Clinical Effects of Raloxifene Hydrochloride in WomenFREE
Publication: Annals of Internal Medicine
Volume 130, Number 5
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Abstract
Purpose:
To review clinical data on raloxifene hydrochloride, a selective estrogen receptor modulator that was recently approved for the prevention of osteoporosis in postmenopausal women.
Data Sources:
English-language articles published from 1980 to May 1998 were identified through MEDLINE searches. Bibliographies, book chapters, and meeting abstracts were reviewed for additional relevant publications.
Study Selection:
Publications that contained information on the background of development, structure, mechanism of action, tissue-selective effects, and adverse effects of raloxifene hydrochloride were included.
Data Extraction:
Data in selected articles were reviewed, and relevant clinical information was extracted.
Data Synthesis:
Raloxifene hydrochloride was developed in an effort to find a treatment for breast cancer and osteoporosis. It binds to the estrogen receptor and shows tissue-selective effects; thus, it belongs to a class of drugs recently described as selective estrogen receptor modulators. Tissue selectivity of raloxifene may be achieved through several mechanisms: the ligand structure, interaction of the ligand with different estrogen receptor subtypes in various tissues, and intracellular events after ligand binding. Raloxifene has estrogen-agonistic effects on bone and lipids and estrogen-antagonistic effects on the breast and uterus. An increase in bone mineral density at the spine, total hip, and total body has been reported with raloxifene but seems to be less than that seen with estrogen or alendronate therapy. Raloxifene has been shown to produce a reduction in total and low-density lipoprotein cholesterol concentrations similar to that produced by estrogen therapy, but high-density lipoprotein cholesterol and triglyceride concentrations do not increase during raloxifene therapy. In the uterus, raloxifene does not stimulate the endometrium. Long-term data on the effects of raloxifene in reduction of risk for fracture; prevention of cardiovascular events; cognitive function; and the incidence of breast, ovarian, and uterine cancer are not available. The most common adverse effect of raloxifene is hot flashes.
Conclusions:
Raloxifene has been shown to have beneficial effects in selected organs in postmenopausal women. Although estrogen remains the drug of choice for hormonal therapy in most postmenopausal women, raloxifene may be an alternative in certain groups of women at risk for osteoporosis.
Cardiovascular disease and osteoporosis are major causes of illness and death in postmenopausal women. Several observational studies (1-4) have demonstrated the protective effects of hormone replacement therapy on total mortality rates, cardiovascular mortality rates, and the incidence of osteoporotic fractures in postmenopausal women. However, long-term estrogen replacement therapy is limited by side effects, which can include breast tenderness, vaginal bleeding, mood fluctuations, and thromboembolism. An increased risk for endometrial cancer with unopposed estrogen therapy and the controversy surrounding breast cancer and estrogen treatment both play a role in reducing patient compliance. Thus, a therapeutic agent that has estrogen-agonistic effects on the skeleton and cardiovascular system and estrogen-antagonistic activities on the uterus and breast would be highly desirable for postmenopausal women.
Antiestrogens are compounds that were initially found to antagonize the uterotrophic effects of estrogen (5). They compete with endogenous estrogens for binding to the estrogen receptor, and they block activation. Tamoxifen is a well-known antiestrogen that has long been used as adjuvant therapy for breast cancer (6). Although considered an antiestrogen, tamoxifen has partial intrinsic agonistic activities that result in preservation of bone mass and reduction of total cholesterol concentrations (7, 8). Like estrogens, however, tamoxifen can stimulate the endometrium and increase risk for endometrial cancer in postmenopausal women (9).
Raloxifene is an antiestrogen that was recently approved for the prevention of osteoporosis in postmenopausal women. Clinical data on the effectiveness, benefits, and risks of raloxifene therapy are rapidly accumulating; therefore, we review data published during the past two decades on the clinical effects of raloxifene in women.
Methods
Articles published from 1980 to May 1998 were identified through MEDLINE searches done by using the terms raloxifene, keoxifene, and selective estrogen receptor modulator. The reference lists of identified articles, pertinent textbook chapters, and meeting abstracts not found in searches of the computerized databases were reviewed for additional relevant publications. Most of the meeting abstracts, however, lacked methodologic details and had not been subjected to peer review; thus, we did not include them in our review. Data were extracted from studies that contained relevant information on the background of raloxifene, its mechanism of action, its in vitro and in vivo effects on various target organs in animals and humans, and its adverse effects.
