Daria B. Neidre

Transdermal Lovastatin Enhances Fracture Repair in Rats

Statins have been shown to stimulate BMP2 transcription and bone formation. This raises the possibility that they could be useful for enhancing rates of fracture repair. Observational studies in patients treated with oral statins for lipid‐lowering have been controversial. The likely reason for their inconsistent effects is that the statin concentration reaching the periphery was too low after oral administration to produce a reproducible biologic effect. Thus, we examined the effects of lovastatin (LV) given transdermally in a well‐described preclinical model of fracture repair. Effects on the healing fracture callus were assessed by biomechanical strength, radiographs, and quantitative morphology. LV was administered transdermally (TD) for 5 days after fracture in several doses (0.1–5 mg/kg/d) and compared with vehicle‐treated control rats and rats treated with LV by oral gavage (PO) at 5–25 mg/kg/d for 5 days from the day of fracture. Radiological evaluation of bones treated with TD LV showed enhanced fracture repair at 2 and 6 wk. BMD in the callus area at 6 wk was also increased in the TD group compared with vehicle‐treated controls (p < 0.05). The force required to break TD‐treated bones (0.1 mg/kg/d for 5 days) was 42% greater than vehicle‐treated controls (p < 0.02), and there was a 90% increase in stiffness (p < 0.01). PO LV at much higher doses (10 and 25 mg/kg/d) showed increased stiffness but no change in other biomechanical properties. By histological examination, a significant increase was also observed in the size of the callus, surrounding proliferating cell nuclear antigen–positive cells, and osteoblast and osteoclast number in TD‐treated rats compared with controls at day 8 after fracture (n = 6). In summary, we found that TD LV in low doses accelerates fracture healing, whereas 10‐fold the lipid‐lowering dose was required to produce any effect when it was administered orally. These studies provide valuable information on the potential of statins and TD delivery as a new and effective therapeutic modality in fracture repair.

Synergistic effect of exercise and statins on femoral strength in rats

It is now widely recognized that in order to optimize bone health in the later years, bone healthy behaviors should begin at a young age and continue throughout life. Prescribed orally to lower lipid levels in adults of all ages, statins have also been shown to stimulate bone formation in vitro by promoting bone morphogenic protein-2 (BMP-2) activity and to stimulate bone formation in vivo. Weight bearing exercise is well known to stimulate bone formation through a mechanism whereby mechanical loading is sensed by the mechano-sensors leading to a cascade of events involving the activation of osteoblasts. For individuals with high cholesterol levels, both of these interventions are recommended throughout adult life. Since statins and exercise stimulate bone formation via different mechanisms, we hypothesized that exercise in combination with oral simvastatin synergistically increases bone mineral density and strength. Mature adult female, Sprague Dawley rats were divided into 4 groups: control (n=9), statin only (n=8), exercise only (n=11), and statin plus exercise (n=11). Simvastatin was given to the two groups at a dose of 10 mg/kg/day in standard rat chow for the entire 5 week period. All rats ate the same mass of food. The two exercise groups ran on a treadmill with progressively greater speeds and time, ending on week 5 at 30 m/min for 60 min. After 5 weeks, rats were euthanized, and excised femurs were scanned for areal bone mineral density (BMD) and tested by three point bending to obtain the following performance measures: maximum force (strength), stiffness, and work-to-fracture. Only the group treated with statins and exercise showed a positive effect on the biomechanical performance of the femurs. Compared to controls, this group had increased maximum force, stiffness, moment of inertia, and BMD. Linear regression analysis revealed that the increased performance was related to increased BMD. We conclude that the combination of oral statins and appropriate exercise increases bone strength better than either individual treatment and may provide optimal protection against osteoporosis.