Pathophysiologic Mechanisms of Bisphosphonate Related Osteonecrosis of the Jaws

描述（由申请方提供）：抗骨吸收药物，如双膦酸盐（BP）和狄诺塞单抗，用于治疗骨恶性肿瘤和代谢性骨病。抗吸收相关性颌骨骨坏死（ONJ）是一种严重的并发症，尤其是 最有效的治疗方案，表现为临床上颌面部骨暴露超过8周，并与严重疼痛、肿胀、感染、瘘管和颌骨骨折相关。ONJ的病理生理学在很大程度上仍然难以捉摸。ONJ在具有不同药理作用的药物下的存在强烈地指出破骨细胞抑制是疾病发病机制的中心。一个令人困惑的，没有答案的问题是ONJ对下巴的偏爱。ONJ最常与接受高剂量抗吸收药的患者的拔牙相关。然而，在成年人中，拔牙主要是由于严重的牙周病或引起牙髓坏死和根尖周病的广泛龋齿。此外，一些ONJ患者没有拔牙史。从这项资助支持的研究中，我们报告了牙齿疾病对大鼠和小鼠ONJ建立的重要性。有趣的是，在两种动物模型中，都存在组织学坏死的骨。然而，仅在33%的骨坏死动物中观察到与临床ONJ一致的骨暴露，表明骨暴露不是骨坏死的先决条件。配备了这些模型，我们已经建立了定性和定量的措施，模仿病人ONJ和评估疾病负担。本文提供的初步数据表明，骨坏死的变化早在两周内就发生了，而拔牙会导致软组织愈合不完全和骨暴露。药物治疗减轻ONJ的严重程度，提供可能的干预策略与临床意义。成骨细胞谱系实验表明，在BP治疗的患有牙科疾病的小鼠的牙槽骨中，成骨细胞前体细胞扩增。重要的是，炎症和BP治疗诱导小鼠颅骨和股骨的骨坏死，这表明，在适当的条件下，其他骨骼也会发生BP相关的骨坏死。我们的目标是描述ONJ的病理生理机制，并探索潜在的干预方法来改善疾病的严重程度。我们假设严重的牙病在抗吸收剂诱导的ONJ中起核心作用。我们建议：1.研究ONJ发生的早期反应，阐明血压下降和拔牙在ONJ进展中的作用。探讨环氧化酶（考克斯）通路在ONJ病理生理中的作用。目的：研究骨内分泌物和炎症对颅骨及股骨缺损愈合的影响。

DESCRIPTION (provided by applicant): Antiresorptive agents, such as bisphosphonates (BPs) and Denosumab, are used to manage bone malignancy and metabolic bone diseases. Antiresorptive related osteonecrosis of the jaws (ONJ), a serious complication, particularly of the most potent regimens, presents as clinically exposed bone in the maxillofacial region for more than 8 weeks, and is associated with severe pain, swelling, infection, fistulae, and jaw fracture. ONJ pathophysiology remains largely elusive. ONJ presence under medications with distinct pharmacologic actions strongly points to osteoclast inhibition as central in disease pathogenesis. A puzzling, unanswered, question is ONJ's predilection for the jaws. ONJ is most commonly associated with tooth extraction in patients receiving high dose antiresorptives. However, in adults, teeth are extracted mainly due to severe periodontal disease or extensive caries that cause pulpal necrosis and periapical disease. Furthermore, several ONJ patients present without history of tooth extraction. From studies supported by this grant, we have reported the importance of dental disease for the establishment of ONJ in rats and mice. Interestingly, in both animal models, histologically necrotic bone is present. However, bone exposure, consistent with clinical ONJ, is seen in only 33% of the animals with osteonecrosis, suggesting that bone exposure is not prerequisite for bone necrosis. Equipped with these models, we have established qualitative and quantitative measures that mimic patient ONJ and evaluate disease burden. Preliminary data, presented herein, indicate that osteonecrotic changes occur as early as two weeks, while extraction of diseased teeth leads to incomplete soft tissue healing and bone exposure. Pharmacologic treatments alleviate ONJ severity, providing possible interventional tactics with clinical implications. Osteoblast lineage experiments demonstrate expansion of osteoblast precursors in the alveolar bone of BP treated mice with dental disease. Importantly, inflammation and BP treatment induce osteonecrosis in calvariae and femurs of mice, suggesting that, given the right conditions, other bones are subject to BP-associated osteonecrosis. Our objective is to characterize pathophysiologic mechanisms of ONJ and explore potential interventional approaches to ameliorate disease severity. We hypothesize that severe dental disease plays a central role in antiresorptive induced ONJ. We propose: 1. To study early responses in ONJ development, and elucidate the effect of BP withdrawal and diseased tooth extractions in ONJ progression, 2. To explore cyclooxygenase (COX) pathway involvement in ONJ pathophysiology, and 3. To study the effects of BPs and inflammation on calvariae and femoral defect healing.