Assessing and improving 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）患者的骨折风险增加，具有更高的糖尿病相关死亡风险，并且由于CKD的代谢复杂性而难以治疗。此外，监测骨折风险（即骨矿物质密度，BMD）的标准实践在该患者人群中具有局限性。目前，CKD-MBD患者的治疗主要集中在抑制甲状旁腺激素升高，如可以用拟钙剂完成。西那卡塞是一种FDA批准的拟钙剂，可有效降低甲状旁腺激素，减缓骨转换，增加骨量，但只能适度降低骨折风险。这表明骨质量的缺陷，而不仅仅是骨丢失，是导致CKD脆性的原因，这一观点得到了CKD骨中胶原交联和基质水合作用改变的最新证据的支持。本研究收集的初步数据发现了骨微损伤的证据，这是以前未在CKD中研究的另一个骨质量的重要因素。已知微损伤与孔隙度相互作用，因此这些问题的组合可能对CKD脆性产生重大影响。总之，使这些患者的骨折风险正常化可能不仅仅需要抑制骨丢失;还必须治疗骨质量。我们假设，使用拟钙剂和雷洛昔芬（一种最近发现对骨组织质量有直接积极影响的骨质疏松症选择性雌激素受体调节剂药物）的联合治疗可以改善CKD骨质量，拟钙剂可减少甲状旁腺激素和骨丢失。我们将使用慢性进展性CKD-MBD模型（Cy/+大鼠）来检验这一假设。本研究将首先量化30和35周龄CKD大鼠骨骼中骨骼微损伤的程度，并与其正常、年龄匹配的同窝出生大鼠进行比较。我们预计CKD会导致皮质孔隙度和微损伤逐渐增加，微裂纹和孔隙度之间会发生相互作用。接下来，将测试拟钙剂和雷洛昔芬组合治疗改善骨数量和质量测量的能力。Cy/+大鼠将从25至35周龄用溶剂、雷洛昔芬、拟钙剂或两种药物治疗。主要结局将通过骨骼分析（微损伤、组织学、microCT、骨密度、力学测试和抗疲劳性）确定，但也将评估治疗对CKD-MBD生化和肾脏成分的影响。我们预测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机械性能。联合治疗应通过积极影响质量和质量而超过两种单一治疗。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。这项研究提供了一个重要的一步，在实现这一目标，通过检查这些变化和他们的潜在的纠正在大鼠模型与自发和进行性发展的慢性肾脏病。

 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.