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Zoledronic Acid Increases the Prevalence of Medication-related Osteonecrosis of the Jaw in Rice Rats (Oryzomys palustris) in a Dose Dependent Manner

Messer, J.G. and Mendieta Calle, J.L. and Jiron, J.M. and Castillo, E.J. and Van Poznak, C. and Bhattacharyya, N. and 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

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