DIFFERENTIAL-EFFECTS OF 1,25-(OH)2D3 AND 22-OXACALCITRIOL ON PHOSPHATE AND CALCIUM-METABOLISM

1,25-dihydroxyvitamin D3 has been used with success in the treatment of secondary hyperparathyroidism associated with chronic renal failure. However, frequently 1,25-(OH)2D3 induces hypercalcemia, especially in those patients ingesting large doses of calcium carbonate, precluding the administration of therapeutic doses of 1,25-(OH)2D3. In addition, control of serum phosphorus is a persistent problem in patients maintained on chronic hemodialysis and 1,25-(OH)2D3 treatment can aggravate the hyperphosphatemia. Thus, ideally an analog of 1,25-(H)2D3 that can suppress PTH with minor effects on calcium (Ca) and phosphate (PO4) metabolism would be an ideal tool to control secondary hyperparathyroidism. We have shown that 22-oxa-1,25-(OH)2D3 (OCT), an analog of 1,25-(OH)2D3 with little calcemic activity, can suppress PTH mRNA in normal rats and in cultured bovine parathyroid cells with equipotency to 1,25-(OH)2D3. To further characterize the differential effects of 1,25-(OH)2D3 and OCT on Ca and PO4 metabolism we performed several experiments in intact and parathyroidectomized (PTX) rats. In metabolic studies in four groups of normal rats 1,25-(OH)2D3 treatment (8 ng/day) significantly increased the intestinal Ca absorption from 15.2 +/- 2.68% to 30.5 +/- 2.85% (P < 0.01), while the same dose of OCT had no effect. A dose of 200 ng/day of OCT increased intestinal Ca absorption similarly to the 8 ng/day dose of 1,25-(OH)2D3, from 10.6 +/- 2.49% to 24.8 +/- 2.35% (P < 0.01). Results for intestinal PO4 absorption were similar to those for Ca. Eight ng/day of 1,25-(OH)2D3 increased intestinal PO4 absorption from 21.8 +/- 1.94 to 32.6 +/- 2.70% (P < 0.01), while the same dose of OCT had no effect. The 200 ng/day dose of OCT increased intestinal PO4 absorption in a manner comparable to the 8 ng/day dose of 1,25-(OH)2D3, from 20.3 +/- 1.92 to 29.2 +/- 1.74% (P < 0.01). Similar patterns were observed for urinary Ca and phosphorus excretion. To further characterize the bone-resorbing effects of 1,25-(OH)2D3 and OCT, studies were performed in three groups of PTX rats fed a PO4-deficient diet. 1,25-dihydroxyvitamin D3 (200 ng/day) increased plasma phosphorus to 6.09 +/- 0.26 mg/dl as compared to 2.41 +/- 0.33 mg/dl in vehicle-treated animals. On the other hand, plasma phosphorus increased to only 3.55 +/- 0.23 mg/dl in OCT-treated animals. We conclude that in normal rats OCT is much less active than 1,25-(OH)2D3 in stimulating both intestinal absorption and urinary excretion of Ca and phosphorus. Also as shown in PTX rats fed a PO4-deficient diet, OCT is much less effective in raising plasma phosphorus most likely by bone resorption. Thus, OCT, an analog of 1,25-(OH)2D3, can suppress PTH without significant changes in plasma Ca and phosphorus making it an ideal drug for the treatment of secondary hyperparathyroidism.