Selective estrogen receptor modulators for postmenopausal osteoporosis: current state of development.

Selective estrogen receptor modulators (SERMs) are structurally different compounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. These drugs have been intensively studied over the past decade and have proven to be a highly versatile group for the treatment of different conditions associated with aging, including hormone-responsive cancer and osteoporosis. Tamoxifen and toremifene are currently used to treat advanced breast cancer and also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis and vertebral fractures. However, although these SERMs have many benefits, they may also be responsible for some potentially very serious adverse effects, such as thromboembolic disorders and, in the case of tamoxifen, uterine cancer. These adverse effects represent a major concern given that long-term therapy is required to prevent osteoporosis. Moreover, both preclinical and clinical reports suggest that tamoxifen, toremifene and raloxifene are considerably less potent than estrogen. The search for the 'ideal' SERM, which would have estrogenic effects on bone and serum lipids, neutral effects on the uterus, and antiestrogenic effects on breast tissue, but none of the adverse effects associated with current therapies, is currently under way. Ospemifene, lasofoxifene, bazedoxifene and arzoxifene, which are new SERM molecules with potential greater efficacy and potency than previous SERMs, are currently under investigation for use in the treatment and prevention of osteoporosis. These drugs have been shown to be comparably effective to conventional hormone replacement therapy in animal models of osteoporosis, with potential indications for an improved safety profile. Clinical efficacy data from ongoing phase III trials are awaited so that a true understanding of the therapeutic potential of these compounds can be obtained.