Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures

皮质骨孔隙度可识别患有脆性骨折的糖尿病受试者

• 批准号: 7943886
• 负责人: THOMAS M LINK
• 金额: $ 42.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943886
• 关键词: Adult; Affect; Age; Animal Model; Ankle; Applications Grants; Architecture; Area; Biological Markers; Body mass index; Bone Density; Bone Diseases; Bone Marrow; Clinical; Cohort Studies; Coin; Data; Diabetes Mellitus; Diagnosis; Diagnostic Procedure; Disease; Distal; Fatty acid glycerol esters; Female; Femur; Finite Element Analysis; Fracture; Functional disorder; Genomics; Goals; Hip Fractures; Hip region structure; Image; Imaging Techniques; Institution; Insulin-Dependent Diabetes Mellitus; Intramural Research; Lateral; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mechanics; Metabolism; Metric; Monitor; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Osteoporosis; Patients; Performance; Peripheral; Pilot Projects; Play; Porosity; Postmenopause; Prevention; Process; Property; Proteomics; Public Health; Radial; Research; Resolution; Risk; Roentgen Rays; Role; Structure; Surrogate Markers; Techniques; Treatment Efficacy; United States National Institutes of Health; Validation; Vertebral column; Woman; abstracting; aged; base; bone; bone mass; bone quality; bone strength; diabetic; diabetic patient; digital; experience; foot; humerus; imaging modality; improved; in vivo; musculoskeletal imaging; non-diabetic; normal aging; novel; patient population; prevent; substantia spongiosa; tibia; trend

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.

描述（由申请人提供）：皮质骨孔隙度识别患有脆性骨折的糖尿病受试者 摘要 本拨款申请的广泛挑战领域是 (03) 生物标志物发现和验证。定量成像技术由于其非侵入性性质，作为生物标志物具有重要意义。对于肌肉骨骼成像尤其如此，其中开发成像生物标志物是为了更好地了解骨骼结构和稳定性。因此，特定的挑战领域 03-AR-102* 侧重于开发新型成像（蛋白质组学或基因组学）方法来识别脆性骨折的风险。该项目将定义并验证新的骨质量测量方法，这些测量方法比骨矿物质密度测量更具预测性。骨矿物质密度（BMD）是目前最成熟的预测骨质疏松症骨折风险的骨生物标志物。双 X 射线吸收测定法 (DXA) 在区分有骨折和无骨折的受试者、预测骨折风险和监测治疗方面表现出良好的性能。然而，在某些疾病实体中，BMD 测量的局限性已得到承认，其中糖尿病性骨病尤为重要。大量研究表明，虽然II型糖尿病受试者的骨折风险增加，但糖尿病患者的骨密度也较高。这一悖论尚未得到充分理解，并且尚未建立更好地评估糖尿病受试者骨折风险的具体诊断技术。美国国立卫生研究院 (NIH) 此前创造了“骨质量”一词，以更好地表征骨强度实体，而骨强度实体无法用骨量或 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发挥着核心作用，在骨质量测量中，关注皮质骨和骨小梁结构的测量最为突出。考虑到糖尿病日益增加的社会经济负担以及这些患者脆性骨折的破坏性后果，寻找一种强效、非侵入性的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。在最近的一个校内研究试点项目中，我们能够研究有或没有低能量骨折的糖尿病受试者和非糖尿病对照的骨骼结构参数。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 研究皮质骨和小梁骨结构。 Hr-pQCT 是一种新颖的成像方式，目前提供最佳的各向同性空间分辨率（体素大小），以可视化体内远端胫骨和桡骨的皮质和骨小梁结构。我们的研究小组在这项技术方面获得了丰富的经验，特别是在图像后处理方面提取结构参数，包括皮质孔隙率和有限元分析得出的骨强度替代标记。我们还对其中一部分患者的腰椎进行了骨髓磁共振波谱分析，以表征骨髓脂肪成分，因为这对于了解糖尿病骨病的病理生理学可能具有重要意义。这项研究的结果表明，虽然 BMD 和小梁结构参数都无法区分脆性骨折和非骨折糖尿病患者组，但基于有限元分析发现皮质骨孔隙度和参数存在显着差异。与正常对照组相比，还发现糖尿病受试者的骨髓脂肪有较高的趋势。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产生重大影响。在这项拨款申请中，我们建议研究四个受试者组的皮质孔隙度，包括患有或不患有糖尿病、患有或不患有脆性骨折的受试者，以对我们的试点研究中发现的结果进行临床验证。我们的假设是，使用 hr-pQCT 衍生的皮质骨孔隙度测量和有限元分析以及 MR 光谱衍生的骨髓脂肪，我们将能够区分有或没有脆性骨折的糖尿病受试者。我们还假设，与患有或不患有脆性骨折的非糖尿病受试者相比，患有脆性骨折的糖尿病受试者将具有不同的皮质骨结构，并且基于 BMD 的参数将无法区分患有骨折的糖尿病患者与未骨折的糖尿病患者和对照组。考虑到糖尿病日益增加的社会经济负担以及这些患者脆性骨折的破坏性后果，寻找一种强效、非侵入性的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。我们相信，根据我们的初步数据，利用我们的新型生物标志物，我们也许能够更好地表征糖尿病患者的骨折风险。