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Farnesyl pyrophosphate synthase Farnesyl pyrophosphate synthase HMG-CoA reductase Mevalonate kinase Phosphomevalonate kinase Squalene synthase Diphosphomevalonate decarboxylase Geranylgeranyl pyrophosphate synthase Hydroxymethylglutaryl- CoA synthase, cytoplasmic Acetyl-CoA acetyltransferase, mitochondrial Zoledronate 3-Hydroxy-3- methylglutaryl- CoA NADPH H+ NADP CoA Mevalonate ATP Mevalonate-5P ADP ATP Mevalonate-5PP ADP Isopentenyl-PP Dimethylallylpyrophosphate PPi Geranyl-PP Isopentenyl pyrophosphate Farnesyl pyrophosphate PPi H+ NADPH PPi NADP Squalene Cholesterol ATP ADP Pi CO2 Isopentenyl pyrophosphate Geranylgeranyl- PP PPi Acetyl-CoA H2O Acetoacetyl-CoA CoA CoA Zoledronate Zoledronate Zoledronate Magnesium Magnesium Magnesium Magnesium Osteoclast Cytosol Zoledronate enters the cell through endocytosis. The endocytic vesicles are acidified and the Zoledronate is released into the cytosol. Zoledronate inhibit farnesyl pyrophosphate by binding in it's active site. Reduced production of farnesyl-PP, geranylgernayl-PP and other sterols which are essential for anchoring cell surface protein via prenylation, and are necessary for osteoclast function and survival. Low concentrations of these lipids prevents osteoclast attachment to the bone, thereby inducing apoptosis of the osteoclast, reducing osteoclast acitivty and bone resorption. Mevalonate Pathway