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 µg/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 µg/kg ZOL rats developed FILP lesions; 2) baseline rats and rats treated with 0 µg/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 µg/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.
Objectives To determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate‐related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue‐level features of BRONJ‐like lesions in this model, and examine the specific anti‐resorptive role of ZOL in BRONJ. Materials and Methods Rice rats (n = 228) consumed high sucrose‐casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9–16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJ‐like lesion prevalence and tissue‐level features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling. Results Prevalence of BRONJ‐like lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar dose‐related plateau in the systemic anti‐resorptive effect of ZOL. ZOL and BRONJ‐like lesions also altered the structural and tissue‐level features of the jaw. Conclusion The relationship between BRONJ‐like lesion prevalence and ZOL dose and duration varies depending on the co‐ or pre‐existing oral risk factor. At clinically relevant doses of ZOL, BRONJ‐like lesions are associated with anti‐resorptive activity.
Marsh rice rats (Oryzomys palustris) are a well-established animal model for periodontitis. Rice rats have a marked susceptibility to a spontaneous form of generalized periodontitis that closely resembles the human disease, 1,3,20,22,23,36,47,48 and more recently, we described a distinctive, localized form of periodontitis in this species, which we defined as food impaction-induced localized periodontitis. 38 We used rice rats with both forms of periodontitis to develop 2 novel models of medication-related osteonecrosis of the jaw, 2,39 a rare but serious side effect of potent antiresorptive medications, such as bisphosphonates and denosumab, which are commonly prescribed for management of bone malignancy or osteoporosis. 33,45,46 Medication-related osteonecrosis of the jaw occurs primarily in patients that receive antiresorptive agents in combination with recent oral trauma (for example, tooth extraction) or preexisting or coexisting inflammatory oral disease (for example, established periodontitis, dental disease). 33,45,46 The potential benefits of rice rats as models in dental and periodontal research suggests that interventions in the oral cavity that require general anesthesia are imminent. Isoflurane, ketamine-dexmedetomidine, ketamine-xylazine, and ketamine-midazolam are well-established anesthetic modalities that are routinely used in conventional laboratory roden ts.
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