Introduction

The advent of selective oestrogen receptormodulators (SERMs) has been the most excitingdevelopment in menopause management for someyears. SERMs are nonsteroidal compounds thathave an oestrogen-like activity in some tissues andan anti-oestrogenic activity in others. Hormonereplacement therapy (HRT), with its uniformoestrogen agonist action in all body tissues, isassociated with beneficial effects on both bonemineral density and serum lipid profile;but it is alsoassociated with risks and adverse effects. Re-analysis of data from 51 epidemiological studiesshowed that HRT users have an increased risk ofhaving breast cancer diagnosed.1 The results of theWomen’s Health Initiative trial have confirmedthis association.2 Concern has been expressed thatendometrial cancer, the incidence of whichincreases in women on unopposed oestrogenreplacement therapy, might not be fully preventedby the addition of cyclic progestogens.3 Adverseeffects of HRT include cyclic or irregular vaginalbleeding, breast enlargement and tenderness, aswell as premenstrual syndrome-like symptoms.These have limited the acceptance of andcompliance with conventional HRT preparations.4

Tamoxifen was the first SERM to be discoveredand is now regarded as a first generation SERM.It acts as either an oestrogen agonist in someorgans and tissues but as an antagonist in others.Because of its known anti-oestrogenic properties,tamoxifen is used in the treatment of breastcancer patients. Contrary to what would beexpected from a pure oestrogen antagonist,tamoxifen was found to increase bone mineraldensity5 and decrease total serum cholesterol.6

The incidence of both benign and malignant

endometrial pathology was also increased inwomen treated with tamoxifen.7

With increased understanding of the functionand structure of the oestrogen receptor,8 thedevelopment of compounds with morefavourable activity profiles became feasible. Theideal activity profile for a SERM for use inpostmenopausal women would have strongoestrogenic effects on the skeleton, thecardiovascular system, the urogenital tract andpotentially the central nervous system, whilepossessing anti-oestrogenic activity in the uterusand the breast. Raloxifene is the first second-generation SERM to be marketed. Its license hasbeen extended to cover the prevention as well asthe treatment of osteoporosis in postmenopausalwomen. Available data on its actions in otherbody tissues are promising.

This review aims to concentrate on thedevelopments made in our understanding of theaction of SERMS since the publication of thereview by Kearney and Purdie in the year 2000.8

Outcomes of raloxifene studies

The Multiple Outcomes of RaloxifeneEvaluation (MORE) trial generated a significantamount of the information available on theclinical effects of raloxifene.9 It was a randomisedcontrolled trial of 7705 postmenopausal womenwith osteoporosis, all of whom fulfilled theWorld Health Organization definition ofosteoporosis (where the bone mineral density ismore than 2.5 standard deviations below theyoung normal mean). Women in the trial wereeither given raloxifiene at a dosage of 60 mg perday, 120 mg per day or a placebo.

Selective oestrogen receptormodulators: an updateSpyros Papaioannou, Geoffrey W Cochrane, David W Purdie

This paper discusses new developments in the area of selectiveoestrogen receptor modulators and more specifically raloxifene. Themost exciting of these developments is the observed reduction in therisk of breast cancer in postmenopausal women on raloxifene therapy.The license of the product has now been extended to cover treatmentas well as prevention of osteoporosis. Furthermore, raloxifene appearsto have a positive impact on the serum lipid profile and there arecontinuing trials investigating whether these changes translate to areduction in cardiovascular morbidity and mortality.

Author details

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Keywordshormonereplacement therapy(HRT), menopause,raloxifene, selectiveoestrogen receptormodulators (SERMS),tamoxifen.

Spyros Papaioannou MD MRCOG,Specialist Registrar, Assisted

Conception Unit, BirminghamWomen’s Hospital, Metchley ParkRoad, Birmingham, B15 2TG, UK.

email: spyrospap@talk21.com

Geoffrey W Cochrane FRCOG,Consultant Obstetrician andGynaecologist, King George

Hospital, Barley Lane, Goodmayes,Essex, IG3 8YB, UK.

David W Purdie MD FRCP Ed FRCOG,Consultant, Centre for Metabolic

Bone Disease, HS BrocklehurstBuilding, Hull Royal Infirmary, Hull,

HU3 2RW, UK.

