HYPONATREMIA-INDUCED OSTEOPOROSIS

描述(由申请人提供)： 骨质疏松症和由此导致的骨质疏松性骨折是美国的主要健康问题。众所周知，年龄和性激素缺乏是骨质疏松症的主要危险因素，而其他导致骨质疏松症的原因也越来越多地被认为是加速骨丢失和增加骨折发生率的原因。最近的研究发现，在患有骨质疏松症的无症状女性中，继发性骨质疏松症的发生率很高：使用药物导致骨质丢失的比例为53%，荷尔蒙和代谢异常的比例为44%，慢性胃肠道疾病、慢性阻塞性肺疾病、器官移植、自身免疫性疾病、遗传性疾病以及骨髓和肿瘤疾病的总比例为18%。因此，从预防和治疗的角度来看，认识导致骨质疏松症的新因素都是重要的。在考虑骨丢失的其他潜在原因时，由于抗利尿激素分泌不当综合征(SIADH)导致的慢性低钠血症患者中原因不明的骨质疏松症的临床病例促使我们将其作为加速骨丢失的另一种潜在原因进行检查。使用本实验室建立的慢性稳定型低钠血症动物模型，在这项拨款申请中提出的初步研究证实，在幼年和老年大鼠中，慢性低钠血症与严重的骨质疏松症有关，并表明低钠水平直接刺激破骨细胞介导的骨吸收。此外，第三次全国健康和营养检查调查(NHANES III)的人体数据分析显示，与血清钠水平正常的人相比，50岁低钠血症的美国成年人患髋部骨质疏松症的优势比显著增加。鉴于低钠血症在老年患者中的高报告患病率(7%-35%)，以及最近发现步态不稳定与跌倒之间的关联，即使是无症状的低钠血症患者，在这一脆弱的老年人口中加速发生骨质疏松症的任何额外增加的风险都将是非常令人担忧的。因此，这些研究将直接解决这一假设，即低钠血症是以前未被认识到的骨质疏松症的原因，也是导致我们老年人口中骨病和骨折的高发病率和死亡率的一个因素。低钠血症或血液中低钠浓度发生在7%-35%的老年患者中。最近，这种疾病被证明会导致步态不稳定和患者跌倒的发生率增加。我们的初步研究表明，低钠血症也会导致动物的显著骨丢失，并与人类骨质疏松风险的增加独立相关。这项拨款申请的研究将确定低钠血症在多大程度上是骨质疏松症的一种以前未被认识到的原因，这可能是导致我们脆弱的老年人口中骨病和骨折的高发病率和死亡率的原因之一。

DESCRIPTION (provided by applicant): Osteoporosis, and resulting osteoporotic fractures, are major health problems in the United States. Whereas age and gonadal hormone deficiency are well known to be major risk factors for osteoporosis, other causes of osteoporosis are increasingly recognized as contributing to accelerated bone loss and increased fracture incidence. Recent studies have found a high frequency of secondary causes of osteoporosis in asymptomatic women with osteoporosis: medication use contributed to bone loss in 53%, hormonal and metabolic abnormalities in 44%, and chronic diseases of the gastrointestinal tract, chronic obstructive pulmonary disease, organ transplantation, autoimmune diseases, genetic diseases, and marrow-based and neoplastic disorders in 18% in aggregate. Consequently, recognition of novel factors leading to osteoporosis is important from both a preventative and a therapeutic perspective. In considering other potential causes of bone loss, clinical cases of unexplained osteoporosis in patients with chronic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) prompted us to examine this as another potential cause of accelerated bone loss. Using an animal model of chronic stable hyponatremia developed in this laboratory, the preliminary studies presented in this grant application verify that chronic hyponatremia is associated with severe osteoporosis in both young and aged rats, and suggest a direct effect of low sodium levels to stimulate osteoclast-mediated bone resorption. Moreover, analysis of human data from the Third National Health and Nutrition Examination Survey (NHANES III) showed a significantly increased odds ratio for osteoporosis in the hip among U.S. adults e50 years with hyponatremia compared to those with normal serum sodium levels. In view of the high reported prevalence of hyponatremia in geriatric patients (7-35%) coupled with a recently discovered association between gait instability and falls in patients with even asymptomatic hyponatremia, any additional increased risk of accelerated osteoporosis in this vulnerable aged population would be of great concern. These studies will therefore directly address the hypothesis that hyponatremia represents a previously unrecognized cause of osteoporosis, and is a contributing factor to the high morbidity and mortality from bone disease and fracture in our elderly population.Hyponatremia, or low sodium concentrations in the blood, occurs in 7-35% of geriatric patients. Recently, this disorder has been shown to cause gait instability and an increased incidence of falls in patients. Our preliminary studies have shown that hyponatremia also causes significant bone loss in animals, and is independently associated with an increased risk of osteoporosis in humans. The studies in this grant application will ascertain to what degree hyponatremia is a previously unrecognized cause of osteoporosis, which may contribute to the high morbidity and mortality from bone disease and fracture in our vulnerable elderly population.