Detection and Treatment of Peri-Implant Osteolysis

种植体周围骨质溶解的检测和治疗

• 批准号: 9267818
• 负责人: D Rick Sumner
• 金额: $ 34.1万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267818
• 关键词: Abbreviations; Address; Affect; Alendronate; Anabolic Agents; Antibodies; Biological Markers; Body Fluids; Bone Resorption; Bone remodeling; Classification; Clinical; Clinical Data; Clinical Management; Clinical Trials; Clinical Trials Design; Cobalt; Control Groups; Cyclophosphamide; Data; Depressed mood; Detection; Diagnosis; Diagnostic; Diagnostic radiologic examination; Disease; Disease Progression; Drug usage; Early Diagnosis; Early identification; Economic Burden; Failure; Felis catus; Functional disorder; Future; Health; IL8 gene; Implant; Inflammation; Interleukin-6; Intervention; Lead; Longevity; Mechanics; Methods; Methylmethacrylate; Modeling; Monitor; Operative Surgical Procedures; Osteoclasts; Osteogenesis; Osteolysis; PTH gene; Pain; Particulate; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Polyethylenes; Preventive measure; Process; Proteomics; Rattus; Replacement Arthroplasty; Reporting; Research; Review Literature; Serum Markers; Solid; Testing; Tissues; Total Hip Replacement; Validation; Work; base; bone; burden of illness; candidate marker; cathepsin K; clinical application; cost; cytokine; improved; novel; novel therapeutics; particle; patient biomarkers; peri-implant osteolysis; pre-clinical; prevent; public health relevance; repository; sample fixation; tool; treatment strategy

 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.

 描述（由申请人提供）：在美国每年进行的关节置换术中，至少有10%是翻修手术，主要适应症为颗粒诱导的骨质溶解和植入物松动。目前有两个关键的，相互关联的障碍，以解决这一临床问题，影响成千上万的人，并预计将在15年内产生重大的经济负担：（i）缺乏能力，早期发现疾病和（ii）无法阻止疾病的进展或治疗非手术建立骨质溶解。骨质溶解的直接原因是骨吸收增加和骨形成减少，这是由植入物脱落的颗粒碎片引发的失败级联的结果。诊断通常取决于影像学体征和/或患者报告的疼痛，这两者都发生在疾病过程的相对晚期。我们的两个中心假设是：（i）生物标志物可被识别并用于在疾病过程的早期诊断骨质溶解，以及（ii）用促进骨形成的药物进行干预可延迟甚至逆转颗粒诱导的种植体周围骨质溶解和种植体松动。这些假设得到了我们最近的数据的支持，这些数据表明，包括组织蛋白酶K在内的几种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蛋白抗体是一种有效的预防措施。我们计划在我们的大鼠模型中鉴定和验证用于早期诊断颗粒诱导的种植体周围骨质溶解的多种生物标志物（目的1），确定在发病机制中必须多早开始干预以防止种植体固定丧失，并确定是否有可能挽救大鼠模型中的固定失败（目的2），并鉴定用于早期诊断的生物标志物，使用来自Rush的全髋关节置换患者的体液的现有18年纵向储存库（Aim 3）。生物标志物验证将通过显示强大的预测能力和将标志物水平与致病过程相关联来完成。该研究将使用蛋白质组学来发现新的候选标记，这可能揭示新的机制途径。我们将测试两种建骨剂（硬骨素抗体和甲状旁腺激素）和一种抗吸收剂（阿仑膦酸钠）影响种植体周围骨吸收和骨形成的能力，从而预防或逆转骨质溶解。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质溶解，并将知道在疾病进展的多早时必须开始药物干预以获得成功治疗。我们希望该项目能够在全关节置换患者中开展未来的临床试验，以非手术方式治疗颗粒诱导的植入物周围骨质溶解。