© 2003 Royal College of Obstetricians and Gynaecologists200

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Bone effects

The MORE trial has shown raloxifene to beeffective in increasing bone mineral density in thespine and the femoral neck and reducing the riskof vertebral fracture in postmenopausal womenwith osteoporosis.This is an important result, aswith the exception of the Women’s HealthInitiative trial2 there are no adequately poweredfracture trials for any HRT regimen.10 Otherrandomised controlled trials that followed theMORE trial have confirmed the effectiveness ofraloxifene in increasing bone mineral density.11

Calcium supplementation was used in the initialtrials that examined the effects of raloxifene onthe skeleton.However, evidence is now emergingthat raloxifene prevents bone loss even in theabsence of calcium supplementation.12

There are limited data describing the combinationof raloxifene with other agents currently used forthe treatment of osteoporosis. Results for thecombined administration of raloxifene (60 mg/day) with alendronate (10 mg/day) have beenreported.13 At one-year follow-up, the combin-ation resulted in a greater increase in bone mineraldensity than with either treatment alone.There isno evidence, as yet, that this difference willtranslate into better protection against fracture.The combination of raloxifene with conventionalHRT is not recommended, since there are no datato suggest that this combination can improveresults in comparison to either treatment alone.The risk of venous thromboembolism, which isincreased by both raloxifene and HRT when usedindependently, could be increased if thetreatments are used in combination.

Cardiovascular effects

The overall effects of raloxifene on the circulatinglipoprotein profile are favourable. Raloxifenereduces total cholesterol and low-density lipo-protein and increases the most cardioprotectivefraction of high-density lipoprotein (HDL),HDL2. However, the magnitude of these changesis lower than those seen with oral HRT.Raloxifene does not significantly change totalHDL and triglyceride levels.14

The results of randomised controlled trials thatinvestigated the effects of raloxifene on twoadditional independent risk factors for thedevelopment of cardiovascular disease have beenreported. Elevated levels of homocysteine andC-reactive protein are associated with greaterrisk of coronary heart disease and myocardialinfraction. Raloxifene was found to significantlyreduce homocysteine levels,15,16 while it had nosignificant effect on levels of C-reactive

protein.16 In comparison, continuous combinedoral HRT (0.625 conjugate equine oestrogenand 2.5 mg medroxyprogesterone acetate perday) increased C-reactive protein levels by 84%and reduced the serum levels of homocysteineby a percentage similar to that of raloxifene.16

Data on the effect of raloxifene on cardiovascularmorbidity and mortality are not yet available.Raloxifene Use for the Heart (RUTH) trial is amultinational trial of women with an establishedor increased risk of coronary heart disease that isexpected to report their findings by 2005.

Endometrial effects

Given the increase in the risk of endometrialpathology associated with tamoxifen treatment,endometrial safety was one of the outcomes ofparticular interest in trials of raloxifene.A subsetof 1781 women from the MORE trial wasfollowed up with annual transvaginal sono-graphy. Endometrial thickness increased by anaverage of 0.01 mm in the raloxifene group anddecreased by 0.27 mm in the placebo group after3 years.17 Fluid was seen in the endometrialcavity of 8.4% of women in the combinedraloxifene group and in 5.7% of controls, but thesignificance of this is uncertain. Raloxifene didnot increase the risk of endometrial cancer aftera median follow up of 40 months.17

Other studies have detected no endometrialchanges in women treated with raloxifene. In athree-year prevention of osteoporosis study of969 postmenopausal women under 60 years ofage, at baseline, Cohen et al.18 observed noincrease in endometrial thickness after treatmentwith 30–150 mg of raloxifene. The subject hasbeen reviewed by Cano et al.19 who concludedthat the experimental and clinical data availablesuggest that raloxifene is inert with respect to theendometrium.

In summary, the subtle changes in thesonographic appearance of the endometriumthat were seen in the MORE trial, but not inother smaller trials, are of uncertain clinicalsignificance. The overall findings suggest thatraloxifene should not increase the incidence ofendometrial pathology in postmenopausalwomen and, therefore, routine endometrialmonitoring by ultrasound or biopsy isunnecessary. Combined therapy with progesto-gens is not warranted. Vaginal bleeding is notexpected in women taking raloxifene, in contrastto continuous combined oestrogen and pro-gestogen therapy when bleeding is not anuncommon problem. If vaginal bleeding occurs,further investigation is necessary.

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Effects on the breast

The effect of raloxifene on breast cancer risk wasnot a primary outcome of the MORE trial.However, the trial identified a 76% reduction inthe incidence of invasive breast cancer amongpostmenopausal women with osteoporosis thatwere treated with raloxifene for three years.17

Cauley et al.20 reported the four-year results, with3004 additional patient years of follow up, in thesame cohort (from the MORE trial). Theycalculated that compared with the placebo, thereduction in the risk of invasive breast cancerafter four years of raloxifene treatment was 72%(relative risk [RR] 0.28 95% confidence interval[CI] 0.17,0.46).This was due to the reduction inthe risk of oestrogen receptor-positive breastcancer by 84% (RR 0.16 95% CI 0.09,0.30)while there was no change in the risk ofdeveloping oestrogen-receptor-negative tum-ours.These data would indicate that 93 womenwith osteoporosis would need to be treated withraloxifene for a period of four years in order toprevent one case of invasive breast cancer. Theauthors conclude that raloxifene continues toreduce the risk of breast cancer in women withosteoporosis after four years of treatmentthrough the prevention of new cases orsuppression of subclinical tumours, or both.

