Bone Turnover Effects on Bisphosphonate Concentration in the Mandible

描述（由申请人提供）：颌骨坏死（ONJ）是一种新出现的病症，通常与癌症治疗中的双磷酸盐使用相关。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该疾病中的致病作用。与未受影响的骨骼部位相比，由于药物输送或药物保留增强，下颌骨局部双膦酸盐浓度较高，可能会增强双膦酸盐的抗破骨作用。这可能会干扰拔牙后所需的骨重塑——通常是 ONJ 的前期事件。或者，下颌部位局部高浓度双磷酸盐释放可能导致直接毒性和对粘膜和上皮组织的损害，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容易出现局部双磷酸盐浓度高或低的解剖部位。 ONJ 的 ASBMR 工作组已将双膦酸盐生物利用度和生物分布的检查确定为该疾病的关键研究问题。因此，本提案的目的是使用我们实验室验证的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，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递送和保留。该提议的核心前提是，下颌骨代表了一个独特的骨骼位置，与不与 ONJ 相关的四肢相比，该位置促进了每个骨表面积的高双磷酸盐浓度。 将使用远红荧光帕米膦酸盐成像化合物在正常、低和高骨转换条件下评估双膦酸盐的递送和保留，以可视化局部双膦酸盐浓度。将评估下颌骨、股骨和胫骨中每个骨表面积的荧光，并将其与骨转换的局部水平相关联，以确定转换在药物递送以及随后的保留或清除中的作用。该提案的研究结果将澄清下颌的局部生理机能是否通过增加输送或高保留而使其容易接触高浓度的双膦酸盐，并将产生数据表明药物假期是否有效，或者可以通过旨在清除局部双膦酸盐浓度的相关策略来加强。通过确定骨架中双膦酸盐浓度的控制因素，这些数据可以定义重要的参数和实验问题，以开发和应用准确有效的未来 ONJ 模型。 公共健康相关性：颌骨坏死 (ONJ) 是一种口腔内骨骼暴露的有害病症，目前尚无公认的研究模型。该提案将确定局部骨转换如何负责双磷酸盐在骨骼中的输送和保留，以及解剖学差异是否可能使下颌骨局部双磷酸盐浓度较高（这是 ONJ 的潜在危险因素）。预计该提案的数据将为开发和应用 ONJ 准确的未来模型定义重要参数和实验问题。

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.