The chronopharmacological effect of
raloxifene, a
selective estrogen-receptor modulator, was evaluated by repeated dosing of ovariectomized rats.
Bilateral ovariectomy or
sham operation was performed at age 12 wks, and animals were kept in rooms with a 12 h light-12 h dark cycle.
Raloxifene (3 mg/kg, once daily for 10 wks) or vehicle was given repeatedly at either 2 h after lights-on (2 HALO) or 14 h after lights-on (14 HALO). Plasma
fibrinogen concentration at the end of the study was reduced by the
drug, and the reduction was significantly prominent in rats in whom the
drug was dosed at 2 HALO rather than 14 HALO. Femur bone density decreased, and urinary excretion of
deoxypyridinoline, an index of
bone resorption capacity of osteoclasts, increased in ovariectomized animals at the end of the study. Treatment with
raloxifene ameliorated these changes in a dosing time-independent manner. Serum
calcium, ALT, and total
protein concentrations at the end of the study also did not differ according to treatment regime, which indicates that
protein synthesis and liver function may not contribute to the effects. This is the first study to determine dosing time-dependent changes in the efficacy of
raloxifene in an animal model of
osteoporosis. Because
fibrinogen concentration is reported to be a marker of cardiovascular events, consideration of dosing time of
raloxifene may be important to obtain a better cardioprotective effect of this medication when it is prescribed to postmenopausal women with
osteoporosis.