A NEW ANALOG OF CALCITRIOL, 19-NOR-1,25-(OH)(2)D-2, SUPPRESSES PARATHYROID-HORMONE SECRETION IN UREMIC RATS IN THE ABSENCE OF HYPERCALCEMIA

The active metabolite of vitamin D, calcitriol (1 alpha,25-(OH)(2)-D-3), suppresses parathyroid hormone (PTH) gene transcription. Although 1 alpha,25-(OH)(2)D-3 is effective in suppressing secondary hyperparathyroidism (SH) in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude, in some patients, the use of ideal therapeutic doses of 1 alpha,25-(OH)(2)D-3 because of hypercalcemia. We have studied a new analog of calcitriol, 19-nor-1 alpha,25-(OH)(2)D-2, that possesses low calcemic and phosphatemic activity. Uremic rats received vehicle, 1 alpha,25-(OH)(2)D-3(2.0, 4.0, or 8.0 ng/rat) or 19-nor-1,25-(OH)(2)D-2 (8.0, 25 or 75 ng/rat) intraperitoneally (IF) every other day for a period of 8 days. Pretreatment and posttreatment values of intact PTH were measured. The normal values for rat intact-PTH were 22 +/- 4.2 pg/mL and for ionized calcium (ICa) 4.77 +/- .07 mg/dL. The only dose of 1 alpha,25-(OH)(2)D-3 that achieved a significantly suppressed PTH (P < 0.01) was the 8.0 ng/rat. PTH decreased from 202 +/- 31 to 90 +/- 20 pg/mL. However, ICa increased from 4.81 +/- 0.08 to 5.08 mg/dL from uremic control (P < 0.02). Conversely, all doses of 19-nor-1,25-(OH)(2)D-2 were effective in suppressing PTH, and none produced an elevation in ICa that was significantly different from that of vehicle-treated uremic rats. The maximum effect was achieved with the 75 ng/rat dose, which decreased PTH from 193 +/- 49 to 53 +/- 16 pg/mL (a decrease in 72.5%). In addition, 1 alpha,25-(OH)(2)D-3, at 8 ng/rat, induced an increase in serum phosphorus to 8.64 +/- 1.15 mg/dL compared with 5.57 +/- 0.50 mg/dL in the uremic controls, Conversely, the largest dose of 19-nor-1,25-(OH)(2)D-2 (75 ng) increased serum phosphorus to only 6.17 +/- 0.68 mg/dL. By the technique of reverse transcription polymerase chain reaction, it was found that 19-nor-1 alpha,25-(OH)(2)D-2 caused a significant decrease in the amount of pre-pro PTH messenger RNA compared with the uremic control. These comparative studies demonstrate the advantage of the analog 19-nor-1,25-(OH)(2)D-2 over its parent compound, 1 alpha,25-(OH)(2)D-3, in the suppression of PTH in the absence of hypercalcemia or hyperphosphatemia. From the clinical point of view, the significant suppressive effect on PTH secretion of this new analog without significant changes in ICa or serum phosphorus makes it an ideal toot for the treatment of secondary hyperparathyroidism in uremic patients. (C) 1995 by the National Kidney Foundation, Inc.