Zoledronic acid increases the prevalence of medication-related osteonecrosis of the jaw in a dose dependent manner in rice rats (Oryzomys palustris) with localized periodontitis

Objective: Investigate role of dose/duration of zoledronic acid (ZOL), a powerful anti-resorptive (pAR), on prevalence of medication-related osteonecrosis of the jaw (MRONJ) in rice rats (Oryzomys palustris), a species with natural susceptibility to food impaction-induced localized periodontitis (FILP). We hypothesize that ZOL induces MRONJ lesions in rice rats with FILP, and that the prevalence of MRONJ rises with increasing dose and duration of ZOL treatment. Methods: We performed a toxicology experiment with clinically-relevant doses of ZOL in female rats (N = 230) fed standard (STD) rodent chow. At age 4 weeks (baseline), 12 rats were necropsied. The rest were randomized into five groups that began to receive 0, 8, 20, 50 or 125 mu g/kg ZOL IV/q 4 weeks. After 12, 18, 24 and 30 weeks, subgroups (N = 9-16) from each of the dose groups were necropsied. High-resolution macroscopic photos of all jaw quadrants were given a gross quadrant grade (GQG) (0-4 or MRONJ) that classified FILP lesion severity and determined presence of gross MRONJ. Quadrants with GQG >= 1 were examined histopathologically. Logistic regression analysis (ZOL dose/duration) of MRONJ prevalence was completed. Results: We found: 1) 75% of 0 mu g/kg ZOL rats developed FILP lesions; 2) baseline rats and rats treated with 0 mu g/kg ZOL had no MRONJ; 3) 29 gross MRONJ cases were identified; 4) all gross MRONJ cases were confirmed histopathologically by the observation of exposed necrotic bone, and 53 new cases were discovered (total = 82); 5) ZOL dose (P < 0.001), but not duration (P = 0.326), was a significant predictor of MRONJ prevalence; 6) 13% prevalence of gross MRONJ among all rats, with 22% prevalence among rats exposed to ZOL oncologic doses (20-125 mu g/kg); 7) 38% prevalence of histopathologic MRONJ among all rats, with 73% prevalence among rats exposed to ZOL oncologic doses. Conclusions: This is the first experiment to show a dose response relationship between clinically relevant doses of ZOL and MRONJ prevalence. (C) 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.