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Raloxifene
General information
Raloxifene is a non-steroidal so-called “selective estrogen receptor modulator” (SERM), that is it binds to estrogen receptors, but this binding produces agonist effects at some sites and antagonist effects at others [ ]. It has estrogen agonist effects on bone and lipid metabolism but estrogen antagonist effects on the breast and endometrium; it is also claimed by its protagonists to have cardioprotective effects, perhaps through an effect on endothelial cells and a reduction in homocysteine concentrations [ ].
Reports of adverse reactions to raloxifene should be considered alongside those reported for tamoxifen and other anti-estrogens. However, earlier reports have pointed to a considerable increase in thromboembolism, as has some recent large-scale work [ ], and it would be premature to draw final conclusions about the conditions in which it can safely be used.
Raloxifene has been studied for its ability to reduce bone loss in postmenopausal women [ ]. In a critical review of raloxifene, published in France, it was concluded that the compound has no advantages compared with a traditional estrogen, and that in view of certain findings in animal studies there is a possibility that it might increase the risk of ovarian cancer; there is also a need to determine whether it is sufficiently safe in women with a history of (or predisposition to) breast cancer [ ].
One also finds a critical view expressed in the USA, where a survey of the literature up to the end of 1999 concluded that while raloxifene might carry a lesser risk of breast cancer than estrogen replacement therapy, it was also less effective in maintaining bone density, and that as regards cardiovascular risk the estrogenic treatment produced a more favorable outcome [ ].
The uses of raloxifene and adverse reactions to it have been reviewed [ ]. Current work seems to show an altogether positive effect of raloxifene (for example 60 mg/day) on bone metabolism and serum lipids in post-menopausal women on chronic hemodialysis, without significant adverse reactions in the short term. However, even the authors of very promising work in this connection point to the difficulty in assessing the long-term safety of the treatment in such women [ ]. Longer-term work elsewhere has pointed particularly to the occurrence of thromboembolic disease, but also of hot flushes, influenza-like symptoms, peripheral edema, and leg cramps. With the exception of thromboembolism these are unpleasant rather than serious, but they still need to be recorded and studied in this very susceptible group of users.
Idoxifene is another of the newer selective estrogen receptor modulators (SERMs), and preclinical data show that it has greater antiestrogenic activity than tamoxifen but lower estrogenic activity. It is not yet clear whether this affects its degree of usefulness or safety when it is used, for example, in cases of metastatic breast cancer. In comparisons of the two drugs in such patients the desired effects were similar and the incidence of adverse effects was essentially the same [ ].
In a randomized phase II trial in 47 such women in whom tamoxifen 20 mg/day had ceased to be effective, idoxifene showed only very slight evidence of activity; possible drug-related adverse effects were similar in frequency to those with tamoxifen (hot flushes/flashes 13% versus 15%, mild nausea 20% versus 15%) [ ]. Endocrine and lipid analysis in both groups showed similar changes.
Many centers continue to examine this and other SERMs, for example in countering menopausal bone loss [ ], in the hope that they can take the place of tamoxifen and provide a means of avoiding the risks of such complications as endometrial cancer, cataract, and stroke [ ].
Drug studies
Observational studies
An extensive literature review has provided a useful assessment of the benefit to harm balance of raloxifene [ ]. The findings were reassuring. One large fracture prevention trial provided the best evidence that raloxifene 60 mg/day for 3 years reduced the relative risk of vertebral fractures by 30–50% in women with prevalent fractures or osteoporosis. The extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol concentrations. Raloxifene was not associated with endometrial hyperplasia, and there was a 72% reduction in the incidence of invasive breast cancer. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and increased risks of hot flushes (flashes) and leg cramps. Compared with other therapies for osteoporosis, raloxifene has a smaller impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, and no effect on the frequency of non-vertebral fractures. In the present state of knowledge it seems clear that raloxifene can be recommended for prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.
Comparative studies
Since both raloxifene and the non-hormonal drug alendronate reduce the incidence of osteoporotic fractures in postmenopausal women it is relevant to determine which approach is better tolerated and thus most likely to promote long-term adherence to therapy. Adverse effects and compliance have been studied in a direct randomized comparison over 12 months in 902 women attending 154 treatment centers in Spain [ ]. They took either raloxifene 60 mg/day or alendronate 10 mg/day. Those who took raloxifene reported significantly better compliance than those who took alendronate; more patients discontinued alendronate prematurely than raloxifene (26% versus 16%. The main reason for premature discontinuation was adverse reactions, particularly gastrointestinal reactions (9.9% with alendronate, 3.4% with raloxifene).
Alendronate 70 mg once weekly and raloxifene 60 mg/day for 12 months have been compared in an international multicenter blinded trial in 487 women with low bone density [ ]. Bone mineral density increased much more with alendronate. Overall tolerability was similar, but the proportion of patients who reported vasomotor events was significantly higher with raloxifene (9.5%) than with alendronate (3.7%); the proportions of patients who reported gastrointestinal events were similar.
Organs and systems
Cardiovascular
Evidence of the wanted or unwanted effects of antiestrogens on the cardiovascular system has been sought in an extensive literature study [ ]. In one published study there was a two- to three-fold rise in the incidence of thromboembolism, similar to that seen with estrogen treatment. There were also some cases of leg cramps and hot flushes [ ].
There have been conflicting reports on the incidence and severity of symptoms such as hot flushes (also known as hot flashes) during long-term treatment with raloxifene for the prevention of osteoporosis. In fact the difference between raloxifene and placebo does not seem to be very great. In a review of three identical randomized trials in which raloxifene 60 mg was given for long periods to healthy postmenopausal women of various ages it was concluded that after 30 months the cumulative incidence of hot flushes was 21% for placebo and 28% for raloxifene, but the difference in frequency was confined to the first 6 months of therapy [ ]. There was no difference between placebo and raloxifene in the maximum severity of symptoms or the rate of early discontinuation, while the period during which hot flushes continued was only a little shorter in the raloxifene group. In a US study in more than 1100 postmenopausal women who took raloxifene 30–150 mg/day the only significant adverse effect of therapy was hot flushes (25% with 60 mg/day and 18% in the placebo group) [ ].
The effects of raloxifene on the vascular endothelium have been studied in 19 subjects who underwent endothelial function testing at baseline and after treatment with placebo or raloxifene (60 mg/day for 6 weeks) [ ]. The findings in this small short-term study were entirely positive. Brachial artery diameter change (flow-mediated dilatation) increased 5.0% with placebo and 8.6% with raloxifene in response to a hyperemic stimulus. The ratio of AUC response to AUC reference with the use of laser Doppler measures was 1.18 for placebo and 1.28 for raloxifene. Flow-mediated dilatation and AUC ratio correlated significantly. The authors concluded that raloxifene enhanced endothelial-mediated dilatation in brachial arteries and digital vessels in these women, and they discussed the drug’s possible cardioprotective effect.
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