Lovastatin and other statins have recently been found to stimulate bone formation systemically as well as locally in rodents. However, their effects locally are far more dramatic than their systemic effects on bone following oral administration. This corresponds to their plasma concentrations which following one oral dose are only transiently elevated for several hours. Statins are metabolized by cytochrome P450 enzymes in the liver to inactive metabolites. We propose that for statins to reach cancellous bone surfaces in concentrations that stimulate bone formation, they need to bypass the liver. We have found that transdermal administration of lovastatin leads to higher and more sustained blood levels, and hypothesize that this is paralleled by a superior pharmacologic effect on nonhepatic peripheral tissues such as bone. In this Phase I application, we plan to confirm this using rats to which lovastatin is delivered topically, and compare the effects to oral administration. Should topical application be confirmed to produce better effects on bone, then a subsequent Phase II application will be directed at examining the optimal topical form of delivery of lovastatin, together with data on effects on systemic toxicity. (Lovastatin comes off patent as cholesterol-lowering agent within the next 2 years. OsteoScreen has a pending filed patent application for statins as bone-active agents.) PROPOSED COMMERCIAL APPLICATIONS: We plan to determine the potential for lovastatin administered transdermally as an anabolic agent for osteoporosis. Our data suggests this route of delivery may lead to enhanced pharmacologic effects of the statin on bone.
