Messer, J.G., Mendieta Calle, J.L., Jiron, J.M., Castillo, E.J., Van Poznak, C., Bhattacharyya, N., Kimmel, D.B. and Aguirre, J.I. (2018) Zoledronic Acid Increases the Prevalence of Medication-related Osteonecrosis of the Jaw in Rice Rats (Oryzomys palustris) in a Dose Dependent Manner. Bone, 108 (3). pp. 79-88. ISSN 1873-2763; 8756-3282

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) when fed standard (STD) rodent chow. We hypothesize that ZOL dose/duration predicts MRONJ prevalence.
METHODS: We performed a toxicology experiment with clinically-relevant doses of ZOL in female rats (N=230) fed STD rodent chow. At weaning (age 4 wks; baseline), 12 rats were necropsied. The rest were randomized into five groups that immediately began to receive 0, 8, 20, 50 or 125µg/kg ZOL IV/q 4 wks. After 12, 18, 24 and 30 wks, rat groups from each dose (N=9-16) were necropsied. High-resolution, macroscopic photos of all jaw quadrants were given a gross quadrant grade (GQG, 0-4) that classified lesion severity and determined presence of gross MRONJ lesions. Quadrants with GQG≥1 were examined histopathologically. Multiple logistic regression analysis (ZOL dose/time) of ONJ prevalence was completed. RESULTS: We found: 1) baseline rats and rats treated with 0µg/kg ZOL had no MRONJ; 2) 75% of 0µg/kg ZOL rats developed FILP lesions; 3) by gross observation, 29 MRONJ cases were identified; 4) by histopathology, all gross MRONJ cases were confirmed and 53 new cases were discovered; 5) ZOL dose (p = ~0.001), but not duration (p = ~0.32), was a significant predictor of MRONJ prevalence; 6) 13% prevalence of gross MRONJ, with 26% prevalence among rats exposed to ZOL oncology doses; 7) 36% prevalence of histopathological MRONJ, with 73% prevalence among rats exposed to ZOL oncology doses. CONCLUSIONS: This animal study demonstrates a very high MRONJ prevalence with a positive relationship of relevant ZOL dose to MRONJ prevalence.

Item Type:	Article
Keywords:	anti-resorptives, periodontitis, toxicology, duration
Date Deposited:	30 Mar 2018 00:45
Last Modified:	30 Mar 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34581