Defining and demystifying bone quality in type 2 diabetes mellitus

2 型糖尿病骨质量的定义和揭秘

基本信息

批准号：
9039584
负责人：
Kendall Moseley
金额：
$ 18.57万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039584
关键词：
Address Aging Area Baltimore Biochemical Biological Assay Biopsy Biopsy Specimen Bone Density Bone Resorption Bone remodeling C-telopeptide Categories Cell Count Cell surface Characteristics Data Deterioration Development Diabetes Mellitus Event Fracture Functional disorder Funding Future Geometry Glucose Intolerance Goals Health Hip Fractures Hip region structure Intervention Knowledge Label Longitudinal Studies Maintenance Measurement Measures Metabolic Metabolism Minerals Morbidity - disease rate N-terminal Non-Insulin-Dependent Diabetes Mellitus Osteoblasts Osteoclasts Osteogenesis Outcomes Research Pathology Persons Physiologic calcification Populations at Risk Porosity Postmenopause Prevention Prevention strategy Procollagen Public Health Recruitment Activity Research Research Personnel Risk Roentgen Rays Serological Serum Site Speed Structure Surface Targeted Research Techniques Testing Tetracyclines Thick Time Width Woman X-Ray Computed Tomography base blood glucose regulation bone bone geometry bone quality bone strength bone turnover catalyst cohort disability frailty glucose tolerance glycemic control impaired glucose tolerance men mineralization molecular marker mortality novel osteogenic polypeptide C prevent skeletal skills training

项目摘要

DESCRIPTION Hip fracture is a catalyst for profound morbidity and mortality. Despite high bone mineral density (BMD), persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture compared to those without diabetes. Conventionally, high BMD predicts favorable skeletal strength. BMD alone is an inadequate predictor of fracture risk in T2DM. The pathophysiology underlying the discordance between BMD and fracture risk in T2DM is unknown. Bone strength and fracture risk depend on 1) bone quantity, defined by BMD, and mailto:lixiang@csr.nih.gov2) bone quality, defined by skeletal parameters including bone geometry, microarchitecture, mineralization and remodeling. The central hypothesis is that during the transition from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM, bone quality deteriorates despite maintenance of bone quantity. This leads to increased fracture risk. The long-term goal of this research is to identify how the biochemical and metabolic derangements characteristic of glucose intolerance are deleterious to bone. The objective of this proposal is to investigate differences in bone quantity and quality across the three categories of glucose homeostasis, specifically normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2DM. Parameters of bone quality have not been examined in persons with IGT and T2DM. The central hypothesis will be tested by pursuing three specific aims: 1) To compare differences in skeletal quantity and bone geometry in NGT, IGT and T2DM. Dual x-ray absorptiometry and quantitative computed-tomography (CT) performed on men and women in the Baltimore Longitudinal Study of Aging across the three categories of glycemic control will be used to compare areal BMD, volumetric BMD and hip geometry from hip structure analysis. 2) To evaluate differences in skeletal quantity and bone microarchitecture & mineralization in NGT, IGT and T2DM. Tetracycline-labeled transiliac bone biopsies will be performed in recruited postmenopausal women in the three categories of glucose homeostasis. Micro-CT and histomorphometry of bone biopsy samples will be evaluated. 3) To analyze differences in parameters of active bone remodeling in NGT, IGT and T2DM. Markers of bone formation and resorption will be measured in the sera of recruited postmenopausal women. Osteoclast and osteoblast number and co-localization will be measured by immunostaining for osteogenic markers in the bone biopsies of recruited subjects. This approach is novel because understanding the changes in bone quality that occur with progressive diabetes will provide the basis to: 1) Assess when deranged glucose homeostasis alters bone quality and thus increases fracture risk; 2) Determine how to screen those at risk for fracture beyond BMD measurement; 3) Determine when to initiate treatment to prevent fracture in T2DM; 4) Decide which existing therapy will best address the underlying pathology of bone fragility in T2DM; 5) Develop new interventions based on the underlying pathology of the bone fragility observed in T2DM.

描述髋部骨折是催化剂的发病率和死亡率的催化剂。尽管骨矿物质密度很高（BMD），但与没有糖尿病的人相比，患有2型糖尿病的人（T2DM）的髋部骨折风险增加。通常，高BMD预测有利的骨骼强度。仅BMD是T2DM断裂风险的预测因子不足。 T2DM中BMD和断裂风险之间不一致的病理生理是未知的。骨骼强度和断裂风险取决于1）由BMD定义的骨骼数量和Mailto：lixiang@csr.nih.gov2）骨质质量，由骨骼参数定义，包括骨骼几何，微体系结构，矿化和重塑。中心假设是，在从正常的葡萄糖耐量（NGT）过渡到降低葡萄糖耐受性（IGT）到明显的T2DM，尽管骨骼数量保持，但骨骼质量会恶化。这导致骨折风险增加。这项研究的长期目标是确定葡萄糖不耐症的生化和代谢扰动特征如何对骨骼有害。该建议的目的是研究三类葡萄糖稳态的骨骼数量和质量差异，特别是正常的葡萄糖耐受性（NGT），葡萄糖耐受性受损（IGT）和T2DM。尚未在IGT和T2DM的人中检查骨质质量的参数。中央假设将通过追求三个特定目的来检验：1）比较NGT，IGT和T2DM中骨骼数量和骨骼几何形状的差异。在巴尔的摩纵向研究中，对三类血糖控制的衰老纵向研究对男性和女性进行了双X射线吸收仪和定量计算学 - 征学（CT），将用于比较HIP结构分析中的面积BMD，大量BMD和髋少量。 2）评估NGT，IGT和T2DM中骨骼数量和骨微结构和矿化的差异。四环素标记的跨骨骨活检将在三类葡萄糖稳态中的绝经后妇女中进行。将评估骨活检样品的微CT和组织形态测定法。 3）分析NGT，IGT和T2DM中主动骨重塑参数的差异。骨形成和吸收的标志物将在绝经后妇女的血清中进行测量。成骨细胞和成骨细胞数和共定位将通过免疫染色来测量招募受试者的骨骼活检中的成骨标记。这种方法是新颖的，因为了解进行性糖尿病的骨骼质量变化将为以下基础提供：1）评估何时葡萄糖稳态何时改变骨骼质量，从而增加骨折风险； 2）确定如何筛选出超出BMD测量的裂缝风险的人； 3）确定何时开始治疗以防止T2DM断裂； 4）确定哪种现有疗法最能解决T2DM中骨骼脆弱性的潜在病理； 5）基于在T2DM中观察到的骨骼脆弱性的潜在病理发展新的干预措施。