CLOMIPHENE PREVENTS CANCELLOUS BONE LOSS FROM TIBIA OF OVARIECTOMIZEDRATS

Estrogen inhibits postmenopausal bone loss and decreases fracture risk . Unfortunately, estrogen replacement therapy has many undesirable sid e effects, the majority of which are due to stimulation of reproductiv e tissues. Tissue specific estrogen agonists provide a promising new a lternative to natural estrogens for hormone replacement. Clomiphene (C LO) is a substituted triphenylethylene antiestrogen based on its abili ty to antagonize estrogen-mediated uterine growth in rodents. CLO is u sed clinically far the treatment of disorders of ovulation in patients wishing to become pregnant. In order to determine whether CLO has tis sue selective actions, me performed a dose-response study in adult (6- month-old) ovariectomized (OVX'd) rats. The rats received daily (gavag e) doses of either 17 alpha-ethynyl estradiol (E) (0.1 mg/kg) or CLO ( 0.01-10 mg/kg) daily for 5 weeks. Long-term loss of ovarian function h ad no effect on serum cholesterol, greatly decreased uterine weight, c ancellous bone area and trabecular number, and increased bone formatio n rate (BFR) and osteoblast and osteoclast perimeters. E treatment of OVX'd rats prevented uterine atrophy, greatly lowered cholesterol, and prevented many of the bone changes. CLO was a very weak estrogen agon ist in supporting uterine weight, a partial agonist in reducing serum cholesterol, and an excellent agonist in maintaining normal bone mass and indices of bone turnover. Wc conclude from these studies that CLO exhibits pronounced tissue selective estrogen agonism in the rat. Spec ifically, CLO is effective in preventing cancellous bone loss in the O VX'd rats and has minimal uterotrophic activity.