FT-IR Microscopy of Mineral Structure

描述（由申请人提供）：骨质疏松症在美国每年造成约150万例骨折，其中30万例发生在髋关节，成本超过170亿美元。美国国立卫生研究院共识会议和世界卫生组织将骨质疏松症定义为“...骨强度受损易导致骨折风险增加”。各种遗传和环境因素，以及骨特性（几何和材料），有助于与骨质疏松症相关的骨丢失，但问题仍然是哪些因素主要导致骨折风险。虽然相对于年轻个体降低的骨矿物质密度（BMD）在临床上常规用于预测骨折风险，但BMD不是强有力的预测因子，大多数骨折发生在BMD高于骨质疏松阈值的患者中。我们最近通过多元逻辑回归分析表明，特定的矿物和基质性质评估的傅里叶变换红外光谱成像（FTIRI）是预测骨折的绝经后妇女，而骨密度与骨折的发病率没有显着相关。在有限数量的样品中，我们还表明，这些FTIR参数与纳米力学性能相关。我们假设结晶度（XST）和胶原成熟度（XLR）的变化部分解释了具有相似BMD的个体中骨折发生率的差异。我们进一步假设这些参数的异质性是骨折发生率的额外决定因素，尤其是在松质骨中。在本研究中，我们将测试4个假设。1)对于任何受试者，在髂嵴皮质骨和松质骨（通常为非骨折部位）中获得的FTIRI数据代表骨折部位（转子下/大转子）的FTIRI数据。此外，只要包括皮质骨和松质骨区域，数据与活检的大小无关。这将使用尸体和临床骨折患者的多次活检进行测试。测量将包括BMD和结构的微CT分析，以及FTIRI。2)FTIRI矿物和基质性质的异质性降低，以及XST和XLR增加，都是人类骨折的预测因素。这将通过将我们的逻辑回归扩展到异质性参数来进行测试。将在特发性青少年骨质疏松症患者中研究组织特性随年龄的变化。组织力学特性将与FTIRI数据相关。3)合成代谢剂（PTH）可以恢复机械性能，以及XST，XLR，和矿物和基质异质性的动物模型，以及在人类的神经退行性疾病。这将通过分析治疗前和治疗后的人体活检以及绵羊模型中的分析进行检验。4)XLR在骨质疏松症中改变，与胶原蛋白取向有关。作为我们持续参数验证的一部分，这将通过比较FTIRI和二次谐波显微镜数据进行测试。这四个假设的测试将提供新的见解的疗效的治疗，并有助于理解的因素导致骨折。

DESCRIPTION (provided by applicant): Osteoporosis is responsible for approximately 1.5 million fractures in the US per year, with 300,000 of these fractures occurring at the hip at a cost exceeding $17 billion. The NIH Consensus conference and the World Health Organization defined osteoporosis as "...compromised bone strength predisposing to an increased risk of fracture". A variety of genetic and environmental factors, as well as bone properties (geometric and material), contribute to the bone loss that is associated with osteoporosis, but the question remains as to which factors primarily contribute to fracture risk. While reduced bone mineral density (BMD) relative to young individuals is routinely used clinically to predict fracture risk, BMD is not a strong predictor, with the majority of fractures occurring in patients with BMD's above the osteoporotic threshold. We have recently shown by multiple logistic regression analysis that specific mineral and matrix properties assessed by Fourier transform infrared spectroscopic imaging (FTIRI) are predictive of fracture in postmenopausal women, while BMD is not significantly associated with fracture incidence. In a limited number of samples we have also shown that these FTIR parameters are correlated with nanomechanical properties. We hypothesize that variation in crystallinity (XST) and collagen maturity (XLR) partially explains the difference in incidence of fractures in individuals with similar BMDs. We further hypothesize that heterogeneity in these parameters is an additional determinant of fracture incidence, especially in trabecular bone. In the proposed studies we will test 4 hypotheses. 1) For any subject, FTIRI data obtained in the cortical and cancellous bone of the iliac crest (generally a non-fracturing site) is representative of that from sites that fracture (subtrochanter/greater trochanter). Further, the data are independent of the size of the biopsy as long as cortical and cancellous bone areas are included. This will be tested using multiple biopsies from cadavers and from clinic patients with fractures. Measures will include micro-CT analysis of BMD and architecture, and FTIRI. 2) Decreased heterogeneity in FTIRI mineral and matrix properties, in addition to increased XST and XLR, are predictive of fracture in humans. This will be tested by extending our logistic regression to heterogeneity parameters. Variation in tissue properties with age will be studied in patients with idiopathic juvenile osteoporosis. Tissue mechanical properties will be correlated with FTIRI data. 3) An anabolic agent (PTH) can restore mechanical properties, and the XST, XLR, and mineral and matrix heterogeneity in animal models as well as in osteoporotic humans. This will be tested by analyses of pre- and post- treatment human biopsies and by analyses in a sheep model. 4) XLR, which is altered in osteoporosis, is related to collagen orientation. As part of our continued parameter validation, this will be tested by comparing FTIRI and second harmonic heneration microscopy data. Testing of these four hypotheses will provide new insights into the efficacy of therapies and contribute to the understanding of factors leading to fracture.