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INTRODUCTION: Osteonecrosis of the jaw (ONJ) is an adverse event that requires association of both systemic risk factors, such as powerful anti-resorptives (pARs; e.g. zoledronic acid [ZOL]), and local oral risk factors (e.g. tooth extraction, periodontitis). Whereas optimal oral health prior to initiate pARs is recognized as critically important for minimizing ONJ risk, the efficacy of preventive/maintenance measures in patients who are taking pARs is understudied. Rice rats fed a standard diet (STD), rich in insoluble fiber, develop localized periodontitis. STD-rats with localized periodontitis treated with ZOL for 18–24 wk develop ONJ. Hence, we hypothesized that controlling/preventing localized periodontitis in the ZOL-treated rats, reduces ONJ occurrence. METHODS: We used two approaches to attempt reducing periodontitis prevalence: 1) periodontal cleaning (PC); and 2) replacing the STD-diet with a nutritionally-equivalent diet high in soluble fiber (SF). 75 four-week-old male rats were weight-randomized into five groups (n = 15) in a 24-week experiment. Three groups ate the STD-diet and two the high SF-diet. STD-diet groups received intravenous (IV) vehicle (VEH) q4wks (STD + VEH), 80 μg/kg ZOL q4wks IV (STD + ZOL), or ZOL plus PC q2wks (STD + ZOL + PC). The SF-diet groups received VEH (SF + VEH) or ZOL (SF + ZOL). Jaws were processed for histopathology and evaluated for ONJ prevalence and tissue-level periodontitis. RESULTS: 1) 40% of STD + VEH rats developed maxillary localized periodontitis with no ONJ; 2) 50% of STD + ZOL rats developed ONJ; 3) 7% of STD + ZOL + PC rats developed ONJ (p < 0.01 vs. STD + ZOL); and 4) one SF + ZOL rat developed localized periodontitis, and no SF + VEH or SF + ZOL rats developed ONJ (p < 0.001 vs. STD + ZOL). CONCLUSIONS: 1) Periodontal cleaning in ZOL-treated rats decreases localized periodontitis severity and reduces ONJ prevalence; and 2) feeding a SF-diet to ZOL-treated rats reduces both incidence of localized periodontitis and ONJ. Our data indicates strong oral microbial community shifts according to oral health condition and trends in the shifts associated with diet.

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.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe, debilitating condition affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). Oral risk factors associated with the development of MRONJ include tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection). In bone tissues, osteocytes play a bidirectional role in which they not only act as the “receiver” of systemic signals from blood vessels, such as hormones and drugs, or local signals from the mineralized matrix as it is deformed, but they also play a critical role as “transmitter” of signals to the cells that execute bone modeling and remodeling (osteoclasts, osteoblasts and lining cells). When the survival capacity of osteocytes is overwhelmed, they can die. Osteocyte death has been associated with several pathological conditions. Whereas the causes and mechanisms of osteocyte death have been studied in conditions like osteonecrosis of the femoral head (ONFH), few studies of the causes and mechanisms of osteocyte death have been done in MRONJ. The three forms of cell death that affect most of the different cells in the body (apoptosis, autophagy, and necrosis) have been recognized in osteocytes. Notably, necroptosis, a form of regulated cell death with “a necrotic cell death phenotype,” has also been identified as a form of cell death in osteocytes under certain pathologic conditions. Improving the understanding of osteocyte death in MRONJ may be critical for preventing disease and developing treatment approaches. In this review, we intend to provide insight into the biology of osteocytes, cell death, in general, and osteocyte death, in particular, and discuss hypothetical mechanisms involved in osteocyte death associated with MRONJ.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). pARs, including nitrogen-containing bisphosphonates (N-BPs; e.g., zoledronic acid, alendronate) and anti-RANKL antibodies (e.g., denosumab), are used to manage bone metastases in patients with cancer or to prevent fragility fractures in patients with osteoporosis. Though significant advances have been made in understanding MRONJ, its pathophysiology is still not fully elucidated. Multiple species have been used in preclinical MRONJ research, including the rat, mouse, rice rat, rabbit, dog, sheep, and pig. Animal research has contributed immensely to advancing the MRONJ field, particularly, but not limited to, in developing models and investigating risk factors that were first observed in humans. MRONJ models have been developed using clinically relevant doses of systemic risk factors, like N-BPs, anti-RANKL antibodies, or AgIs. Specific local oral risk factors first noted in humans, including tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection, etc.), were then added. Research in rodents, particularly the rat, and, to some extent, the mouse, across multiple laboratories, has contributed to establishing multiple relevant and complementary preclinical models. Models in larger species produced accurate clinical and histopathologic outcomes suggesting a potential role for confirming specific crucial findings from rodent research. We view the current state of animal models for MRONJ as good. The rodent models are now reliable enough to produce large numbers of MRONJ cases that could be applied in experiments testing treatment modalities. The course of MRONJ, including stage 0 MRONJ, is characterized well enough that basic studies of the molecular or enzyme-level findings in different MRONJ stages are possible. This review provides a current overview of the existing models of MRONJ, their more significant features and findings, and important instances of their application in preclinical research.

Objective Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. Methods At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 μg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. Results 40–80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. Conclusions Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.