Data Synthesis
Background
Raloxifene (LY 139481) or its hydrochloride salt, previously known as keoxifene (LY 156758), was discovered almost two decades ago (10, 11). Raloxifene hydrochloride, commonly referred to as raloxifene, is a benzothiophene derivative that was synthesized in an effort to find, for use in the treatment of breast cancer, antiestrogens that had greater estrogen antagonism and less intrinsic estrogen-agonist activity than tamoxifen (12) (Figure). Raloxifene binds to the rat uterine estrogen receptor and inhibits estradiol-stimulated uterine hypertrophy (11). It also inhibits proliferation of breast cancer cells and growth of carcinogen-induced mammary tumors in rats (13-15). In addition, it preserves bone mineral density and decreases serum cholesterol concentrations (16, 17). In recent clinical trials in postmenopausal women, raloxifene had beneficial effects on the skeleton; this led to the approval of raloxifene for the prevention of osteoporosis (18). Raloxifene is now available as an alternative to estrogen replacement therapy for women at risk for osteoporosis.
Figure. Chemical structures of raloxifene hydrochloride and 17
β -estradiol.
A Selective Estrogen Receptor Modulator
A variety of synthetic compounds classified as antiestrogens are known to have both estrogen-agonistic and estrogen-antagonistic properties. These mixed effects depend on tissue and species differences and on the overall hormonal milieu (19). The term selective estrogen receptor modulator (SERM) was recently used to describe compounds that interact with the estrogen receptor but have tissue-specific activities [20]. Raloxifene, for example, acts as an estrogen antagonist on the uterus and breast but displays estrogen-agonistic activities on bone mass and lipids. Although the term SERM is loosely defined and the underlying mechanism of action remains unclear, this class of drugs may include 1) various agents previously known as antiestrogens, such as 16-epiestriol, ethamoxytriphetol, clomiphene, and tamoxifen; 2) a 19-nortestosterone derivative, tibolone; 3) raloxifene and its analogues, such as LY 117018; and 4) newer triphenylethylene derivatives, such as droloxifene, toremifene, idoxifene, and levormeloxifene (5, 19, 21). Information on the newer SERMs is limited, and most data in humans are being generated in ongoing clinical trials.
Structure
Raloxifene is a nonsteroidal benzothiophene compound (Figure). Several modifications to the 2-arylbenzothiophene core have shown that the 6-hydroxy and the 4′-hydroxy substituents of raloxifene are important for estrogen receptor binding and for mimicking the corresponding 3- and 17β-hydroxy groups of 17β-estradiol (22). An estrogen-antagonistic region of raloxifene is characterized by a piperidine side chain. The orthogonal orientation of this basic side chain may contribute to raloxifene's lack of uterotrophic effects (23). Replacement of the 6-hydroxy substituent with various functional groups has resulted in a reduction in cholesterol-lowering effect and antiproliferative action, whereas substitution of the 4′-hydroxy group with small electronegative substituents did not change the in vivo profile (22). Substitution of a larger group at the 4′ position, however, resulted in increased uterine stimulation. Several raloxifene analogues are under investigation for their potential applications in a variety of diseases in which estrogen is thought to play a pathogenic role, such as uterine leiomyoma and endometriosis (22, 24).
Mechanism of Action: Raloxifene Compared with Estrogen
Like all steroid hormone receptors, the estrogen receptor has both ligand-binding and DNA-binding domains. When the ligand 17β-estradiol, an endogenous estrogen, activates the estrogen receptor, a ligand-receptor complex is formed. The activated receptor then dissociates from a heat-shock protein complex and undergoes dimerization. The DNA-binding domain of the receptor binds to an estrogen response element in the promoter of target genes. After binding to DNA, the complex interacts with transcription factors and promotes transcription, which leads to numerous intracellular events. Estrogen-specific gene transcription is thought to be mediated by distinct regions of the estrogen receptor known as the transcriptional activation function-1 (AF-1) and transcriptional activation function-2 (AF-2) domains. The estrogen receptor also mediates gene transcription from AP-1 sites by interacting with the AP-1 transcription factors fos and jun (25, 26).
