Assessment of Bone Composition Through a Novel Liquid/Solid State MRI Method

摘要 每年有150万美国人患髋关节、脊柱或手腕的脆弱性骨折，这是一种常见的原因。 疼痛、畸形和残疾的人。此外，照顾这些骨折患者每年花费近100亿美元。 基于脆性骨折是由低骨量引起的假设，世界卫生组织 (WHO)已经根据测量的骨密度确定了这些骨折的风险个体 通过双能X线吸收测定法（DXA）与正常年轻成人进行比较。然而，骨折 基于区域骨矿物质密度的预测已被证明既不敏感也不特异。整个 骨强度由骨组织的材料性质及其几何形状决定。面骨矿物质 密度不测量体积骨矿物质密度，骨硬度的主要决定因素， 强度，并且不能区分骨组织组成的变化与骨组织体积的变化 和/或几何形状。这种区别在诊断和治疗与骨关节炎相关的骨骼疾病时很重要。 低骨量虽然大多数脆性骨折被认为是由骨质疏松症引起的， 骨组织的矿物质成分正常，但骨组织的体积减少; 50%的 髋部骨折且没有其他原因导致低骨量的绝经后妇女， 维生素D.维生素D缺乏会导致骨软化症，其中矿物质成分和骨组织 两者的数量都在减少。事实上，对于低骨量髋部骨折的患者， 组织学评价，13-33%为骨软化。正确评估根本原因 骨质减少，无论是骨质疏松症或骨软化症，是重要的，作为治疗方案，这两个 条件是不同的，其中骨质疏松症可以用双膦酸盐，PTH，钙，磷酸盐治疗 和维生素D补充剂;而骨软化症需要更详细的评估，因为 诊断是广泛的，并且每个疾病实体需要稍微不同的治疗方法。以来 治疗骨质疏松症和骨软化症是不同的，当务之急是病人的病因低 骨密度得到正确诊断。因此，我们建议开发一种基于MRI的技术， 测量骨组织矿物质和基质组成以及骨结构。为此，我们假设 液体+固体MR成像可用于：基于骨骼区分代谢性骨病， 组织矿物质成分和结构特性;并估计正常和病理的负荷能力 骨头这项研究的成功完成将证明使用这种非侵入性和非电离 影像学技术，以区分骨质疏松症和骨软化症，使医生可以选择适当的 治疗高危患者。这将为开发专门的MRI软件和硬件提供动力 这将使得有可能将液体+固体状态MR成像常规地集成到临床扫描仪中， 专门的外围MRI扫描仪，可用于对高危患者进行大规模筛查。 申请人的近期职业目标是获得液体和固体磁共振领域的专业知识 成像，在拟议的项目中产生初步结果，有助于知识体系，获得 基金会赠款，继续工作，并走向独立，作为一个科学家和首席研究员。 在整个研究过程中，导师和共同导师将通过以下方式对申请人进行监督 每两个月举行一次非正式定期会议和正式会议，以评估申请者沿着 项目时间轴。此外，申请人将接受MR成像的实践和理论培训， 骨生物学和病理生理学培训。他将参加各种研讨会， 赠款写作讲习班和领导能力发展讲习班。咨询委员会由 该领域经验丰富的科学家（Boskey，Bouxsein，Glimcher和Neer博士）将监测申请人的 每六个月举行一次会议，评估申请人是否准备好 根据申请人满足以下标准，进入独立授予阶段： 在磁共振成像原理、线圈构建和调谐、骨生物学和 病理生理学;按照研究时间轴研究项目的进展; 指导阶段结束;根据研究工作提交基金会奖励提案;以及 独立思考，并计划出R 01级赠款提案。申请人须设计及 在独立阶段的第二年开始时提交R 01赠款，以确保资金的连续性。 申请人的职业目标是发展成为一名独立的肌肉骨骼调查员， 骨生物力学和成像，以实现最终的公共卫生目标，帮助减少脆性骨折 与骨骼病变相关的风险及其对患者和医疗保健系统的影响。当DXA 影像学是一种有用的工具，可以提高人们的认识，评估高危人群的脆性骨折风险， 与这种方式相关的固有局限性以及骨骼固态和液态MR的最新进展 成像为开发下一代诊断系统提供了新的动力， 准确识别骨骼状态改变的根本原因。

ABSTRACT Fragility fractures of the hip, spine or wrist affect 1.5 million Americans annually and are a common cause of pain, deformity and disability. Moreover, caring for these fracture patients costs nearly $10 billion annually. Based on the assumption that fragility fractures are caused by low bone mass, the World Health Organization (WHO) has identified individuals at risk for these fractures based on their areal bone mineral density measured by dual energy X-ray absorptiometry (DXA) compared to that of a normal young adult. However, fracture predictions based on areal bone mineral density have been shown to be neither sensitive nor specific. Whole bone strength is determined by the material properties of the bone tissue and its geometry. Areal bone mineral dnesity does not measure volumetric bone mineral density, the major determinant of bone stiffness and strength, and does not distinguish changes in bone tissue composition from changes in bone tissue volume and/or geometry. This distinction is important when diagnosing and treating skeletal diseases associated with low bone mass. While it is assumed that most fragility fractures are caused by osteoporosis, where the mineral composition of the bone tissue is normal, but the volume of bone tissue is decreased; 50% of postmenopausal women who fracture their hip and have no other cause for low bone mass, are deficient in vitamin D. Vitamin D deficiency can result in osteomalacia, where the mineral composition and bone tissue volume are both decreased. Indeed, of patients with low bone mass who fractured their hip, when their bone tissue was evaluated histologically, 13-33% were osteomalaciac. Correct assessment of the underlying causes of osteopenia, whether osteoporosis or osteomalacia, is important, as the treatment protocols for these two conditions are different, where osteoporosis may be treated with Bisphosphonates, PTH, Calcium, phosphate and vitamin D supplementation; whereas osteomalacia requires a more detailed evaluation, as