MODULATION OF LOCAL BONE TISSUE MATERIAL PROPERTIES

点击翻译按钮获取中文摘要

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.