Role of Periodontitis in Osteonecrosis of the Jaw Pathophysiology in Rice Rats

描述（由申请方提供）：在接受强效抗吸收药（pAR）（包括唑来膦酸（ZOL）和狄诺塞单抗）治疗的人类癌症患者中发生抗吸收相关颌骨骨坏死（ARONJ）。ARONJ的低发生率（~2%）表明PAR是必要的，但本身不足以引起ARONJ。约75%的ARONJ患者报告了最近的离散口腔事件，最常见的是拔牙（“事件相关”），约25%的患者报告了最近的离散口腔事件。 ARONJ患者属于“自发性”类别。在50岁及以上的人群中，约1/3的拔牙涉及牙周病累及的牙齿。牙周炎（PD）是许多ARONJ病例系列中的偶然发现。这两个事实表明，PD不是一个随机发现，而是一个干预因素，促进了服用PAR的人的“自发”和“事件相关”ARONJ。尽管临床研究表明ARONJ风险随着pAR治疗的剂量和持续时间而增加，但尚未进行确证性临床前实验。我们改进了水稻大鼠，一种自然发展中重度PD的动物模型（R 03），其中肿瘤剂量的ZOL（HD-ZOL）诱导ARONJ样病变。我们还发现HD-ZOL治疗大鼠的牙龈上皮增殖和牙龈变薄减少。我们的中心假设是ARONJ是一个三步过程：a）牙科因素（例如，PD，牙周感染牙齿的拔除）诱导炎症/感染和加速口腔硬组织坏死，B）PAR减慢坏死骨的去除，并减少牙龈上皮增殖和引起牙龈变薄，导致c）坏死的牙槽骨积聚，其导致覆盖骨的牙龈粘膜的损失，死骨暴露于口腔，以及出现ARONJ损伤。在强有力的初步数据的指导下，该假设将通过两个具体目标进行测试：目标#1：通过进行三个实验来评估ARONJ样病变的发生率，以确定牙周炎和PAR在水稻大鼠中ARONJ样病变发展中的作用：a）ZOL的剂量和暴露时间（实验1），B）PD的程度（实验1和2），以及c）预先存在的PD对拔牙后愈合的影响，包括ARONJ的发展（实验3）。我们将通过组织学和CT来确定PD程度并确定ARONJ样病变，以确定这些相关性和发病率。目标二：通过测定不同剂量ZOL作用不同时间后大鼠牙龈上皮细胞增殖和厚度，确定ZOL对大鼠牙龈上皮细胞的影响。预期拟定的研究将证明：a）中度/重度PD是ARONJ的促成因素; B）PAR的剂量和暴露时间影响ARONJ样病变的发生率，以及c）ZOL降低牙龈厚度和增殖。这些结果将产生积极的影响，因为它们将：a）揭示预防/治疗ARONJ的关键途径; B）更明确地披露/确立PAR和PD与ARONJ之间因果关系的性质，为将来的临床试验提供依据，这些临床试验将探索不同PD水平患者中PAR的给药和治疗间隔，和c）公开了ZOL的另一种组织作用部位，其可以解释另一种类型的自发性ARONJ。

DESCRIPTION (provided by applicant): 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.