A NEW ANALOG OF 1,25-(OH)(2)D-3, 19-NOR-1,25-(OH)(2)D-2, SUPPRESSES SERUM PTH AND PARATHYROID-GLAND GROWTH IN UREMIC RATS WITHOUT ELEVATIONOF INTESTINAL VITAMIN-D-RECEPTOR CONTENT

We have previously reported that 19-nor-1,25-(OH)(2)D-2, a new analog of 1,25-(OH)(2)D-3, suppresses parathyroid hormone (PTH) secretion in uremic rats in the absence of hypercalcemia or hyperphosphatemia. In t he current study, we examined the effect of 19-nor-1,25-(OH)(2)D-2 on parathyroid gland growth and intestinal vitamin D receptor (VDR) conte nt. After induction of uremia by 5/6 nephrectomy, rats were divided in to five experimental groups and received intraperitoneal injections of vehicle, 1,25-(OH)(2)D-3 (2 or 6 ng/rat), or 19-nor-1,25-(OH)(2)D-2 ( 25 or 100 ng/ rat) three times a week for 8 weeks. Twelve normal rats received vehicle and served as the normal control group. During the co urse of the study, rats were maintained on a 1.0% calcium and 0.8% pho sphorus diet. The higher dose of 1,25-(OH)(2)D-3, 6 ng, significantly decreased PTH from 52.7 +/- 10.2 pg/mL in the uremic control group to 25.7 +/- 6.7 pg/mL (P < 0.01). This dose of 1,25-(OH)(2)D-3, however, increased serum levels of both ionized calcium (4.71 +/- 0.05 to 4.85 +/- 0.06 mg/dL; P < 0.05) and phosphorus (4.34 +/- 0.30 to 6.67 +/- 0. 63 mg/dL; P < 0.01). Both doses of 19-nor-1,25-(OH)(2)D-2 decreased se rum PTH as effectively as 1,25-(OH)(2)D-3 without changes in serum cal cium or phosphorus. The 100-ng dose of 19-nor-1,25-(OH)(2)D-2 decrease d PTH to 20.7 +/- 3.1 pg/mL (P < 0.01) and suppressed parathyroid glan d growth by more than 50%. Both doses of 19-nor-1,25-(OH)(2)D-2 also d ecreased endogenous 1,25-(OH)(2)D-3 levels compared with uremic contro l rats (25 ng:30.4 +/- 2.0, P < 0.05, and 100 ng:27.9 +/- 3.2, P < 0.0 1, v 48.4 +/- 6.6 pg/mL). The 6-ng dose of 1,25-(OH)(2)D-3 elevated in testinal VDR content (138.5 +/- 20.0 fmol/mg protein) compared with an imals receiving both doses of 19-nor-1,25-(OH)(2)D-2 (25 ng:84.0 +/- 1 1.9, P < 0.05, and 100 ng:78.4 +/- 10.9, P < 0.01). This was probably attributable to the marked decrease in endogenous 1,25(OH)(2)D-3 level s caused by both doses of 19-mor-1,25-(OH)(2)D-2 because intestinal VD R correlated directly with serum 1,25-(OH)(2)D-3 (r = 0.963; P = 0.008 ). Thus, 19-nor-1,25-(OH)(2)D-2 appears to exert a selective action on the parathyroid glands compared with the intestine. Its low calcemic and phosphatemic properties may result from the decreased endogenous 1 ,25-(OH)(2)D-3 levels that lead to a reduction in intestinal VDR. This selectivity makes this analog ideal for the treatment of secondary hy perparathyroidism. (C) 1997 by the National Kidney Foundation, Inc.