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Abstract

Selective estrogen-receptor modulators are molecules with specific estrogen-receptor binding affinity. Each selective estrogen-receptor modulator induces a unique conformation in the ligand–receptor complex, which leads to transcriptional activation and/or inhibition. Raloxifene 60 mg/day, a benzothiophene selective estrogen-receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. This article provides an update on new studies and further analyses of clinical trial data for raloxifene. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial of women with osteoporosis has described the efficacy of raloxifene in decreasing vertebral fracture risk over 4 years. The Continuing Outcomes Relevant to Evista^© (CORE) trial, designed to assess the effects of raloxifene on breast cancer prevention, is a 4-year continuation of MORE. The skeletal and cardiovascular effects of raloxifene in the CORE study were similar to those observed in MORE. The relative risk of developing breast cancer was significantly decreased in women treated with raloxifene, compared with placebo, after 4 years in MORE and 8 years in the CORE trial. The incidence of uterine bleeding, endometrial hyperplasia and endometrial cancer was similar between raloxifene and placebo after 8 years of treatment. Raloxifene use is associated with a higher incidence of hot flashes and leg cramps, and an increased risk of venous thromboembolic events.

Keywords

clinical trial fracture osteoporosis postmenopausal raloxifene selective estrogen-receptor modulator women's health

In response to the need for clear terminology describing interactions between potent molecular ligands and the estrogen receptor (ER), a new descriptor was introduced into the medical literature approximately 10 years ago. This term, selective ER modulator (SERM), characterizes a wide range of molecules (including estrogens themselves) with a high binding affinity for the ER, but each inducing a unique conformation in the ligand–receptor complex. Each conformation initiates a specific intracellular molecular cascade, involving cellular cofactors, leading to activation and/or inhibition of particular transcriptional pathways [1 –5]. Only recently have we begun to translate this molecular-level specificity into implications at the clinical level. Since the ERs (including ERα and ERβ) are present in numerous tissues and are involved in many human physiological pathways, understanding the clinical implications of these molecular interactions is of vital interest in modern medical research.

Although several multifunctional compounds now designated as SERMs (e.g., clomiphene and tamoxifen) were developed earlier for clinical use [6], exploration of the SERM concept itself began approximately 20 years ago with the emergence of raloxifene. Raloxifene is a benzothiophene SERM originally investigated for a potential role in breast cancer treatment [7,8]. Subsequently, raloxifene underwent extensive clinical investigation, with the goal of understanding the breadth and depth of its ER-mediated actions [9]. Raloxifene, in the 60 mg/day oral dosage, was approved by the US FDA for the prevention of postmenopausal osteoporosis in December 1997, and for the treatment of post-menopausal osteoporosis in September 1999. Today, over 50,000 women have participated or are participating in clinical trials with this drug, and over 40 million prescriptions for raloxifene have been written worldwide. As the clinical database for raloxifene expands, an updated clinical review of raloxifene is warranted.

Osteoporosis prevention trials in healthy postmenopausal women

As a foundation for clinical evaluation, a brief summary of the completed, pivotal, randomized clinical trials (randomized, controlled trials) of raloxifene is required. The first of these trials was designed to evaluate raloxifene as an inhibitor of postmenopausal bone loss and, thus, a preventative drug for osteoporosis. This trial enrolled normal, postmenopausal study subjects (mean age 55 years) with a mean baseline number of standard deviations below average bone density (T-score) of approximately −1, reflecting the rapid, early menopausal bone loss routinely seen in this population. These subjects were randomized to 0, 30, 60 or 150 mg/day of raloxifene, and all received 400–600 mg/day of oral elemental calcium supplementation. The European arm of this study (n = 601) was evaluated after 2 years of treatment [10], and the combined European and North American study population (n = 1145) from identical protocols was evaluated after 3 years [11]. At the conclusion of the original 3-year study, participants were offered an extension, and 328 subjects in the placebo and raloxifene 60 mg/day groups continued in a similar study structure for a full 5 years of therapy [12]. One of the raloxifene arms was replaced with unopposed conjugated equine estrogens (CEE) in a related, 3-year, multinational study, which enrolled hysterectomized postmenopausal women [13].

