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Calcemic Activity of 19-Nor-1,25(OH)₂D₂ Decreases with Duration of Treatment

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

Correspondence to Dr. Alex J. Brown, Box 8126, 660 S. Euclid, St. Louis, MO 63110. Phone: 314-362-8232; Fax: 314-362-8237; E-mail: abrown{at}imgate.wustl.edu

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-norD₂ or[³H]1,25(OH)₂D₃ after 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-norD₂ or 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-norD₂ or 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-norD₂ or 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-norD₂ or 1,25(OH)₂D₃ showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD₂ or 1,25(OH)₂D₃. In conclusion, the low calcemic activity of 19-norD₂ seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog.

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