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（由适用提供）：在美国每年进行的每年进行的总关节置换量的至少10％是修订手术，粒子诱导的骨溶解和植入物松弛作为主要指示。目前有两个关键的，相互关联的障碍来解决这一临床问题，这会影响成千上万的人，预计将在15年内造成重大的经济燃烧：（i）缺乏早期发现疾病的能力和（ii无法阻止疾病进展或无能为力地处理既定的骨质分解，尤其是无效的骨质造成的造成骨骼的骨骼造成的骨骼造成的骨骼造成的骨骼造成的骨折。从诊断中脱落的碎片通常取决于放射线症状和/或患者报告的疼痛，这两者在我们的两个中心假设中相对较晚。植入物松动。我们计划在大鼠模型中识别和验证多种生物标志物，以早期诊断颗粒引起的植入物周围的溶解溶解（目标1），确定必须在发起干预措施的发病机理中如何早期进行干预以防止植入物的固定损失，并确定是否有可能在大鼠模型中挽救固定的固定量（目标2），并确定了现有的18岁左右的固定剂（AIM 2），并确定较早的临时诊断，并确定了经常诊断的范围，并确定了经过限制的临时诊断，并确定了长期诊断的范围，并确定了长时间的诊断剂，并确定了长期诊断的时间，并确定了较长的固定剂（AIM 2）。 Rush的髋关节替代患者（AIM 3）。生物标志物验证将通过表现出强大的预测能力和将标记水平与致病过程相关联来实现。该研究将使用蛋白质组学发现新颖的候选标记，这可能揭示了新型的机械途径。我们将测试两种骨建造剂（硬化蛋白抗体和甲状旁腺骑马酮）和一种抗敏化剂（Alendronate）影响植入物周围骨骼骨骼和骨形成的能力，从而预防或反向骨化分解。如果成功的话，我们将能够比目前可能更早地识别出植入物周围的骨溶解，并且会知道在疾病进展中必须如何启动药物干预才能成功治疗。我们预计该项目将导致总关节置换患者的未来临床试验，以非疗法治疗颗粒诱导的植入剂骨溶解。