25,26(OH)2D3: EFFECT ON METABOLISM OF 1,25(OH)2D

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The long term objective of this study is to assess the clinical efficacy of 25, 26-dihydroxyvitamin D (25, 26(OH)2D3) in treating hypercalcitriolemic states such as primary hyperparathyroidism, sarcoidosis, lymphoma induced hypercalcemia and absorptive hypercalciuria. The specific aims are 1) to determine the optimum dose and length of dosing of 25, 26(OH)2D3 to maximize reduction of serum 1, 25-dihydroxyvitamin D (1, 25(OH)2D) in an animal model; 2) to determine the mechanism of 25, 26(OH)2D3- mediated reduction of serum 1, 25(OH)2D in an animal model; and 3) to evaluate the effectiveness of 25, 26(OH)2D3 administration to patients with various disease states characterized by high circulating 1, 25,(OH)2D concentrations and hypercalcemia, hypercalciuria, or both. Preliminary investigations have disclosed that pharmacologic amounts of 25, 26(OH)2D3 have a unique ability to significantly reduce the circulating concentration of 1, 25(OH)2D, the physiologically active form of vitamin D, while demonstrating little or no biological activity of its own. This observation will be further investigated by administering various doses of 25, 26(OH)2D3 to rats for different intervals of time and measuring serum 1, 25,(OH)2D. Studies will then be extended to the canine to examine by what mechanism (i.e., increased metabolic clearance, decreased synthesis or both ) 25, 26(OH)2D3 promotes a reduction in serum 1, 25(OH)2D concentration. This will be accomplished by administering a trace dose of radioactive 1, 25(OH)2D3 to dogs, before and after appropriate 25, 26(OH)2D3 dosing, and quantifying the plasma disappearance of radioactivity. Form these studies, patients with inoperative primary hyperparathyroidism, sarcoidosis, lymphoma-induced hypercalcemia and absorptive hypercalciuria will be admitted to the General Clinical Research Center and undergo a basic evaluation of calcium homeostasis while on a constant metabolic diet before and after 25, 26(OH)2D3 dosing. If warranted, assessment of 1, 25(OH)2D3 clearance and synthetic rates can also be obtained. These studies may indicate that pharmacologic amounts of 25, 26(OH)2D3 are effective in lowering 1, 25,(OH)2D concentration where surgery (e.g. primary hyperparathyroidism), or drug therapy such as steroids (e.g. sarcoidosis or lymphoma) is contraindicated. Similar studies in patients with renal stone disease should disclose should disclose the true extent of vitamin- d dependency of intestinal calcium absorption in absorptive hypercalciuria.