Geranyl Geraniol And The Treatment Of Bisphosphonate Related Osteonecrosis Of The Jaw In Rat Model

Part 1 establish the model of bisphosphonate related osteonercrosis of jaw in ratsObjective To investigate the relationship between different doses of zoledronic acid(ZA)and bisphosphonate-related osteonecrosis of jaw(BRONJ)by establishing the model of osteonecrosis of jaw in rats with different doses of ZA.Methods Fourty male wistar rats were divided into four groups(ten rats per group),four groups were injectd intraperitoneally with 33?g/kg,66?g/kg and 132?g/kg ZA or saline(control)respectively,three times a week for 8 weeks,and weight was measured weekly.In the 8th week,all rats was subjected to extraction of the first left mandibular molar.Twelve weeks after the last injection,all rats were sacrificed.The jaws were clinically,radiologically and histopathologically examined.Results The weight of experimental groups was lower than it in control group after extraction(P<0.05).The unclosed mucosa on the extraction sites was observed in 86.7% experimental rats,however,mucosa on extraction sites in all control group were healed completely(P<0.05).Radiologically examination revealed radiolucent areas on the extraction sites were higher than the control group(P<0.05).Histopathologically examination showed 70% rats in experimental group developed osteonecrosis,especially in higher dose group,whereas,osteoporosis was not observed in control group(P<0.05).BRONJ in extraction sites in all control group were healed completely(P<0.05).Conclusions The study showed severe BRONJ is closely associated with high dose of ZA,low dose of ZA just induces BRONJ with a slight degree injury,or is unable to induce BRONJ.Thus,Patients treated with high dose of ZA is facing great threat.Part 2 Gerany1 geraniol and the treatment of bisphosphonate related osteonecrosis of the jaw in rat modelObejective Establish the rat model of bisphosphonate related osteonecrosis of the jaw(BRONJ)to investigated the effects of geranyl geraniol(GGOH)on these rats and probe the pathogenesis of BRONJ.Methods Thirty male wistar rats were randomly divided into three groups: the control group(n=10),ZA group(n=10)and GGOH group(n=10).The control group were injected with saline intraperitoneally three times a week for 8 weeks,while the ZA group were injected intraperitoneally with zoledronic acid(ZA)by the dose of 66?g/kg three times a week for 8 weeks,the GGOH group were injected with 66?g/kg ZA three times a week in the first 8 weeks,then in the rest 4 weeks,were injected with GGOH by the dose of 0.1mg/kg three times a week.All the rats were subjected to extraction of the first left mandibular molar under anesthesia in the 8th week.Drew blood of all the rats to detect the concentration of CTX-I,OC,BMP-2 and VEGF by ELISA.Twelve weeks after the last injection,all rats were sacrificed to draw the mandibular of all the rats,HE stained sections of the mandibular were detected to find the necrotic bone area.Immumohistochemical stained sections were examined to find the expression of MMP-9,BMP-2 and VEGF.Results HE stained sections revealed that necrotic bone was observed in ZA group as well as in the GGOH group,and the lesion in the ZA group(77.88±13.47%)was more serious than in the GGOH group(41.9±6.41%)(P<0.001),yet the control group had the very slight injury(2.63±1.87%).The results of ELISA also present that the concentration of the OC,BMP-2 and VEGF in blood in GGOH group was all significantly higher than in the ZA group(P<0.001),but lower than in the control group(P<0.001).higher expression of MMP-9,BMP-2 and VEGF was observed in the mandibular in GGOH group than in the ZA group(P<0.001),but lower than in the control group(P<0.001).Conclusions the occurrence of BORNJ has close relation with ZA,the inhibition in angiogenesis may the important pathogenesis of BRONJ.The data of the present study indicate that GGOH have the effects on the treatment of BRONJ,and further study is needed to verify whether it could be a key drug to treat BRONJ.