Therapeutic potential of oestrogen receptor ligands in development for osteoporosis.
Accelerated bone loss secondary to loss of ovarian function at menopause is well recognised as a major risk factor for osteoporotic fractures in postmenopausal women. Postmenopausal bone loss can be prevented or arrested by oestrogen replacement therapy (ERT). It has also been reported that ERT protects against cardiovascular disease by improving the serum lipid profile, however there are mixed reports concerning these benefits. Unopposed ERT causes an unacceptable increase in the risk of endometrial cancer and proliferative effects in mammary tissue resulting in an increased risk of breast cancer. While this can be counteracted by combining ERT with a low-dose of a progestin, withdrawal bleeding and the continuing uncertainty about the effect of oestrogen on the risk of breast cancer contribute to poor compliance for long-term use. Because of the known and suspected risks of oestrogen therapy it has been estimated that in the US < 40% of women on ERT will continue treatment beyond one year. An ideal therapy would retain the desirable skeletal and cardiovascular effects of oestrogen, lack oestrogenic activity on the endometrium and reduce the incidence of breast cancer. The concept of selective oestrogen receptor modulation (SERM) has been demonstrated for a number of compounds including tamoxifen, raloxifene, droloxifene, GW-5638 and levormeloxifene. However, the clinical utility of these agents will depend on the profile of tissue-specific effects and the extent to which they are translated into in vivo efficacy. A SERM is defined as a compound that has oestrogen agonism on one or more of the desired target tissues, such as bone or liver, and has antagonism and/or minimal agonism (i.e., clinically insignificant) in reproductive tissue, such as the breast or uterus. Although tamoxifen acts as a SERM, it is also associated with an increased incidence (4% gynaecological symptoms greater than placebo control) of endometrial cancer. Indeed, there have been a number of mechanistic-based studies to explain the increased incidence of endometrial carcinomas in tamoxifen treated patients, which provide an in vitro insight into the adverse clinical observations in vivo. Attempts to improve on the pharmacological profile of tamoxifen have resulted in compounds that differ in their oestrogen agonist/antagonist characteristics, including the pure oestrogen antagonists. This suggests that it may be possible to develop a molecule with a desired profile of tissue-specific agonist/antagonist activities by establishing bone and cardiovascular protective effects but having no effects (or even behaving as an antagonist) in the reproductive tissues.
GlaxoSmithKline, Department of Bone and Cartilage Biology, 709 Swedeland Road, King of Prussia, PA 19406, USA.
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Nuttall