Alendronate is a second-generation bisphosphonate taken orally or IV and used for the treatment of conditions such as osteoporosis, Paget’s disease and hypercalcemia. Alendronate targets the mevalonate pathway in osteoclasts, the cells responsible for the break down of bone tissue. The mevalonate pathway starts off with acetyl-CoA forming acetoacetyl-CoA using acetyl-CoA acetyltransferase in the mitochondria. Acetyl-CoA and acetoacetyl-CoA then form HMG-CoA via HMG-CoA synthase. HMG-CoA is converted to mevalonate using the enzyme HMG-CoA reductase. Mevalonate kinase converts mevalonate into mevalonate-5P, which is then metabolized into mevalonate-5PP by phosphomevalonate kinase. Isopentenyl-PP is then formed from mevalonate-5PP via diphosphomevalonate decarboxylase. Farmesyl pyrophosphate converts isopentenyl-PP to geranyl-PP, then to farnesyl-PP. Farnesyl-PP goes on to form geranylgeranyl-PP through geranylgeranyl pyrophosphate synthase or squalene through squalene synthase. Squalene goes through a series of reactions to eventually form cholesterol. Alendronate binds to bone hydroxyapatite and when bone resorption occurs, alendronate enters the osteoclasts through endocytosis. Acidification of the endocytic vesicles releases the alendronate. Alendronate inhibits farnesyl pyrophosphate synthase, which reduces the production of downstream isoprenoid lipids like farnesyl-PP and geranylgeranyl-PP. these lipids are needed for a process called prenylation, to anchor cell surface proteins in the osteoclast membrane. Without prenylation, the osteoclast cannot attach to the bone, therefore they are unable to function and undergo apoptosis. This decreases bone resorption/ break down as the osteoclasts are no longer able to survive. Adverse effects like GI disturbances like peptic ulcers and oesophagitis, muscle and bone pain, stomach pain, osteonecrosis, diarrhea, constipation, nausea, flatulence, headache, dizziness and inflammatory responses may occur from taking alendronate.

Alendronate Pathway (New) References