Several observational and experimental studies have investigated the potential anabolic effects of statins on undisturbed bone but only a few recent studies have examined the effect of statins on skeletal repair. The goal of the study is to investigate any potential early anabolic effect of the systemic administration of simvastatin in low doses (based on earlier safety and efficacy studies on undisturbed bone) on fracture healing.

Fifty-four skeletally mature male New Zealand White rabbits were used for the study. The rabbits were assigned to one of three experimental groups: a control group, and two groups that were orally administrated a diet with 10 and 30 mg/kg/day of simvastatin, respectively. A complete biochemical blood count was performed to exclude drug-induced complications. Half of the animals of each group were sacrificed at 15 days and the other half at 30 days after surgery at which time intervals healing quality was assessed. The bones were subjected to biomechanical testing, histomorphometric analysis and peripheral Quantitative Computed Tomography.

In animals received simvastatin of 30 mg/kg/day a significant reduction of BMD, stiffness, and energy absorbed to failure were observed. At 15 days, the amount of cartilaginous callus formation was reduced, and the void space was significantly increased, in the animals of both groups that received simvastatin when compared to the control group (p< .05).

Our results suggest that simvastatin doses of 30mg/ kg/day may have a negative anabolic effect on callus formation in rabbits, whereas doses of 10 mg/kg/day seem not to produce a significant positive or a negative effect, especially at the early stages of fracture remodeling.

Introduction: Approximately 15% of fractures account for delayed or impaired healing. The popularity of new

Methods: that enhance fracture healing along with conventional ones is growing. The purpose of this study was to determine the effects, the safety and the efficacy of systemic simvastatin administration to bone healing.

Materials and Methods: Unilateral mid-ulnar osteotomies (approximately 2.0 mm wide) were performed to 56 skeletally mature male rabbits. The limbs were assigned to one of three groups: those treated with 30 mg/kg/day of simvastatin per os, those administered with 10 mg/kg/day of simvastatin orally and the control group. The rabbits were killed at two or four weeks postoperatively after taking blood samples for biochemical analysis to detect drug-induced side effects. After the rabbits were killed, the limbs were scanned with peripheral quantitative computed tomography to assess the area and mineral content of the mineralized callus. The bones were subjected to mechanical bending testing and histomorphometry.

Results: At 2 weeks the total density for the mineralized callus was on average 531.7±32.7 for the control group, 466.05±10.6 for the first group (p< .01) and at 4 weeks the total density was 617.5±12.42 for the control group, 551.26±27.61 for the first group, and 553.72±20.66 for the second group respectively (p< .001). Biomechanical properties were similar to all groups at 2 and 4 weeks. The% cartilage portion area was 17.28±2.61 for the control group, 11.89±1.84 for the first group (p< .001) and 14.06±2.17 for the second group (p< .05).

Discussion: The data show that daily systemic administration of simvastatin in 30 mg/kg/day or 10 mg/kg/day do not seem to produce a clear anabolic effect in fracture healing through the remodeling phase.

Conclusion: The use of simvastatin to promote fracture healing is still under study. The limitations from its use are the side effects from its systematic administration over 30 mg/kg/day. Most likely, alternative ways of administration should be considered for future studies.