Progression and etiology of cortical porosity in diabetic bone disease

摘要 糖尿病骨疾病，其脆性骨折的风险增加，越来越被认为是一种不同的实体 这不能用骨质疏松症的标准方法进行充分评估。严重的皮质缺乏症 骨结构，特别是皮质孔隙率的增加，与T2D的骨折发生率有关。大脑皮层 孔洞对骨强度有有害影响，在骨折的萌生和扩展中起着至关重要的作用。尽管 皮质孔洞的生物力学意义、病理性皮质的起源和时间演化 T2D的孔隙度是未知的。开发专门针对预防或逆转 T2D中的病理性皮质孔洞和相关的骨脆性，我们必须了解其驱动机制 这些大的皮质毛孔的发育。今天，这些机制尚不为人所知，尽管其中许多机制已经存在 假设，包括皮质内“小梁化”和哈弗斯网络的扩展。我们假设 确定皮层孔隙空间的含量和空间分布将揭示生物系统 影响气孔膨胀的。靠近骨内膜边缘的小孔内的骨髓可能提示皮质内 “小梁化”，即骨髓腔渗入皮质包膜。或者，内有船只 分布在皮质各处的气孔可能表明气孔是通过血管网络扩张而形成的。这个 识别与毛孔扩张相关的生物系统将阐明适当的细胞靶点 药物开发。这项拟议的研究的总体目标是了解人类的纵向进化 糖尿病骨病，并研究驱动皮质增加的潜在生物学过程 在T2D环境中的孔隙率。我们建议首次对T2D患者的毛孔进展进行纵向研究， 这将使用一种新的组合高分辨率外周定量计算机断层扫描来执行 (HR-pQCT)和对比度增强磁共振成像方法，目的如下： 确定T2D的孔隙率增加是否与骨髓分布和成分改变有关，II： 确定T2D中孔隙率的增加是否与血管分布和血管健康改变有关，以及III： 确定T2D状态或骨髓或血管指标是否预测纵向孔隙率增加和 力量。为了达到目标I和II，我们将在T2D的横断面队列中进行多模式成像 患者和匹配的对照组受试者。为了解决目标III，我们将对这些主题进行为期两年的纵向跟踪 学习。这项工作将确定皮质孔隙含量是否可以作为未来皮质的预测因子 并开始阐明生物驱动因素和可能的药物靶点，以防止或逆转 T2D相关的病理性多孔性和骨脆性，为未来的治疗研究奠定了基础。 随着破坏性糖尿病脆性骨折的数量增加，这些研究有可能 巨大的临床影响。

SUMMARY Diabetic bone disease, with its elevated risk for fragility fracture, is increasingly recognized as a distinct entity that cannot be assessed sufficiently with standard methods used for osteoporosis. Severe deficits in cortical bone structure, specifically increased cortical porosity, are associated with fracture prevalence in T2D. Cortical porosity has deleterious effects on bone strength, and is critical in fracture initiation and propagation. Despite the biomechanical importance of cortical porosity, the origins and temporal evolution of pathological cortical porosity in T2D are unknown. To develop treatments specifically targeted to the prevention or reversal of pathological cortical porosity and associated bone fragility in T2D, we must understand the mechanisms driving development of these large cortical pores. Today, these mechanisms are unknown though many have been posited, including endocortical `trabecularization' and expansion of the Haversian network. We hypothesize that determining the content and spatial distribution of cortical pore space will reveal biological systems influencing pore expansion. Marrow within pores near the endosteal border may indicate endocortical `trabecularization', or infiltration of the marrow cavity into the cortical envelope. Alternatively, vessels within pores distributed throughout the cortex may indicate pore formation via expansion of the vascular network. The identification of biological systems associated with pore expansion will elucidate appropriate cellular targets for drug development. The overall goal of this proposed study is to understand the longitudinal evolution of human diabetic bone disease and to investigate the underlying biological processes that drive increased cortical porosity in the setting of T2D. We propose the first longitudinal study of pore progression in T2D patients, which will be performed using a novel combined high-resolution peripheral quantitative computed tomography (HR-pQCT) and contrast enhanced magnetic resonance (MR) imaging approach, with the following aims: I: Determine if increased porosity in T2D is associated with altered marrow distribution and composition, II: Determine if increased porosity in T2D is associated with altered vessel distribution and vascular health, and III: Determine if T2D status or marrow or vessel metrics predict longitudinal increase in porosity and decrease in strength. To address aims I and II, we will perform multimodal imaging in a cross-sectional cohort of T2D patients and matched control subjects. To address aim III, we will follow these subjects in a 2-year longitudinal study. This work will establish whether cortical pore content can serve as a predictor of future cortical degradation, and begin to elucidate biological drivers and possible drug targets for the prevention or reversal of T2D-associated pathological porosity and bone fragility, laying the groundwork for future therapeutic studies. With the number of devastating diabetic fragility fractures increasing, these studies have the potential for immense clinical impact.