Defining and demystifying bone quality in type 2 diabetes mellitus

髋部骨折是严重发病率和死亡率的催化剂。尽管骨密度（BMD）较高，但2型糖尿病（T2DM）患者髋部骨折的风险比非糖尿病患者高。通常，高骨密度预示着良好的骨骼强度。单纯的骨密度不足以预测2型糖尿病患者的骨折风险。T2DM患者骨密度与骨折风险不一致的病理生理机制尚不清楚。骨强度和骨折风险取决于1)骨量（由BMD定义）和（mailto:lixiang@csr.nih.gov2）骨质量（由骨骼参数定义，包括骨几何、微结构、矿化和重塑）。核心假设是，在从正常糖耐量（NGT）到糖耐量受损（IGT）再到显性T2DM的转变过程中，尽管骨量维持，但骨质量恶化。这导致骨折风险增加。本研究的长期目标是确定葡萄糖不耐受特征的生化和代谢紊乱如何对骨骼有害。本研究的目的是研究三种类型葡萄糖稳态，特别是正常糖耐量（NGT）、糖耐量受损（IGT）和T2DM的骨数量和质量差异。IGT和T2DM患者的骨质量参数尚未检测。中心假设将通过追求三个具体目标来检验：1)比较NGT、IGT和T2DM患者骨骼数量和骨骼几何形状的差异。在巴尔的摩衰老纵向研究中，对三种血糖控制的男性和女性进行双x射线吸收测定和定量计算机断层扫描（CT），将用于比较髋关节结构分析的面积骨密度、体积骨密度和髋关节几何形状。2)评价NGT、IGT和T2DM患者骨量和骨微结构矿化的差异。四环素标记的经髂骨活检将在三种类型的葡萄糖稳态绝经后妇女中进行。显微ct和组织形态学将评估骨活检样本。3)分析NGT、IGT和T2DM患者骨重构活性参数的差异。将在招募的绝经后妇女的血清中测量骨形成和吸收的标志物。破骨细胞和成骨细胞的数量和共定位将通过骨活检中成骨标志物的免疫染色来测量。这种方法是新颖的，因为了解进展性糖尿病患者骨质量的变化将为以下方面提供基础：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测量之外的骨折风险；3)确定何时开始治疗以预防T2DM患者骨折；4)确定哪种现有治疗方法最能解决T2DM患者骨脆性的潜在病理问题；5)基于T2DM中观察到的骨脆性的潜在病理，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.