Calcemic Activity of 19-Nor-1,25(OH)2D2Decreases with Duration of Treatment

Abstract

Abstract. 19-Nor-1,25(OH)2D2(19-norD2) has been shown to suppress parathyroid hormone effectively, but with lower calcemic activity than 1,25(OH)2D3. The present study investigated potential mechanisms to explain the reduced calcemic response to 19-norD2. Tissue localization of [3H]19-norD2or[3H]1,25(OH)2D3after a single injection was not different. Intestinal calcium absorption and bone mobilization, measured in vitamin D-deficient rats 24 h after single injections of 60 or 600 pmol of 19-norD2or 1,25(OH)2D3, were enhanced to a similar degree by the two compounds. However, when normal rats were treated every other day with 240 pmol of 19-norD2or 1,25(OH)2D3, increases in serum calcium were identical 24 h after the first injection but diverged thereafter with significantly lower serum calcium in the 19-norD2-treated rats by 5 d. Intestinal calcium absorption and bone calcium mobilization were reassessed in vitamin D-deficient rats after seven daily injections of 600 pmol of 19-norD2or 1,25(OH)2D3, and both parameters were significantly lower in the 19-norD2-treated rats. Pharmacokinetic analysis after seven daily injections of 600 pmol of 19-norD2or 1,25(OH)2D3showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD2or 1,25(OH)2D3. In conclusion, the low calcemic activity of 19-norD2seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog.