Biomarkers for Charcot Arthropathy in Diabetic Patients

描述(申请人提供)：神经性夏科特关节病是糖尿病的一种并发症，在很大比例的患者中会导致足部骨折、关节破坏(半脱位和/或脱位)、严重的足部畸形、溃疡、不稳定，甚至可能截肢。需要及早发现和及时干预，以最大限度地减少这种日益流行的疾病的严重后果。然而，由于缺乏敏感和特异的生物标志物，新治疗方法的开发目前受到限制，这些生物标志物是神经病理性夏科关节病发病和治疗结果的敏感和特异指标。我们的长期目标是改进神经病理性夏科特关节病的治疗，并确定哪些受试者有发生这种令人衰弱的并发症的高风险。有证据表明，神经性夏科关节病患者的足部骨密度(BMD)较低，在减负治疗过程中，足部BMD进一步降低。这一先导性数据应用的目的是建立基于体积定量计算机断层扫描(VQCT)的足部骨密度作为急性神经性夏科关节病的候选生物标志物，并收集初步数据用于样本量计算，以支持未来将足部骨密度作为神经性夏科关节病生物标志物的研究。这项试点拨款申请有两个具体目的：1)展示VQCT衍生足部BMD在多大程度上预测糖尿病、周围神经病变和急性神经性Charcot关节病患者的治疗结果；2)确定使用VQCT衍生足部BMD评估糖尿病和周围神经病变患者发生神经性Charcot关节病的风险的可行性。这些具体目标将通过一项重复的测量队列研究来实现，其中将收集临床和放射数据：(1)对于患有神经性夏科关节病并正在接受标准卸载治疗方案(目标1)的患者，在基线、3个月、6个月和每年；(2)对于糖尿病和周围神经病变但尚未发展为神经病理性夏科关节病的患者(目标2)，在基线和每年进行。对基线和后续变化的分析将确定VQCT衍生的足部骨密度在多大程度上是治疗结果的指标(目标1)。目的将2名受试者与1名受试者进行比较，以确定足部体积骨密度评估发生神经性Charcot关节病风险的能力。在这一领域开发生物标记物具有重要意义，因为它可以确定有患神经病理性夏科关节病的风险的受试者，并支持开发新的治疗方案，减少这一重要患者群体的严重并发症数量。

DESCRIPTION (provided by applicant): Neuropathic Charcot arthropathy is a complication of diabetes mellitus which in a high percentage of patients leads to foot fracture, joint destruction (subluxation and/or dislocation), severe foot deformity, ulceration, instability, and possibly amputation. Early detection and timely intervention are necessary to minimize the severe consequences of this increasingly prevalent condition. The development of new treatments is currently limited, however, by the lack of biomarkers that are sensitive and specific indicators of neuropathic Charcot arthropathy disease onset and treatment outcomes. Our long term goals are to improve neuropathic Charcot arthropathy treatments and to identify subjects who are at high risk for developing this debilitating complication. There is evidence that those with neuropathic Charcot arthropathy have low foot bone mineral densities (BMDs) and that foot BMDs further decrease during off-loading treatment. The objectives of this pilot data application are to establish volumetric quantitative computed tomography (VQCT)-derived foot BMD as a candidate biomarker for acute neuropathic Charcot arthropathy and to collect preliminary data for sample-size calculations in support of future studies to qualify foot BMD as a biomarker of neuropathic Charcot arthropathy. This pilot grant application has two specific aims: 1) to demonstrate the extent to which VQCT-derived foot BMDs predict treatment outcomes in subjects with diabetes mellitus, peripheral neuropathy, and acute neuropathic Charcot arthropathy and 2) determine the feasibility of using VQCT-derived foot BMDs to assess the risk of developing neuropathic Charcot arthropathy in subjects with diabetes mellitus and peripheral neuropathy. These specific aims will be achieved through a repeated measures cohort study in which clinical and radiological data will be collected: (1) at baseline, three months, six months and yearly for subjects who have neuropathic Charcot arthropathy and are undergoing the standard off-loading treatment protocol (Aim 1), and (2) at baseline and yearly for subjects with diabetes and peripheral neuropathy but who have not developed neuropathic Charcot arthropathy (Aim 2). Analysis of the baseline and follow-up changes will determine the extent to which VQCT-derived foot BMDs are indicators of treatment outcomes (Aim 1). Aim 2 subjects will be compared to Aim 1 subjects to determine the ability of volumetric foot BMD to estimate the risk for developing neuropathic Charcot arthropathy. Developing biomarkers in this area is significant because it can lead to identifying subjects at risk for developing neuropathic Charcot arthropathy and support the development of new treatment regimens that reduce the number of severe complications for this important patient group.