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

描述（由申请人提供）：双膦酸盐相关性颌骨骨坏死（BRONJ），目前/以前接受过双膦酸盐治疗且未接受过辐射照射的口腔中暴露的骨骼，已成为具有广泛健康影响的重要临床问题。BRONJ在癌症患者中的发病率最高，已经确定了几个关键的危险因素，包括双膦酸盐剂量、感染的存在和牙科干预。癌症患者的双膦酸盐剂量比骨质疏松患者高10倍，并且与BRONJ存在明显的剂量依赖关系。在癌症患者中常见的免疫抑制与BRONJ的病理生理有关，因为在这些暴露的病变中发现了许多细菌菌株。侵入性牙科手术使BRONJ的风险增加了10倍，超过75%的BRONJ病例是由某种形式的牙科干预引起的。在临床前模型中，我们的实验室已经证明，在双磷酸盐治疗后，下颌骨内存在坏死骨基质（与临床BRONJ所见的暴露骨相反）。我们假设下颌骨内这些骨基质坏死的区域，明显缺乏活骨细胞，并且已经破坏了小管网络，代表了BRONJ的前兆。本建议的目的是确定这种基质坏死与BRONJ（口腔内暴露的骨）之间是否存在联系。在目的1中，我们将测量骨细胞活力（乳酸脱氢酶组织化学；LDH），骨细胞凋亡（caspase-3免疫组织化学）和骨管网络完整性（基本品红染色），这些样本来自患有和不患有BRONJ的患者，以及年龄/性别匹配的尸体对照。在Aim 2中，我们将在犬模型中结合高剂量静脉注射双膦酸盐、免疫抑制治疗和拔牙，以确定双膦酸盐诱导的基质坏死与暴露的口腔骨病变表现之间是否存在联系（临床BRONJ）。Aim 2将在拔牙和非拔牙部位使用与Aim 1相似的组织学结果，以及与骨愈合相关的额外结果测量（骨体积、血管密度）。这项研究的结果将大大促进我们对双膦酸盐对口腔骨骼的影响的理解。如果我们的假设是正确的，这些数据将为我们对BRONJ病理生理的理解开辟新的领域，并为未来的研究提供新的模型系统。

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.