The chronotherapeutic effects of 1-alpha-(OH)
vitamin D3, a
pro-drug of 1,25(
OH)2
vitamin D3 (
1,25(OH)2D3), were evaluated by repeated dosing of the
drug in aged
stroke-prone spontaneously hypertensive male rats, a model of
osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle.
Drug (0.5 microg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as
body weight loss,
hypercalcemia and
hyperphosphatemia was significantly less when the
drug was given at 14 h after lights on (14 HALO). Serum 1,25(
OH)2
vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in
parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the
bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of
vitamin D3 for suppressing
bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active
vitamin D3 in an animal model of
osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active
vitamin D3 for the treatment of
osteoporosis.