Statins and their potential for osteoporosis

Abstract

The observation made several years ago that statins dramatically increase bone formation rates in rodents has provoked a much interest. Statins are natural product extracts that inhibit the enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting step in hepatic cholesterol biosynthesis. As a consequence, they reduce serum cholesterol and the subsequent risk of heart attack. These drugs are among the most widely prescribed in Western countries, with more than three million Americans taking a statin every day. Because there is no currently available and acceptable oral agent that stimulates formation of substantial amounts of new bone, this raises the possibility that safe oral agents such as these may be the longsought-after anabolic agent for the treatment of patients with established osteoporosis. Most of the statins exist as prodrugs (lactones), which do not inhibit HMG-CoA reductase but are readily converted by esterases to the active form. Although the first statins were natural product extracts, several of the more recent ones are synthetic, and appear to be more powerful and with different pharmacokinetic properties from the original statins. The statins were selected for their capacity to target the liver and most are subject to metabolism by cytochrome P450 enzymes in the liver. Some of these hepatic metabolites are active and some are inactive. Most of the statins are very lipid-soluble and enter cells easily, but some of the newer, synthetic statins, such as pravastatin and robuvastatin, are more water-soluble and probably depend on specific carrier mechanisms in hepatic cells for entry into these cells.