Osteoporosis treatment trials in postmenopausal women with osteoporosis

Once prevention studies were underway, raloxifene was evaluated in the postmenopausal osteoporotic population, in whom fracture end-points were the primary outcomes. The multi-center, blinded, randomized, placebo-controlled 3-year Multiple Outcomes of Raloxifene Evaluation (MORE) involved 7705 postmenopausal women with osteoporosis by WHO criteria (T-score <−2.5), with a mean age of approximately 67 years, from 25 countries [14,15]. The study population was divided into two subgroups: those with prevalent vertebral fractures and those without. In each of these subgroups, patients were randomized to raloxifene 120 or 60 mg/day, or placebo. All subjects received 500 mg/day of elemental calcium and 400–600 IU/day of cholecalciferol as supplements. Patients without prevalent fracture while receiving 60 mg raloxifene had a 50% reduction in the risk of vertebral fracture (relative risk [RR]: 0.5; 95% confidence interval [CI]: 0.4–0.8); patients with a prevalent fracture had a 30% reduction (RR: 0.7; 95% CI: 0.6–0.9). All subjects who were randomized in the original MORE trial were eligible to participate in the Continued Outcomes Relevant to Evista^© (CORE) study, a 4-year extension of MORE [16]. Of the original 7705 MORE participants, 4011 agreed to participate in the CORE trial. All subjects receiving raloxifene (60 or 120 mg/day) in MORE were given raloxifene 60 mg/day in the CORE study. Placebo subjects in MORE continued receiving placebo in the CORE trial. Most subjects experienced a drug-free period of several months between the end of MORE and the beginning of the CORE evaluation. In addition, during CORE, study subjects were permitted to take other bone-active agents.

Effects of raloxifene on the skeleton

A skeletal antiresorptive agent must inhibit bone loss to be useful in osteoporosis prevention. Prevention of bone loss with raloxifene therapy was demonstrated in the 3-year analysis of the randomized, controlled prevention trial [11], and this effect continued unchanged through 5 years of therapy [12]. Women who had a lumbar spine bone mineral density (BMD) T-score in the osteopenic range (−1.0 to −2.5 by WHO criteria) at study initiation and were treated with raloxifene had an 87% decrease in RR (0.13; 95% CI: 0.00–0.37; p = 0.001) for the development of osteoporosis; that is, a lumbar spine BMD declining to a T-score of less than −2.5, compared with placebo, at 5 years. Women who had a normal BMD at the lumbar spine at study initiation and were treated with raloxifene also had a 77% lower RR (0.23; 95% CI: 0.00–0.81; p = 0.038) of developing osteopenia at this site at 5 years compared with those who received placebo. After an National Health And Nutrition Examination Survey (NHANES)-III correction of the reference range for baseline BMD values at the total hip, over 2500 women in the original MORE cohort were found to have osteopenia at this site at baseline [17]. An analysis conducted on this subgroup of women with osteopenia at the total hip and without prevalent vertebral fracture showed that the RR for new vertebral fractures was reduced by 47% with raloxifene therapy (RR: 0.53; 95% CI: 0.32–0.88). Therefore, 5-year data from a primary prevention study demonstrate that raloxifene therapy reduces the risk for the development of osteoporosis. Furthermore, a post hoc analysis of women with osteopenia at the total hip and without a prevalent vertebral fracture, a subset of the MORE cohort, demonstrated that raloxifene therapy reduces the risk of a first fracture. Histomorphometric indices of paired bone biopsies in normal postmenopausal women have confirmed the mechanism of action and skeletal safety of raloxifene, in parallel with estrogen effects [18,19]. The CEE comparator study showed that the BMD effects of CEE were greater in magnitude than those observed with raloxifene [13]. A recently published study adds to the prevention theme, as bone loss secondary to exercise-induced weight loss in postmenopausal women was also prevented with raloxifene therapy [20].

