Anti-estrogens and postmenopausal osteoporosis

Abstract

Two recent developments in clinical investigation have led to emergence of interest in so-called “antiestrogens” as potential therapeutic modalities in osteoporosis. The first is the confirmation in numerous well-executed clinical studied that estrogen is, indeed, the most effective therapeutic agent available for the prevention of the bone loss leading to osteoporosis in postmenopausal women. The second is increasing evidence, both basic and clinical, that many agents, rather than being simply “estrogens” or “antiestrogens” are more appropriately characterized as mixed estrogen agonistantagonists, and therefore have the potential of affecting various estrogen-sensitive systems in a highly selective manner. Most of the currently available data on effect of antiestrogens in osteoporosis come from studies with tamoxifen. This agent, widely used in the treatment of bone cancer, has been shown to be bone sparing in a number of retrospective survey investigations, and more recently in prospective, blinded, placebo-controlled studies as well. Data showing apparent estrogen-agonist activity in the skelton, in the face of clear estrogen-antagonist action in other tissues, has led to an intense search for the mechanism of this “selective” action. Animal models have been employed to screen compounds for the desired combinations of selective actions. One of the interesting new compounds in this area is raloxifene. This benzothiophen derivative has been shown in the ovariectomized rat model to have potent estrogen-agonist actions in the skelton, reducing bone turnover and preserving bone mineral density in the face of estrogen deficiency. In addition, its actions on serum lipids appear also to be estrogen agonistic. On the other hand, this compound behaves as a potent estrogen antagonist in the uterus, demonstrating no endometrial stimulatory action, while blocking estrogen action in the same organ. In recently completed Phase 2 clinical trials in postmenopausal women, raloxifene has been shown to reduce born turnover, as measured by a variety of serum and urine biochemical markers. It lowers LDL cholesterol in these women as well, but has no apparent uterine stimulatory activity.