Assessing and modifying bone quality in chronic kidney disease

描述(由申请人提供)：慢性肾脏疾病-矿物质和骨骼疾病(CKD-MBD)导致复杂的骨骼和代谢表型。正因为如此，患有晚期肾病的患者发生骨折的风险增加。在与年龄相关的骨丢失患者中，骨密度(BMD)估计是预测骨折发展的有用指标。然而，在CKD，情况并不明朗。虽然它可能有用，但其他代谢紊乱的存在表明，骨质量在CKD相关骨折的发病机制中可能比与年龄相关的骨丢失起到更大的作用。CKD-MBD患者目前的治疗重点是抑制甲状旁腺激素的升高。这是通过补充骨化三醇来实现的。虽然骨化三醇对骨质疏松症患者的影响已经被研究，但它对慢性肾脏病患者的骨质量和骨折风险的影响目前尚不清楚。此外，最近的分析表明，雷洛昔芬，一种选择性雌激素受体调节剂，可能是晚期肾脏疾病患者的有用干预措施。这得到了服用雷洛昔芬的患者有益的肾脏结果的支持，以及证据表明通过另一种非细胞机制来改善骨骼质量。因此，我们假设CKD会导致骨质量的改变，这种改变可以通过雷洛昔芬及其与骨化三醇的联合使用来纠正。这将通过使用慢进性CKD-MBD模型-Cy/+大鼠进行测试。这项研究将比较正常大鼠和Cy/+大鼠的骨骼组织质量(与质量无关)。这将通过检查30周龄大鼠骨骼的骨骼质量变化来实现。具体地说，结果将包括组织水平的机械性能、矿化、胶原成分(交联物、形态和力学)和骨基质水化(MRI)。我们预计CKD大鼠将表现出较低的骨强度、较低的矿化程度、较低的胶原硬度、较低的基质结合水和较高的胶原非酶交联性。第二个主要目标是检查雷洛昔芬对Cy/+大鼠骨异常的影响。25周龄的动物将接受5周的治疗(相当于一个骨重建周期)。主要结果将通过骨骼分析(组织学、显微CT、骨密度、机械测试和骨质量测量)来确定，尽管CKD-MBD的生化、肾脏和血管成分也将被评估。将进行基因表达分析，以开始确定与生物力学骨骼质量变化有关的信号通路。我们预测雷洛昔芬将通过改善骨质量来改善骨的力学性能，而骨化三醇将通过增加骨量来改善力学性能。联合治疗应该通过对质量和质量的积极影响而超过所有其他治疗方法。了解CKD对骨质量的不利影响是预防这些患者骨折的关键一步。这项研究通过检测慢性肾脏疾病自发和进行性发展的大鼠模型中的这些变化及其潜在的纠正，为实现这一目标提供了重要的一步。

DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) results in complex skeletal and metabolic phenotypes. Because of this, patients with advanced kidney disease have an increased risk of fractures. In patients with age-related bone loss, bone mineral density (BMD) estimates are a helpful predictor of fracture development. In CKD, however, the picture is unclear. While it may be of use, the presence of other metabolic derangements indicate that bone quality likely plays a greater role in the pathogenesis of CKD-related fractures than in those associated with age-related bone loss. Current treatment in patients with CKD-MBD is focused on suppressing elevations in parathyroid hormone. This is accomplished by calcitriol supplementation. While the effect of calcitriol in osteoporotic patients has been studied, its impact on bone quality and fracture risk n CKD patients is currently unknown. Also, recent analyses suggest that raloxifene, a selective estrogen receptor modulator, might be a useful intervention for patients with late stage kidney disease. This is supported by beneficial renal outcomes in patients on raloxifene as well as evidence demonstrating an additional non-cellular mechanism by which to improve bone quality. So, we hypothesized that CKD leads to alterations in bone quality that can be corrected by raloxifene and its combination with calcitriol. This will be tested through the use of a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will compare the quality of skeletal tissue (independently of mass) in normal and Cy/+ rats. This will be accomplished by examining bones from 30-week-old rats for changes in bone quality. Specifically, outcomes will include tissue-level mechanical properties, mineralization, collagen composition (cross-linking, morphology, and mechanics), and bone matrix hydration (MRI). We expect rats with CKD to display lower bone strength, lower mineralization, lower collagen stiffness, lower matrix-bound water, and higher non-enzymatic cross-linking of collagen. The second major goal is to examine the effects of raloxifene on bone abnormalities present in Cy/+ rats. 25-week-old animals will be treated for 5 weeks (equivalent to one bone remodeling cycle). Primary outcomes will be determined by skeletal analyses (histology, microCT, bone density, mechanical testing, and bone quality measures), though the biochemical, renal, and vascular components of CKD-MBD will be assessed as well. Gene expression analyses will be performed to begin to identify signaling pathways involved in changes in biomechanical bone quality. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality, while calcitriol will improve mechanical properties by increasing bone mass. Combination therapy should exceed all other treatments by positively impacting both quality and mass. An understanding of the detrimental impact of CKD on bone quality is a crucial step in preventing fractures in these patients. This study provides an important step in achieving this goal by examining these changes and their potential corrections in a rat model with the spontaneous and progressive development of chronic kidney disease.