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Submitted on January 11, 2005
Accepted on June 8, 2005
Wyeth Research, Women's Health Research Institute, Collegeville, Pennsylvania
* To whom correspondence should be addressed. E-mail: kommb{at}wyeth.com.
We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator (SERM), bazedoxifene acetate, including its ability to bind to and activate estrogen receptors, promote increased bone mineral density and bone strength in rats, and effects impacting the uterine endometrium, breast cancer cell proliferation, and CNS-associated vasomotor responses in an animal model. Bazedoxifene bound to ER
with an IC50 of 26 nM, an affinity similar to that of raloxifene. Bazedoxifene did not stimulate proliferation of MCF-7 cells, but did inhibit 17
-estradiol-induced proliferation with an IC50 of 0.19 nM. In an immature rat uterine model, bazedoxifene (0.5 mg/kg and 5.0 mg/kg) was associated with less increase in uterine wet weight than either ethinyl estradiol (10 µg/kg) or raloxifene (0.5 mg/kg and 5.0 mg/kg). Histological analysis revealed that co-administration of bazedoxifene also appeared to reduce raloxifene-stimulated endometrial luminal epithelial cell and myometrial cell hypertrophy. In ovarectomized rats, bazedoxifene was associated with significant increases in bone mineral density at 6 weeks compared with control, and better compressive strength of bone samples from the L4 vertebrae compared with samples from ovarectomized animals. In the morphine-addicted rat model of vasomotor activity, bone-sparing doses of bazedoxifene alone were not associated with 17-estradiol inhibition of increased vasomotor activity. Bazedoxifene acetate represents a promising new treatment for osteoporosis, with a potential for less uterine and vasomotor effects than SERMs currently used in clinical practice. Controlled clinical trial data will be needed to confirm these effects.
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