of high bone turnover including osteolytic bone metastases where they are concentrated underneath the activated osteoclasts; B. BPs are subsequently released from the bone mineral during bone resorption; C. BPs are then internalized by the activated osteoclasts; D. Within the osteoclasts (and also breast cancer cells) the N-BPs inhibit the activity of farnesyl diphosphonate (FPP) synthase, a key enzyme in the mevalonate pathway. FPP is necessary for prenylation of small guanine triphosphatases (GTPases)--such as Ras, and Rho, which are involved in intracellular signaling; E. Inhibition of the mevalonate pathway will ultimately cause osteoclasts to undergo apoptosis. Experimental studies have shown that inhibition of this pathway by BPs, will also results in inhibition of malignant cell growth and survival in cell culture and animal models.