Bisphosphonate-related osteonecrosis of the jaw: Bridging the clinical-preclinica

描述(由申请人提供)：双膦酸类相关颌骨坏死(BRONJ)，指的是目前或以前接受双膦酸类药物治疗的口腔中出现裸露的骨，且未经放射治疗，已成为一个严重的临床问题，具有广泛的健康影响。BRONJ的发病率最高的是癌症患者，已经确定了几个关键的危险因素，包括双磷酸盐的剂量、感染的存在和牙科干预。癌症患者服用的双膦酸盐剂量是骨质疏松患者的10倍，与BRONJ存在明显的剂量依赖关系。免疫抑制在癌症患者中很常见，与BRONJ的病理生理有关，因为在这些暴露的皮损中发现了许多细菌菌株。侵入性牙科手术使BRONJ的风险增加10倍，超过75%的BRONJ病例是由某种形式的牙科干预引起的。在一个临床前模型中，我们的实验室已经证明了在双膦酸类药物治疗后，下颌骨内存在坏死骨基质(与BRONJ临床所见的裸露骨相反)。我们推测，下颌骨内的这些骨基质坏死区明显缺乏可存活的骨细胞，并破坏了小管网络，是BRONJ的先兆。这项建议的目的是确定这种基质坏死和BRONJ(口腔中暴露的骨)之间是否存在联系。在目标1中，我们将检测BRONJ患者和非BRONJ患者以及年龄/性别匹配的身体的下颌骨标本中的骨细胞活性(乳酸脱氢酶组织化学；LDH)、骨细胞凋亡(caspase-3免疫组织化学)和骨小管网络完整性(碱性品红染色)。在目标2中，我们将结合大剂量静脉注射双膦酸盐、免疫抑制治疗和拔牙，在犬模型中确定双膦酸盐诱导的基质坏死与暴露的口腔骨损伤的表现之间是否存在联系(临床BRONJ)。目标2将在拔牙和非拔牙部位利用与目标1相似的组织学结果，以及与骨愈合相关的额外结果指标(骨体积、血管)。这项研究的结果将极大地促进我们对双膦酸盐对口腔骨骼影响的了解。如果我们的假设是正确的，这些数据将为我们对BRONJ病理生理学的理解开辟新的天地，并为未来对这种情况的研究提供一个新的模型系统。 公共卫生相关性： 双膦酸盐是一种用于癌症治疗和骨质疏松症的常见药物，与一种被称为双膦酸盐相关性颌骨坏死(BRONJ)的疾病有关。这项研究将评估临床BRONJ样本中的基质坏死和骨细胞活性丧失，并确定这些变化是否可以在临床前模型中概括。这个项目的结果有可能在我们对BRONJ病理生理学的理解上开辟新的天地，并为未来对这种情况的研究提供一个新的模型系统。

DESCRIPTION (provided by applicant): Bisphosphonate-related osteonecrosis of the jaw (BRONJ), the presence of exposed bone in the oral cavity with current/previous bisphosphonate treatment and without prior exposure to radiation, has emerged as a significant clinical problem with broad health implications. The highest incidence rate of BRONJ exists in cancer patients and several key risk factors have been identified including bisphosphonate dose, presence of infection, and dental interventions. Cancer patients are treated with 10 times higher bisphosphonate doses than osteoporosis patients and there is a clear dose-dependent relationship to BRONJ. Immunosuppression, common among cancer patients, is implicated in the pathophysiology of BRONJ as numerous bacterial strains are found within these exposed lesions. Invasive dental procedures increase the risk of BRONJ by 10-fold and over 75% of all BRONJ cases are precipitated by some form of dental intervention. In a preclinical model our laboratory has shown the existence of necrotic bone matrix within the mandible (as opposed to the presence of exposed bone as seen clinically with BRONJ) following bisphosphonate-treatment. We hypothesize these regions of bone matrix necrosis within the mandible, which are clearly void of viable osteocytes and have disrupted canalicular networks, represent a precursor to BRONJ. The goal of this proposal is to determine if a connection exists between this matrix necrosis and the BRONJ (exposed bone in the oral cavity). In Aim 1 we will measure osteocyte viability (lactate dehydrogenase histochemistry; LDH), osteocyte apoptosis (caspase-3 immunohistochemistry) and canalicular network integrity (basic fuchsin staining) in mandible samples from patients with and without with BRONJ, as well as age/sex matched cadaver controls. In Aim 2 we will combine high doses of intravenous bisphosphonates, immunosuppressive therapy, and dental extraction in a canine model to determine if a link exists between bisphosphonate-induced matrix necrosis and manifestation of exposed oral bone lesions (clinical BRONJ). Aim 2 will utilize similar histological outcomes as Aim 1 at both extraction and non-extraction sites, as well as additional outcome measures related to bone healing (bone volume, vascularity). The results of this study will significantly advance our understanding of the effect of bisphosphonates on the bones of the oral cavity. If our hypothesis is correct these data would break new ground in our understanding of BRONJ pathophysiology and provide a new model system for future studies of this condition. PUBLIC HEALTH RELEVANCE: Bisphosphonates, a common class of drug used for cancer treatment and osteoporosis, are associated with a condition known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study will assess matrix necrosis and loss of osteocyte viability in clinical BRONJ samples and determine whether these changes can be recapitulated in a preclinical model. The results of this project have the potential to break new ground in our understanding of BRONJ pathophysiology and provide a new model system for future studies of this condition.