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Clomiphene Prevents Cancellous Bone Loss from Tibia of Ovariectomized Rats

Department of Orthopedics and Biochemistry and Molecular Biology (M.A.J., R.T.T.), Mayo Clinic, Rochester, Minnesota 55905; and the Department of Skeletal Diseases (D.E.M., H.U.B.), Lilly Corporate Center, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Russell T. Turner, 3-69 Medical Science Building, Department of Orthopedic Research, Mayo Clinic, Rochester, Minnesota 55905.

Estrogen inhibits postmenopausal bone loss and decreases fracture risk. Unfortunately, estrogen replacement therapy has many undesirable side effects, the majority of which are due to stimulation of reproductive tissues. Tissue specific estrogen agonists provide a promising new alternative to natural estrogens for hormone replacement. Clomiphene (CLO) is a substituted triphenylethylene antiestrogen based on its ability to antagonize estrogen-mediated uterine growth in rodents. CLO is used clinically for the treatment of disorders of ovulation in patients wishing to become pregnant. In order to determine whether CLO has tissue selective actions, we performed a dose-response study in adult (6-month-old) ovariectomized (OVX’d) rats. The rats received daily (gavage) doses of either 17 -ethynyl estradiol (E) (0.1 mg/kg) or CLO (0.01–10 mg/kg) daily for 5 weeks. Long-term loss of ovarian function had no effect on serum cholesterol, greatly decreased uterine weight, cancellous bone area and trabecular number, and increased bone formation 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 agonist 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. We conclude from these studies that CLO exhibits pronounced tissue selective estrogen agonism in the rat. Specifically, CLO is effective in preventing cancellous bone loss in the OVX’d rats and has minimal uterotrophic activity.

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