Pathophysiologic Mechanisms of Bisphosphonate Related Osteonecrosis of the Jaws

描述(申请人提供)：抗吸收药物，如双磷酸盐(BPS)和Denosumab，用于治疗骨恶性肿瘤和代谢性骨疾病。抗吸收相关性颌骨坏死(ONJ)是一种严重的并发症，尤其是 大多数有效的方案，表现为临床暴露在颌面部超过8周的骨，并与严重的疼痛、肿胀、感染、瘘管和颌骨骨折有关。ONJ的病理生理学在很大程度上仍然难以捉摸。在具有不同药理作用的药物作用下，ONJ的存在强烈地表明破骨细胞抑制是疾病发病机制的中心。一个令人费解、尚未回答的问题是《纽约时报》对大白鲨的偏爱。在接受大剂量抗吸收药物的患者中，ONJ最常与拔牙有关。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，几名ONJ患者没有拔牙病史。从这笔赠款支持的研究中，我们已经报道了牙病对在大鼠和小鼠中建立ONJ的重要性。有趣的是，在两种动物模型中，都存在组织学上的坏死骨。然而，与临床ONJ一致的骨暴露仅见于33%的骨坏死动物，这表明骨暴露不是骨坏死的先决条件。有了这些模型，我们已经建立了模拟患者ONJ和评估疾病负担的定性和定量指标。本文提供的初步数据表明，骨质坏死性改变最早在两周内就会发生，而拔除患病牙齿会导致软组织愈合不完全和骨暴露。药物治疗减轻了ONJ的严重程度，提供了具有临床意义的可能的干预策略。成骨细胞谱系实验表明，BP治疗的牙病小鼠的牙槽骨中成骨细胞前体细胞扩张。重要的是，炎症和BP治疗导致小鼠的头盖骨和股骨发生骨坏死，这表明，在适当的条件下，其他骨骼也会受到BP相关的骨坏死的影响。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诱导的ONJ中起着中心作用。我们建议：1.研究ONJ发育的早期反应，阐明BP撤除和拔牙在ONJ进展中的作用；2.探讨环氧合酶(COX)通路在ONJ病理生理学中的作用；3.研究BP和炎症对颅骨和股骨缺损区愈合的影响。

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.