Anti-resorptive-related osteonecrosis of the jaw (ARONJ) occurs in human cancer patients treated with powerful anti-resorptives (pAR) including zoledronic acid (ZOL) and denosumab. The low incidence of ARONJ (~2%) suggests that pARs are necessary, but not by themselves sufficient to cause ARONJ. ~75% of ARONJ patients report a recent discrete oral event, most often tooth extraction ("event-related"), leaving ~25% of ARONJ patients in the "spontaneous" category. In fifth decade and older humans, ~1/3 of tooth extractions involve periodontally-involved teeth. Periodontitis (PD) is an incidental finding in many ARONJ case series. These two facts suggest that instead of being just a random finding, PD is an intervening factor that promotes "spontaneous" and "event-related" ARONJ in persons taking pARs. Though clinical studies suggest that ARONJ risk increases with dose and duration of pAR treatment, no confirmatory preclinical experiments have been conducted. We refined the rice rat, an animal model of naturally developing moderate-severe PD (R03), in which oncology doses of ZOL (HD-ZOL) induce ARONJ-like lesions. We also showed reduced gingival epithelial proliferation and gingival thinning in HD-ZOL treated rats. Our central hypothesis is that ARONJ is a three-step process: a) dental factors (e.g., PD, extraction of periodontally-infected teeth) induce inflammation/infection and accelerated oral hard tissue necrosis, b) pARs slow the removal of the necrotic bone, and reduce gingival epithelial proliferation and cause gingival thinning, resulting in c) necrotic alveolar bone accumulation that leads to a loss of gingival mucosa overlying bone, exposure of dead bone to the oral cavity, and the appearance of an ARONJ lesion. Guided by strong preliminary data, this hypothesis will be tested by two specific aims:
Aim #1 : determine the roles of periodontitis and pARs in the development of ARONJ-like lesions in rice rats by conducting three experiments to assess the incidence rate of ARONJ-like lesions in relation to: a) dose and exposure time to ZOL (Exp 1), b) degree of PD (Exp 1&2), and c) influence of preexisting PD on post-extraction healing, including development of ARONJ (Exp 3). We will determine PD degree and identify ARONJ-like lesions grossly, by histology and ?CT to establish these associations and incidence rates.
Aim #2 : Determine the effects of ZOL on the gingival epithelium of rice rats by assessing gingival epithelial proliferation and thicknes in rats after different ZOL doses for different durations. The proposed research is expected to demonstrate that: a) moderate/severe PD is an enabling factor for ARONJ;b) dose and exposure time to pARs affect the incidence of ARONJ-like lesions, and c) ZOL decreases gingival thickness and proliferation. These outcomes will have a positive impact because they will: a) disclose key avenues for prevention/treatment of ARONJ;b) more firmly disclose/establish the nature of the causal relationship of pARs and PD to ARONJ to build a rationale for future clinical trials that explore dosing and treatment intervals of pARs in patient with varying levels of PD, and c) disclose an alternative tissue action site for ZOL that may explain another type of spontaneous ARONJ.

Public Health Relevance

The proposed research is relevant to public health because a proven role for periodontitis as an enabling cofactor for causing anti-resorptive-related osteonecrosis of the jaw (ARONJ)-like lesions in rice rats will allow identifying key avenues for prevention and treatment of ARONJ. The project is also significant because demonstrating that zoledronic acid (ZOL) induces ARONJ with an incidence rate that depends on dose and exposure duration, will more firmly establish the nature of causal relationship of potent antiresorptives (pARs) to ARONJ, and provide a rationale for clinical trials to explore dosing and treatment intervals in patients with varying levels of PD. Thus, the proposed research is relevant to the parts of NIH's mission that 1) foster fundamental creative and innovative research strategies, as a basis to advance the Nation's capacity to protect and improve health;and 2) pursuit of fundamental knowledge to extend healthy life and reduce the burdens of illness and disability.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wan, Jason
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University of Florida
Schools of Veterinary Medicine
United States
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