FT-IR Microscopy of Mineral Structure in Osteoporosis

描述（由申请人提供）：骨质疏松症每年影响全球超过7500万女性和男性，每年造成的损失高达500亿美元。为了确定骨质疏松症骨的成分变化，我们首创了傅里叶变换红外光谱成像（FTIRI），用于测量约7um的空间分辨率的骨活检，并将该技术与组织学，显微ct和力学一起应用于评估骨质疏松症的治疗方法。迄今为止，双膦酸盐（BP）是预防脆性骨折和对抗骨质流失最有效的药物。由于这些药物与骨矿物质结合的能力，它们在骨中的半衰期可达10年。最近，与使用bp相关的不良事件的报道引发了“药物假期”的概念。在这个“假期”中，在不同的使用周期后停止BP治疗，随后是任意的无BP期。关于这个“毒品假期”是否应该开始，或者何时开始，或者应该持续多长时间，目前还没有明确的声明。此外，“药物假期”对“骨质量”的影响尚不清楚。“骨质量”定义的因素包括骨的组成、微结构和微裂缝的存在，这些因素与“骨量”一起影响骨折的风险。我们的研究表明，BP治疗在微米水平上降低了骨材料的异质性。这种损失有助于裂纹扩展，从而导致断裂。我们的基本假设是，FTIRI和micro-CT证实的异质性缺失增加了bp治疗患者的骨折风险。我们进一步假设，仅“药物假期”不会改变骨质量，这是由成分或异质性的变化决定的。基于这些观点，以及PTH增加异质性的初步发现，我们建议采用BP加PTH的治疗方法。关于这些治疗在微纳米水平上对骨成分的影响的信息很少，然而这些信息对于研究人员设计临床试验和推荐治疗方法是重要的。我们将通过两个具体目标来解决我们的假设。1)通过对以下患者进行髂嵴活检，表征“血压假期”前后的骨组成：a)接受不同时期BP治疗后2年的患者。“假期”或pth治疗。b)长期血压患者有不同的“假期”期。c)长期血压高且血压转换正常的患者。d)在小鼠中进行平行研究，以确定bp在什么时间点对组织异质性的影响达到峰值，以及异质性是否随时间变化。微裂缝也将在髂骨活检中测量。2)验证骨非均质性延伸到纳米水平的假设，以及微纳米非均质性的改变对骨力学性能的影响。我们将i)开发和应用纳米红外来定义健康，患病和治疗的骨和松质动物骨骼中的矿物质和基质异质性。ii)通过分析经甲状旁腺激素处理的人体组织及其对照，证实我们的发现。iii)将组织异质性（来自FTIRI和纳米ir）与宏观和纳米水平的机械性能联系起来。如果成功，这些研究将解决目前关于骨质疏松症治疗方案的争论。

DESCRIPTION (provided by applicant): Osteoporosis affects more than 75 million women and men yearly, world-wide, at annual costs > $50 billion. To define compositional changes in osteoporotic bone, we pioneered Fourier transform infrared spectroscopic imaging (FTIRI) for measurement of bone biopsies at a spatial resolution of ~7um and applied this technique along with histology, micro-CT and mechanics to evaluate therapies for osteoporosis. Bisphosphonates (BP), to date, are the most effective drugs used to prevent fragility fractures and combat bone loss. These drugs can have a half-life in bone >10 years due to their ability to bind to bone mineral. Recently, reported adverse events associated with the use of BPs triggered the notion of a "drug holiday". During this "holiday", BP treatment is ceased after variable periods of usage, followed by arbitrary BP-free periods. There is no definitive statement on if, or when this "drug holiday" should start or how long it should last. Moreover, the effect ofa "drug holiday" on "bone quality" is unknown. "Bone Quality" defines those factors including composition, micro-architecture and presence of microcracks, which along with "Bone Quantity" contribute to fracture risk. Our studies showed BP treatment decreased bone material heterogeneity at the micron-level. This loss can contribute to crack propagation and hence fracture. Our underlying hypothesis is that loss of heterogeneity, evidenced through FTIRI and micro-CT, contributes to fracture risk in BP-treated patients. We further hypothesize that "Drug Holidays" alone, do not alter bone quality as determined by changes in composition or heterogeneity. Based on these ideas, and the preliminary finding that PTH increases heterogeneity, we suggest a treatment approach using a BP followed by PTH. Little information exists on the effects of such treatments on bone composition at the micro- or nano-levels, yet this information is important to enable investigators to design clinical trials and recommend therapies. We will address our hypotheses using 2 specific aims.1) To characterize the composition of bone before and after a "BP holiday", using iliac crest biopsies from: a) Patients after variable periods of BP-treatment followed by a 2 yr. "holiday" or PTH-treatment. b) Patients on long-term BP with variable "holiday" periods. c) Patients on long-term BP with high and normal turnover. d) Parallel studies in mice to determine at what point in time BPs attain their peak effect on tissue heterogeneity and whether or not heterogeneity changes with time. Microcracks will also be measured in iliac crest biopsies. 2) To test the hypothesis that bone heterogeneity extends to the nano-level, and that alterations in both micro- and nano-heterogeneity impact bone mechanical properties. We will i) Develop and apply nano- IR to define mineral and matrix heterogeneity in healthy, diseased and treated osteonal and cancellous animal bones. ii) Confirm our findings by analysis of human PTH-treated tissues and their controls. iii) Correlate tissue heterogeneity (from FTIRI and nano-IR) with mechanical performance at the macro- and nano-levels. If successful, these studies will address current debates regarding treatment protocols for osteoporosis.