A 1-year extension of the MORE trial was conducted according to the original design, but patients were allowed to take other skeletal antiresorptive drugs, although less than 13% of the patients receiving raloxifene actually did so [21]. Raloxifene treatment continued to decrease the vertebral fracture risk over 4 years, and the decreased fracture risk in the fourth year was indistinguishable from that seen during the first 3 years of the study. In addition, although raloxifene did not reduce the risk of nonvertebral fractures in the MORE trial, a post hoc analysis demonstrated that subjects with severe vertebral fractures (defined as a >40% reduction in vertebral height) at baseline experienced significant decreases in risks of both vertebral (RR: 0.74; 95% CI: 0.54–0.99; p = 0.048) and nonvertebral (RR: 0.53; 95% CI: 0.29–0.99; p = 0.046) fractures with raloxifene therapy, compared with placebo [22]. These results demonstrate the continued and persistent skeletal action of raloxifene over 4 years of therapy. As a 4-year extension of MORE, the CORE trial was designed to assess the effects of raloxifene on breast cancer prevention, and nonvertebral fractures were recorded as a secondary end point. The overall risk of new nonvertebral fractures was unchanged in the raloxifene group compared with the placebo group, but in a subset of women with severe (>40% height reduction) prevalent vertebral fractures, the risk of nonvertebral fractures at six major sites (clavicle, humerus, wrist, pelvis, hip and lower leg) was significantly decreased compared with placebo (incidence rate ratio: 0.78; 95% CI: 0.63–0.96) [23].

Histomorphometric analyses of bone biopsies obtained from subsets of patients in MORE confirmed the previous findings in women without osteoporosis, as the antiresorptive effect seen with raloxifene was similar to that seen with estrogen therapy [24,25]. An analysis of the MORE population at 3 years suggested that only approximately 4% of the fracture risk protection associated with raloxifene treatment was explained by the change in BMD [26]. The change in serum osteocalcin in these patients was a better, but still imperfect, predictor of fracture risk [27]. Subsequently, a newer serum marker of bone metabolism, type I procollagen N-terminal propeptide (P1NP), was found to better correlate with fracture risk reduction than other biochemical markers [28]. Another analysis of the MORE database demonstrated that the action of raloxifene in reducing osteoporotic fractures is largely independent of a wide variety of clinically derived risk factors [29]. In addition, studies have demonstrated the skeletal effects (BMD and bone markers) of raloxifene in various populations of postmenopausal women not included in the original randomized, controlled trials [30 –35].

Effects of raloxifene on the cardiovascular system

Among the many (presumably) ER-mediated actions of this SERM in postmenopausal women, the cardiovascular (CV) effects of raloxifene have been intensively studied, but continue to elude clear definition. At the initiation of the first randomized, controlled trials of raloxifene, interest in the CV effects of estrogen was at its peak, but the results from large, randomized, controlled trials with estrogen were not yet available. The question was originally formulated as “will raloxifene behave as an estrogen-agonist or an estrogen-antagonist in the CV system?” CV event-outcome data are ultimately required to answer this question, but surrogate biomarkers of CV risk may also be employed. Epidemiological studies have linked numerous biomarkers with CV risk in specific populations, and biomarker data are more easily and rapidly obtained than event outcomes. Therefore, short-duration studies were designed to examine the effects of raloxifene on CV biomarkers, while awaiting event-based results in the large, randomized, controlled trials of raloxifene. A 6-month study conducted by Walsh and associates enrolled 390 healthy post-menopausal females, randomized to placebo, raloxifene 60 or 120 mg/day, or CEE 0.625 mg/day combined with medroxyprogesterone acetate (MPA) 2.5 mg/day [36]. A full battery of biomarkers was reported in the initial and subsequent analyses (Table 1) [37,38]. Some of these markers, such as low-density lipoprotein cholesterol (LDL-C), homocysteine and tumor necrosis factor (TNF)-α, appeared to change in a similar manner and magnitude in the raloxifene and CEE/MPA arms. Other markers, such as high density lipoprotein cholesterol (HDL-C) and lipoprotein (Lp)a, changed in a manner suggesting an advantage for CEE/MPA; while changes in triglycerides (TG), fibrinogen and high-sensitivity C-reactive protein (hsCRP) suggested a superior response with raloxifene. The implications regarding event outcomes associated with significant changes in any of these markers are yet to be established, but these results have demonstrated that the original premise was misdirected [39,40]. Raloxifene behaves neither as an estrogen agonist nor an estrogen antagonist, but displays a unique profile of effects in the CV system, clearly distinguishable from, but not necessarily superior or inferior to, the CEE/MPA profile.

Table 1.

Effects of placebo, raloxifene 60 mg/day and HRT on serum markers of cardiovascular disease risk.

