Raloxifene as a multifunctional medicine?

Recent developments in the new endocrinology of selective oestrogen receptor modulators (SERMs) seem to have the potential to transform therapeutics. The emerging data on the multiple effects of raloxifene have generated great excitement that this might be the first multifunctional medicine. Raloxifene was developed for preventing osteoporosis and, like oestrogen, may reduce the risk of cardiovascular disease. In addition, raloxifene may reduce the incidence of breast cancer without increasing that of endometrial cancer. Selective oestrogen receptor modulators such as raloxifene introduce important new concepts for the physician, but how did we get to this point and what is the evidence to support the claims?

The description of the target site specificity of tamoxifen and raloxifene opened the door for novel applications of the drugs originally known as non-steroidal antiestrogens.¹,² Until then the drugs had been considered only as treatments for breast cancer,³ but then tamoxifen was advanced as a breast cancer preventive agent in high risk women.⁴ Tamoxifen would never have been acceptable as a preventive agent if it had had an antioestrogenic action on bone, resulting in an increased incidence of osteoporosis. The realisation that “antioestrogens” could not only block oestrogen action in the breast but also mimic oestrogen in bone¹,⁵ resulted in a paradigm shift for preventing breast cancer. Drugs could be developed for preventing osteoporosis, with the beneficial side effect of preventing breast cancer.³ The rationale for this strategy was based on the fact that half of the women who develop breast cancer have no identifiable risk factors,⁶ making a prevention strategy targeting high risk women⁷ an incomplete solution to the problem.

Armed with a clear concept, raloxifene was the result. This drug was approved for osteoporosis prevention on the basis of its oestrogen-like activity,⁸ but what about its effect on the incidence of breast cancer? The hypothesis³ was tested in a trial evaluating the effect of raloxifene (60 and 120 mg daily) on fractures in postmenopausal women.⁹ Raloxifene produced a 76% decrease in breast cancer incidence. That’s the good news: the concept works. However, although these data seem extremely good, they are a secondary endpoint and cannot be viewed as comparable to a primary endpoint from a prospective clinical trial. The pharmacology of selective oestrogen receptor modulators is predictable, but raloxifene is not ready to be marketed for breast cancer prevention. Attempts to compare the relative efficacy of raloxifene with that of tamoxifen in the recent US tamoxifen prevention trial are inappropriate since the study populations were completely different.⁷ Tamoxifen was tested in women aged 35-75, at increased risk of breast cancer but the power of the study lies in the event rate. The tamoxifen trial had a 50% decrease in invasive and non-invasive breast cancer, with a total of 264 invasive breast cancers and 104 cases of ductal carcinoma in situ.⁷ The raloxifene osteoporosis study, in older postmenopausal women, had a total of only 40 cases of invasive breast cancer and 14 cases of ductal carcinoma in situ.⁹

The results with raloxifene⁹ must be viewed as proof of principle³ and as a valuable preliminary clue to plan a prospective clinical trial. In the STAR (study of tamoxifen and raloxifene) trial, currently underway in the United States and Canada, 22 000 high risk postmenopausal women are being randomised to tamoxifen (20 mg daily) or raloxifene (60 mg daily, the dose used to prevent osteoporosis).¹⁰ No premenopausal women will be recruited because raloxifene has not been tested in premenopausal women—it is, after all, an osteoporosis drug. The STAR trial will evaluate breast cancer incidence at seven years, with secondary endpoints of cardiovascular disease, osteoporosis, and endometrial cancer.

Since raloxifene lowers circulating cholesterol concentrations,¹¹ it is also being tested in women at increased risk of coronary heart disease in the RUTH (raloxifene use for the heart) trial, with cardiovascular disease as a primary endpoint.¹⁰ On completion of the STAR and RUTH trials there will be additional prospective data to support, or refute, claims for raloxifene as a multifunctional drug.

The future for selective oestrogen receptor modulators looks promising, but what can be said now for the practitioner? In the United States tamoxifen is approved for treating and preventing breast cancer. It has been tested prospectively for 25 years.¹² Raloxifene is approved for preventing osteoporosis, but now there is evidence that it may reduce the incidence of breast cancer in the older population. A risk reduction for breast cancer contrasts with the effect of hormone replacement therapy, but it must be emphasised that neither tamoxifen nor raloxifene ameliorates menopausal symptoms so they are not substitutes for hormone replacement therapy. Most importantly, although raloxifene is a chemical cousin of tamoxifen, it has not been tested as a breast cancer treatment so there is no evidence to suggest that a switch from tamoxifen to raloxifene would be wise. In fact it may be dangerous, as there is also no information about what dose to use. What can be said is that raloxifene’s efficacy as an osteoporosis agent is documented, and proof of multifunctionality must await the results of ongoing trials. Nevertheless, it is clear that a new era of preventive therapeutics has arrived, and through the clinical trials process a range of novel multifunctional drugs will become a reality within the next decade.