Assessing and improving bone quality in chronic kidney disease

评估和改善慢性肾病患者的骨质量

基本信息

批准号：
9051266
负责人：
Erin Margaret Bronte McNerny
金额：
$ 5.36万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-17 至 2018-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9051266
关键词：
Affect Age American Animal Model Area Biochemical Biology Bone Density Bone Diseases Bone Matrix Bone Tissue Chronic Kidney Failure Clinical Collaborations Collagen Combined Modality Therapy Creatinine Data Defect Development Disease Disease Progression Environment Evaluation FDA approved Fatigue Fracture Goals Hip Fractures Histology Hormones Hydration status Individual Kidney Kidney Diseases Length Link Measurement Measures Mechanics Mentors Mentorship Metabolic Microscopic Minerals Modeling Monitor Osteoporosis Outcome Parathyroid gland Patients Pharmaceutical Preparations Plasma Population Porosity Property Raloxifene Rattus Research Resistance Risk Scientist Selective Estrogen Receptor Modulators Staging Structure Testing Tissues Training Work age group base bone bone loss bone mass bone quality bone turnover calcium phosphate cinacalcet comorbidity crosslink drug efficacy effective therapy experience high risk human disease improved microCT mortality normal aging novel patient population pre-clinical prevent primary outcome public health relevance skeletal treatment effect

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) patients have increased fracture risk, have a higher risk of fracture-related mortality, and are difficult to treat due to CKD's metabolic complexity. Furthermore, standard practices for monitoring fracture risk (i.e. bone mineral density, BMD) have limitations in this patient population. Currently, treatment for CKD-MBD patients is primarily focused on suppressing elevated parathyroid hormone, as can be accomplished with a calcimimetic. Cinacalcet, an FDA approved calcimimetic, effectively reduces parathyroid hormone, slows bone turnover and increases bone mass, yet it only modestly reduces fracture risk. This suggests a defect in bone quality, not just bone loss, is contributing to CKD fragility, and this notion is supported by recent evidence of alterations in collagen cross-linking and matrix hydration in CKD bone. Preliminary data collected for this study found evidence of bone microdamage, another important factor of bone quality which is previously unstudied in CKD. Microdamage is known to interact with porosity, thus the combination of these issues may have significant impact on CKD fragility. In summary, normalizing fracture risk in these patients will likely require more than simply suppressing bone loss; the bone quality must also be treated. We hypothesize that the quality of CKD bone can be improved using a combination treatment of calcimimetic, to reduce parathyroid hormone and bone loss, and raloxifene, a selective estrogen receptor modulator drug for osteoporosis recently revealed to have direct positive effects on bone tissue quality. We will test this hypothesis using a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will first quantify the extent of skeletal microdamage in the bones of 30 and 35-week old CKD rats in comparison to their normal, age-matched littermates. We expect CKD to cause progressively increasing accumulation of cortical porosity and microdamage, with interactions occurring between microcracks and porosity. Next, the ability of combination calcimimetic and raloxifene treatment to improve measures of bone quantity and quality will be tested. Cy/+ rats will be treated from 25 to 35 weeks of age with vehicle, raloxifene, calcimimetic, or both drugs. Primary outcomes will be determined by skeletal analyses (microdamage, histology, microCT, bone density, mechanical testing, and resistance to fatigue), though the treatments' effects on the biochemical and renal components of CKD-MBD will be assessed as well. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality and reducing microdamage formation, while calcimimetic treatment will improve mechanical properties by increasing bone mass and reducing porosity. Combination therapy should exceed both single 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 spontaneous and progressive development of CKD.

描述（由申请人提供）：慢性肾病-矿物质和骨病 (CKD-MBD) 患者骨折风险增加，骨折相关死亡风险更高，并且由于 CKD 监测代谢的复杂性而难以治疗。目前，CKD-MBD 患者的骨折风险（即骨矿物质密度，BMD）存在局限性，这可以通过抑制甲状旁腺激素的升高来实现。西那卡塞是 FDA 批准的拟钙剂，可有效降低甲状旁腺激素，减缓骨转换并增加骨量，但它只能适度降低骨折风险，这表明骨质量缺陷（而不仅仅是骨丢失）会导致 CKD 脆性。这一观点得到了 CKD 骨中胶原蛋白交联和基质水化变化的最新证据的支持，本研究收集的初步数据发现了骨微损伤的证据，骨微损伤是骨质量的另一个重要因素。此前尚未在 CKD 中研究过微损伤与孔隙度的相互作用，因此这些问题的结合可能会对 CKD 脆性产生重大影响。总而言之，使这些患者的骨折风险正常化可能需要的不仅仅是抑制骨质流失。我们认为，使用拟钙剂和雷洛昔芬（一种选择性雌激素受体调节剂药物）的联合治疗可以改善 CKD 骨的质量，以减少甲状旁腺激素和骨质流失。最近发现，骨质疏松症对骨组织质量有直接的积极影响，我们将使用缓慢进展的 CKD-MBD 模型（Cy/+ 大鼠）来测试这一假设。这项研究将首先量化 30 只骨骼的骨骼微损伤程度。和 35 周龄 CKD 大鼠与其正常、年龄匹配的同窝大鼠相比，我们预计 CKD 会导致皮层孔隙度和微损伤逐渐增加，微裂纹和微损伤之间会发生相互作用。接下来，将测试拟钙剂和雷洛昔芬联合治疗改善骨量和骨质量的能力，将在 25 至 35 周龄期间用媒介物、雷洛昔芬、拟钙剂或两种药物进行治疗。结果将由骨骼分析（微损伤、组织学、显微 CT、骨密度、机械测试和抗疲劳性）决定，尽管治疗对生化和肾脏成分的影响我们预计雷洛昔芬将通过改善骨质量和减少微损伤形成来改善骨的机械性能，而拟钙剂治疗将通过增加骨量和减少孔隙率来改善骨的机械性能，联合治疗应超过两者。通过对骨质量和质量产生积极影响，了解 CKD 对骨质量的影响是预防这些患者骨折的关键一步。这项研究通过检查这些变化及其影响，为实现这一目标迈出了重要的一步。自发性和进行性发展的 CKD 大鼠模型中的潜在校正。