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

摘要

Abstract 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 4weeks (baseline), 12 rats were necropsied. The rest were randomized into five groups that began to receive 0, 8, 20, 50 or 125μg/kg ZOL IV/q 4weeks. After 12, 18, 24 and 30weeks, 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 0μg/kg ZOL rats developed FILP lesions; 2) baseline rats and rats treated with 0μg/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 Conclusions This is the first experiment to show a dose response relationship between clinically relevant doses of ZOL and MRONJ prevalence. Highlights ? Rice rats developed high prevalence of maxillary food impaction localized periodontitis (FILP). ? Medication-related Osteonecrosis of the Jaw (MRONJ) in rice rats occurred in association with FILPs. ? MRONJ lesions in rice rats grossly and histologically resemble those seen in humans. ? Higher doses of zoledronic acid (ZOL) in this model were associated with higher prevalence of MRONJ.