An MRI-Based Method for Measuring Bone Mineral and Matrix Densities in Humans

描述(由申请人提供)：骨质疏松症和骨脱矿性疾病(如骨软化症)是导致骨密度降低和骨的机械能力降低的骨骼疾病，容易发生骨折。骨质疏松症是一种结构性骨骼疾病，骨矿物质和基质都会丢失，而骨脱矿性疾病只涉及骨矿物质的缺乏。因此，骨组成密度比(RBCD)，即骨密度与骨基质密度的比值，将是区分这两类疾病的合适指标。RBCD与骨矿化度(DMB)密切相关，DMB用每体积基质中的矿物质质量表示。目前的诊断方法，如双能X射线吸收法(DXA)，只能测量骨密度，因此无法区分这两类疾病。辅助诊断方法，如骨活检，有时可以区分这些疾病，但这种程序是侵入性的。由于这两种疾病经常在老年人中同时发生，这类患者经常被误诊为只有骨质疏松症，而他们的骨脱钙障碍得不到治疗。这项拟议的工作建立在申请人实验室最近进行的研究的基础上。该项目寻求将基于核磁共振的骨基质和矿物质密度测量方法，在专门硬件上验证的动物标本上，转变为可以在人类上进行的单一定量检查。假设是，拟议的检查将能够使用临床MRI设备区分骨质疏松症和矿化受损障碍，而不会像DXA或定量计算机断层扫描(QCT)或侵入性骨活检那样存在与电离辐射相关的风险。拟议的工作将包括确定这一过程的最佳磁场强度，从总骨质子池中分离骨基质相关质子信号的方法，调整MRI脉冲序列以平衡图像分辨率和扫描时间，设计图像强度参考样本，以及改进用于从图像强度计算密度的算法。随后，将对正常和化学脱钙骨标本进行检查，以确认该方法的准确性和重复性。这些样品的真实密度将用重量法测量。最后一步是将这种方法转化到临床上，进行一项小型试点研究，涉及健康志愿者和患有这两种不同类型障碍的受试者，以证明该方法在区分疾病状态方面的可行性。 公共卫生相关性：骨质疏松症是一种骨骼疾病，在美国有1000万成年人受到影响。这种疾病在标准的临床诊断扫描、双能X射线吸收法(DXA)上模拟骨脱矿障碍，因此骨脱钙障碍经常被误诊为骨质疏松症，而骨质疏松症在老年人中更常见。这项拟议的研究旨在证明一种基于MRI的方法的可行性，该方法可以在不使用电离辐射或侵入性骨活检的情况下，通过测量骨矿物质和基质密度来容易地区分骨质疏松症和矿化受损障碍。

DESCRIPTION (provided by applicant): Osteoporosis and bone-demineralizing disorders (e.g. osteomalacia) are skeletal diseases that cause decreased bone mineral density and reduce the mechanical competence of bone, predisposing to fractures. Whereas osteoporosis is a structural bone disease where both bone mineral and matrix are lost, bone- demineralizing disorders involve a deficit in bone mineral only. Therefore, the ratio of bone constituent densitie (RBCD), given as the ratio of bone mineral density to bone matrix density, would be a suitable metric by which to distinguish these two groups of diseases. The RBCD is closely related to the degree of mineralization of bone (DMB), which is expressed as mass of mineral per volume of matrix. Current diagnostic methods, such as dual-energy x-ray absorptiometry (DXA), measure only bone mineral density and, thus, are unable to distinguish between these two groups of diseases. Secondary diagnostic methods, such as bone biopsy, can sometimes discriminate between these diseases, but this procedure is invasive. Because these two disorders often co-occur in the elderly, such patients are often misdiagnosed as having only osteoporosis, leaving their bone-demineralizing disorder untreated. The proposed work builds on recent research conducted in the applicant's lab. This project seeks to adapt MRI-based methods for bone matrix and mineral density measurements, proven on animal specimens in specialized hardware, into a single quantitative examination that can be performed on humans. The hypothesis is that the proposed examination will be able to distinguish between osteoporosis and disorders of impaired mineralization using clinical MRI equipment and without the risks associated with ionizing radiation, as in DXA or quantitative computed tomography (QCT), or invasive bone biopsy. The proposed work will include determining the optimal magnetic field strength for this procedure, the method for isolation of bone matrix-associated proton signal from the total bone proton pool, the adjustment of the MRI pulse sequence to balance image resolution with scan time, the design of image intensity reference samples, and the improvement of algorithms used to calculate densities from image intensities. The resulting examination will then be applied to normal and chemically demineralized bone specimens in order to confirm the method's accuracy and reproducibility. The true densities of these specimens will be measured by gravimetry. The final step will be to translate this method to the clinic in a small pilot study involving healthy volunteers and subjects with these two different classes of disorders in order to demonstrate the method's feasibility to distinguish between disease states. PUBLIC HEALTH RELEVANCE: Osteoporosis is a bone disorder that afflicts 10 million adults in the United States. This disorder mimics bone- demineralizing disorders on the standard clinical diagnostic scan, dual energy x-ray absorptiometry (DXA), and so bone-demineralizing disorders are often misdiagnosed as osteoporosis, which is vastly more prevalent in the elderly. The proposed research seeks to prove the feasibility of an MRI-based method which can readily distinguish between osteoporosis and disorders of impaired mineralization based on measurement of both bone mineral and matrix densities without the use of ionizing radiation or invasive bone biopsy.