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ABSTRACT
Hormone receptors and, specifically, estrogen receptors were described
about four decades ago. For estrogens, there are two receptors, estro-
gen receptor alpha (ERα) and estrogen receptor β (ERβ). The two recep-
tors are coded by different genes and their tissue expression varies across
organs. ERα is predominantly expressed in reproductive tissues (uterus,
breast, ovaries) liver and central nervous system, whereas ERβ is
expressed in other tissues such as bone, endothelium, lungs, urogenital
tract, ovaries, central nervous system and prostate. More than seventy
molecules that belong to the SERMS class have been described. There
are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydron-
aphtylenes, indoles and benzopyrans. All of these non-hormonal com-
pounds are capable of activating the ER, reduce bone turnover rate
and, as an antiresorptive, clearly improve bone density. Estrogens
reduce bone turnover rate and, as an antiresorptive, clearly improve
bone density. They are also beneficial for the relief of menopausal symp-
toms. An ongoing debate that extends over the decades, relates to to
overall benefit/risk profile of estrogen or estrogen-progestin therapy since
these therapies can increase the risk of serious health disorders, such as
breast cancer. SERMs have increased our understanding of hormone-
receptor regulatory mechanisms. Their development has permitted a tar-
geted efficacy profile avoiding some of the side effects of the hormone
therapy. Their clinical utility relies today mostly on the effects on breast
cancer and bone. (Arq Bras Endocrinol Metab 2006;50/4:720-734)
Keywords: Raloxifene; Tamoxifene; Estrogen receptors; Bone turnover;
Breast cancer
RESUMO
Moduladores Seletivos do Receptor Estrogênico (SERMs).
Os receptores hormonais e especificamente os receptores estrogênicos,
foram descritos há cerca de 40 anos. Para os estrógenos, existem dois
tipos: o alfa (ERα) e os beta (ERβ), os quais são codificados por diferentes
genes e sua expressão tissular varia de tecido para tecido. O ERα se
expressa predominantemente no aparelho reprodutivo (útero, mamas,
ovários), fígado e sistema nervoso central (SNC). O ERβ se expressa em
outros tecidos como osso, endotélio, pulmões, urogenital, além dos
ovários, SNC e próstata. Mais de setenta moléculas pertencentes ao
grupo dos SERMs têm sido descritas, em 5 grupos químicos: trife-
niletilenos, benzotiofenos, tetrahidronaftilenos, indols e benzopiranos.
Todos estes compostos não hormonais são capazes de ativar o ER,
reduzindo a remodelação óssea e melhorando a densidade mineral
óssea. Os estrógenos reduzem a remodelação óssea e aumentam a
densidade mineral óssea, como também melhoram os sintomas da
menopausa. Um debate permanente existe a respeito da relação
risco/benefício da terapia estrógeno-progestínica, em virtude do
aumento do risco de problemas de saúde mais sérios como câncer de
mama. Os SERMs aprimoraram o conhecimento sobre os mecanismos
de regulação hormônio-receptor, e o seu desenvolvimento permitiu
original article
Selective Estrogen Receptor Modulators
( SERMS )
Adolfo Diez-Perez
Autonomous University of
Barcelona, Department of
Internal Medicine, Hospital del
Mar-URFOA-IMIM,
Barcelona, Spain.
Received in 05/30/
Accepted in 06/10/
Diez-Perez
uma eficiente modalidade de ação terapêutica
hormonal, evitando-se alguns dos efeitois adversos
da terapia hormonal per si. (Arq Bras Endocrinol
Metab 2006;50/4:720-734)
Descritores: Raloxifeno; Tamoxifeno; Receptores
estrogênicos; Remodelação óssea; Câncer mamário
ESTROGEN RECEPTOR ACTIVATION BY
ESTROGENS AND SELECTIVE ESTROGEN
RECEPTOR MODULATORS (SERMS)
H
ORMONE RECEPTORS AND, SPECIFICALLY, estrogen
receptors were described about four decades ago
(1-3). For estrogens, there are two receptors, estrogen
receptor alpha (ERα) and estrogen receptor β (ERβ).
