Osteoporosis Treatment Response Assessed by Micromechanical Modeling of MRI Data

描述（由申请人提供）：治疗和预防骨质疏松症的新型强效药物已经上市或正在开发中。这些研究的主要终点仍然是骨折发生率，次要终点通常是骨矿物质密度（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，并且需要很长的观察周期，因此导致成本过高和开发周期长。骨密度一直是一个不可靠的治疗效果指标，与药物引起的骨折复位程度相比，骨密度的增加往往不成比例地小，与发生在小梁骨（TB）网络中的更大的结构变化相反。3D高分辨率核磁共振成像（¿-MRI）的进步现在可以获取图像，从中可以建立结核病网络的拓扑结构。然而，尽管取得了这些进展，但结构仅起替代作用，尚不清楚哪些参数及其组合在治疗响应方面是最佳的，哪些参数及其组合最能代表强度。微力学建模的进步现在允许TB力学能力的微有限元（¿-FE）计算，可能提供对疾病进展和回归的力学影响的见解。在初步工作中，我们在一小群患者中检验了量化抗吸收治疗效果的可行性，并在基于胫骨远端MR图像计算全刚度矩阵后证明了弹性模量的显著改善。虽然令人鼓舞，但从体内图像中获得机械参数作为临床试验可能终点的可行性需要进一步审查。在这个项目中，我们提出了一个假设，即治疗引起的骨力学参数的变化，根据体内mri的¿-FE计算估计，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)进一步开发具有改进的运动校正和序列配准能力的体内mri数据处理算法；(2)评估在活体mri条件下完整标本图像中分辨率和噪声对衍生力学指标的影响，以及通过先前或正在进行的模拟来确定处理效果，并比较标本ct图像的力学指标；(4)对三个纵向mri研究进行结构指标分析。

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.