The SERMs compete with endogenous estrogens for binding to the receptor and may either activate or block estrogen action. The detailed molecular mechanism by which estrogens and SERMs exert their biological effects on different tissues has not been fully elucidated and remains an area of intensive research. As summarized below, selective responses are thought to be mediated at three different sites: ligand (estrogen compared with SERM), receptor (estrogen receptor subtypes), and effector site (specific intracellular events in different tissues) (27).
Several recent studies have provided insight into the differences between the modes of action of estrogens and SERMs. Both 17β-estradiol and raloxifene bind to the same ligand-binding domain of the estrogen receptor. The receptor-binding affinity of raloxifene, its binding mechanism, and the structural alterations to the estrogen receptor that it induces differ from those of 17β-estradiol (23, 28, 29). Because of structural differences among the various ligands that bind to the estrogen receptor, different patterns of estrogen-induced responses can result. In the 17β-estradiol-estrogen receptor complex, for example, helix 12 of the estrogen receptor ligand-binding domain overlies the ligand-binding cavity, enabling the AF-2 domain to interact with coactivators. In the raloxifene-estrogen receptor complex, however, helix 12 does not overlie the cavity, and this may prevent coactivator recruitment to the estrogen receptor ligand-binding domain (29). Thus, differences among ligands produce subtle conformational differences in the resulting ligand-receptor complexes, which ultimately modulate downstream transcriptional effects.
Differential activation of the AF-1 and AF-2 domains by 17β-estradiol and raloxifene may also explain the tissue-selective actions of the two ligands. In the presence of either 17β-estradiol or raloxifene, the human transforming growth factor-β (TGF-β) gene is activated (30). Deletion of the AF-1 domain abolished 17β-estradiol-induced but not raloxifene-induced TGF-β promoter activation, whereas deletion of the AF-2 domain inhibited activation of TGF-β by raloxifene but not by an estrogen.
Evidence supports various other mechanisms to explain the differences between the action of estrogen and that of raloxifene. The binding of different estrogens and SERMs, including raloxifene, to the estrogen receptor has been shown to affect the kinetics of estrogen receptor interaction with specific DNA elements, which then affects gene transcription (31). Raloxifene can also interact with DNA response elements other than the estrogen response element and the AP-1 site (31, 32). In addition, it may interact with unique subsets of coactivators and co-repressors; interfere with the formation of estrogen receptor-associated proteins with the estrogen receptor; or display estrogen receptor-independent nongenomic effects, as tamoxifen does (33-35).
The estrogen receptor, a main target of estrogens and SERMs, was thought to exist in one form until recently, when estrogen receptor subtype β was cloned (36, 37). The original receptor was renamed estrogen receptor- α. This discovery may provide key insights into the mechanism of action for estrogen and SERMs and may reveal additional levels of complexity important to regulation. Numerous estrogens and SERMs have been found to bind to estrogen receptor-α and estrogen receptor-β with different affinities (38). Differences in binding affinities may result in differences in receptor activation, gene transcription, and biological effects. Moreover, estrogen receptor-α and estrogen receptor-β vary in their tissue distributions. Estrogen receptor-α messenger RNA (mRNA) is strongly expressed in the pituitary gland, uterus, testis, kidney, and adrenal gland, whereas estrogen receptor-β transcripts are found in the ovary, testis, prostate, thymus, and spleen (37, 38). Both estrogen receptor-α and estrogen receptor-β mRNA are expressed in osteoblasts, breast epithelial cells, and the brain (39-41). As yet, information on estrogen receptor-α and estrogen receptor-β protein levels in different tissues is not available. Nevertheless, it can be hypothesized that if a certain estrogen or SERM selectively activates estrogen receptor-α or estrogen receptor-β in different tissues, this might result in different concentrations and ratios of receptor dimers and might activate different signaling pathways. At AP-1 sites, raloxifene is a partial agonist of estrogen receptor-α and a potent transcription activator of estrogen receptor-β. In contrast, 17β-estradiol has divergent effects on estrogen receptor-α-induced and estrogen receptor-β-induced transcriptional activation. 17β-estradiol activates estrogen receptor-α and inhibits transcription due to estrogen receptor-β. At the classic estrogen response element, however, the transactivation properties of estrogen receptor-α and estrogen receptor-β were similar in response to 17β-estradiol, raloxifene, tamoxifen, and antiestrogen ICI 164384 (42).
