MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AW

提案（改编自申请人摘要）：AH，特征为过量 肠道钙吸收，是肾结石的主要原因。 虽然 在这种情况下，骨丢失是出乎意料的，一些骨密度研究已经 这表明它是常见的，特别是在严重的疾病。 的目标 该项目旨在更好地阐明骨的病理生理机制， 严重AH中的钙丢失和高尿症，以便制定更合理的 治疗方式。 研究人员的假设是：1）主要的 重度AH受试者骨丢失的原因是骨形成减少， 骨吸收正常或轻度增加; 2）高钙尿症 在严重的AH中，主要是由肠钙吸收过多引起的， 但在某些情况下，骨头可能也有作用 在本提案中，申请人将通过比较25 AH来检验每个假设 两个匹配的对照组，25名正常志愿者和25名 固定的高钙尿患者（由以下引起的高钙尿模型： 增加骨吸收）。 假设1将使用骨进行检验 组织形态计量学（终点：骨形成和骨吸收的差异 指标）和骨转换标志物（终点：血清骨 特异性碱性磷酸酶和尿游离脱氧吡啶啉和N- 端肽）。 假设2将通过两个单独的生理 挑战：1）纤维素磷酸钠（SCP），一种吸收不良的粉末 阻止肠道钙吸收，将用于评估 肠对尿钙的贡献（终点： 尿钙（mg/d）; 2）奈膦酸盐，一种阻断骨吸收的药剂， 将用于检查骨骼对尿钙的贡献 （终点：尿钙减少（mg/d））。 受试者将接受基线住院评估，同时服用恒定的 含10 mmol Ca、100 mmol Na和25.8 mmol P的代谢饲料。评价 将包括血清化学，甲状旁腺激素（PTH），维生素D 代谢物、骨转换标志物、24小时尿钙和钙 通过直接和间接测量吸收和骨矿物质密度。 他们 将在三天的治疗期间在门诊进行重新评估 持续代谢饮食的SCP 他们也将作为住院患者进行研究 在两周和三个月的治疗后， 阿仑膦酸钠

PROPOSAL (Adapted from the applicant's abstract): AH, characterized by excess intestinal calcium absorption, is a major cause of nephrolithiasis. Although bone loss is unexpected in this condition, several bone density studies have demonstrated that it is common, particularly in severe disease. The goal of this project is to better elucidate the pathophysiologic mechanisms for bone loss and hypercalciuria in severe AH to allow formulation of more rational treatment modalities. The investigators hypotheses are that: 1) the main cause of bone loss in subjects with severe AH is reduced bone formation in the setting of normal or slightly increased bone resorption; and 2) hypercalciuria in severe AH is primarily caused by excessive intestinal calcium absorption, but the bone may contribute to it in some subjects. In this proposal, the applicant will test each hypothesis by comparing 25 AH patients with two matching control groups, 25 normal volunteers and 25 immobilized hypercalciuric patients (a model for hypercalciuria resulting from increased bone resorption). Hypothesis 1 will be tested using bone histomorphometry (endpoints: difference in bone formation and resorption indices) and bone turnover markers (endpoints: difference in serum bone specific alkaline phosphatase and urine free deoxypyridinoline and N- telopeptides). Hypothesis 2 will be probed via two separate physiologic challenges of: 1) sodium cellulose phosphate (SCP), a poorly absorbed powder which blocks intestinal calcium absorption, will be used to assess the contribution of the intestine to urinary calcium (endpoint: decrement in urinary calcium in mg/d); 2) Nendronate, an agent that blocks bone resorption, will be used to examine the contribution of the bone to urinary calcium (endpoint: decrement in urinary calcium in mg/d). Subjects will have baseline inpatient evaluation while consuming a constant metabolic diet containing 10 mmol Ca, 100 mmol Na and 25.8 mmol P. Evaluation will include serum chemistries, parathyroid hormone (PTH), vitamin D metabolites, bone markers of turnover, 24-hour urinary calcium, and calcium absorption by direct and indirect measurements and bone mineral density. They will be reevaluated in an outpatient setting during three days of treatment with SCP on constant metabolic diet. They will also be studied as inpatients on constant metabolic diet after two weeks and after three months of treatment with alendronate.