Bazedoxifene Acetate: A Selective Estrogen Receptor Modulator with Improved Selectivity

Abstract

We assessed the preclinical characteristics of a novel, stringently screened selective estrogen receptor modulator, bazedoxifene acetate, including its ability to bind to and activate estrogen receptors and promote increased bone mineral density and bone strength in rats, and the effects impacting the uterine endometrium, breast cancer cell proliferation, and central nervous system-associated vasomotor responses in an animal model. Bazedoxifene bound to estrogen receptor-alpha 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 17beta-estradiol-induced proliferation with an IC50 of 0.19 nm. In an immature rat uterine model, bazedoxifene (0.5 and 5.0 mg/kg) was associated with less increase in uterine wet weight than either ethinyl estradiol (10 microg/kg) or raloxifene (0.5 and 5.0 mg/kg). Histological analysis revealed that coadministration of bazedoxifene also appeared to reduce raloxifene-stimulated endometrial luminal epithelial cell and myometrial cell hypertrophy. In ovariectomized rats, bazedoxifene was associated with significant increases in bone mineral density at 6 wk, compared with control, and better compressive strength of bone samples from the L4 vertebrae, compared with samples from ovariectomized animals. In the morphine-addicted rat model of vasomotor activity, bone-sparing doses of bazedoxifene alone were not associated with 17beta-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 selective estrogen receptor modulators currently used in clinical practice. Controlled clinical trial data will be needed to confirm these effects.

Muscle GLUT4 regulation by estrogen receptors ERβ and ERα

“…At present, no overall conclusion can be made about whether all ER␤ ligands will be diabetogenic. The ER␤ ligands developed by various pharmaceutical companies all appear to have tissue selectivity, and they may not all influence ER␤ in skeletal muscle (19,20). However, it might be a good precautionary measure to examine effects on GLUT4 early in the development of ER␤ agonists that are being developed to target disease.…”

Metabolic Disposition of [14C]Bazedoxifene in Healthy Postmenopausal Women

“…Bazedoxifene is a new selective estrogen receptor modulator (SERM) that is in clinical development for the prevention and treatment of postmenopausal osteoporosis (Komm et al, 2005;Ronkin et al, 2005), a disorder characterized by decreased bone mass and weakening of the microarchitecture of bone tissue, resulting in increased bone fragility and a propensity for fractures (Cummings and Melton, 2002). Bone loss and formation are mediated at the cellular level by the balanced activity of osteoclasts, which remove old bone, and osteoblasts, which form new bone (Gass and Dawson-Hughes, 2006).…”

Current pharmacotherapy of osteoporosis

“…In animal-model studies on bazedoxifene, there was a dosedependent influence on the retention of bone mass [16]. Moreover, there was no influence of bazedoxifene on the overgrowth of endometrium or myometrium.…”

“…W badaniach z bazedoxifenem na modelu zwierzęcym stwierdzono zależny od dawki wpływ na zachowanie masy kostnej [16]. Dodatkowo wykazano brak wpływu stosowania bazedoxifenu na przerost nabłonka śluzówki macicy i myometrium.…”