Renal Osteodystrophy: A Fresh Approach

描述（由申请方提供）：慢性肾脏疾病（CKD）患者存在矿物质和骨代谢异常，与高发病率和死亡率相关。最相关的骨异常包括抑制或极高的骨转换和骨丢失。骨转换异常和骨丢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。肾性骨病的非侵入性诊断方法是实施靶向治疗以降低发病率和死亡率的迫切需要。这项研究的长期目标是通过无创检测骨转换异常和预防骨丢失来提高CKD患者的生存率和生活质量。这将允许管理特定的治疗，并应有助于减少疾病负担和影响美国2000多万患者的普遍健康问题的成本。核心假设是肾性骨营养不良（ROD）可以非侵入性定义。具体而言，我们将测试以下假设：1。a）ROD的骨体积成分（骨丢失）可通过双能X线吸收测定法（DXA）和定量计算机断层扫描（QCT）进行评估;然而，QCT在识别骨丢失方面更敏感;和，B）骨丢失发生在高转换和低转换患者中。在骨丢失患者中，至少有20%的患者骨转换率低。2. ROD的周转组分可以通过PTH结合骨吸收和形成的既定和/或新的生化标志物进行无创评估。具体目标如下：1.比较DEXA和QCT诊断CKD-5患者骨丢失和确定CKD-5骨丢失患者低骨转换的患病率。2.确定用于定义ROD转换成分的非侵入性测试的最佳组合：为此，将对230例患者进行为期2年的前瞻性随访，每年通过QCT和DXA测定骨量，以确定识别骨丢失的最敏感方法。基线时骨质疏松症患者和1年或2年时发生骨丢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。将确定用于定义营业额组成部分ROD的最佳标志物或标志物组合。实现这些目标将允许在不使用侵入性检查的情况下实施特定治疗，并将有助于降低发病率，提高生存率，并改善这一不幸患者人群的生活质量。公共卫生相关性：心血管和脑血管钙化与骨转换和骨丢失异常有关，导致高发病率和死亡率。骨转换异常和骨丢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），用于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.