The C-3α Epimer of 25-Hydroxycholecalciferol from Endogenous and Exogenous Sources Supports Normal Growth and Bone Mineral Density in Weanling Rats

Abstract

Background: The C-3α epimer of 25-hydroxycholecalciferol [3-epi-25(OH)D₃] is elevated in infants.

Objectives: We tested whether increasing cholecalciferol intake results in a dose-response in plasma 3-epi-25(OH)D₃ We also examined bone and mineral metabolism in response to 3-epi-25(OH)D₃ treatment.

Methods: Sprague Dawley rats (4 wk old) were randomly assigned (n = 6/group of each sex) to AIN-93G diets with cholecalciferol at 1 (control), 2, or 4 IU/g diet for objective 1 and to diets with 3-epi-25(OH)D₃ at 0.5 or 1 IU/g diet or 25-hydroxycholecalciferol [25(OH)D₃] at 0.5 IU/g diet for objective 2 for 8 wk. Measurements at weeks 0, 4, and 8 included body weight and length, plasma vitamin D metabolites, bone biomarkers, and bone mineral density determined by using dual-energy X-ray absorptiometry. Lumbar vertebra 3 (L3) geometry and volumetric bone mineral density (vBMD) were measured using microcomputed tomography. Differences between groups were identified for males and females separately.

Results: Weight and food intake were not different between groups. Elevated plasma 3-epi-25(OH)D₃ was observed only in females in the 4 IU cholecalciferol/g diet group (mean ± SD: 24.7 ± 17.1 ng/mL), compared with the control group (5.3 ± 1.4 ng/mL; P = 0.001). By week 8, both male and female rats in the 3-epi-25(OH)D₃ groups had >87% greater plasma 3-epi-25(OH)D₃ concentrations relative to the 25(OH)D₃ reference group (P < 0.0001). At week 8 in males only, parathyroid hormone was significantly lower (P = 0.019) in both 3-epi-25(OH)D₃ groups than in the 25(OH)D₃ group, and L3 total vBMD was higher (P = 0.004) in the 0.5 IU 3-epi-25(OH)D₃ group than in the 25(OH)D₃ group.

Conclusions: Endogenously generated 3-epi-25(OH)D₃ is more prominent in female than in male rats. Exogenous 3-epi-25(OH)D₃ was as effective as 25(OH)D₃ in supporting bone mineral accretion in both sexes. It thus appears that 3-epi-25(OH)D₃ has biological activity and should be further explored.

Keywords: bone; dose-response; epimer; parathyroid hormone; vitamin D; weanling rats.