Defining and demystifying bone quality in type 2 diabetes mellitus

描述髋部骨折是导致严重发病率和死亡率的催化剂。尽管骨矿物质密度（BMD）较高，但与非糖尿病患者相比，2型糖尿病（T2 DM）患者髋部骨折的风险增加。通常，高BMD预示着有利的骨骼强度。单独的BMD不能充分预测T2 DM患者的骨折风险。T2 DM患者BMD和骨折风险之间不一致的病理生理学机制尚不清楚。骨强度和骨折风险取决于1）骨量，由BMD定义，和mailto：lixiang@csr.nih.gov 2）骨质量，由骨骼参数定义，包括骨几何形状，微结构，矿化和重塑。核心假设是，在从正常葡萄糖耐量（NGT）到糖耐量受损（IGT）再到显性T2 DM的转变过程中，尽管骨量保持不变，但骨质量会恶化。这导致骨折风险增加。这项研究的长期目标是确定葡萄糖耐受不良的生化和代谢紊乱特征如何对骨骼有害。本提案的目的是研究三种葡萄糖稳态类型（特别是正常葡萄糖耐量（NGT）、糖耐量受损（IGT）和T2 DM）的骨量和质量差异。尚未在IGT和T2 DM患者中检查骨质量参数。将通过追求三个特定目标来检验中心假设：1）比较NGT、IGT和T2 DM中骨骼数量和骨骼几何形状的差异。在巴尔的摩老龄化纵向研究中，对男性和女性进行了双重X线骨密度测定和定量计算机断层扫描（CT），对三种血糖控制类别进行比较，以比较区域BMD、体积BMD和髋关节结构分析的髋关节几何形状。2)探讨NGT、IGT和T2 DM患者骨量、骨微结构和矿化的差异。将在招募的三种葡萄糖稳态的绝经后女性中进行四环素标记的髂骨间骨活检。将评价骨活检样本的显微CT和组织形态计量学。3)分析NGT、IGT和T2 DM患者主动骨重建参数的差异。将在招募的绝经后女性的血清中测量骨形成和骨吸收的标志物。将通过对招募受试者骨活检组织中的成骨标志物进行免疫染色来测量破骨细胞和成骨细胞数量和共定位。这种方法是新颖的，因为了解进行性糖尿病发生的骨质量变化将提供基础：1）评估葡萄糖稳态紊乱何时改变骨质量，从而增加骨折风险; 2）确定如何筛选BMD测量以外的骨折风险; 3）确定何时开始治疗以预防T2 DM骨折; 4）决定哪种现有疗法最能解决T2 DM中骨脆性的潜在病理学; 5）基于在T2 DM中观察到的骨脆性的潜在病理学开发新的干预措施。

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.