Detection and Treatment of Peri-Implant Osteolysis

 描述(申请人提供)：在美国每年进行的关节置换手术中，至少有10%是翻修手术，主要指征是颗粒诱导的骨溶解和种植体松动。目前解决这一临床问题有两个相互关联的关键障碍，它影响着数以万计的人，预计将在15年内造成重大经济负担：(1)缺乏及早发现疾病的能力；(2)无法阻止疾病进展或非手术治疗已确定的骨溶解。骨溶解的直接原因是骨吸收增加和骨形成抑制，这是植入物脱落的颗粒碎片引发的失效级联反应的结果。诊断通常取决于放射学体征和/或患者报告的疼痛，这两者都发生在疾病过程的较晚阶段。我们的两个中心假设是：(I)生物标志物可以被识别并用于在疾病过程的早期诊断骨溶解；(Ii)促进骨形成的药物干预可以延缓甚至逆转颗粒诱导的种植体周围骨溶解和种植体松动。我们最近的数据支持这些假说，包括组织蛋白酶K在内的几个生物标志物是早期诊断的有力候选者，我们的研究表明硬化素抗体是一种有效的预防措施。我们计划在我们的大鼠模型(目标1)中识别和验证用于颗粒诱导的种植体周围骨溶解的早期诊断的多个生物标记物(目标1)，确定在发病机制中必须在多早的时候启动干预以防止种植体固定丢失，并确定是否有可能挽救大鼠模型中失败的固定(目标2)，并使用现有的来自Rush全髋关节置换患者的18年体液纵向储存库(目标3)来识别用于简单诊断的生物标记物(目标3)。生物标记物验证将通过显示强大的预测能力和通过将标记物水平与致病过程相关联来完成。这项研究将使用蛋白质组学来发现新的候选标记，这可能会揭示新的机制途径。我们将测试两种骨生成剂(硬化素抗体和甲状旁腺激素)和一种抗吸收药(阿伦磷酸钠)影响种植体周围骨吸收和骨形成的能力，从而防止或逆转骨溶解。如果成功，我们将能够比目前可能的更早地识别种植体周围骨溶解，并将知道必须在疾病进展的多早阶段启动药物干预才能成功治疗。我们期望该项目能在全关节置换术患者中引导未来的临床试验，以非手术方式治疗颗粒诱导的种植体周围骨溶解。

 DESCRIPTION (provided by applicant): At least 10% of the total joint replacements performed annually in the U.S. are revision surgeries, with particle-induced osteolysis and implant loosening as the major indication. There are currently two critical, interrelated barriers to addressing this clinical problem, which affects tens of thousands of people and is predicted to create a major economic burden within 15 years: (i) lack of ability to detect disease early and (ii inability to arrest disease progression or to treat established osteolysis non-surgically. The proximate cause of osteolysis is elevated bone resorption and depressed bone formation, the consequence of a failure cascade initiated by particulate debris shed from the implants. Diagnosis usually depends upon radiographic signs and/or patient-reported pain, both of which occur relatively late in the disease process. Our two central hypotheses are that (i) biomarkers can be identified and used to diagnose osteolysis early in the disease process and (ii) intervention with pharmacological agents that promote bone formation can delay or even reverse particle-induced peri-implant osteolysis and implant loosening. These hypotheses are supported by our recent data showing that several biomarkers, including cathepsin K, are strong candidates for early diagnosis and our study showing that sclerostin antibody is an effective preventive measure. We plan to identify and validate multiple biomarkers for early diagnosis of particle-induced peri-implant osteolysis in our rat model (Aim 1), determine how early in pathogenesis that intervention must be initiated to prevent loss of implant fixation and determine if it is possible to rescue failed fixation in the rat model (Aim 2), and identify biomarkers for erly diagnosis, using an existing 18 year longitudinal repository of body fluids from total hip replacement patients at Rush (Aim 3). Biomarker validation will be accomplished by showing strong predictive ability and by correlating marker levels with pathogenic processes. The study will use proteomics to discover novel candidate markers, which may reveal novel mechanistic pathways. We will test the ability of two bone- building agents (sclerostin antibody and parathyroid hormone) and one anti-resorptive agent (alendronate) to affect peri-implant bone resorption and bone formation and, thereby, prevent or reverse osteolysis. If successful, we will be able to identify peri-implant osteolysis much earlier than is currently possible and will know how early in disease progression that pharmacological intervention must be initiated for successful treatment. We expect the project to lead to future clinical trials in total joint replacement patients to treat particle-induced peri-implant osteolysis non-surgically.