The pharmacokinetic properties of a compound may also play a role in tissue-specific responses. Raloxifene is known to be extensively metabolized to its glucuronide conjugates so that only low levels of free raloxifene are detected in the circulation, although the parent raloxifene compound is predominantly present at the tissue level (43). Conversion of the major metabolites back to raloxifene is known to occur in various tissues and may explain tissue selectivity. However, differential conversion in major target organs, such as the uterus and the skeleton, has not been seen (44). Therefore, the tissue selectivity of raloxifene is probably not explained by the deconjugation of the metabolite to the parent compound in different tissues.
The potential mechanisms of the tissue selectivities of SERMs are shown in Table 1. Which of these in vitro effects is primarily responsible for the differences between the in vivo actions of estrogen and those of SERMs remains to be determined.
Effects on Bone
The association of estrogen deficiency with osteoporosis is well known, but the molecular mechanism is not understood in detail. For studying the mechanisms and effects of various pharmacologic agents in the estrogen-deficient state, the rodent model has proven useful. After ovariectomy, trabecular bone loss in rats was evident within 4 to 6 weeks, along with changes in levels of several cytokines, growth factors, and bone turnover markers (45). Administration of raloxifene or estrogen restored TGF-β mRNA levels and reduced interleukin-6 levels so that they were approximate to those seen in sham controls (46, 47). Raloxifene treatment also reduced levels of bone turnover markers in ovariectomized rats so that they were comparable to those of sham controls (48).
Raloxifene treatment has beneficial effects on bone mineral density. Administration of raloxifene to ovariectomized rats attenuated decline in bone mineral density of the lumbar vertebra, distal femur, and proximal tibia (17, 49, 50), and the efficacy of this treatment was similar to that of estrogen therapy (51, 52). In adult ovariectomized rats with established osteopenia, raloxifene and estrogen were both effective in preventing further cancellous bone loss. Neither drug, however, increased cancellous bone area or restored osteopenic bone mass to normal (53). Combined treatment with raloxifene and estrogen did not enhance the efficacy of either therapy alone, although concurrent treatment with parathyroid hormone produced additive effects on bone mass [54]. These data suggest that raloxifene 1) inhibits bone loss by reducing bone resorption through the same mechanism as estrogen and 2) does not have an anabolic action on the skeleton. Bone histomorphometric studies in rats confirmed that raloxifene treatment prevented cancellous bone resorption after ovariectomy in a manner similar to that of estrogen treatment (55, 56).
In humans, raloxifene acts as an estrogen agonist in the skeleton. A trial done in postmenopausal women whose bone mineral density at the lumbar spine was defined as normal or osteopenic but not osteoporotic (according to World Health Organization criteria) showed that various doses of raloxifene and 400 to 600 mg of elemental calcium daily decreased levels of bone turnover markers and significantly increased bone mineral density (18). At 2 years, raloxifene (60 mg/d) had increased bone mineral density by 1.2% at the femoral neck and by 1.6% at the spine and total hip. Total-body bone mass had increased by 1.4%. In the placebo group, which received calcium supplements, the decreases in bone mineral density at the femoral neck, lumbar spine, total hip, and total body were 0.6% to 1.3%. The results of studies that directly compared changes in bone mineral density in postmenopausal women receiving raloxifene and postmenopausal women receiving estrogen have not yet been published, but the absolute levels of gain in bone mineral density in the published raloxifene study (18) seem to be lower than those seen with estrogen or alendronate. Studies examining multiple outcomes of raloxifene therapy are under way, and a preliminary report in postmenopausal women with osteoporosis has shown a significant reduction in vertebral fractures (57).