The two receptors are coded by different genes and
their tissue expression varies across organs. ERα is pre-
dominantly expressed in reproductive tissues (uterus,
breast, ovaries) liver and central nervous system,
whereas ERβ is expressed in other tissues such as bone,
endothelium, lungs, urogenital tract, ovaries, central
nervous system and prostate (4-10). Both ERs are
formed by a single polypeptide chain with 565
aminoacids for the ERα and 530 for the ERβ (11).
There are 6 homologous regions, A to F, with the ERβ
lacking the carboxiterminal F domain (12). The
domains of the estrogen receptors include sites for
nuclear location, hormone binding, dimerization,
DNA binding and transcription activation (12-16).
Estrogens and SERMS activate estrogen genes by a
series of events that occur after their binding to the
ER. The interaction of the hormone with the naïve
receptor induces conformational changes of the lig-
and-receptor binding to nuclear proteins or adaptor
proteins or corregulators (17,18) that induces the dis-
sociation of heat-shock proteins associated with the
inactive receptor. This results in receptor activation
and and an interaction with DNA (19). This ligand-
receptor complex binds to DNA response elements,
called Estrogen-Response-Elements (ERE), located in
the promoter region of the estrogen target genes, ini-
tiating the transcription process and mRNA synthesis.
The final result of the process, either inducing or
inhibiting gene transcription by the ligand-ER dimer,
depends on the type of cell and the presence of cor-
regulator proteins and gene promoters. Rapid acting,
non-genomic pathways are also activated by estrogens
and SERMS such as those dependent upon NO
(vasodilatation, ischemic myocardial damage, response
to endothelial damage, coronary artery relaxation or
vasodilation in hypertensive rats) (20-24). Figure 1
summarizes the general activation pathways of the
estrogen receptor.
Several characteristics differentiate ER activa-
tion induced by estrogens from those induced by
SERMS. Estrogen and raloxifene, a prototypical
SERM, occupy the same ER ligand binding site (25)
but induce conformational changes in the receptor
that are distinct (26). This is a relevant point, name-
ly that the different structure of the ligand-receptor
complex depends on the molecular characteristics of
the ligand. The ER contains a ligand-binding
domain, which includes a series of amino acids called
Activating Function-2 (AF-2) essential for the activa-
tion of genes that mediate the estrogen effect in
reproductive tissues as the breast or uterus. There-
fore, the different ligands can induce different gene
transcription processes. For example, the union of
the ligand binding domain with tamoxifene, another
SERM, results in a partial agonistic effect in the
uterus whereas this same interaction is fully antago-
nistic in the breast. In contrast, when binding to
estradiol, the conformation of the ligand-receptor
complex permits an interaction with a coactivator
that results in a fully agonistic effect in breast tissue
(27). Similar to tamoxifene, the Raloxifene-ER com-
plex displays a conformational shape in which the
interaction with the corregulatory protein is not fea-
sible and the transcription process cannot be pro-
duced, thus resulting in an antagonistic effect (28).
In general, because of these differences in the 3-
dimenstinal conformation of the ligand-receptor
complex, there is a wide range of subsequent actions
from full activation in the case of estradiol to com-
plete antagonism in the case of the pure antiestro-
gens. The different SERMS exhibit intermediate
properties because they induce transitional confor-
mations closer to one or the other boundary (29).
The tissue itself, of course, plays a role in terms of
subsequent gene steps. In bone tissue, for example,
candidate genes either activated or repressed at the
ERα and ERβ level by estrogen or SERMS are dif-
ferent (30). Moreover, estrogen and SERMS exert
different effects on estrogen response element (ERE)
transcriptional activity (31). Although the mecha-
nism of activation of estrogen receptor is not fully
clarified, the discovery of SERMS greatly contributed
to our understanding of their intrinsic functions,
opening the way for the discovery of selective “a la
carte” ligands for different hormone receptors. The
‘a la carte’ concept refers to the potential to produce
clinically desirable effects while avoiding those that
constitute a problem.
Diez-Perez
itive breast cancer cells (55) and in clinical cases (56).
Arzoxifene is another SERM of this group currently in
a phase III trial. In breast cancer cells lines, arzoxifene
has a more potent effect than raloxifene but is similar or
more potent in skeletal systems (57-59).
