An estrogen receptor basis for raloxifene action in bone

Although controversy remains regarding direct effects of estrogen on bone, in vivo data clearly show that estrogens suppress bone turnover, resulting in decreased bone resorption and formation activity. Selective estrogen rec eptor modulators (SERMs), such as raloxifene, produce effects on bone which are very similar to those of estrogen. In vitro, both raloxifene and estro gen inhibit mammalian osteoclast differentiation and bone resorption activi ty, but only in the presence of IL-6. Data from a number of ovariectomized rat model manipulations (i.e. hypophysectomy, low calcium diet and drug com binations) demonstrate a strong parallel between the antiosteopenic effects of raloxifene and estrogen. A characteristic action of estrogens on the sk eleton is inhibition of longitudinal bone growth, an effect which is not ob served with other resorption inhibitors, including calcitonin and bisphosph onates. Consistent with an estrogen-like mechanism on bone, raloxifene inhi bits longitudinal bone growth in growing rats. In addition to the overall s imilarity of the bone activity profile in animals? estrogen and raloxifene also produce similar effects on various signaling pathways relative to the antiosteopenic effect of these two agents. For example, IL-6, a cytokine in volved in high turnover bone resorption following estrogen deficiency in ra ts, is suppressed by both raloxifene and estrogen. Raloxifene and estrogen also produce a similar activation of TGF-beta 3 (a cytokine associated with inhibition of osteoclast differentiation and activity) in ovariectomized r ats. Like 17 beta-estradiol: raloxifene binds with high affinity to both es trogen receptor-a (ER alpha) and estrogen receptor-a (ERP). Crystal structu re analyses have shown that 17 beta-estradiol and raloxifene bind to ERa wi th small, but important, differences in three dimensional structure. These subtle differences in the conformation of the ligand:receptor complex are l ikely the basis for the key pharmacological differences between estrogens a nd the various SERMs (i.e. raloxifene vs tamoxifen). Raloxifene also produc es estrogen-like effects on serum cholesterol metabolism and the vasculatur e. Thus, while raloxifene exhibits a complete estrogen antagonist in mammar y tissue and the uterus, it produces beneficial effects on the cardiovascul ar system and prevents bone loss via an estrogen receptor mediated mechanis m. (C) 1999 Elsevier Science Ltd. All rights reserved.