Abstract: PURPOSE: To establish medication-related osteonecrosis of jaw-liked animal model in osteoporosis rats. METHODS: Thirty six-month-old female osteoporosis Sprague-Dawley rats were created by bilateral ovariectomy. After 12 weeks, all rats were administrated by subcutaneous injections of alendronate(1.0 mg/kg/day dosage) for 60 days then randomized into two groups: Group 1 (control group) no intervention after ALN administration; group 2 (experimental group) bilateral maxillary and mandible first molars were extracted after ALN administration. Five rats were randomly euthanized at 2 weeks, 4 weeks and 8 weeks after interventions from each group, and underwent clinical, serological, histopathologic and histomorphometric evaluations. SPSS 19.0 software package and R program were used for statistical analysis. RESULT: MRONJ lesions were observed in group 2 rats 2 weeks after operation, the occurrence rate was significantly greater than group 1 (P<0.01); Mandible had higher incidence of 56.7% than maxillar which had a probability of BRONJ of 26.7%. The time-varying serum concentration of RANKL and OPG were unrelated with the occurrence. Hematoxylin-Eosin staining demonstrated that trabecular bone structure of MRONJ lesion areas was disorganized, large number of empty bone sinkholes were generated by the nuclear of osteocyte karyolysis (P<0.05). According to the degrees of osteonecrosis lesion and soft tissue damage, the morbidity and pathological degree of group 1 were significantly lower than that of group 2(P<0.05). The degree of MRONJ lesions was escalated over time. Micro-CT revealed that the MRONJ lesion area had microcracks and osteolysis. The value of Tb.N and BMD had significant changes in Stage 2 MRONJ rats compared to other stages(P<0.05). The difference of Tb.Sp between stage 0 and non-MRONJ rats was statistically significant(P<0.05). CONCLUSIONS: The MRONJ animal model had been successful established by subcutaneous injection of high dose ALN for 60 days associated with teeth extraction in osteoporosis rats, the typical lesions had been observed 2 weeks after intervention; while the animal model stabled 8 weeks after operation. The lesion degree of BRONJ had close relation to time. With regard to local risk factors of BRONJ, this study confirmed that teeth extraction was a remarkable risk factor of BRONJ. The variation of serum RANKL/OPG ratio might be related to BRONJ, Tb.Sp might be effective bone morphogenetic marker associated with BRONJ in the early stage, and microcracks had been observed in the lesion area.

Key words: MRONJ, Osteoporosis, Animal model, Risk factors, Alendronate, Teeth extraction