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

 描述（由申请人提供）：颌骨骨坏死（ONJ）是一种罕见但严重的口腔并发症，其特征是症状包括疼痛的骨暴露或瘘管形成，在数月至数年内无法消退。最初在接受含氮双膦酸盐（BPs）治疗的患者中描述，后来在一些服用其他抗吸收或抗血管生成药物的患者中也发现了这种情况。在某些情况下，需要对坏死的口腔颌面骨进行消融手术，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，因此近年来在牙科保健专业人员和患者中引起了不确定性和担忧。 美国口腔颌面外科医师协会（AAOMS）建议将“药物假期”作为一种可能的预防措施。然而，FDA确定，没有实质性数据可用于指导关于药物假期的开始或持续时间的决定，这可能部分是由于BP在骨骼系统中的半衰期延长。此外，由于BP已上市近15年，因此大量患者接受了BP治疗，而接受BP治疗但停止治疗的患者可能会在其骨骼系统中保留较长时间的遗留BP。因此，它可能是必要的，以实现更有效的预防前牙槽程序，积极清除吸附的BP从颌骨。 C.E. McKenna（南加州大学，南加州大学）和I. Nishimura（加州大学洛杉矶分校，UCLA）最近使用荧光标记的BP证明，一种BP可以取代羟基磷灰石模拟骨矿物中的另一种BP。在本申请中，我们提出这种基于“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。我们将测试的假设，如利塞膦酸盐的预吸附功能性BP可能会有效地取代非功能性BP口内注射到下巴。因此，将非功能性BP应用于牙槽程序（如拔牙）的部位应局部取代功能性BP，从而显著降低或减轻发生BRONJ的风险，同时保留经尿道吸附药物的益处。在该I期STTR项目中，我们将在小鼠模型中进行概念验证研究，并通过局部口内注射建立药物分布特征。我们的项目结合了ONJ机制（Nishimura，UCLA）与BP药物化学和生物学（F.H. Ebetino，BioVinc LLC，C.E. McKenna，USC）。

 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).