When interpreting these results it should beremembered that women with osteoporosis arethought to be at a lower risk of breast cancerthan the general population.21 However, theplacebo-treated control group in this study,which included women with osteoporosis,manifested the expected risk of breast cancer andhence the precise relationship between bonemass and cancer risk remains to be elucidated.21

Urogenital effects

Raloxifene does not improve symptoms ofurogenital atrophy. Some experience exists onthe concurrent administration of local oestrogen,either in the form of vaginal creams or oestradiolcontaining vaginal rings, in women on raloxi-fene. Parsons et al.23 reported that the response ofthe vaginal mucosa to either conjugated equineoestrogens or to Replens® (LDS ConsumerProducts, Cedar Rapids, IA), a nonhormonaltreatment for vaginal atrophy, was not altered inwomen on raloxifene. These products mightprovide a solution to the problem of sympto-matic vaginal atrophy in postmenopausal womenconsidering raloxifene treatment. In an analysisof the adverse event reports across eightrandomised clinical trials, no increases insymptoms of vaginal atrophy or frequency of

urinary tract infections were noted withraloxifene therapy.24

Effects on the central nervous system

Oestrogen may have beneficial effects oncognition, or reduce the risk of decline incognitive function in postmenopausal women.Whether the same applies to raloxifene is thesubject of research. Yaffe et al.25 reported theresults of three-year follow up in 7478 womenwith osteoporosis that were enrolled in theMORE study.25 Six tests of cognitive functionwere administered at baseline, at six months andat one, two, and three years of follow up.Therewere no significant differences between womenwho were assigned to receive raloxifene (at dosesof 60 or 120 mg/day) and women on placebo.However, the authors comment that when thewomen in the two raloxifene groups werecombined, there was a trend towards less declinein verbal memory (RR 0.77) and attention (RR0.87). At the present time, no definite statementshould be given to patients regarding raloxifeneand central nervous system function.

Adverse effects of raloxifene

The most serious adverse effect of raloxifenetreatment is the increase in the risk of venousthromboembolism. In the MORE trial therelative risk of a thrombotic event in comparisonwith the placebo was 3.1 (95% CI 1.5–6.2).9 Therisk appears to be similar to that seen in womentaking conventional HRT. Until further databecome available, it is recommended thatraloxifene should be stopped prior to prolongedimmobilisation or major elective surgrery.8

Raloxifene does not improve the vasomotorsymptoms of the menopause. Reports of adverseevents in clinical trials that compared raloxifenewith a placebo showed the overall incidence ofhot flushes to be 24.6% in women in theraloxifene group and 18.3% in women in theplacebo group. However, the number of womenwith severe hot flushes and the women that citedhot flushes as a reason for discontinuing treat-ment did not differ significantly betweentreatment groups in the placebo-controlledstudies.24 Hot flushes tended to be morecommon in younger women (who were closerto the time of the menopausal transition) than inolder women. Raloxifene has been found toincrease the incidence of leg cramps.24

Raloxifene use in premenopausalwomen

There is limited information about the effects of

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raloxifene on oestrogen-dependent conditionssuch as fibroids and endometriosis in humans.Results in animal models are encouraging. In theguinea pig model of leiomyoma, raloxifene hadinhibitory effects.22 A study to examine theeffects of raloxifene on laparoscopically-documented endometriosis in women ofreproductive age is underway. Until clinical dataare available, raloxifene use in premenopausalwomen should be confined to clinical trialsettings. Raloxifene would be expected to be ahuman teratogen.

Other SERMs

Toremifene is a compound similar to tamoxifenthat has been found to be safe and as effective astamoxifen in the treatment of advanced breastcancer in postmenopausal women.26 It has beenapproved by the US Federal Drug Admini-stration for this indication, but is not licensed inthe UK.

Other SERMs are at different phases of clinicaldevelopment after showing potential in animalstudies. They include droloxifene, which hasbeen found to be effective in the treatment ofmetastatic breast cancer, lasofoxifene, whichprevented bone loss and decreased total serumcholesterol in ovariectomised rats27 andarzoxifene (LY353381), which is similar to, butmore potent than, raloxifene.

Conclusion

In conclusion, SERMS are a class of non-hormonal medicines that can interact withoestogen receptors in different tissues in a tissue-specific way, expressing oestrogen agonist orantagonist activity.Raloxifene has proven efficacyin the treatment and prevention of osteoporosis,while its effects in the risks of breast cancer andcardiovascular morbidity are being researchedwith positive preliminary results. No SERM hasyet been identified which reduces menopausalsymptoms – particularly hot flushes. ■

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