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Differential Effects of 1,25-Dihydroxy-Vitamin D₃ and 19-Nor-1,25-Dihydroxy-Vitamin D₂ on Calcium and Phosphorus Resorption in Bone

Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.

Correspondence to Dr. Eduardo Slatopolsky, Department of Internal Medicine, Renal Division, 660 South Euclid Avenue, Box 8126, St. Louis, MO 63110-1093. Phone: 314-362-7208; Fax: 314-362-7875; E-mail: eslatopo{at}imgate.wustl.edu

Abstract. 1,25-Dihydroxy-vitamin D₃ [1,25-(OH)₂D₃] suppresses the secretion and synthesis of parathyroid hormone (PTH) and has been used in the treatment of secondary hyperparathyroidism. However, 1,25-(OH)₂D₃ can induce hypercalcemia, which often precludes its use. Therefore, an analog of 1,25-(OH)₂D₃ that would retain its therapeutic effects but produce minor effects on calcium and phosphorus metabolism could be an ideal tool for the treatment of secondary hyperparathyroidism. It has been shown that 19-nor-1,25-dihydroxy-vitamin D₂ [19-nor-1,25-(OH)₂D₂], an analog of 1,25-(OH)₂D₃, can suppress PTH levels in uremic rats at doses that do not affect plasma ionized calcium levels. The experiments presented here, using parathyroidectomized rats fed diets deficient in either calcium (0.02%) or phosphorus (0.02%), were performed to compare the effects of 1,25-(OH)₂D₃ and 19-nor-1,25-(OH)₂D₂ on calcium and phosphorus resorption in bone. Parathyroidectomized rats received daily intraperitoneal injections of vehicle, 1,25-(OH)₂D₃ (100 ng), or 19-nor-1,25-(OH)₂D₂ (100 or 1000 ng) for 9 d. Plasma calcium and phosphorus levels were monitored during the study, and ionized calcium levels were determined at the end of the study. By 9 d, 1,25-(OH)₂D₃ (100 ng/d) increased total calcium levels to 12.4 ± 0.26 mg/dl, compared with 6.32 ± 0.25 mg/dl (P < 0.001) in control animals. The same dose of 19-nor-1,25-(OH)₂D₂ (100 ng/d) was much less potent (9.45 ± 0.28 mg/dl, P < 0.001). Similar results were seen with ionized calcium levels [19-nor-1,25-(OH)₂D₂, 3.61 ± 0.12 mg/dl; 1,25-(OH)₂D₃, 5.03 ± 0.16 mg/dl; P < 0.001]. Ionized calcium levels were also lower in rats receiving the higher dose (1000 ng) of 19-nor-1,25-(OH)₂D₂ (4.59 ± 0.09 mg/dl, P < 0.05). Similar results were seen in rats fed the phosphorus-deficient diet. 1,25-(OH)₂D₃ (100 ng) increased plasma phosphorus levels from 4.30 ± 0.39 mg/dl in vehicle-treated rats to 7.43 ± 0.26 mg/dl (P < 0.001). The same dose of 19-nor-1,25-(OH)₂D₂ had no effect (5.19 ± 0.32 mg/dl), whereas the high dose (1000 ng) increased plasma phosphorus levels (7.31 ± 0.24 mg/dl) in a manner similar to that of 1,25-(OH)₂D₃ (100 ng). Therefore, 19-nor-1,25-(OH)₂D₂ is approximately 10 times less effective in mobilizing calcium and phosphorus from the skeleton, compared with 1,25-(OH)₂D₃. With its ability to suppress PTH at noncalcemic doses, 19-nor-1,25-(OH)₂D₂ is a potential therapeutic tool for the treatment of secondary hyperparathyroidism in chronic renal failure.

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