The effects of raloxifene on biochemical markers of bone turnover in women have been studied (18, 58). Raloxifene reduced the levels of markers of bone formation, such as serum osteocalcin and bone-specific alkaline phosphatase, and markers of bone resorption, such as serum tartrate-resistant acid phosphatase and the ratio of urinary type I collagen C-telopeptide to creatinine in postmenopausal women (18).
In a bone remodeling kinetic study in postmenopausal women, bone resorption was significantly decreased in both raloxifene recipients and estrogen recipients after 4 weeks of treatment (59). At 31 weeks, however, bone formation was reduced only in estrogen recipients. Whether this observation has physiologic significance remains to be determined. In a long-term study (18), this imbalance between bone resorption and bone formation was not seen. A positive calcium balance, a reduction in urinary calcium excretion, and a modest improvement in the efficiency of calcium absorption were also noted (59).
Effects on Lipids
Estrogen therapy has favorable effects on cardiovascular risk factors, including serum lipid levels. It increases high-density lipoprotein (HDL) cholesterol concentrations and decreases low-density lipoprotein (LDL) cholesterol concentrations in humans as well as in animal models of atherosclerosis, partly because of estrogen receptor-mediated upregulation of the hepatic LDL receptor (60).
Treatment of ovariectomized rats with raloxifene resulted in a dose-dependent reduction of serum total cholesterol concentrations (17, 61). Although the decrease in total cholesterol concentrations produced by raloxifene did not reach the levels achieved by estrogens, raloxifene had prolonged effects and maintained the reduction better than estrogens did (46, 61, 62). The degree of cholesterol reduction correlated with the extent of raloxifene binding to estrogen receptors, suggesting that the effect was mediated by estrogen receptors and was not secondary to decreased intake of dietary fat or to weight loss (61). In contrast, rats receiving raloxifene had a reduction in HDL cholesterol concentrations. This may have been due to the presence of apolipoprotein E on rat HDL particles, which enhances clearance through hepatic LDL receptors (61).
In addition to its hypocholesterolemic effect, raloxifene may have other cardioprotective effects because of its antioxidant properties. Oxidative modifications of LDL have been implicated in atherogenesis, and raloxifene has been shown to inhibit LDL oxidation in murine peritoneal macrophages (63).
In rabbits, raloxifene inhibited aortic accumulation of cholesterol (64). In a recent study in monkeys, however, raloxifene did not have protective effects with respect to atherosclerosis despite reduction of cholesterol concentrations (65). The difference between the rabbit and the monkey models of atherosclerosis may be due to differences in animal species, drug dosage, duration of therapy, diet, or methods used to quantify the extent of atherosclerosis.
In studies of raloxifene in postmenopausal women, decreases of 6.4% in total cholesterol concentrations and 10% to 12% in LDL cholesterol concentrations were found with a dosage of 60 mg/d; HDL cholesterol and triglyceride levels were unaffected (18, 58). Lipoprotein(a) levels were decreased by 7% to 8% and fibrinogen levels were reduced by 12% to 14%, but plasminogen activator inhibitor-1 levels were unchanged (66). The effect of raloxifene on LDL cholesterol concentrations was similar to that of estrogen therapy, but raloxifene had a smaller effect on lipoprotein(a) and a greater effect on fibrinogen than estrogen did (66).
The beneficial effects of estrogen therapy on the cardiovascular system can be explained only partly by estrogen's cholesterol-lowering effects. Other favorable properties of estrogen—including reduced arterial vasoconstriction produced by regulation of the generation of nitric oxide and other vasoactive peptides, antiatherosclerotic actions independent of plasma lipids, improved insulin and glucose metabolism, and improved hepatic cholesterol metabolism—may play an additional critical role in the cardiovascular system (67). However, no reports have shown that raloxifene exerts these effects. In addition, no available data support the idea that raloxifene treatment can reduce cardiovascular events in humans. Contradictory results in animal models of atherosclerosis (64, 65) clearly emphasize the need for long-term outcome data on protection against cardiovascular disease in humans.
