Effect Of Different Simvastatin Administration Method On The Bone Healing Of Rat Rib Fracture

Objective:To explore the effect of different simvastatin administration method on the bone healing of rat rib fracture,as well as observing whether short-term withdrawal of simvastatin induces dysfunction,to provide evidence for further clinical application of simvastatin in fracture.Methods:Forty-eight health SD(Sprague-Dawley)rats were used.Following the surgical procedures,the sixth rib was located then fractured 1.5 cm from the vertebral column and from the ear margin of 2 cm using a pair of fine scissors in ten-week-old male rats under intraperitoneal anesthesia.After modeling success,all rats were randomly divided into four groups,rats in the control group were given DMSO(Dimethyl sulfoxide)via intragastric administration.Rats in the administration one week group received 10 mg/kg/d SIM(simvastatin)in the first week,then the SIM administration was discontinued,and all the animals were observed up to 28 days.In other words,the rats were given DMSO in the second,third,fourth week.Animals in the reduced administration group received 10 mg/kg/d SIM in the first week,7.5 mg/kg/d SIM in the second week,5 mg/kg/d SIM in the third week,2.5 mg/kg/d SIM in the fourth week.Rats in the administration four weeks group received 10 mg/kg/d SIM for four weeks.All samples were sacrificed at days 7,14,21,28 and later analyzed by X-ray,histological examination.At the same time blood was collected from the eyeball of rats and the level of RANKL,OPG,RANKL/OPG were observed by Elisa.Results:X-ray showed that all groups were healed with no malunion and angulation healing.At one week callus was appeared early in the administration group.After 2-4 weeks,the fracture line became blurred,and the fracture area was similar to the surrounding bone tissue in the reduced administration group.The callus was still obvious in the administration one week group.Histology analysis by HE staining showed at 1 week newly formed cartilage and trabecular bone was earlier in the administration group compared with control group.After 2-4 weeks,the trabecular bone at each group became mature and large,and the woven and lamellar bone began to develop,however at 4 week the woven bone and compact lamellar bone formation in the administration one week group was slower than the reduced administration and continued four week group,and the orientation of the bone was inconsistent.Elisa showed the serum RANKL change was more statistically significant than OPG,which was reached peak value at third weeks and felled at four weeks in the administration one week group.There was no significant difference of serum RANKL in the four weeks of the reduced administration group,maybe related to the reduction of dose.The data showed that the level of OPG was increased in second weeks after administration,and it was confirmed that simvastatin could promote the expression of OPG,however,it was decreased after three weeks.It is possible that OPG will no longer play a leading role in this period.The OPG/RANKL ratio was consistent with the change of their respective trends,and there was no statistically significant difference of OPG/RANKL in reduced administration group.Conclusion:Rib fracture model is a non-heavy bearing model which is suitable for establishing fracture model.Simvastatin could promote bone healing and different administration method may influence bone healing.Acute discontinuation of simvastatin delayed fracture healing,reduction of simvastatin step by step is beneficial to the healing of fracture.The specific signal mechanism still needs further analysis.