Osteoporosis Treatment Response Assessed by Micromechanical Modeling of MRI Data

描述(申请人提供)：治疗和预防骨质疏松症的新药已有或正在开发中。这些研究的主要终点仍然是骨折发生率，次要终点通常是骨密度(BMD)，这两者都充满了问题。前者需要非常多的研究对象，因为骨折是相对罕见的事件，需要较长的观察期，从而导致成本过高和开发周期较长。骨密度一直是一个不可靠的治疗效果指标，相对于药物导致的骨折复位程度，骨密度往往表现出不成比例的小幅增加，与小梁骨(TB)网络中发生的更大的结构变化形成对比。3D高分辨率磁共振成像(？-MRI)的进步现在允许获取图像，从而可以建立结核病网络的拓扑结构。然而，尽管有这些进展，结构只起到替代作用，并且就治疗反应而言，尚不知道哪些参数及其组合是最佳的，以及哪些参数及其组合最能代表强度。微观机械建模的进步现在允许对结核病机械能力的微观有限元(？-FE)计算，潜在地提供了对疾病进展和回归的力学含义的洞察。在前期工作中，我们研究了在一小群患者中量化抗吸收治疗效果的可行性，并根据在胫骨远端获得的磁共振图像计算出完整的僵硬矩阵后，显示出弹性模量值的显著改善。在令人鼓舞的同时，从活体图像中获得机械参数作为临床试验的可能终点的可行性需要进一步的研究。在这个项目中，我们提出了一种假设，即治疗引起的骨骼力学参数的变化，是基于活体磁共振成像的有限元计算，代表了治疗反应的定量测量。拟议的研究涉及四个具体目标，旨在：(1)进一步开发处理在体-MRI数据的算法，改进运动校正和序列配准能力；(2)在活体-MRI条件下，以及通过模拟先前或正在进行的模拟，评估分辨率和噪声对完整标本图像中导出的力学指数的影响，以确定处理效果，并将力学指标与样本？-CT图像的力学指标进行比较；(4)对三项纵向-MRI研究进行结构指数评估。

DESCRIPTION (provided by applicant): New powerful drugs for treatment and prevention of osteoporosis are already available or are currently under development. The primary endpoint for these studies continues to be fracture incidence, the secondary endpoint typically is bone mineral density (BMD), both of which are fraught with problems. The former requires a very large number of study subjects as fractures are relatively rare events and require long observation periods, therefore resulting in excessive costs and long development cycles. BMD has been an unreliable indicator of treatment efficacy showing often disproportionately small increases relative to the extent of fracture reduction caused by the drug, in contrast to the much larger architectural changes that occur in the trabecular bone (TB) network. Progress in 3D high-resolution MRI (¿-MRI) now allows acquisition of images from which the topology of the TB network can be established. Nevertheless, in spite of these advances, structure plays only a surrogate role and it is not known which parameters and combinations thereof are optimal in terms of responding to treatment, and which are most representative of strength. Advances in micromechanical modeling now permit micro finite-element (¿-FE) computations of TB mechanical competence, potentially providing insight into the mechanical implications of disease progression and regression. We have, in preliminary work, examined the feasibility of quantifying the effect of antiresorptive treatment in a small cohort of patients and demonstrated significant improvement in the elastic moduli after computing the full stiffness matrix on the basis of MR images acquired in the distal tibia. While encouraging, the feasibility of deriving mechanical parameters from in vivo images as possible end points in clinical trials demands further scrutiny. In this project we advance the hypothesis that the treatment-induced changes in the bone's mechanical parameters, estimated from ¿-FE calculations on the basis of in vivo ¿-MRI, represent a quantitative measure of treatment response. The proposed research, involving four specific aims, seeks to (1) further develop algorithms for processing in vivo ¿-MRI data with improved motion correction and serial registration capabilities; (2) evaluate the effect of resolution and noise on the derived mechanical indices in images of intact specimen under conditions of in vivo ¿-MRI as well as by simulation previously or currently in progress to determine the effect of treatment and comparing the mechanical with of specimen ¿-CT images; (4) apply ¿-FE analysis to three longitudinal ¿-MRI studies performed structural indices.