Renal Osteodystrophy: A Fresh Approach

描述（由申请人提供）：慢性肾脏疾病（CKD）患者存在矿物质和骨代谢异常，这与高发病率和死亡率相关。最相关的骨异常包括抑制或极度升高的骨转换和骨质流失。转换异常和骨质流失都与进行性钙化有关，这解释了高发病率和死亡率。骨活检是诊断骨异常的金标准，但很少进行。为了实施靶向治疗以降低发病率和死亡率，迫切需要无创诊断肾骨病的手段。该研究的长期目标是通过无创检测骨转换异常和预防骨质流失来提高CKD患者的生存和生活质量。这将允许实施特定疗法，并应有助于减少影响美国2 000多万患者的普遍健康问题的疾病负担和费用。中心假设是肾性骨营养不良（ROD）可以无创定义。具体来说，我们将检验以下假设：1。a) ROD的骨体积成分（骨质流失）可通过双能x线吸收仪（DXA）和定量计算机断层扫描（QCT）进行评估；然而，QCT在识别骨质流失方面更为敏感；b)骨质流失发生在高营业额和低营业额的患者身上。在骨质流失的患者中，至少有20%的患者骨转化率低。2. 通过PTH结合已建立的和/或新的骨吸收和形成的生化标志物，可以无创地评估ROD的周转率成分。将实现下列具体目标：DEXA与QCT在CKD-5患者骨质流失诊断中的比较及骨质流失患者低骨转换发生率的测定2. 确定最佳的无创检测组合来确定ROD的转换成分：为此，230例患者将被随访2年以上，每年通过QCT和DXA测定骨量，以建立最敏感的识别骨质流失的方法。基线骨质疏松症患者和1 - 2年发生骨质流失的患者将接受骨活检和抽血，以测量骨转换、形成和吸收的血清标志物。将确定定义周转成分ROD的最佳标记或标记组合。这些目标的实现将允许在不使用侵入性检查的情况下实施特定的治疗，并将有助于降低发病率，提高生存率，提高这一不幸患者群体的生活质量。公共卫生相关性：心脑血管钙化与骨转换异常和骨质流失有关，导致高发病率和死亡率。骨转换异常和骨质流失发生在慢性肾病患者中，骨活检（一种侵入性检查）被认为是诊断这些骨异常的必要条件。拟议的研究将建立非侵入性手段（一组血液检查和成像方法）来识别和表征这些骨骼异常，这对诊断、预防、治疗和更好地了解致病机制具有重要意义。

DESCRIPTION (provided by applicant): Patients with chronic kidney disease (CKD) present with abnormalities in mineral and bone metabolism, which are associated with high morbidity and mortality. The most relevant bone abnormalities encompass suppressed or extremely elevated bone turnover and bone loss. Both turnover abnormalities and bone loss are associated with progressive calcifications, explaining the high morbidity and mortality. Bone biopsies are the gold standard for the diagnosis of bone abnormalities but are rarely performed. Noninvasive means to diagnose renal bone disease are urgently needed for implementation of targeted therapy to reduce morbidity and mortality. The long-term goal of the proposed study is to improve survival and quality of life in CKD patients by noninvasive detection of abnormalities in bone turnover and prevention of bone loss. This will allow administration of specific therapies and should contribute to reduction of disease burden and cost of a pervasive health problem affecting over 20 million patients in the United States. The central hypothesis is that renal osteodystrophy (ROD) can be defined noninvasively. Specifically, we will test the following hypotheses: 1. a) Bone volume component of ROD (bone loss) can be assessed by dual energy X-ray absorptiometry (DXA) and by quantitative computed tomography (QCT); however, QCT is more sensitive in recognizing bone loss; and, b) Bone loss occurs in patients with high and low turnover. Among patients with bone loss, there are at least 20% with low bone turnover. 2. The turnover component of ROD can be assessed noninvasively by PTH combined with established and/or novel biochemical markers of bone resorption and formation. The following specific aims will be pursued: 1. Comparison of DEXA and QCT for diagnosis of bone loss in CKD-5 patients and determination of the prevalence of low bone turnover in CKD-5 patients with bone loss. 2. Identification of the optimal combination of noninvasive tests for definition of the turnover component of ROD: For this purpose, 230 patients will be followed prospectively over 2 years, bone mass will be determined by QCT and DXA annually to establish the most sensitive means of identifying bone loss. Patients with osteoporosis at baseline and patients who develop bone loss at 1 or 2 years will be offered to undergo bone biopsy and blood drawing to measure serum markers of bone turnover, formation, and resorption. The best marker or combination of markers for definition of the turnover component ROD will be identified. Attainment of these goals will allow implementation of specific therapies without the use of invasive work-up and will assist in reducing morbidity, increasing survival, and improving quality of life in this unfortunate patient population. PUBLIC HEALTH RELEVANCE: Cardiovascular and cerebrovascular calcifications are linked to abnormalities in bone turnover and bone loss resulting in high morbidity and mortality. Bone turnover abnormalities and bone loss occur in chronic kidney disease patients and bone biopsy (an invasive test) is considered essential for diagnosis of these bone abnormalities. The proposed studies will establish noninvasive means (a panel of blood tests and imaging methods) for recognition and characterization of these bone abnormalities which has significant implications, regarding diagnosis, prevention, treatment and a better understanding of the pathogenic mechanisms.