FT-IR Microscopy of Mineral Structure

描述(申请人提供)：骨质疏松症每年在美国造成约150万处骨折，其中30万处发生在髋部，花费超过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“……容易导致骨折风险增加的骨骼强度受损”。各种遗传和环境因素，以及骨特性(几何和材料)，导致了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的骨密度降低通常用于临床预测骨折风险，但骨密度并不是一个强有力的预测指标，大多数骨折发生在骨密度高于骨质疏松阈值的患者中。我们最近通过多元Logistic回归分析表明，傅立叶变换红外光谱成像(FTIRI)评估的特定矿物质和基质特性可以预测绝经后妇女的骨折，而骨密度与骨折发生率没有显著相关性。在有限数量的样品中，我们还表明这些FTIR参数与纳米机械性能相关。我们假设结晶度(XST)和胶原成熟度(XLR)的差异部分解释了具有相似BMD的个体骨折发生率的差异。我们进一步假设，这些参数的异质性是骨折发生率的另一个决定因素，尤其是在松质骨中。在拟议的研究中，我们将检验4个假设。1)对于任何受试者，在髂骨顶骨皮质和松质骨(通常是非骨折部位)获得的FTIRI数据代表骨折部位(粗隆下/大粗隆)。此外，只要包括皮质骨和松质骨区域，这些数据与活检的大小无关。这将通过从身体和临床骨折患者身上进行多次活组织检查来检验。措施将包括对BMD和建筑进行微型CT分析，以及FTIRI。2)FTIRI矿物和基质性质的异质性降低，加上XST和XLR的增加，是人类骨折的预测因素。这将通过将我们的Logistic回归扩展到异质性参数来进行测试。特发性青少年骨质疏松症患者的组织特性随年龄的变化将被研究。组织机械特性将与FTIRI数据相关联。3)合成代谢剂(PTH)可以恢复动物模型和人类骨质疏松模型的力学性能、XST、XLR以及矿物质和基质的异质性。这将通过对治疗前和治疗后的人类活检组织的分析以及在绵羊模型中的分析来检验。4)XLR在骨质疏松症中发生改变，与胶原定位有关。作为我们持续参数验证的一部分，我们将通过比较FTIRI和二次谐波再生显微镜数据来测试这一点。对这四个假说的检验将为治疗的有效性提供新的见解，并有助于理解导致骨折的因素。

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.