MRI of Proximal Femur Bone Quality for Monitoring Short-Term Response to Osteoporosis Therapy

项目摘要 骨质疏松症是一种骨脆性疾病，容易导致个人骨折，是一种主要的公共卫生问题。 有问题。每年发生200多万次骨质疏松性骨折，造成超过170亿美元的直接损失 骨折护理的年度成本。髋部骨折占这些费用的70%，因为它们具有最具破坏性的 临床后果：髋部骨折后第一年的死亡率高达24%。骨质疏松症是 由骨量减少和骨骼微结构恶化引起，两者共同削弱骨骼。 有几种骨骼强化药物可以降低骨折风险，在安慰剂对照试验中，这些药物 根据骨骼部位的不同，药物降低骨折风险的效果也不同。不幸的是，它是 不知道哪种药物或药物组合最能有效降低整体骨折风险，尤其是骨折风险 臀部有风险。这一知识差距的存在是因为临床试验人员在髋关节缺乏一个终点 允许进行优势试验--旨在确定最佳的骨骼强化药物或方案-- 具有可行的成本、样本量和跟踪时间。目前，骨折和骨密度(BMD)是 食品和药物管理局(FDA)批准的用于临床试验的终点，但骨折发生率较低 发病率和骨密度变化非常缓慢。此外，治疗后骨密度的变化只反映了4%-52%的 降低骨折风险方面的差异。因此，数以万计的受试者需要面对面的支持 这是一项旨在证明一种药物优于另一种药物的主动比较试验。骨 在骨质疏松症的临床试验中，微结构没有得到常规的监测，即使它的恶化 包括在世界卫生组织对骨质疏松症的疾病定义中。我们最近做了 应用临床磁共振技术证实活体成像髋关节微结构的可行性 成像(MRI)扫描仪。我们已经证明了对HIP微体系结构参数的评估(通过数字和 体积拓扑分析)和强度(通过有限元分析)是可重现的，并提供 DXA未捕获的有关骨骼质量和骨折风险的信息。与计算机断层扫描不同 (CT)，MRI可以以足够高的分辨率成像来描述骨的微结构，并且不管理 电离辐射，这是短期连续成像的理想选择。与以前的微体系结构成像不同 已使用MRI或高分辨率在桡骨远端或胫骨远端进行的研究 外周定量计算机断层扫描(HR-pQCT)，我们现在可以成像骨的微结构 髋部，最具破坏性的骨折部位。在这项研究中，我们现在的目标是证明MRI测试的价值， 除了DXA的价值之外，它还用于监测髋关节的短期治疗反应。这项工作将为 除髋部骨密度外，使用髋部微结构和力量作为生物标志物的基础 多中心研究中的治疗反应并作为潜在的替代终点以减少样本量和 加快骨质疏松症临床试验。这将减轻骨质疏松性骨折给社会带来的负担。

Project Summary Osteoporosis, a disease of bone fragility predisposing an individual to fracture, is a major public health problem. Over two million osteoporotic fractures occur per year, resulting in greater than $17 billion in direct annual costs for fracture care. Hip fractures account for 70% of these costs as they have the most devastating clinical consequences; the mortality rate in the first year after hip fracture is as high as 24%. Osteoporosis is caused by reduced bone mass and deterioration in bone microarchitecture, which together weaken bone. Several bone-strengthening drugs are available to reduce fracture risk, and in placebo-controlled trials, these drugs have different efficacies for fracture risk reduction depending on the skeletal site. Unfortunately, it is unknown which drug or drug combination works best to reduce overall fracture risk and in particular fracture risk in the hip. This gap in knowledge exists because clinical trialists lack an endpoint in the hip that would permit superiority trials -- aimed at determining the best bone-strengthening drug or regimen -- to be performed with feasible costs, sample sizes, and follow-up times. Currently, fracture and bone mineral density (BMD) are the Food and Drug Administration (FDA)-approved endpoints used in clinical trials, but fractures have a low incidence and BMD changes very slowly. In addition, changes in BMD after therapy only reflect 4-52% of the variance in fracture risk reduction. As a result, tens of thousands of subjects are necessary to power head-to- head, active comparator trials aimed at demonstrating the superiority of one agent over another. Bone microarchitecture has not routinely been monitored in osteoporosis clinical trials, even though its deterioration is included in the World Health Organization disease definition of osteoporosis. We have recently demonstrated the feasibility of imaging hip microarchitecture in vivo using a clinical magnetic resonance imaging (MRI) scanner. We have shown that assessment of hip microarchitectural parameters (via digital and volumetric topological analysis) and strength (via finite element analysis) is reproducible and provides information about bone quality and fracture risk that is not captured by DXA. Unlike computed tomography (CT), MRI can image at a resolution high enough to depict bone microarchitecture and does not administer ionizing radiation, which is ideal for short-term serial imaging. And unlike prior microarchitectural imaging studies, which have been performed in the distal radius or distal tibia using either MRI or high-resolution peripheral quantitative computed tomography (HR-pQCT), we can now image bone microarchitecture in the hip, the most devastating fracture site. In this study, we now aim to demonstrate the value of the MRI test, beyond the value of DXA, for monitoring short-term therapy response in the hip. This work will lay the foundation for the use of hip microarchitecture and strength, in addition to hip BMD, as a biomarker of treatment response in multicenter studies and as a potential surrogate endpoint to reduce sample sizes and accelerate osteoporosis clinical trials. This will reduce the burden of osteoporotic fractures on society.