Effect of 1α,25-dihydroxycholecalciferol analogs on bone resorption in vitro

Abstract The rat fetal bone culture has been used to investigate the effectiveness of 1α,25-dihydroxycholecalciferol analogs in stimulating bone resorption in vitro . Through manipulation of the substituents of the 1α,25-dihydroxycholecalciferol basic structure and subsequent changes in bone resorption, the structural activity relationships of these vitamin D 3 analogs have been evaluated. Ulnae and radii prelabeled with 45 Ca were cultured for 5 days in the presence of the vitamin D 3 analogs. 1α,24R-dihydroxy-25-fluorocholecalciferol was a powerful stimulator of 45 Ca release and was similar in potency to 1α,25-dihydroxycholecalciferol. Addition of a second hydroxyl to the side chain, as with 1α,24,25-trihydroxycholecalciferol or esterification of the hydroxyl in position 3 with succinic acid (1α,25-dihydroxycholecalciferol-3-hemisuccinate), resulted in an approximate 30-fold and 6-fold reduction in activity, respectively. Esterification of the 25 hydroxyl with succinic acid (1α-25-dihydroxycholecalciferol-25-hemisuccinate) reduced the activity 250-fold. Rotation of the A ring by 180° (5,6-trans-1α,25-dihydroxycholecalciferol) diminished the bone resorbing activity 50-fold, pointing out the importance that the position of the methylene group on Ring A has in affecting calcium release. Acetylation of both the 1 and 25 hydroxyl groups (1α,25-diacetoxycholecalciferol) greatly reduced resorption (> 11,000-fold).