Serum marker of cardiovascular disease risk	Median change from baseline (%)

	Placebo	Raloxifene 60 mg/day	HRT
Low-density lipoprotein cholesterol	1	−11†	−13†
High-density lipoprotein cholesterol	1	1	11†‡
High-density lipoprotein-2 cholesterol	0	15§	33§¶
Triglycerides	0	−4	20†‡
Apolipoprotein A-I	−1	2	12†‡
Apolipoprotein B	0	−9†	−4¶
Lipoprotein (a)	3	−4§	−16†‡
Fibrinogen	−2	−12†	−3¶
Plasminogen activator inhibitor-1	−10	−2	−29†‡
Prothrombin fragment 1 and 2	−3	2	16
Fibrinopeptide A	13	9	16
High sensitivity C-reactive protein	0	−6	84*†‡
Homocysteine	0	−8*†	−6.6*†
Tumor necrosis factor-α	2	−14*§	−9*§
Interleukin-6	−4	−3	7

HRT consisted of conjugated equine estrogens 0.625 mg/day and medroxyprogesterone acetate 2.5 mg/day given in a continuous, combined fashion. p-values were

†

p < 0.001 compared with placebo

‡

p < 0.001 compared with raloxifene

p < 0.05 compared with placebo

p < 0.05 compared with raloxifene

p < 0.001 compared with baseline.

HRT: Hormone replacement therapy.

Adapted from [36 –38].

Results from other studies have been published subsequent to the Walsh study. A large, 6-month study in a European population comparable to that in the Walsh study confirmed the earlier findings [41]. However, HDL-C levels were increased significantly in the raloxifene-treated group, whereas the Walsh study showed no change in this parameter. A subset of patients in the MORE trial demonstrated comparable reductions of LDL-C with raloxifene therapy [42]. The panel of biomarkers of CV risk has been expanded, and explorations of vascular compliance and vasodilation have been added in several recent studies. Additional examples demonstrate changes in both biochemical markers that are similar to those induced with various estrogen preparations, and those which are affected differently by raloxifene and estrogen. Various measures of vascular compliance are also affected differentially, and not totally consistently, from study to study [43 –61]. Reductions in ambulatory blood pressure and improvements in vascular compliance may or may not be observed with raloxifene 60 mg/day or hormone replacement therapy (HRT) [62 –64]. In women at increased CV risk, a HRT regimen improved endothelial function and reduced plasma endothelin-1, while raloxifene 60 mg/day had no significant effect [65]. In women with treated coronary artery disease, no effects of raloxifene therapy were demonstrated on various measures of flow-mediated dilation, or on serum lipoprotein or fibrinogen levels [66].

An analysis of arterial CV event outcomes in MORE demonstrated no significant difference between the arterial CV event rate in raloxifene-and placebo-treated groups overall [67]. A separate analysis was carried out in a subset of women (1035 of the 7705 MORE participants) with increased CV risk, defined using the entry criteria for the Raloxifene Use in The Heart (RUTH) trial [68], a large, ongoing randomized, controlled trial designed to define CV end points with raloxifene treatment. In this subset of patients with high CV risk, raloxifene treatment resulted in a 40% reduction in RR (0.60; 95% CI: 0.38–0.95) in the arterial CV event rate (including both CV and cerebrovascular events) versus placebo. During the MORE trial, no increased risk of arterial CV events occurred during any study year in either the overall MORE cohort or the subset at high risk for CV events [69]. These findings allayed concerns that raloxifene use might lead to an early increased incidence of CV events, as seen in some large, randomized, controlled trials with estrogen. A summary and review of these results was recently published [70].

Head-to-head comparative, randomized, controlled trials evaluating the effects of SERMs on CV end points have not been performed. Nevertheless, analyses (some post hoc) from large studies involving postmenopausal women at high CV risk treated with either CEE/MPA, tamoxifen or raloxifene have been published (Table 2) [67,71,72]. It is instructive to consider the effects of CEE/MPA, tamoxifen and raloxifene, respectively, on CV outcomes, despite the significant differences between studies in the baseline characteristics of the study populations (Table 2), and with the important caution that each of these studies had different primary end points. In keeping with the diverse effects of these agents on CV marker end points observed in short-term studies, the theme can be carried into the initial clinical findings with CV event outcomes. The question of whether raloxifene is an estrogen agonist or antagonist in the CV system may be moot. Each agent will likely have a unique profile of effects, perhaps leading to different net clinical outcomes.