Effects on the Breast
Raloxifene was initially synthesized as a treatment for breast cancer (10, 11). Early studies (14) showed that it inhibited the proliferation and invasiveness of estrogen-responsive breast cancer cell lines. Similarly, it inhibited the growth of carcinogen-induced mammary tumors in rats and prevented tumor appearance in a rat model of mammary carcinoma (13, 15, 68, 69). Although raloxifene has a higher affinity for the estrogen receptor than tamoxifen does, it is less efficacious than tamoxifen (14, 68). In patients with disseminated tamoxifen-resistant breast cancer, raloxifene hydrochloride treatment did not produce a complete or even a partial response (70). In contrast, other SERMs seem to be more efficacious than raloxifene in controlling breast cancer cell growth. The triphenylethylene derivatives toremifene, droloxifene, and idoxifene have been tested in postmenopausal women with advanced breast cancer, and toremifene has already been approved for the treatment of metastatic breast cancer (71, 72).
Raloxifene may also have some preventive activity against the development of breast cancer (68). A combination of raloxifene and 9- cis-retinoic acid prevented mammary tumors in rats (73). The risk for breast cancer during raloxifene therapy and any preventive effects of raloxifene with respect to breast cancer in women are being evaluated, and the preliminary results of two large trials (74, 75) indicate that raloxifene seems to reduce risk for breast cancer after 2 years of therapy in postmenopausal women. Therefore, raloxifene may be an alternative to classic estrogen treatment for the prevention of osteoporosis in women who have a personal history or a strong family history of breast cancer and women who are not willing to take estrogens because of side effects or fear of cancer.
Effects on the Female Reproductive System
Compared with estrogen and tamoxifen, raloxifene lacks estrogen-agonistic activity on uterine tissue (76). In animals, it behaves as an estrogen antagonist in the endometrium. Endometrial hypertrophy induced by estradiol and the growth of endometrial carcinoma stimulated by tamoxifen have been inhibited by raloxifene (11, 77). In ovariectomized rats treated with raloxifene, estrogenic effects on the uterus, such as uterine epithelial cell height, myometrial thickness, and stromal expansion, did not differ from those of untreated ovariectomized rats (17, 52). A slightly higher uterine wet weight seen with raloxifene treatment was attributed to water retention. Results of human studies further confirm that raloxifene does not have stimulatory effects on the uterus (78). In these studies, endometrial thickness was unchanged during raloxifene therapy, and no patients developed proliferative endometrium (18, 78). This effect of raloxifene may, therefore, suggest a lower risk for endometrial cancer than that seen with estrogen and tamoxifen, although no long-term data are available (74).
In a study of premenopausal women receiving raloxifene, only subtle antagonistic changes on the endometrium were noted. Raloxifene administration did not alter the length of the menstrual cycle or inhibit ovulation, and general patterns of gonadotropins, estradiol, and progesterone secretion throughout the menstrual cycle were not affected (79). These data suggest that the estrogen-antagonistic effect of raloxifene on the uterus is blunted in the hormonal milieu of high circulating estrogens and that raloxifene is unlikely to be useful in the treatment of estrogen-responsive diseases, such as endometriosis or uterine leiomyoma, despite beneficial effects seen in vitro and in animal models (24).
Therefore, it seems that the effects of raloxifene on the uterus depend on the overall hormonal environment. In the estrogen-deficient state (for example, in postmenopausal women), raloxifene acts as an estrogen antagonist and does not stimulate the uterus. A high-estrogen milieu (for example, in premenopausal women) blunts the antagonistic effects of raloxifene on the uterus.
Data on raloxifene's action in the ovary are limited. An in vitro study (80) showed an estrogen-antagonistic effect of raloxifene on granulosa cells. In rats treated with raloxifene, however, the incidence of ovarian tumors was increased in a carcinogenicity study (81). Studies in premenopausal women showed that estradiol levels increased in the second half of the cycle during raloxifene treatment, but it is unclear whether the increase was due to elevated follicle-stimulating hormone production or to a direct effect on the ovary (79). Whether raloxifene acts as an estrogen agonist or an estrogen antagonist at the ovary is unknown, and the relevance of ovarian tumor development in rats needs to be carefully examined in a clinical study in humans.
