Biomarkers for Charcot Arthropathy in Diabetic Patients

描述（由申请人提供）：神经性Charcot关节病是糖尿病的一种并发症，在很高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，并可能截肢。早期发现和及时干预是必要的，以尽量减少这种日益普遍的疾病的严重后果。然而，由于缺乏对神经性Charcot关节病发病和治疗结果敏感和特异性指标的生物标志物，新疗法的发展目前受到限制。我们的长期目标是改善神经性Charcot关节病的治疗，并确定发生这种衰弱性并发症的高风险受试者。有证据表明，神经性Charcot关节病患者的足部骨矿物质密度（bmd）较低，并且在卸载治疗期间足部骨密度进一步降低。该试点数据应用的目的是建立体积定量计算机断层扫描（VQCT）衍生的足部骨密度作为急性神经性Charcot关节病的候选生物标志物，并收集样本量计算的初步数据，以支持未来研究将足部骨密度作为神经性Charcot关节病的生物标志物。该试点资助申请有两个具体目的：1)证明vqct衍生足部bmd预测糖尿病、周围神经病变和急性神经性Charcot关节病患者治疗结果的程度；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关节病风险的可行性。这些具体目标将通过一项重复测量队列研究来实现，该研究将收集临床和放射学数据：(1)基线、3个月、6个月和每年对患有神经性Charcot关节病并正在接受标准卸载治疗方案的受试者（Aim 1），以及(2)基线和每年对患有糖尿病和周围神经病变但未发生神经性Charcot关节病的受试者（Aim 2）。基线和随访变化的分析将确定vqct衍生的足部骨密度在多大程度上是治疗结果的指标（目的1）。将Aim 2受试者与Aim 1受试者进行比较，以确定体积足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志物具有重要意义，因为它可以识别有患神经性Charcot关节病风险的受试者，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的数量。

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.