Determination of Skeletal Muscle Mass by Creatine Dilution

描述（由申请人提供）：肌肉减少症是与年龄相关的肌肉损失，伴随着力量和身体表现的下降，瘦质量的损失是衰老的一个显著和普遍的特征。然而，研究表明，瘦质量与身体表现（步行速度、站立表现）、残疾、住院和死亡率等结果之间的关联并不一致。在最好的情况下，现有技术评估的瘦质量或肌肉质量与功能预后的相关性很弱；力量和其他肌肉质量是功能衰退的更可靠的预测指标。这种不一致的一种解释与现有肌肉质量评估工具的问题有关：测量误差和/或可行性问题困扰着现有技术，包括24小时尿肌酐排泄；双能x射线吸收测定法；计算机断层扫描（CT）；和磁共振（MR）成像。考虑到评估肌肉质量的现有方法的局限性，很明显，临床可行的直接测量肌肉质量将使我们更全面地了解肌肉质量与健康之间的关系。肌酸稀释法是测量全身骨骼肌质量的一种新方法。简而言之，总肌酸池大小，以及全身骨骼肌质量，可以通过给个体口服氘化肌酸（d3-肌酸），然后测量单个尿液样本中的标记肌酸酐（d3-肌酸酐）来估计。我们假设，通过这种方法测量的全身骨骼肌质量与力量和身体表现有关，并且全身骨骼肌质量减少的个体将增加跌倒，骨折和功能障碍的风险。我们将使用传统的方法，如接受者-操作者曲线，以及新的方法，包括净重分类指数和预测曲线，来研究由肌酸稀释法确定的全身骨骼肌质量是否优于阑尾瘦肉质量（来自DXA）、年龄、BMI和力量，以预测老年男性跌倒、骨折、死亡率和活动受限的风险。我们计划通过一项正在进行的男性骨质疏松性骨折（MrOS）研究的辅助研究来有效地验证这些假设，这是一项大型、特征明确、前瞻性、多中心的研究。我们建议在已经资助的研究Visit 4中增加这一措施。我们将与葛兰素史克（GSK）合作，后者将捐赠标记的肌酸剂量，并在收集的尿液中完成检测。如果我们的假设被证明是正确的，肌酸稀释法评估全身骨骼肌质量将成为一个重要的研究工具，用于阐明肌肉减少症的病理生理。通过提供一种高度精确的方法来监测反应，肌酸稀释法将有助于开发新的药物来逆转与年龄相关的肌肉损失。这个简单的测试可以在临床上作为DXA的替代方法，用于识别有身体衰退风险的男性，并完善肌肉减少症的定义。

DESCRIPTION (provided by applicant): Sarcopenia is the age-related loss of muscle that is accompanied by reduced strength and physical performance, and the loss of lean mass is a dramatic and universal feature of aging. However, research has shown inconsistent associations between lean mass and outcomes such as physical performance (walking speed, chair stands performance), disability, hospitalization and mortality. At best, lean mass or muscle mass as assessed by existing techniques is weakly associated with functional outcomes; strength and other qualities of muscle are more robust predictors of functional decline. One explanation for such inconsistency is related to problems with the existing tools for assessment of muscle mass: measurement error and/or feasibility issues plague existing techniques including 24-hour urinary excretion of creatinine; dual energy x- ray absorptiometry (DXA); computed tomography (CT); and magnetic resonance (MR) imaging. Given the limitation in existing methods to assess muscle mass, it is clear that a clinically feasible, direct measure of muscle mass will allow for a more complete understanding of the relation between muscle mass and health. A novel measure of total body skeletal muscle mass is the creatine dilution method. Briefly, the total creatine pool size, and thus total body skeletal muscle mass, can be estimated by orally dosing individuals with deuterated creatine (d3-creatine) and then subsequently measuring labeled creatinine (d3-creatinine) in a single urine sample. We posit that total body skeletal muscle mass as measured by this method is related to strength and physical performance, and that individuals with decreased total body skeletal muscle mass will have an increased risk of falls, fractures and functional impairments. We will use traditional methods such as receiver-operator curves, and newer approaches including the net reclassification index and predictiveness curves, to investigate whether total body skeletal muscle mass as determined by the creatine dilution method is superior to appendicular lean mass (from DXA), age, BMI and strength in predicting the risk of falls, fractures, mortality and mobility limitationin older men. We plan to efficiently test these hypotheses via an ancillary study to the ongoing Osteoporotic Fractures in Men (MrOS) study - a large, well-characterized, prospective, multicenter study. We propose to add this measure to the already funded study Visit 4. We will partner with GlaxoSmithKline (GSK), who will donate the labeled creatine dose and complete the assays in the collected urine. Should our hypotheses prove correct, the creatine dilution method for assessing total body skeletal muscle mass would become a critical research tool used to elucidate the pathophysiology of sarcopenia. By providing a highly precise method to monitor response, the creatine dilution method will aid the development of novel agents for reversing age-related muscle loss. This simple test could be used clinically as an alternative to DXA to identify men at risk of physical decline and to refine sarcopenia definitions.