Effects on the Pituitary Gland and the Brain
Raloxifene seems to act as a pure estrogen antagonist in the pituitary gland. It antagonizes the biphasic actions of estrogen on the gonadotroph by blocking the short-term inhibitory effect and the long-term stimulatory effect of estradiol on gonadotropin-releasing hormone-induced release of luteinizing hormone (82, 83). Microimplants of raloxifene into the preoptic brain were found to disrupt spontaneous surges in luteinizing hormone levels in estrogen-treated ovariectomized rats (84). Studies in male volunteers and premenopausal women showed that raloxifene blunted estrogen-induced changes in serum levels of anterior pituitary hormones. In the presence of high estradiol concentrations, however, it did not prevent surges in luteinizing hormone levels or ovulation despite antagonistic action on the pituitary gland (78, 85).
Estrogen therapy may delay the onset and progression of Alzheimer disease, and the effects of raloxifene on cognitive function are being assessed. The effects of raloxifene in Alzheimer disease are unknown. The question of whether the drug will act as an estrogen agonist or an estrogen antagonist in the brain is now being evaluated in ongoing clinical trials.
Miscellaneous Effects
In animal models, ovariectomy is usually associated with weight gain. Ovariectomized rats given raloxifene had less weight gain than untreated ovariectomized control rats because of decreased food consumption (17, 61). However, this effect was not always reproducible and has not been seen in other animal models or in humans (52, 58, 64).
Adverse Effects
At a dosage of 60 mg/d, the incidence of hot flashes with raloxifene was higher than that produced by estrogen, but it did not differ from that seen with placebo (18, 66, 81). At a dosage of 120 mg/d, a high incidence of hot flashes (22%) was noted. However, few women in the raloxifene groups dropped out because of hot flashes. The incidence of breast tenderness and vaginal bleeding with raloxifene was similar to that seen with placebo and was significantly less than that produced by estrogen therapy (18, 66). In a trial of metastatic breast cancer, a higher dosage of raloxifene (200 mg/d) resulted in a higher percentage of hot flashes, fatigue, leg cramps, and nausea (70). The most serious side effect associated with raloxifene is a threefold increase in risk for venous thromboembolism (81, 86), an increase similar to that seen with estrogen therapy. This risk estimate would be about 2 to 3 cases per 10 000 women per year. No evidence of an increased risk for newly diagnosed breast or uterine cancer associated with raloxifene has been seen after 2 years of follow-up in two large, separate trials in postmenopausal women (74, 75). In fact, preliminary results show that the incidence seems to be significantly decreased with raloxifene compared with placebo.
Conclusions
Raloxifene, a SERM, acts as both an estrogen agonist and an estrogen antagonist in different tissues (Tables 2 and 3). It shows estrogen-agonistic effects on the skeleton and lipids but exerts antagonistic effects on breast and uterine tissue. Currently, it is approved only for the prevention of osteoporosis in postmenopausal women, and data on long-term efficacy and safety are limited. Effects on fracture incidence; cardiovascular events; cognitive function; incidence of breast, ovarian, and endometrial cancer; and mortality rates associated with raloxifene therapy are not yet firmly established. Raloxifene does not relieve menopausal symptoms, such as hot flashes. Although some women may prefer the beneficial effects of raloxifene on the breast and endometrium to the effects of classic estrogen therapy, raloxifene seems to be less effective than estrogen at the skeleton. In addition, the possible benefits of estrogen therapy on the cardiovascular system and the central nervous system have not been shown with raloxifene. In most postmenopausal women (especially those in the early postmenopausal years, when the incidence of hot flashes is high and bone loss is rapid), estrogen seems to be a better choice than raloxifene. A better understanding of the mechanisms of action of estrogen and SERMs may eventually lead to the development of newer agents with better efficacy and safety profiles.
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Information & Authors
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Published In
Annals of Internal Medicine
Volume 130 • Number 5 • 2 March 1999
Pages: 431 - 439
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Published in issue: 2 March 1999
Published online: 15 August 2000
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Clinical Effects of Raloxifene Hydrochloride in Women. Ann Intern Med.1999;130:431-439. doi:10.7326/0003-4819-130-5-199903020-00015
Clinical Effects of Raloxifene Hydrochloride in Women. Ann Intern Med.1999;130:431-439. doi:10.7326/0003-4819-130-5-199903020-00015
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