Tetrahydronafthylenes. Lasofoxifene is the main
representative of this group. In vivo animal experiments
have shown a great affinity for ER-α (60). The effect of
these molecules in ovariectomized (OVX) rat models is
prevention of bone loss and positive changes in lipid
profile. In male orchidectomized old rats, these SERMS
are also efficacious in preventing bone loss and preserv-
ing biomechanical properties (61,62). Lasofoxifene is
currently in advanced states of development (phase 3
clinical trials). Trioxifene, another member of the
group, was abandoned because of side effects (63).
Indoles. Bazedoxifene and pipendoxifene are the
2 main molecules of this group. In a phase 3 clinical
trial, bazedoxifene demonstrated bone protective, cho-
lesterol lowering and no uterine effects in OVX and
intact rat models (64). This class of SERMS antagonizes
C3 gene and counteracts naloxone-induced vasomotor
responses in rats (65). In addition, mechanical strength
of bone is improved in treated animals (66).
Benzopyrans. A number of compounds belong
to this group. Ormeloxifene is used as contraceptive
(67). The development of Levormeloxifene was
stopped because of uterine safety issues (68). Other
molecules in active development are SP500263 (69),
EM-800 and EM-652 (70,71) among others.
SERMS AND BONE
Estrogens play an important role in female bone
homeostasis; in the estrogen deficient state, bone
resorption is increased. As a result of these predictable
postmenopausal findings, estrogens have been exten-
sively used as the main therapy to prevent bone loss in
postmenopausal women. Estrogens reduce bone
turnover rate and, as an antiresorptive, clearly improve
bone density. They are also beneficial for the relief of
menopausal symptoms. An ongoing debate, that
extends over the decades, relates to to overall bene-
fit/risk profile of estrogen or estrogen-progestin ther-
apy since these therapies can increase the risk of seri-
ous health disorders, such as breast cancer (72,73).
It is in this area that SERMS became attractive.
Breast cancer patients treated with tamoxifen showed
protection against postmenopausal bone loss (74).
This observation led to a new appreciation that estro-
gen-like molecules (SERMS) can act in some organs
or tissues as estrogen agonists and in some others as
antagonists. The fundamental premise of SERMS is
based upon this concept, namely that they can be both
estrogen agonist and antagonists...
Preclinical models
Tamoxifen
The most extensively used animal model to evaluate
the action of SERMs on bone has been the ovariec-
tomized (OVX) rat. In rats, tamoxifen reduces bone
resorption, uterine growth (74,75) and reduces the
number and size of osteoclasts. Similar effects on bone
have been observed in dogs and immobilised male rats
(76,77). However, the antiresorptive potency of
tamoxifen is inferior to 17β-estradiol (78) and has no
effect when the endogenous production of estrogens is
normal (79).
Raloxifene
OVX rats treated with raloxifene show significantly
lower rates of bone remodeling (80) and preservation
of bone mineral density (BMD) as measured by single
photon absorptiometry (53) in distal femur metaphysis
and in proximal tibia, and by dual-energy X-ray
absorptiometry (54) in lumbar vertebrae and femur.
This prevention of bone loss is similar to that achieved
with ethinyl-estradiol (EE) (54,81). Histomorphome-
try in OVX rat models have demonstrated a reduction
of bone resorption area in trabecular surfaces similar
for raloxifene and EE treated animals (81,82).
Biomechanical testing shows an increased
strength in rats treated with raloxifene and EE vs. con-
trol rats (81) in both the femoral neck and vertebrae.
In another study in which raloxifene, EE, tamoxifen
and alendronate were all assessed (53), all drugs except
tamoxifen showed increased strength in comparison to
control animals. Moreover, treatment with raloxifene
was associated with a smaller number of microcracks
(83). A raloxifene analogue, LY 117018, inhibited
osteocyte apoptosis induced by oophorectomy in a rat
model (84).
Table 1. SERMS: Chemical groups (33).
Triphenylethylenes Tetrahydronafthylenes Tamoxifen Lasofoxifene Droloxifene Nafoxidine Idoxifene Indoles Clomiphene Bazedoxifene Toremifene Benzopyrans Benzotiophenes EM- Raloxifene Levormeloxifene Arzoxifene
Diez-Perez
In transient cotransfection experiments using a
transforming growth factor-β promoter-chloram-
phenicol acetyltransferase reporter construct (TGFβ
promoter-CAT reporter) and an ER expression plas-
mid in human MG63 osteosarcoma cells (85) it has
been shown that TGFβCAT expression was signifi-
cantly up-regulated by raloxifene (7-fold), and by 17β-
estradiol or tamoxifen (2-fold). This suggests that
raloxifene regulates TGFβ3 gene expression with two
possible sequellae: promotion of osteoblast numbers
and inhibition of osteoclast differentiation (85).
