MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AW

提案（改编自申请人摘要）：AH，以过量为特征

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.