the differential diagnosis is extensive, and each disease entity requires a somewhat different treatment approach. Since the treatment of osteoporosis and osteomalacia are different, it is imperative that the etiology of a patient's low bone mass be properly diagnosed. Therefore, we propose to develop a MRI based technique capable of measuring both bone tissue mineral and matrix composition and bone structure. To that end, we hypothesize that liquid+solid state MR imaging can be used to: differentiate metabolic bone diseases on the basis of bone tissue mineral composition and structural properties; and estimate the load capacity of normal and pathologic bones. Successful completion of this study will prove the feasibility of using this non-invasive and non-ionizing imaging technique to differentiate osteoporosis from osteomalacia, so that physicians may select appropriate treatment for at risk patients. This will provide an impetus to develop specialized MRI software and hardware that will make it possible to integrate liquid+solid state MR imaging routinely into clinical scanners or specialized peripheral MRI scanners that can be used for mass screening of at risk patients. The immediate career goals of the applicant are to gain expertise in the field of liquid and solid state MR imaging, generate preliminary results in the proposed project, contribute to the body of knowledge, obtain foundation grants to continue work, and move towards independence as a scientist and a principal investigator. The applicant will be supervised closed by the mentor and the co-mentor over the course of the study via informal regular meetings and formal meetings every two months to assess the applicant's progress along the project timeline. Additionally, the applicant will receive hands on and theoretical training on MR imaging, and training in bone biology and pathophysiology. His training will be augmented by attending various seminars, grant writing workshops and leadership development workshops. An advisory committee made up of experienced scientists in the field (Drs. Boskey, Bouxsein, Glimcher and Neer) will monitor the applicant's progress through meetings every six months and will be tasked with assessing the applicant's readiness to move on to the independent phase of the award, based on the applicant's fulfillment of the following criteria: independent and solid foundation in MR imaging principles, coil building and tuning, bone biology and pathophysiology; progress in research project as per study timeline; submission of three manuscripts by the end of the mentored phase; submission of a foundation award proposal based on research work; and ability to think independently and plan out a R01 level grant proposal. The applicant will be required to design and submit a R01 grant at the beginning of year two of the independent phase to assure funding continuity. The applicants' career goal is to develop as an independent musculoskeletal investigator with expertise in bone biomechanics and imaging to achieve the ultimate public health aim of helping to reduce fragility fracture risk associated with skeletal pathologies and their impact on patients and the health care system. While DXA imaging has been a useful tool to raise awareness and assess fragility fracture risks in individuals at risk, the inherent limitations associated with this modality and the recent advances in skeletal solid and liquid state MR imaging have provided a fresh impetus to develop the next generation of diagnostic systems capable of accurately identifying the underlying cause(s) of altered skeletal states.