Different SERMs, as well as the natural ligand,
estradiol, can activate more predominantly one or the
other estrogen receptors (alpha or beta) creating con-
formational changes of the ER-ligand complex that
vary for different ligands (86). Furthermore, the vari-
ous ligands can activate different intracellular pathways
along with different response elements (26). Altogeth-
er, genomic responses for the various SERMS differ
within this class and in relationship to estradiol effects
on these 2 receptor subtypes (31).
Other SERMs
In rats, levormeloxifene increases lumbar spine and
tibial bone mass in a rat model, with a decrease in
osteocalcin and cholesterol levels. The uterus is not
affected (30,87). In monkeys, it has been also demon-
strated that bone remodelling is controlled and bone
loss is prevented (88). The actions of Idoxifene,
another SERM that activates the ER through the clas-
sical estradiol pathway, on bone are similar, serving as
a full antagonist on mammary and uterine tissue
(89,90). Droloxifene is efficacious in the prevention of
bone loss in OVX rats as well as in the reduction of
serum cholesterol levels again without deleterious
effects on the uterus (44,91-94). Ormeloxifene can
also prevent bone loss in animal models (95,96).
Lasofoxifene protects against bone loss, reduces
cholesterol levels and exerts a positive effect on bone
strength in male rats (97). This compound is in the lat-
est stages of clinical development. Two other SERMs,
also in advanced phase III trials are bazedoxifene and
arzoxifene, both showing protective effects against
ovariectomy-induced bone loss. Arzoxifene has shown
to reduce the rate of bone remodelling with positive
effects on bone quality as well as reduction of choles-
terol levels in OVX rats (98).
A raloxifene analogue, LY117018 HCl, is also
effective in reducing bone loss in OVX rats (99). In
addition, the administration of this analogue permits a
significant reduction of the minimal effective dose of
human parathyroid hormone (PTH) required in the
treatment of osteopenic rats (59,100). Other com-
pounds are FC1271a (101) and HMR-3339 (47)
both with promising results in preclinical studies.
CLINICAL EFFECTS OF SERMs ON BONE
Tamoxifen
The effects of tamoxifen on bone have been evaluated
mainly in breast cancer patients who received the
product as adjuvant therapy. A number of observations
(102-106) have shown a decrease in bone formation
(102,104,106) and bone resorption by biochemical
markers (105-107).
Initial retrospective (107) and prospective
studies (108,109) that compared tamoxifen-treated
women against the placebo group, found no signifi-
cant differences in BMD at the lumbar spine or
femoral neck. Subsequent prospective and random-
ized studies also carried out with breast cancer
patients (102,103), revealed, over a 3-year period,
significant prevention of bone loss in women. Grey
et al. (105) studied the effect of tamoxifen on BMD
in healthy, late postmenopausal women who were
on average 11 years postmenopausal. There was no
significant difference in hip BMD but an incease in
lumbar spine BMD. Different from these observa-
tions in a breast cancer prevention study in pre-
menopausal healthy women, progressive reductions
in BMD in a tamoxifen-treated group was observed
Similarly, Wright et al. (105) found no differ-
ences in tamoxifen-treated subjects when histomor-
phometric changes in cancellous bone was assessed. In
the tamoxifen group, bone formation rate was signifi-
cantly decreased, the total bone-remodelling span was
longer and the trabecular connectivity indexes were
increased.
In the Breast Cancer Prevention Trial (34), a
randomized, placebo-controlled clinical study aiming
at determining the potential of tamoxifen for breast
cancer prevention in pre- or postmenopausal women
at increased risk, 13,338 women were monitored over
5 years. Women in the treatment group (n= 6,681)
were given a 20 mg daily dose of tamoxifen, while the
remaining (n= 6,707) received a placebo. Although
the overall rate of fractures was about the same in both
groups, tamoxifen-treated women sustained fewer hip,
spine and Colles’ fractures. Since in this trial pre- and
postmenopausal women were both included and no
spinal radiographs were carried out, relevant data may
have been overlooked.