Table 2.

Selected baseline characteristics and incidence of cardiovascular events in women at high risk of cardiovascular disease in HERS, NSABP-BCPT and MORE.

Baseline characteristics	HERS*		NSABP-BCPT†		MORE‡

	Placebo (n = 1165)	HRT (n = 1156)	Placebo (n = 532)	Tamoxifen 20 mg/day (n = 516)	Placebo (n = 317)	Raloxifene 60 mg/day (n = 359)
Age (years)	67 ± 7	67 ± 7	58 ± 10	58 ± 10	72 ± 5	72 ± 5
Body mass index (kg/m²)	29 ± 5	29 ± 5	29 ± 6	29 ± 6	26 ± 4	26 ± 4
History of diabetes mellitus (% yes)	16	17	9.4	11.0	13.6	19.8
Blood pressure (mm Hg)
- Systolic	134 ± 18	135 ± 18	133 ± 20	133 ± 19	148 ± 22	1 50 ± 22
- Diastolic	73 ± 10	73 ± 10	80 ± 10	80 ± 10	83 ± 12	83 ± 11
Cholesterol (mg/day)
- Low-density lipoprotein	144 ± 38	144 ± 37	134 ± 34	134 ± 34	168 ± 41	169 ± 36
- High-density lipoprotein	50 ± 13	50 ± 13	57 ± 15	57 ± 15	57 ± 14	57 ± 14
Follow-up time (months)	81.6	81.6	48 ± 20	47 ± 21	48	48
Total coronary events	0.99	1.39	0.66
(RR, 95%CI)	(0.84–1.17)	(0.73–2.67)	(0.37–1.19)

Primary outcome end points differed in the original design of each of these studies. All values are mean ± standard deviation, unless otherwise indicated. In each study, the baseline characteristics were not statistically significantly different between the placebo and corresponding treatment group.

The HERS enrolled a total of 2763 postmenopausal women with coronary heart disease, which included a history of at least one of the following: myocardial infarction, coronary artery bypass graft surgery, percutaneous angioplasty or >50% angiographic narrowing of a coronary artery. The original HERS study was a randomized, blinded, placebo-controlled trial lasting 4.1 years. These data were from 2321 women who consented to the subsequent 2.7-year, unblinded, follow-up phase after HERS, for an overall total of 6.8 years of therapy [71].

†

The NSABP-BCPT enrolled a total of 13,388 women at increased risk for breast cancer (5-year predicted breast cancer risk >1.66%), of which 1048 women had a follow-up for cardiovascular outcomes and a self-reported history of coronary heart disease, defined as either myocardial infarction or angina prior to randomization into the study [72].

‡

The MORE trial enrolled a total of 7705 postmenopausal women with osteoporosis, defined as having a prevalent vertebral fracture or bone mineral density T-score <−2.5 below that of young normal premenopausal women [67]. These data were from a subset of 1035 women with an increased risk of cardiovascular disease (four or more risk points according to the Mosca definition [68]). CI: Confidence interval; HERS: Heart and Estrogen/progestin Replacement Study; HRT: Hormone replacement therapy; MORE: Multiple Outcomes of Raloxifene Evaluation; NSABP-BCPT: National Surgical Adjuvant Breast and bowel Project – Breast Cancer Prevention Trial; RR: Relative risk; T-score: Number of standard deviations below average bone density.

Effects of raloxifene on breast tissue

Since the antiproliferative actions of raloxifene in mammary tissue led to early exploration of the drug for breast cancer treatment [7], the idea that raloxifene might also have activity in reducing the risk of newly diagnosed breast cancer is not surprising. Such an effect in postmenopausal women with osteoporosis was established early in the MORE trial [15], and a subsequent report on the effects of raloxifene on breast cancer incidence after 4 years documented the early durability of these effects [73,74]. Analyses in the MORE trial have demonstrated that the rate of development of breast cancer is correlated with circulating serum estradiol levels, and that the effects of raloxifene in reducing breast cancer rates are greatest in women with high serum estradiol levels [75]. The recent CORE trial results demonstrate that raloxifene reduces the RR of newly diagnosed, invasive breast cancer by 66% (RR: 0.34; 95% CI: 0.18–0.66) after 8 years of treatment [16]. The Study of Tamoxifen And Raloxifene (STAR) trial, comparing the long-term effects of these two drugs on the prevention of breast cancer in at-risk women, is due to issue its first conclusions in 2006 [76].

