Ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: potential benefits in bone and breast.

Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique. This review first discusses the rationale for developing ospemifene, including its mechanism of action, and then focuses on the clinical development of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Included are discussions of the effects of ospemifene on the endometrium, serum lipids, coagulation markers, bone, and breast cancer. In conclusion, ospemifene is a SERM with a unique estrogen agonist/antagonist tissue profile that was recently approved in the US for the treatment of dyspareunia associated with vulvar and vaginal atrophy in postmenopausal women. Ospemifene warrants further clinical investigation for the treatment and prevention of osteoporosis and breast cancer.

Ospemifene, vulvovaginal atrophy, and breast cancer.

The incidence and severity of vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women. Although other SERMs have antagonistic effects on the vagina, ospemifene exerts an estrogen-like effect on the vaginal epithelium. This review will focus on data demonstrating the antiestrogenic activity of ospemifene in several unique breast cancer animal models, and the implications for utilizing ospemifene in patients with breast cancer suffering from VVA. Additional research addressing the expanded use of ospemifene in breast cancer patients is also warranted.

Expression and function of TbetaRII-B, a variant of the type II TGF-beta receptor, in human chondrocytes.

OBJECTIVE: Transforming growth factor-beta (TGF-beta) has profound effects on chondrocyte proliferation and matrix production, and dysregulation of TGF-beta action has been implicated in osteoarthritis. The mechanisms by which the diverse actions of TGF-beta are regulated in chondrocytes are unclear. Although it is well documented that TGF-beta signaling is transduced by types I and II receptors, other TGF-beta receptors may play critical roles by regulating signaling receptor activity. Our objective was to examine the expression of TbetaRII-B, a splice variant of the type II TGF-beta receptor, and to analyze its role in regulating TGF-beta signaling in human chondrocytes. METHODS: TbetaRII-B expression was examined in human cartilage tissue specimens, human chondrocyte cell lines C28/I2 and tsT/AC62, and human primary chondrocytes by Western blot and reverse-transcriptase-polymerase chain reaction. Ligand binding and heteromerization of TbetaRII-B with other TGF-beta receptors on the cell surface were analyzed by affinity labeling, immunoprecipitation, and two-dimensional SDS-PAGE. Regulation of TGF-beta responses by TbetaRII-B was determined by examining Smad2 phosphorylation, Smad3-specific signaling, transcriptional activity, and type II collagen levels. RESULTS: TbetaRII-B is expressed in normal and osteoarthritic human cartilage. Furthermore, it is a dynamic component of the TGF-beta receptor system in human chondrocytes, forming heteromeric complexes with the types I and II TGF-beta receptors, betaglycan and endoglin. Importantly, overexpression of TbetaRII-B leads to enhanced TGF-beta signaling and responses in chondrocytes. CONCLUSIONS: These results suggest that TbetaRII-B may play a key role in the regulation of TGF-beta action in human chondrocytes.