The Effect of Etelcalcetide on Bone-tissue Properties in End Stage Kidney Disease

摘要 慢性肾脏病（CKD）患者的肾脏相关死亡风险令人担忧。的进展 CKD的标志是异常的生物化学，包括破坏矿物质稳态和甲状旁腺激素升高 激素（PTH）或甲状旁腺功能亢进（HPT）。慢性HPT目前被认为是负责 CKD患者的骨量急剧丢失和骨折风险增加，因此患者的PTH水平 监测以确定骨折风险。此外，这些患者通常给予PTH降低药物 包括拟钙剂这些药物通过使甲状旁腺主细胞中的钙敏感受体敏感而起作用， 降低PTH的分泌。虽然这些药物已被证明可以降低CKD患者的骨折风险， 透析，很少有人知道他们对骨量和质量的影响。有趣的是，正常的CKD患者 骨量和受控的PTH水平保持在增加的骨折风险。因此，在我们的研究中存在着一个关键的差距。 了解在疾病过程和治疗中，什么骨骼特性决定了骨强度， CKD骨病。最近，人们越来越多地认识到骨质量在决定 整体骨强度。骨质量是指骨的结构、化学成分和骨的生物学特性的组合。 骨基质，以及由此产生的整个骨和组织水平的机械性能。然而，迄今为止， 在CKD和拟钙治疗的情况下，骨质量的空间匹配，或共定位， 在已知组织年龄的骨骼样本中。基于上述科学前提，本提案的目标是测试 拟钙药物通过改善骨质量降低骨折风险的假设。具体而言，这项研究将， 除了测量骨结构的变化之外，还可以在空间上匹配基质组成的测量， 拟钙剂治疗前后的组织水平机械性能。第一个目标是确定 拟钙剂治疗对Cy/+大鼠基质组成和机械性能的影响， CKD的进展模型。这将通过运行共定位拉曼光谱来完成，以确定 基质组成和纳米压痕来确定大鼠股骨切片上的组织水平机械性能。 在治疗前后给予荧光标记，以识别每个时间点形成的骨区域 并控制组织年龄。结果将包括矿物和基质的半定量测量 含量、结晶度和碳酸盐含量以及组织硬度和刚度的测量。为 第二个目的，将使用来自CKD患者的髂嵴间骨活检完成类似的研究， 重度HPT。将再次控制样本的组织年龄，并进行共定位拉曼光谱分析 和纳米压痕。来自上述目的的数据将使我们能够在改变之间产生新的相关性。 在骨基质性质和组织水平力学方面，帮助我们开始填补我们理解的关键空白， CKD骨病此外，由于这项研究在实验室和诊所之间导航，它提供了 一个极好的机会，一个医生，科学家在培训。

ABSTRACT Chronic kidney disease (CKD) patients are at an alarming risk of fracture-related mortality. The progression of CKD is marked by abnormal biochemistries including disrupted mineral homeostasis and elevated parathyroid hormone (PTH), or hyperparathyroidism (HPT). Chronic HPT is currently thought to be responsible for the dramatic loss of bone mass and increased fracture risk in CKD patients, and thus patients have PTH levels monitored to determine their fracture risk. Further, these patients are commonly given PTH-lowering drugs including calcimimetics. These drugs act by sensitizing the calcium-sensing receptor in parathyroid chief cells, lowering their PTH secretion. While these drugs have been shown to reduce fracture risk in CKD patients on dialysis, there is little known about their effect on bone mass and quality. Interestingly, CKD patients with normal bone mass and controlled PTH levels remain at an increased fracture risk. Thus, there is a critical gap in our understanding of what skeletal properties dictate bone strength in both the disease process and treatment of CKD bone disorder. Recently, there has been increasing recognition of the role of bone quality in determining overall bone strength. Bone quality refers to a combination of bone architecture, chemical composition of the bone matrix, and the resulting whole bone and tissue-level mechanical properties. To date, however, measures of bone quality in the setting of CKD and calcimimetic treatment have not been spatially matched, or colocalized, in bone samples of known tissue age. Based on the above scientific premise, the goal of this proposal is to test the hypothesis that calcimimetic drugs reduce fracture risk by improving bone quality. Specifically, this study will, in addition to measuring changes in bone architecture, spatially match measures of matrix composition and tissue-level mechanical properties before and after calcimimetic treatment. The first Aim is to determine the effects of calcimimetic treatment on matrix composition and mechanical properties in the Cy/+ rat, a slowly progressive model of CKD. This will be accomplished by running colocalized Raman spectroscopy to determine matrix composition and nanoindentation to determine tissue-level mechanical properties on rat femur sections. Fluorescent labels will be given before and after treatment to identify regions of bone formed at each time point and to control for tissue age. Outcomes will include semi-quantitative measurements of mineral and matrix content, crystallinity, and carbonate content as well as measurements of tissue hardness and stiffness. For the second Aim, a similar study will be accomplished using transiliac crest bone biopsies from CKD patients with severe HPT. Specimens will again be controlled for tissue age and will undergo colocalized Raman spectroscopy and nanoindentation. Data from the above Aims will allow us to generate novel correlations between alterations in bone matrix properties and tissue-level mechanics, helping us begin filling the critical gap in our understanding of CKD bone disease. Additionally, because this study navigates between the laboratory and clinic, it provides an excellent opportunity for a physician-scientist in training.