The effects of raloxifene and estrogen are also apparent in measures of mammographic breast density, which is an important risk factor for breast cancer. In a subpopulation from one of the raloxifene osteoporosis prevention studies, breast density was found to undergo mild age-related declines in the raloxifene and placebo groups, but was significantly increased in the CEE-treated group [77]. These findings have subsequently been confirmed [78,79].

Effects of raloxifene on the uterus

Since data from preclinical studies had suggested that raloxifene, unlike tamoxifen, is a pure antagonist of estrogen action in the endometrium, one of the most important goals of the clinical study of raloxifene has been to establish endometrial effects in postmenopausal women. The initial Phase II studies showed that raloxifene at high doses behaves as an estrogen antagonist in the endometrium [80]. A lack of uterine stimulatory effect with raloxifene therapy has now been established in several studies with various clinical markers; for example, the incidence of vaginal bleeding is not increased compared with placebo [81 –84], and uterine bleeding, endometrial hyperplasia and endometrial cancer were confirmed to be no more frequent in raloxifene-treated patients than in those receiving placebo in the 4-year update on the uterine safety of raloxifene therapy [85]. Histological evaluation of the endometrium showed no indication of stimulation by raloxifene [86]. Uterine artery perfusion is unchanged with raloxifene therapy [87]. A newly published evaluation of data from the CORE trial demonstrated that raloxifene is not associated with a change in the incidence of uterine cancer, endometrial hyperplasia or postmenopausal bleeding, versus placebo, over 8 years of therapy [88]. However, raloxifene was associated with a 50% reduction in the incidence of endometrial cancer (RR: 0.50; 95% CI: 0.29–0.85), compared with untreated controls, in a recent abstract describing a large case–control study [89]. The RR of ovarian cancer was 0.5 in nearly 10,000 patients in randomized, controlled trials with raloxifene, but with only 16 total cases, this difference is not statistically significant [90].

Recently, increased attention has been focused on the effects of estrogen and SERMs on the extrauterine pelvic structures, involving muscle and soft tissue in the pelvic floor. This focus has resulted partly from data from the Heart and Estrogen/progestin Replacement Study (HERS), showing that estrogen replacement therapy (ERT) may adversely affect the incidence of urinary incontinence [91]. These data contrast with long-held assumptions that ERT therapy in post-menopausal women may have beneficial effects on the pelvic floor. In addition, early clinical data from some selected SERMs under development, notably levormeloxifene, suggest that such therapy may lead to deterioration of pelvic structures, resulting in increases in uterovaginal prolapse and urinary incontinence [92]. In this setting, documentation of the effects of raloxifene on extrauterine pelvic tissues has been of particular interest. Although a small study of this issue led to inconclusive results [93], long-term data from large, randomized, controlled trials with raloxifene suggest very different effects from those of ERT and other SERMs. An analysis of nearly 7000 postmenopausal women participating in three osteoporosis studies (MORE and the two identical prevention studies noted previously) found a significant, 50% RR of pelvic floor surgery in the raloxifene group [11,12,94]. A recent analysis of 963 participants at ten study sites in the MORE trial found no effect of raloxifene therapy on the incidence of urinary incontinence [95]. In 619 hysterectomized, healthy postmenopausal women from one of the raloxifene osteoporosis prevention studies, the self-reported incidence of urinary incontinence was 7% in women receiving ERT, but only 1% in women receiving either raloxifene or placebo [96].