Diez-Perez
Ott et al. (127). In a group of 54 women enrolled in
the MORE study, 2 transiliac bone biopsies were
obtained at baseline and after two years of treatment.
The results confirmed the safety of the drug on bone
tissue since no woven bone, mineralization defect, cell
toxicity or medullary fibrosis were observed. More-
over, the decreased number of empty osteocytic lacu-
nae also suggested an anti-apoptotic effect on the
osteocyte. More recent experimental data further con-
firm this anti-apoptotic effect of raloxifene on
osteoblastic and osteocytic cells (128).
For years osteoporosis has been defined as a
disease induced by a decrease in bone mass. Recent-
ly, a National Institute of Health Consensus Panel
(129) has redefined the disease as a skeletal disorder
characterized by an alteration in bone strength that
predisposes a person to an increased risk of fracture.
This concept of bone strength represents a new par-
adigm in our concepts about the disease (130-132).
Added to the traditional element of bone mass are
other aspects of bone strength such as geometry,
microarchitecture, remodelling rate, mineralization
degree and homogeneity and fatigue damage
The relationship between the decrease in bone
mineral density, assessed in any of the skeletal regions
and measured by different techniques, with an
increased fracture risk has been widely demonstrated
(138-140). Marshall et al. (139) demonstrated in a
meta analysis that one standard deviation decrease in
bone mineral density (BMD) in lumbar spine, hip or
proximal radius increased the risk of fracture in these
locations by a 50 to 60%. While this relationship
between a reduction in BMD and fracture risk is very
powerful, the relationship between an increase in
BMD and a reduction in fracture risk is much less cer-
tain (118,141-145). This relationship is of particular
interest for raloxifene, a drug that has a limited effect
to increase BMD. Sarkar et al. (146) analyzed the
relationship between the observed increase in BMD in
the placebo and in the raloxifene-treated patients
from the MORE trial. Only a 4% of the fracture
reduction could be explained by changes in BMD.
These observations argue that other properties of
bone, presumably affected by raloxifene in a positive
manner, are more likely to account for most of the
antifracture efficacy of the drug.
Bone turnover replaces old bone with fresh new
bone. When in balance and not excessive, bone
turnover is a beneficial feature of skeletal homestasis.
However, in the adult, bone turnover is usually not bal-
anced, with bone resorption exceeding bone forma-
tion, and sometimos excessive. In these settings, bone
turnover can be deleterious for bone (130). The rapid
reduction in the fracture risk observed after only a few
months of starting antiresorptives can be explained by
their effects to reduce bone turnover well before any
improvement in BMD (130,147) .Bone remodeling
rate is also a determinant of intrinsic material properties
of the bone tissue such as the mean degree of mineral-
ization or their homogeneity (148,149). Clinical data
on raloxifene-treated patients demonstrate that the
drug preserves a normal degree of mineralization and
homogeneity (150), in accordance with the preclinical
data. Collagen composition is also modulated by the
remodeling rate since the crosslinking of the molecules
influences the mechanical competence and can vary
with aging (151).
There is considerable debate on what is the
normal remodelling rate and the potential deleteri-
ous effects of an excessive suppression given that
microdamage repair could be impaired (152). Micro-
damage increases with age, but also negatively corre-
lates with the rate of bone remodeling and is associ-
ated with high doses of antiresorptives in experimen-
tal animals (153,154). Therefore, the theoretical
concern is that an antiresorptive agent might depress
remodelling excessively (155) impairing the replace-
ment of old bone by fresh new units. Although no
fracture data support this highly controversial theory,
SERMs do not suppress bone turnover to an extent
that would cause such concerns. In fact, the data
show that raloxifene restores bone turnover to pre-
menopausal levels (156,157) and experimental data
demonstrate that the drug actually reduces microc-
rack density in bone tissue (84).
It has been demonstrated that the simultane-
ous use of a bisphosphonate with PTH impairs the
bone forming response (156,157). Preliminary data
suggest the opposite when the combined drug is
raloxifene (158). Furthermore, in patients previously
treated with raloxifene a full response to PTH was
observed (159). Altogether SERMs appear to be a
better partner for anabolic agents than some bispho-
sphonates. Also, in young postmenopausal women
raloxifene will not jeopardize an anabolic effect in
case PTH should be needed in subsequent therapeu-
tic considerations.
