MODULATION OF LOCAL BONE TISSUE MATERIAL PROPERTIES

描述（由申请人提供）：密质骨矿物质密度为 在正常骨结构内不均匀分布。这反映 在机械性能（强度和刚度）局部变化中， 我相信这有助于限制弯曲那些平面的肌肉和韧带有 最大的机械影响。对正常骨矿物质代谢的挑战可能 影响这种物质分布，并对结构产生不成比例的影响， 整体矿物损失。例如，绝经后骨质疏松症， 骨转换增加，骨量普遍减少，但 这既不能完全解释与骨折发生率的强烈关联， 在大多数情况下，未受影响和骨折患者之间的实质性重叠 骨质量的临床筛选措施。根据先前存在的材料 异质性，材料特性的任何变化，无论是随机的，均匀的，或 系统性，可能会对机械性能产生重大影响， 结构。因此，治疗性干预措施旨在简单地影响 在不考虑局部机械因素的情况下， 性能变化在防止断裂方面可能无效。 在密质骨中，骨转换的增加可被视为分支 血管生成的问题：新的骨单位和它们的血管，必须从 已经存在的骨单位和血管如果雌激素缺乏与 随着血管和骨细胞分支的全面增加， 重塑的影响将出现在高浓度的 已经存在的骨单位这种情况将立即产生系统性的 与原始密度无关的局部骨密度变化， 而是与已有的重塑模式有关此外，我们假设， 在雌激素缺乏的情况下，新骨的密度较低， 由骨细胞组成的细胞群。如果骨细胞 密度与最终矿化的改变有关， 骨，材料特性分布的更永久性变化将 然后再继续 我们将用切除卵巢的绵羊雌激素模型来检验这些假设 耗尽将测试桡骨/尺骨的结构阻尼、刚度， 和强度，然后将其分成区域进行材料测试， 组织学重塑活动将通过动态和静态进行量化 组织形态计量学和骨密度模式分析。最后，当地 将测定骨细胞群密度并与骨细胞密度进行比较。 矿物质测量，以及局部组织的矿物质独立测量 年龄通过这种方式，我们将解决密质骨材料的问题 绝经后骨质疏松症在结构、材料、细胞 人口和生化水平。

DESCRIPTION (provided by applicant): Compact bone mineral density is distributed non-uniformly within the normal bone structure. This is reflected in local variation in mechanical properties (strength and stiffness) that we believe helps to limit bending to those planes where muscles and ligaments have maximal mechanical influence. Challenges to normal bone mineral metabolism may affect this material distribution, and have structural effects disproportionate to the overall mineral loss. For instance, in postmenopausal osteoporosis, there is increased turnover of bone, and a generalized loss of bone mass, but this fully explains neither the strong association with fracture incidence, nor the substantial overlap between unaffected and fracture patients in most clinical screening measures of bone quality. Given the pre-existing material heterogeneity, any change in material properties, be it random, uniform, or systematic, is likely to have significant effects on the mechanical behavior of the structure. Therefore, therapeutic interventions designed to simply affect an overall increase in bone mass without considering regional mechanical property variation may be ineffective in preventing fracture. In compact bone, an increase in bone turnover may be seen as a branching problem in angiogenesis: new osteons, and their blood vessels, must arise from pre-existing osteons and blood vessels. If estrogen depletion were associated with a global increase in vascular and osteonal branching, the major early effects of remodeling would be seen in regions with high concentrations of pre-existing osteons. Such a scenario would produce an immediate systematic change in regional bone density that would be related not to original density, but to pre-existing remodeling patterns. Furthermore, we hypothesize that the new bone that is laid down in the estrogen-depleted condition is less densely populated by osteocytes than in the intact animal. If changes in osteocyte density were associated with alterations in the final mineralization of new bone, a more permanent change in the distribution of material properties would then ensue. We will test these hypotheses using the ovariectomized-sheep model of estrogen depletion. The radius/ulna will be tested for structural damping, stiffness, and strength before sectioning into regions for materials testing and histology. Remodeling activity will be quantified by dynamic and static histomorphometry, and by analysis of osteonal density patterns. Finally, local osteocyte population densities will be determined and compared with osteonal mineral measurements, and with mineral-independent measurements of local tissue age. In this way, we will address the issue of compact bone material heterogeneity in postmenopausal osteoporosis at the structural, materials, cell population, and biochemical levels.