Differential effects of 1,25-(OH)2D3 and 22-oxacalcitriol on phosphate and calcium metabolism

• Published in: Kidney international Vol. 43; no. 3; pp. 561 - 566
• Main Authors: Finch, Jane L., Brown, Alex J., Kubodera, Noboru, Nishii, Yashuho, Slatopolsky, Eduardo
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.03.1993; Nature Publishing
• Subjects: Animals; Biological and medical sciences; Calcitriol - adverse effects; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Calcium - metabolism; Female; General and cellular metabolism. Vitamins; Hypercalcemia - chemically induced; Hypercalcemia - prevention & control; Hyperparathyroidism, Secondary - drug therapy; Hyperparathyroidism, Secondary - metabolism; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - metabolism; Medical sciences; Pharmacology. Drug treatments; Phosphates - metabolism; Rats; Rats, Sprague-Dawley; Endocrinopathy; Phosphates; Calcium; Rat; Cholecalciferol(1,25-dihydroxy); Rodentia; Parathyroidectomy; Metabolism; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Parathyroid diseases; Animal; Surgery; Hyperparathyroidism
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.1993.83

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-(OH)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 calcemie 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-dihydroxy vitamin 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.