Competitive Equilibrium-based Displacement of Bisphosphonates as Novel Therapeutic Approach for BRONJ

 描述(申请人提供)：颌骨坏死(ONJ)是一种罕见但严重的口腔并发症，其特征是疼痛的骨暴露或瘘管的症状，这些症状在几个月到几年内不会消失。它最初是在接受含氮双膦酸盐(BPS)治疗的患者中描述的，后来也在一些服用其他抗吸收或抗血管生成药物的患者中发现。在某些情况下，需要对坏死的口腔和颌面部骨骼进行消融手术，严重影响患者的生活质量。临床报告表明，牙科手术显著增加了发生ONJ的风险，从而在近年来引起了牙科保健专业人员和患者的不确定性和担忧。美国口腔颌面外科医生协会(AAOMS)已建议将“戒毒日”作为一种可能的预防措施。然而，FDA确定，没有实质性的数据可用来指导关于药物假期开始或持续时间的决定，这可能部分是由于苯系物在骨骼系统中的半衰期过长。此外，由于BPS已经上市近15年，大量患者已经接受了BPS治疗，那些接受BPS治疗但停止治疗的患者可能会在他们的骨骼系统中较长时间保留传统的BPS。因此，为了达到更有效的预防目的，在牙槽突手术前积极清除颌骨中吸附的BP可能是必要的。C.E.McKenna(南加州大学，USC)和I.Nishimura(加州大学洛杉矶分校，UCLA)最近利用荧光标记的BP证明了一种BP可以取代另一种BP，从羟基磷灰石模拟骨骼矿物。这表明，以前吸附在骨骼中的药理活性BP可能会被新给药的非药理活性BP所取代。在这一应用中，我们提出了这种基于竞争平衡的BP置换作为双膦酸盐相关ONJ(BRONJ)的一种新的预防方式。我们将检验这样一种假设，即预先吸附的功能性BP，如利塞膦酸盐，可以有效地被口腔内注射到颌骨的非功能性BP所取代。因此，在拔牙等牙槽手术的部位应用无功能BP应该会取代局部的功能BP，从而显著减少或减轻发生BRONJ的风险，同时保留骨骼吸收药物的好处。在这个第一阶段的STTR项目中，我们将在小鼠模型中进行概念验证研究，并建立局部口腔内注射的药物分布图。我们的计划结合了ONJ机制(Nishimura，UCLA)和BP药物化学和生物学(F.H.Ebetino，BioVincLLC，C.E.McKenna，USC)的互补优势。

 DESCRIPTION (provided by applicant): Osteonecrosis of the jaw (ONJ) is a rare but severe oral complication, which is characterized by symptoms consisting painful bone exposure or fistulation that do not resolve over several months to years. It was initially described in patient treated with nitrogen-containing bisphosphonates (BPs), and was also found later in some patients taking other antiresorptive or antiangiogenic medications. In some cases, ablation surgery of necrotic oral and maxillofacial bones has been required, significantly affecting patients' life quality. Clinical reports have indicated that dental procedures markedly increase the risk of developing ONJ, thus causing uncertainty and apprehension among dental healthcare professionals and patients in recent years. "Drug holiday" has been recommended by American Association of Oral and Maxillofacial Surgeons (AAOMS) as a possible preventive measure for the patients. However, the FDA determined that there was no substantial data available to guide decisions regarding the initiation or duration of a drug holiday, which may partially be due to BPs' prolonged half-life in the skeletal system. In addition, because BPs have been marketed for nearly 15 years, a large number of patients have been treated with BPs and those patients who had received BPs but discontinued the therapy may retain the legacy BPs in their skeletal system for an extended period. Therefore, it may be essential to actively remove adsorbed BP from jawbone prior to dentoalveolar procedures in order to achieve more effective prevention. C.E. McKenna (University of Southern California, USC) and I. Nishimura (University of California Los Angeles, UCLA) recently demonstrated using fluorescently labeled BPs that one BP can displace another from hydroxyapatite modeling bone mineral. This suggests that a previously adsorbed pharmacologically active BP in bone could be displaced by a newly administered pharmacologically inactive BP. In this application, we propose this "competitive equilibrium"-based displacement of BPs as a novel preventive modality of bisphosphonate-related ONJ (BRONJ). We will test the hypothesis that a pre-adsorbed functional BP such as risedronate may be effectively displaced by a non-functional BP administered by intraoral injection to the jaw. As such, application of a non-functional BP to the site of dentoalveolar procedures such as tooth extraction should displace the functional BP locally and thus significantly reduce or abate the risk of developing BRONJ while preserving the benefit of skeletally adsorbed drug. In this Phase I STTR project, we will perform a proof- of-concept study in a mouse model and establish the drug distribution profile with local intraoral injection. Our program combines complementary strengths in ONJ mechanism (Nishimura, UCLA) with BP drug chemistry and biology (F.H. Ebetino, BioVinc LLC, C.E. McKenna, USC).