•accelerated Fracture Healing by Transdermal Lovastatin

INTRODUCTION Normal fracture healing is a complex, multi-step process involving cellular events influenced and regulated by local and systemic factors. The most common biological failure in fracture healing involves an improperly formed callus during the first weeks following fracture. Recent advances in understanding the regulatory factors controlling fracture healing have suggested that a number of compounds may be used to stimulate bone growth and initiate and enhance the cascade of events involved in callus formation and maturation. BMPs, particularly BMP2 which is well known for its osteogenic activity, is highly expressed in the healing callus during fracture repair [1] which suggests an important role of these proteins in fracture healing. Statins, a group of natural products widely prescribed for their capacity to inhibit the enzyme HMG Co-A reductase, and therefore decrease cholesterol biosynthesis, have been shown to increase transcription of the BMP-2 gene, and stimulate bone formation [2]. It has been recently demonstrated that statin treated fractures in mice show accelerated healing either when the statins are administered systemically or directly to the fracture area [3-4]. Observational studies in patients given statins for lipidlowering oral doses have been difficult to evaluate, since some have shown a positive effect on fracture prevention, and some have shown no effect. Since the likely reason for the lack of a convincing effect in all of these retrospective human studies is that the statin concentration reaching the periphery has been too low in the doses used to produce a reproducible biologic effect, we examined the effects of lovastatin (LV) given transdermally (TD) in a well-described preclinical rat model of fracture repair. Given the unique potency of statins to stimulate bone formation, the goal of this study was to determine the efficacy of transdermally delivered LV to enhance callus formation and fracture healing in this model.