Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures

描述（由申请人提供）：皮质骨孔隙度-糖尿病受试者与脆性骨折摘要广泛的挑战领域，这项赠款申请是（03）生物标志物的发现和验证。定量成像技术，由于其非侵入性的性质，获得了作为生物标志物的实质性意义。这对于肌肉骨骼成像尤其如此，其中开发成像生物标志物以更好地了解骨结构和稳定性。因此，特定挑战领域03-AR-102* 侧重于开发新的成像（蛋白质组学或基因组学）方法，以识别脆性骨折的风险。该项目将定义和验证比骨矿物质密度测量更具预测性的骨质量新指标。骨矿物质密度（BMD）是目前最好的骨生物标志物，以预测骨质疏松症的骨折风险。双能X线骨密度仪（DXA）在区分骨折和非骨折受试者、预测骨折风险和监测治疗方面表现良好。然而，在某些疾病实体的BMD测量的局限性已被承认，其中糖尿病性骨疾病是非常重要的。大量研究表明，虽然II型糖尿病患者的骨折风险增加，但糖尿病患者的BMD也较高。这种矛盾尚未得到很好的理解，具体的诊断技术，以更好地评估骨折的风险，糖尿病患者尚未建立。NIH以前创造了“骨质量”一词，以更好地表征骨强度的实体，这些实体不能用骨量或BMD很好地量化。人们普遍认为骨质量在糖尿病患者脆性骨折数量增加中起着重要作用，在骨质量的测量中，那些关注皮质骨和松质骨结构的测量是突出的。寻找一种强有力的非侵入性骨质量生物标志物来更好地预测糖尿病患者的脆性骨折显然是一个主要的挑战领域，因为糖尿病的社会经济负担日益增加，脆性骨折对这些患者造成了毁灭性的后果。在最近的一个校内研究试点项目中，我们能够研究糖尿病患者和非糖尿病对照组的骨结构参数。我们使用定量CT（QCT）获得BMD测量值，并使用高分辨率外周QCT（hr-pQCT）和高分辨率MRI研究皮质骨和松质骨结构。Hr-pQCT是目前提供最佳各向同性空间分辨率（体素大小）的新型成像模式，可在体内可视化胫骨远端和桡骨的皮质骨和骨小梁结构。我们的研究小组已经获得了这项技术的丰富经验，特别是关于图像后处理，以提取结构参数，包括皮质孔隙率和有限元分析衍生的骨强度替代标记。我们还对这些患者的一个子集进行了腰椎骨髓MR波谱分析，以表征骨髓脂肪成分，因为这对了解糖尿病性骨病的病理生理学可能具有重要意义。本研究的结果表明，虽然BMD和骨小梁结构参数都不能区分脆性骨折和非骨折糖尿病患者组，但基于有限元分析的皮质骨孔隙率和参数存在实质性的显著差异，并且发现糖尿病受试者与正常对照组相比有更高的骨髓脂肪的趋势。这些发现需要通过研究更大的患者群体来证实，但可能对量化糖尿病受试者脆性骨折的风险具有实质性意义。在这项资助申请中，我们建议研究四个受试者组的皮质孔隙率，有和没有糖尿病，有和没有脆性骨折，以临床验证我们的试点研究中发现的结果。我们的假设是，使用hr-pQCT推导出的皮质骨孔隙率测量值和有限元分析以及MR光谱推导出的骨髓脂肪，我们将能够区分有和没有脆性骨折的糖尿病受试者。我们还假设脆性骨折的糖尿病受试者与非糖尿病受试者相比具有不同的皮质骨结构，并且基于BMD的参数将无法区分骨折的糖尿病患者与未骨折的糖尿病患者和对照组。寻找一种强有力的非侵入性骨质量生物标志物来更好地预测糖尿病患者的脆性骨折显然是一个主要的挑战领域，因为糖尿病的社会经济负担日益增加，脆性骨折对这些患者造成了毁灭性的后果。我们相信，基于我们的初步数据，我们的新生物标志物，我们可能能够更好地表征糖尿病患者的骨折风险。

DESCRIPTION (provided by applicant): Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures Abstract The broad challenge area for this grant application is (03) Biomarker Discovery and Validation. Quantitative imaging techniques have, due to their non-invasive nature, gained substantial significance as biomarkers. This is in particular true for musculoskeletal imaging where imaging biomarkers are developed to better understand bone structure and stability. Thus the specific challenge area 03-AR-102* focuses on developing novel imaging (proteomic, or genomic) approaches to identify the risk for fragility fractures. This project will define and validate novel measures of bone quality that are more predictive than bone mineral density measurements. Bone mineral density (BMD) is currently the best-established bone biomarker to predict fracture risk in osteoporosis. Dual X-ray absorptiometry (DXA) has shown good performance in differentiating subjects with and without fractures, predicting fracture risk and monitoring therapy. However, in certain disease entities limitations of BMD measurements have been acknowledged and among these diabetic bone disease is of outstanding importance. A large number of studies have shown that while fracture risk in subjects with type II diabetes is increased, diabetics also have a higher BMD. This paradox has not been well understood and specific diagnostic techniques to better assess fracture risk in diabetic subjects have not been established. The NIH has previously coined the term "bone quality" to better characterize entities of bone strength which are not well quantified with bone mass or BMD. It is generally accepted that bone quality must play a central role in the increased number of fragility fractures in diabetics and among the measures of bone quality those focusing on cortical and trabecular bone architecture are outstanding. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. In a recent intramural research pilot project we were able to study bone structure parameters in diabetic subjects with and without low energy fractures and non-diabetic controls. We obtained BMD measurements using quantitative CT (QCT) and studied cortical and trabecular bone structure with high resolution peripheral QCT (hr-pQCT) and high resolution MRI. Hr-pQCT is a novel imaging modality currently providing the best isotropic spatial resolution (voxel size) to visualize cortical and trabecular bone structure in vivo at the distal tibia and radius. Our research group has acquired extensive experience with this technique, in particular concerning image post-processing to extract structural parameters including cortical porosity and finite element analysis derived surrogate markers of bone strength. We also performed bone marrow MR spectroscopy of the lumbar spine in a subset of these patients to characterize bone marrow fat composition, as this may be of significant importance in understanding pathophysiology of diabetic bone disease. The results of this study showed, that while neither BMD nor trabecular structure parameters were able to differentiate fragility fracture and non-fracture diabetic patient groups, substantial, significant differences in cortical bone porosity and parameters based on finite element analysis were found. Also a trend was found for higher bone marrow fat in diabetic subjects versus normal controls. These findings need to be confirmed by studying larger patient groups, yet could potentially have substantial implications for quantifying risk of fragility fractures in diabetic subjects. In this grant application we propose to study cortical porosity in four subject groups, with and without diabetes and with and without fragility fractures to clinically validate the results found in our pilot study. Our hypothesis is that using hr-pQCT derived measures of cortical bone porosity and finite element analysis as well as MR spectroscopy derived bone marrow fat we will be able to differentiate diabetic subjects with and without fragility fractures. We also hypothesize that diabetic subjects with fragility fractures will have different cortical bone structure compared to non-diabetic subjects with and without fragility fractures and that BMD based parameters will not be able to differentiate diabetics with fractures versus diabetics and controls without fracture. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. We believe, based on our preliminary data, that with our novel biomarkers we may be able to better characterize fracture risk in diabetic patients.