1α-hydroxyvitamin D2 is less toxic but not bone selective relative to 1α-hydroxyvitamin D3 in ovariectomized rats

Identification of bone selective vitamin D analogues would provide an interesting substance class for the treatment of osteoporosis. The synthetic prodrug 1 alpha -hydroxyvitamin D-2 [1 alpha (OH)D-2] has been shown to combine equal bone-preserving activity with distinctly reduced calcemic effects relative to la-hydroxyvitamin D-3 [1 alpha (OH)D-3] in 3-month-old ovariectomized (OVX) rats. Therefore, 1 alpha (OH)D-2 may be a bone-selective compound. The aim of this study was to compare the bone protective and the calcemic activities of chronically administered 1 alpha (OH)D-2 and 1 alpha (OH)D-3 in 6-month-old OVX rats over a broad dose range from ineffective to toxic doses. Ninety-six female 6-month-old Fischer-344 rats were used for this experiment. Eighty rats were bilaterally OVX, 8 rats were sham-operated (SHAM), and 8 rats were killed at the time of surgery as a baseline control. Groups of OVX rats received vehicle alone (n = 16) or daily doses in the diet of 0.025, 0.05, 0.1, and 0.2 mug of 1 alpha (OH)D-3 or 1 alpha (OH)D-3 per kg body weight (BW) per day (n = 8 each). After calcein doublelabeling, all animals were killed 3 months post-OVX. Orally administered 1 alpha (OH)D-2 was significantly less toxic compared with la(OH)D, in terms of BW gain and kidney calcium content. The effects of la(OH)D, and 1 alpha (OH)D, on serum calcium and urinary calcium excretion were generally similar at all doses in this study. Both 1 alpha (OH)D-2 and 1 alpha (OH)D-3 prevented the estrogen deficiency-induced bone loss in OVX rats, and induced profound bone anabolic effects at high dosages. 1 alpha (OH)D-3 and 1 alpha (OH)D-2 also dose-dependently increased total bone mineral density (BMD), cortical area, and cortical thickness in the tibial diaphysis of OVX rats. Bone resorption as assessed by osteoclast numbers (Oc.Ns) in vertebral cancellous bone and urinary excretion of deoxypyridinoline (DPD) was dose-dependently suppressed by 1 alpha (OH)D-2 and 1 alpha (OH)D-3. These data show that although 1 alpha (OH)D-2 was slightly but significantly less toxic compared with 1 alpha (OH)D-3, it did not have increased skeletal effects at any dose. Taken together, our findings argue against selective metabolic activation of 1 alpha (OH)D-2 in bone.