Renal Osteodystrophy: A Fresh Approach

 描述（由申请方提供）：肾性骨营养不良（ROD）代表肾功能丧失导致的骨组织学异常。它在肾功能丧失期间早期开始，并且在几乎所有接受透析的慢性终末期肾病患者（CKD-5D）中可见。ROD的一个主要组成部分是导致CKD相关骨质疏松症的骨丢失。CKD患者发生髋部骨折的比率是普通人群的4.4倍，相关费用高，发病率高，年死亡率为64%。CKD骨质疏松症与绝经后骨质疏松症明显不同。目前，由于与种族特异性骨转换状态相关的挑战，没有统一接受的CKD骨质疏松症治疗方案。因此，大多数医生不愿意治疗这种疾病，尽管它对健康和生活质量有深远的影响，并且与血管钙化有关。这些血管钙化增加了心血管事件的风险，这是CKD-5D患者年死亡率超过20%的主要原因。拟定的对照随机研究的目的是检验当根据患者的周转状态进行个体化治疗时，CKD骨质疏松症可以成功治疗的概念。该研究将证明，通过增加低转换患者的骨形成，以及通过减少正常或高转换患者的骨吸收，可以实现骨丢失的逆转。本研究的第二个目的是提供这些治疗是否也会延缓血管钙化进展的新信息。测量FGF 23、Wnt途径活性、骨吸收和形成的指标的血液测试将被遵循，以了解潜在的机制，并评估它们对预测骨量和血管钙化变化的有用性。确诊骨质疏松症的CKD-5D患者将根据骨转换状态入组两个治疗组之一。每组将根据人种、年龄和性别适应性随机分配至治疗组或对照组。在低转换组中，将给予特立哌酮联合西那卡塞，在正常或高转换组中，将给予阿仑膦酸钠。将在基线和治疗一年后通过定量计算机断层扫描测量骨密度。同时还将通过多探测器计算机断层扫描测量冠状动脉、主动脉和心脏瓣膜的钙化。如果这项概念验证研究成功，它将为CKD-5D患者的骨质疏松症提供迄今为止无法获得的治疗，从而改变流行的临床实践范式。这将通过降低骨折风险、骨痛和心血管风险为CKD患者提供直接益处，同时大大改善他们的生活质量。这些改进还将通过降低高昂的相关治疗费用带来重大的社会经济效益。这项拟议的研究与NIDDK的使命高度相关，即传播基于科学的信息，以改善内分泌、代谢和肾脏疾病患者的健康和生活质量。

 DESCRIPTION (provided by applicant): Renal osteodystrophy (ROD) represents the bone histologic abnormalities resulting from loss of renal function. It starts early during the loss of kidney function and is seen in virtually all chronic end stage kidney disease patients on dialysis (CKD-5D). A major component of ROD is bone loss leading to CKD-associated osteoporosis. Debilitating hip fractures occur in patients with CKD at a rate 4.4 times higher than in the general population, with associated high costs, morbidity and an annual mortality of 64%. CKD osteoporosis is distinctly different from post-menopausal osteoporosis. Presently, no uniformly accepted CKD osteoporosis treatment protocol exists because of challenges related to racially specific bone turnover states. Therefore, most physicians are reluctant to treat this disorder despite the profound impact on health and quality of life, and its association with vascular calcifications. These vascular calcifications confer an increased risk for cardiovascular events which are the major cause of the over 20% annual mortality rate in CKD-5D patients. The goal of the proposed controlled randomized study is to test the concept that CKD osteoporosis can be successfully treated when treatment is individualized by patients' turnover status. The study will demonstrate that reversal of bone loss can be achieved by increasing bone formation in low turnover patients, and by reducing bone resorption in normal or high turnover patients. A second aim of this study is to provide new information whether these treatments will also retard progression of vascular calcifications. Blood tests measuring FGF23, indicators of Wnt pathway activity, bone resorption and formation will be followed to understand potential mechanisms and to evaluate their usefulness for prediction of changes in bone mass and vascular calcifications. CKD-5D patients with established osteoporosis will be enrolled into one of two treatment arms based on bone turnover status. Each arm will be adaptively randomized by race, age and gender into treatment or control groups. In the low turnover arm, teriparatide combined with cinacalcet will be given, and in the normal or high turnover arm, alendronate will be administered. Bone mineral density will be measured at baseline and after one year of treatment by quantitative computed tomography. Calcifications of the coronaries, aorta and heart valves will also be measured at the same times by multi-detector computed tomography. If this proof-of-concept study is successful, it will offer a heretofore unavailable treatment for osteoporosis i CKD-5D patients thus changing the prevailing clinical practice paradigm. This will provide immediate benefit to CKD patients by reducing fracture risk, bone pain, and cardiovascular risk, while greatly improving their quality of life. These improvements will also convey major socioeconomic benefits by decreasing the high associated treatment costs. The proposed study is highly relevant to the NIDDK's mission of disseminating science-based information to improve the health and quality of life for patients with endocrine, metabolic and kidney diseases.