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

摘要 慢性肾脏疾病(CKD)患者面临着与骨折相关的死亡的惊人风险。中国的发展历程 慢性肾脏病的特点是生化异常，包括矿物质平衡紊乱和甲状旁腺功能升高。 激素(PTH)或甲状旁腺功能亢进症(HPT)。慢性HPT目前被认为是导致 慢性肾脏病患者的骨量急剧减少和骨折风险增加，因此患者有甲状旁腺素水平 监测以确定其骨折风险。此外，这些患者通常会服用降低甲状旁腺素的药物。 包括钙仿生学。这些药物通过敏化甲状旁腺主细胞中的钙感受器发挥作用， 降低它们的甲状旁腺素分泌。虽然这些药物已被证明可以降低慢性肾脏病患者的骨折风险 透析对骨量和骨质的影响知之甚少。有趣的是，CKD患者的正常 骨量和控制的甲状旁腺素水平仍然处于增加的骨折风险中。因此，在我们的 了解骨骼特性在骨质疏松症的发病过程和治疗过程中决定骨强度的因素 CKD骨病。最近，人们越来越多地认识到骨骼质量在决定 整体骨骼强度。骨质量指的是骨的结构、化学成分的组合 骨基质，以及由此产生的整个骨骼和组织层面的力学性能。然而，到目前为止，措施 CKD和拟钙剂治疗环境中的骨质量的关系尚未在空间上匹配或共同定位， 在已知组织年龄的骨骼样本中。基于上述科学前提，这一提议的目标是验证 一种假说，即类钙质药物通过改善骨骼质量来降低骨折风险。具体来说，这项研究将， 除了测量骨骼结构的变化外，还在空间上匹配基质成分和 拟钙化治疗前后组织水平的力学性能。第一个目标是确定 拟钙处理对慢性期Cy/+大鼠基质成分和力学性能的影响 慢性肾脏病的累进模型。这将通过运行共焦拉曼光谱来完成 基质组成和纳米压痕以确定大鼠股骨切片上的组织水平的机械特性。 将在治疗前后给予荧光标记，以识别在每个时间点形成的骨骼区域 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硬度的测量。对于 第二个目标是，一项类似的研究将使用来自慢性肾脏病患者的横纹骨活组织检查完成。 严重的HPT。样本将再次控制组织年龄，并将接受共焦拉曼光谱 和纳米压痕。来自上述目标的数据将使我们能够在变化之间产生新的关联 在骨基质特性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临床之间穿梭，它提供了 对于一名内科科学家来说，这是一个很好的培训机会。

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.