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)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更高。传统上，高骨密度预示着良好的骨骼强度。BMD本身不足以预测T2 DM的骨折风险。T2 DM患者骨密度与骨折风险不一致的病理生理学基础尚不清楚。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。中心假设是，在从正常糖耐量(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，但骨质量仍会恶化。这会导致骨折风险增加。这项研究的长期目标是确定以葡萄糖耐量异常为特征的生化和代谢紊乱是如何对骨骼有害的。这项建议的目的是研究三种类型的葡萄糖稳态在骨量和质量上的差异，特别是正常糖耐量(NGT)、糖耐量受损(IGT)和T2 DM。尚未对IGT和T2 DM患者进行骨质量参数检测。中心假设将通过追求三个具体目标来检验：1)比较NGT、IGT和T2 DM在骨量和骨几何方面的差异。在巴尔的摩老龄化纵向研究中，对三种血糖控制类别的男性和女性进行了双重X射线吸收测量和定量计算机断层扫描(CT)，以比较髋部结构分析中的面积骨密度、体积骨密度和髋部几何形状。2)比较NGT、IGT和T2 DM在骨量、骨微结构和矿化方面的差异。四环素标记的过渡骨活检将在三类葡萄糖稳态的绝经后妇女中进行。将评估骨活检样本的显微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。骨形成和骨吸收的标记物将在招募的绝经后妇女的血清中进行测量。在招募的受试者的骨活检中，破骨细胞和成骨细胞的数量和共定位将通过成骨标记物的免疫染色来测量。这一方法是新颖的，因为了解进展性糖尿病发生的骨质量变化将为以下方面提供基础：1)评估糖代谢紊乱何时改变骨骼质量，从而增加骨折风险；2)确定如何筛查骨密度以外的骨折高危人群；3)确定何时开始治疗以预防T2 DM骨折；4)决定现有治疗方法将最好地解决T2 DM骨脆性的根本病理；5)根据T2 DM观察到的骨骼脆性的基本病理，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.