Effects of raloxifene on the CNS

In the postmenopausal phase of a woman's life, few concerns are stronger than those related to cognitive function and Alzheimer's disease [97], and results in large, randomized, controlled trials with estrogen highlight these concerns. Cognitive function was studied using a number of validated tools in the MORE trial, with the conclusion that raloxifene therapy had no significant positive or negative effects on cognitive function over 3 years of therapy [98,99]. Exploration of this issue has continued in certain subpopulations of study subjects [98,100], as suggestions of a potential beneficial effect were noted with some of the instruments used. Small studies have produced mixed results regarding the effects of raloxifene therapy on mood, memory and other short-term effects in the CNS [101,102]. In a recent re-analysis of the MORE trial database, it was found that a higher (120 mg/day) dose of raloxifene resulted in a significantly reduced risk for the development of mild cognitive impairment after 3 years of therapy, versus placebo [103]. This topic is still in its infancy, both for raloxifene and estrogen itself. However, understanding the etiology of the cognitive declines associated with aging, and exploring possible avenues for blocking or reversing this process, must carry the highest priority for research efforts in the future [104].

Side effects associated with raloxifene therapy

Two drug-related side effects have been associated with raloxifene therapy ever since the initial analyses of large, randomized, controlled trials. A significantly increased incidence of both hot flushes and leg cramps was observed in pivotal raloxifene studies [105,106], but discontinuation rates were not affected. Leg cramps are not associated with the incidence of venous thromboembolic (VTE) events. In addition, it was found that the incidence of hot flushes is age dependent, with the rate in both placebo- and raloxifene-treated groups being lower in the older participants in the MORE trial [73]. Recent menopause and previous hormone therapy both correlate with the incidence of hot flushes with raloxifene [107], but hot flushes generally do not interfere with treatment in women eligible for raloxifene therapy [108].

The only drug-related adverse event that has been consistently observed in pivotal randomized, controlled trials with raloxifene is VTE [85]. The recent publication of the 8-year safety analysis from the MORE–CORE studies summarizes the longitudinal assessment of this effect [109]. An increased incidence of VTE events in raloxifene-treated patients has been established during the first 1–2 years of therapy (peak incidence in the first few months), but in subsequent years, the risk appears to decline toward that of the placebo group. Although the incidence is 1.7-times that in the placebo group at the 8-year time point, this difference is no longer statistically significant. No raloxifene dose–response relationship has been observed for this event. In the early years of treatment, the increase in risk appears to be similar to that observed with various ERT preparations [110] and tamoxifen [111]. The mechanism leading to increased VTE events in raloxifene-, as well as in estrogen- and tamoxifen-treated patients, remains obscure. Raloxifene should not be used in patients with a history of documented VTE disease.

Metabolic effects of raloxifene

Understanding the mechanism of action of a drug such as raloxifene is complicated, challenging and elusive, not least due to the near ubiquity of the ER target. Some recent observations on the ‘metabolic’ effects of raloxifene may eventually give insights into the mode of action of the drug. Metabolic markers of estrogenicity with raloxifene therapy have been reported [112]. The drug stimulates serum sex hormone-binding globulin and thyroxine-binding globulin (TBG) levels. Serum follicle-stimulating hormone and prolactin levels are reduced, but serum estradiol and estrone levels do not change [113,114]. Clinically significant effects on thyroid function were not observed in the pivotal randomized, controlled trials with raloxifene, but serum TBG levels may be increased [115,116]. In patients with primary hyperparathyroidism, estrogen therapy had been noted to decrease serum calcium levels, and raloxifene was shown to have a similar effect, without affecting serum parathyroid hormone, 1,25-dihyroxyvitamin D, alkaline phosphatase or urinary calcium excretion [117].

Compliance with raloxifene therapy

The focus in the clinical application of raloxifene therapy is on the prevention of osteoporosis. As with any prevention strategy, compliance with therapy may become the most crucial issue distinguishing between therapeutically effective alternatives. Some evaluations have suggested that raloxifene might have characteristics compatible with good compliance [118 –121]. However, rigorous comparative studies on compliance are not available, and are exceedingly difficult to perform without bias or confounders clouding the conclusions. There has been no real change to the conclusion that compliance is poor with any of the available therapies for osteoporosis prevention [122 –125].

Conclusion

Raloxifene now has an extensive clinical trial database of over 50,000 patients. It has been shown to reduce the incidence of vertebral fractures in postmenopausal women with osteopenia and osteoporosis, and in patients with and without prevalent vertebral fractures. Additional, potentially beneficial effects are being evaluated in ongoing large, randomized, controlled trials. Aside from the increase in VTE incidence associated with the drug, raloxifene appears to have a very good safety profile. Raloxifene is a unique therapeutic agent, with a multifaceted clinical profile in the postmenopausal woman.

