1α-Hydroxyvitamin D2 Is Less Toxic but Not Bone Selective Relative to 1α-Hydroxyvitamin D3 in Ovariectomized Rats

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Abstract
Identification of bone selective vitamin D analogues would provide an interesting substance class for the treatment of osteoporosis. The synthetic prodrug 1α‐hydroxyvitamin D2 [1α(OH)D2] has been shown to combine equal bone‐preserving activity with distinctly reduced calcemic effects relative to 1α‐hydroxyvitamin D3 [1α(OH)D3] in 3‐month‐old ovariectomized (OVX) rats. Therefore, 1α(OH)D2 may be a bone‐selective compound. The aim of this study was to compare the bone protective and the calcemic activities of chronically administered 1α(OH)D2 and 1α(OH)D3 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 μg of 1α(OH)D2 or 1α(OH)D3 per kg body weight (BW) per day (n = 8 each). After calcein double‐labeling, all animals were killed 3 months post‐OVX. Orally administered 1α(OH)D2 was significantly less toxic compared with 1α(OH)D3 in terms of BW gain and kidney calcium content. The effects of 1α(OH)D2 and 1α(OH)D3 on serum calcium and urinary calcium excretion were generally similar at all doses in this study. Both 1α(OH)D2 and 1α(OH)D3 prevented the estrogen deficiency‐induced bone loss in OVX rats, and induced profound bone anabolic effects at high dosages. 1α(OH)D3 and 1α(OH)D2 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 1α(OH)D2 and 1α(OH)D3. These data show that although 1α(OH)D2 was slightly but significantly less toxic compared with 1α(OH)D3, it did not have increased skeletal effects at any dose. Taken together, our findings argue against selective metabolic activation of 1α(OH)D2 in bone.