24-Oxo and 26,23-lactone metabolites of 1,25-dihydroxyvitamin D3 have direct bone-resorbing activity

Abstract The biological activities of several 24-oxo and 26,23-lactone metabolites of vitamin D were determined in bone organ cultures. The 24-oxo metabolites were significantly more potent bone-resorbing agents than the lactones. 1,25-(OH) 2 -24-oxo-D 3 had 0.18× the bone-resorbing activity of 1,25-(OH) 2 D 3 in fetal rat limb bones and was equipotent with 1,25-(OH) 2 D 3 in neonatal mouse calvaria. In the limb bone system, 1,23,25-(OH) 3 -24-oxo-D 3 had 0.08× the activity of 1,25-(OH) 2 D 3 . 1,25-(OH) 2 D 3 and 1,25-(OH) 2 -24-oxo-D 3 had a similar time course of bone-resorbing effects in both bone culture systems. The most potent of the lactones, 1,25 S -(OH) 2 D 3 -26,23 R -lactone, had approximately 0.009× the activity of 1,25-(OH) 2 D 3 and approximately 500 times the activity of the 25 S -OH-D 3 -26,23 R -lactone. The 25 S and 1,25 S lactones were more potent than the 25 R and 1,25 R isomers. In experiments designed to determine whether either 1,25-(OH) 2 -24-oxo-D 3 or 25 R -OH-D 3 -26,23 S -lactone could prevent the bone-resorbing activity of 1,25-(OH) 2 D 3 , no inhibitory effects were observed. The results suggest that conversion to the lactones represents a substantial inactivation step, whereas conversion to 24-oxo-derivatives results in less reduction in biological activity.