Executive summary

Effects on the skeleton

The osteoporosis prevention trials demonstrated inhibition of bone loss after 5 years of raloxifene therapy. After raloxifene treatment for 5 years, women who had osteopenia at baseline had a decreased risk for the development of osteoporosis, and those with normal bone mineral density (BMD) at baseline had a decreased risk for the development of osteopenia.

In a 1-year extension of the 3-year Multiple Outcomes of Raloxifene Evaluation (MORE), raloxifene treatment decreased the vertebral fracture risk over 4 years, and the fracture efficacy in the fourth year was indistinguishable from that seen during the first 3 years of MORE. The Continuing Outcomes Relevant to Evista^© (CORE) trial, designed to assess the effects of raloxifene on breast cancer prevention, was a 4-year continuation of MORE. At 8 years in MORE and CORE, raloxifene maintained BMD increases versus placebo, but did not reduce the risk of nonvertebral fractures.

An analysis of the MORE cohort suggested that changes in BMD with raloxifene treatment explain less than 10% of the vertebral fracture risk reduction at 3 years.

Effects on the cardiovascular system

Short-duration studies examined the effects of raloxifene treatment on serum biomarkers for cardiovascular disease risk. Raloxifene treatment decreased the levels of low density lipoprotein cholesterol, apolipoprotein B, lipoprotein (a), fibrinogen, homocysteine and tumor necrosis factor-α, but did not change levels of high density lipoprotein cholesterol or high-sensitivity C-reactive protein, compared with placebo.

There was no significant difference in the arterial cardiovascular event rate between the placebo and raloxifene groups in MORE over 4 years of treatment, or during any year of the study. However, in a subgroup of women who had a high cardiovascular risk, raloxifene treatment in MORE was seen to result in a 40% reduction in the relative risk of arterial cardiovascular event rate versus placebo.

Effects on breast tissue

In MORE, postmenopausal women with osteoporosis who were randomized to raloxifene treatment had a lower rate of development of breast cancer at 4 years, compared with placebo. In the CORE trial, raloxifene treatment was associated with a 66% decrease in the relative risk of newly diagnosed, invasive breast cancer through 8 years of treatment.

Effects on the uterus

Several studies have demonstrated that raloxifene therapy has no significant uterine stimulatory effects. Histological evaluation of the endometrium also showed no indication of stimulation. The incidence of uterine bleeding, endometrial hyperplasia and endometrial cancer were found to be similar in raloxifene- and placebo-treated patients in a 4-year uterine safety update, and in 8-year data from the CORE trial.

Effects on the CNS

An evaluation from the MORE trial found that raloxifene therapy at 3 years had no significant positive or negative effects on validated measures of cognitive function after 3 years.

Side effects associated with raloxifene therapy

Pivotal raloxifene trials have found a significantly increased incidence of hot flushes and leg cramps associated with raloxifene use, but study discontinuation rates were not affected. These trials have also found an increased risk of venous thromboembolic events to be associated with raloxifene treatment.

Compliance

Initial evaluations suggested that raloxifene might have characteristics compatible with good compliance, but rigorous studies on compliance are not available.

Future perspective

The understanding of the clinical effects of this drug is still far from complete. It is clear that conclusions emerging from molecular-level research – that each SERM is likely to have a unique profile of actions – are now also being confirmed at the clinical level. It is no longer appropriate to put labels like ‘estrogen-agonist’ or ‘estrogen-antagonist’ on the actions of raloxifene, even within specific tissues. Clinical research with raloxifene has widely expanded the research potential for future SERMs.

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Raloxifene: A Selective Estrogen-Receptor Modulator for Postmenopausal Osteoporosis – a Clinical Update on Efficacy and Safety

Abstract

Keywords

Osteoporosis prevention trials in healthy postmenopausal women

Osteoporosis treatment trials in postmenopausal women with osteoporosis

Effects of raloxifene on the skeleton

Effects of raloxifene on the cardiovascular system

Effects of raloxifene on breast tissue

Effects of raloxifene on the uterus

Effects of raloxifene on the CNS

Side effects associated with raloxifene therapy

Metabolic effects of raloxifene

Compliance with raloxifene therapy

Conclusion

Future perspective

References