Abstract :
Bisphosphonates are an important class of osteotropic compounds that are effective in treating benign and malignant skeletal diseases characterized by enhanced osteoclast-mediated bone resorption (i.e., osteoporosis, Paget’s disease, and tumor-induced osteolysis). The evolution of bisphosphonates has led to compounds with ever-increasing potency. First-generation bisphosphonates, including etidronate and clodronate, contained simple side chains and were relatively weak inhibitors of bone resorption. Second-generation compounds, including pamidronate, alendronate, and ibandronate, have an aliphatic R2 side chain containing a single nitrogen atom. These nitrogen-containing bisphosphonates (N-BPs) are up to 100-fold more potent than the first-generation compounds. Zoledronic acid, a novel N-BP with an imidazole substituent, has demonstrated more potent inhibition of osteoclast-mediated bone resorption than all other bisphosphonates in both in vitro and in vivo preclinical models. Recent data suggest that N-BPs inhibit farnesyl diphosphate (FPP) synthase, an enzyme in the mevalonate biosynthetic pathway that is critical for protein prenylation and activation of important signaling molecules. Inhibition of FPP synthase also leads to production of triphosphoric acid 1-adenosin-5′yl ester 3-[3-methylbut-3-enyl] ester (ApppI), which induces apoptosis of osteoclasts and tumor cells. Our current knowledge of the pharmacology of N-BPs at the molecular level largely explains their observed effects on bone metabolism and tumor growth in animal models and their clinical activity in the treatment of benign and malignant bone diseases.
