The multifactorial consequences of menopausal estrogen deficiency affect 
numerous tissues throughout the body. Supplemental hormonal therapies carry the 
burden of a risk/benefit ratio that must be highly individualized. Selective 
estrogen receptor modulators (SERMs) are estrogen receptor (ER) 
agonist/antagonists designed to induce benefits comparable with estrogen while 
minimizing adverse effects. Here, we review the estrogen agonist/antagonist 
profile of ospemifene, a novel triphenylethylene derivative recently approved to 
treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to 
menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with 
approximately equal affinities. In preclinical models, ospemifene increased 
vaginal and uterine epithelial thickness and mucification to the same extent as 
estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; 
there also was no stimulatory effect on endometrial cells. In rat and human 
mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on 
estrogen-induced cell responses and cell proliferation, supporting an 
antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic 
effect on bone, as seen by improved bone mineral density, strength, mass, and 
histomorphometry in preclinical models, consistent with improvements in markers 
of bone resorption and formation in postmenopausal women. Based on the 
preclinical evidence, ospemifene has beneficial estrogen-like effects on the 
vaginal epithelium, preliminary evidence to support a neutral endometrial 
profile, antiproliferative effects in breast, and estrogenic effects in bone. 
Taken together, especially regarding estrogen-like effects on the vaginal 
epithelium, ospemifene presents a profile of tissue-specific effects that appear 
novel among available SERMs and well-suited for the treatment of VVA.