Bone Turnover Effects on Bisphosphonate Concentration in the Mandible

描述（由申请人提供）：颌骨骨坏死（ONJ）是一种新出现的疾病，与双膦酸盐的使用有关，通常在癌症治疗的背景下。目前，尚不清楚双膦酸盐在ONJ的调节中起什么作用，如果有的话。到目前为止，还没有公认的ONJ模型。然而，已经提出了几种机制来描述双膦酸盐在疾病中的致病作用。与未受影响的骨骼部位相比，由于药物传递或药物滞留增强，下颌骨局部高浓度的双膦酸盐可能会增强双膦酸盐的抗破骨作用。这可能会干扰牙齿移除后所需的骨重塑-通常是ONJ的先前事件。另外，从下颌骨部位大量释放局部双膦酸盐可能导致直接毒性和对粘膜和上皮组织的损伤，可能导致局部坏死。正确设计ONJ模型需要了解下颌骨是否代表一个容易出现高或低局部双膦酸盐浓度的解剖部位。ONJ的ASBMR特别工作组已确定检查双膦酸盐的生物利用度和生物分布是该疾病的一个关键研究问题。因此，本提案的目的是使用近红外荧光成像化合物作为局部双膦酸盐浓度的示踪标记物，与其他未受影响的骨骼部位相比，量化下颌骨中双膦酸盐的传递和保留。该建议的中心前提是，与与ONJ无关的四肢相比，下颌骨代表了一个独特的骨骼位置，促进了每骨表面积高双膦酸盐浓度。使用远红色荧光帕米膦酸盐成像化合物可视化局部双膦酸盐浓度，评估正常、低和高骨转换条件下双膦酸盐的输送和保留。下颌骨、股骨和胫骨的每骨表面积荧光将被评估，并与局部骨转换水平相关，以确定转换在药物递送和随后的保留或清除中的作用。该研究结果将阐明颌骨局部生理是否通过增加输送或高潴留使其易受高浓度双膦酸盐的影响，并将产生数据，表明药物假期是否有效，或者可以通过清除局部双膦酸盐浓度的相关策略来促进。通过确定控制骨架中双膦酸盐浓度的因素，这些数据可以为ONJ准确有效的未来模型的开发和应用定义重要的参数和实验问题。

DESCRIPTION (provided by applicant): Osteonecrosis of the jaw (ONJ) is an emerging condition that has been associated with bisphosphonate use, typically in the context of cancer treatment. Currently, it is unknown what role, if any, bisphosphonates play in the regulation of ONJ. As of yet there are no accepted models of ONJ. However, several mechanisms have been proposed to describe a causing role for bisphosphonates in the disease. High local bisphosphonate concentration in the mandible due to enhanced drug delivery or enhanced drug retention may amplify anti- osteoclastic effects of bisphosphonates compared to non-affected skeletal sites. This may interfere with bone remodeling required following tooth removal- typically a preceding event in ONJ. Alternatively, high local bisphosphonate release from mandibular sites may lead to direct toxicity and damage to mucosal and epithelial tissues, potentially leading to local necrosis. Proper design of models for ONJ requires an understanding of whether the mandible represents an anatomic site prone to high or low local bisphosphonate concentration. The ASBMR task force on ONJ has identified the examination of bisphosphonate bioavailability and biodistribution as a key research question for the disease. Therefore, the purpose for this proposal is to quantify the delivery and retention of bisphosphonates in the mandible compared to other non-affected skeletal sites using near-infrared fluorescent imaging compounds validated by our lab as tracer markers for local bisphosphonate concentration. The central premise of this proposal is that the mandible represents a unique skeletal location that promotes high bisphosphonate concentration per bone surface area when compared to limbs not associated with ONJ. Bisphosphonate delivery and retention will be assessed under normal, low, and high bone turnover conditions using a far-red fluorescent pamidronate imaging compound to visualize local bisphosphonate concentration. Fluorescence per bone surface area will be assessed in the mandible, femur, and tibia, and correlated with local levels of bone turnover to determine the role of turnover in the delivery, and subsequent retention or clearance of drug. Findings from this proposal will clarify whether the local physiology of the jaw predisposes it to high concentrations of bisphosphonate through increased delivery or high retention, and will generate data suggesting whether drug holidays are effective, or can be boosted through relevant strategies designed to clear local bisphosphonate concentration. By determining the factors governing bisphosphonate concentration in the skeleton, these data can define important parameters and experimental questions for the development and application of accurate and valid future models for ONJ. PUBLIC HEALTH RELEVANCE: Osteonecrosis of the jaw (ONJ) is an detrimental condition of exposed bone in the oral cavity for which there are currently no accepted models for study. This proposal will determine how local bone turnover is responsible for the delivery and retention of bisphosphonates in the skeleton, and whether anatomic differences may predispose the mandible to high local bisphosphonate concentration-a potential risk factor for ONJ. It is expected that data from this proposal will define important parameters and experimental questions for the development and application of accurate and future models of ONJ.