Systemic treatment with resveratrol prevented medication‐related osteonecrosis lesions‐like of the jaws (MRONJ) in rats

Abstract

Background : The use of drugs such as bisphosphonates has been linked to adverse effects, such as osteonecrosis of the jaws associated with medication. Resveratrol has characteristics anti-oxidant, anti-inflammatory, antiresorptive and effects on apoptosis control and this substance could be important in preventing the occurrence of MRONJ associated with bisphosphonates.Aim/Hypothesis : This study aimed at verifying the effect of resveratrol (RESV) on the prevention of medication-related osteonecrosis of the jaws (MRONJ) in estrogen-deficient rats treated with zoledronate (ZLD). Material and Methods: Fifth adult Wistar rats distributed in the following groups-(1) OVT; RESV ( n -10)-ovariectomy; resveratrol; (2) OVT; PLA ( n -10)-ovariectomy; placebo; (3) OVT; ZLD ( n -10)-ovariectomy; zoledronate, (4) OVT; RESV; ZLD ( n -10)-ovariectomy; resveratrol; zoledronate, (5) SHAM;PLAC ( n -10)-no ovariectomy; placebo. The ONM was induced by means of the exodontia of the lower molars bilater-ally. After euthanasia, the left hemi-jaws were submitted to computerized microtomography (Micro-CT) and after that to immunohistochemistry. The right hemi-jaws were collected for analysis of gene expression. The animals' blood was also collected for the serum analysis of the Carboxyterminal Telopeptide of Type I Collagen (CTX), through Elisa. Data were submitted to statistical analysis using the ANOVA Tukey or Kruskal Wallis Dunn tests, with a significance level of 5%.Results : Histomorphometric analysis showed that zoledronate increased the percentage of non-vital bone tissue (TONV) and reduced the percentage of (neo-formed bone tissue) TONF compared to the groups that did not receive zoledronate ( P < 0.05). In addition, when resveratrol was administrated isolated, higher TONF values were observed comparing to OVT;ZOL; PLAC group ( P < 0.05). The number of TRAP-positive cells reduced in the presence of zoledronate ( P < 0.05), while the mRNA levels of TRAP increased with ZLD treatment, with or without resveratrol in relation to the other groups ( P < 0.05). Treatment with resveratrol increased SOD levels when compared to OVT; ZLD; PLAC and OVT; ZLD; RESV ( P < 0.05). Conclusion and ClinicalImplications : It can be concluded that resveratrol reduced MRONJ induced by zoledronic acid in estrogen-deficient rats. And as a clinical implications the chronic and systemic use of resveratrol may prevent the appearance of osteonecrosis of the jaws associated with medications.