Future SERMs
A large number of compounds selectively regulating
the estrogen receptor are under development and have
been briefly reviewed in the preclinical section. Some
have reached clinical research stages. Levormeloxifene
Diez-Perez
(160, 161) has been studied for its pharmacokinetics,
safety, dosing and antiresorptive effects. However its
development was stopped after the phase II trials when
uterine safety problems where detected (162). Idox-
ifene has demonstrated positive effects on BMD after
12 months of treatment (163) and decreased turnover
in osteopenic postmenopausal women (164). Three
SERMS are currently in advanced (phase III) stages of
their clinical development: bazedoxifene, lasofoxifene
and arzoxifene.
EXTRASKELETAL EFFECTS OF SERMS
SERMs and the breast
Tamoxifen has a well-established efficacy for breast
cancer patients (34-36). Raloxifene showed a positive
effect on invasive estrogen-receptor positive breast
cancer after 3 years in postmenopausal women with
osteoporosis (118) and this outcome is sustained after
8 years of treatment, with no apparent loss of effect or
rebound effect (165). These observational data have
recently been confirmed in the recent preliminary
report on the results of the RUTH trial (166). Finally,
the STAR trial comparing the efficacy of raloxifene vs
tamoxifen in more than 19,000 women at high risk for
breast cancer has shown a similar number of invasive
breast cancer cases in both raloxifene and tamoxifen
groups (167). In some countries raloxifene is already
approved for prevention of breast cancer and all the
data suggest the efficacy of the drug for this indication.
Given their positive effects on bone, this beneficial
effect could extent the clinical utility of the drug.
However, the results of both the RUTH and STAR
trial are not fully analyzed yet and we await peer-
reviewed publication documenting these early obser-
vations. Other SERMs are currently under study for
this indication.
Cardiovascular effects
Tamoxifen induces a small but significant increase in
the incidence of deep venous thrombosis and pul-
monary embolism and in the risk of stroke (168). Sim-
ilarly, raloxifene use is associated with a 1.7-fold
increase in the risk of venous thromboembolic events
although the overall incidence is quite low (absolute
risk difference of 0.9 per 1000 woman-years) (169).
What has been more extensively assessed is the effect of
raloxifene on coronary and cerebrovascular events. In
post hoc results for a subgroup of the MORE trial,
namely, women at high risk for arterial events, ralox-
ifene decreased the incidence of coronary events and
stroke (170). However, after 8 years of treatment the
incidence of overall cardiovascular, coronary or cere-
brovascular adverse events did not differ significantly
between the raloxifene and placebo treated groups
(171). Patients at increased risk of cardiovascular
events showed no evidence of a beneficial or harmful
effect. The preliminary report on the RUTH trial
results confirm a neutral effect on coronary events and
incidence of stroke, although a small increase in the
stroke-associated mortality has been reported (166). In
addition, the preliminary report of the STAR trial sug-
gests a lower incidence in deep venous thrombosis and
pulmonary embolism in women receiving raloxifene vs.
those treated with tamoxifen (167). Again a full analy-
sis is needed in all these aspects of both studies.
Other health problems and SERMs
An increase in the number of hot flases limits the use
of available SERMs in a number of postmenopausal
women (169). Some preclinical results suggest that
new SERMs might avoid this problem (172). Tamox-
ifen is associated with an increased incidence of
endometrial carcinoma (173), vaginal bleeding (174)
and uterine sarcoma (175). Raloxifene has not report-
ed to increase vaginal bleeding, ovarian or uterine can-
cer (117,169,176). Analyses of the safety results from
the raloxifene trials also suggest positive effects on uri-
nary incontinence (177) with neutral effects on cogni-
tive function (178). Points related to cardiovascular
issues have already been noted.
CONCLUSIONS
SERMs have increased our understanding of hor-
mone-receptor regulatory mechanisms. Their develop-
ment has permitted a targeted efficacy profile avoiding
some of the side effects of the hormone therapy. Their
clinical utility relies today mostly on the effects on
breast cancer and bone. Future members of this class
may offer an improved risk-benefit profile and could
represent an integral approach for the health problems
of postmenopausal women.
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