Pros and cons of existing treatment modalities in osteoporosis: a comparison between tibolone,SERMs and estrogen (+/-progestogen) treatments

Tibolone, selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene, and estrogen (±progestogen) treatments prevent bone loss in postmenopausal women. They exert their effects on bone via the estrogen receptor (ER) and the increase in bone mass is due to resorption inhibition. The effect of SERMs on bone mineral density is less than that with the other treatments, but the SERM raloxifene still has a positive effect on vertebral fractures. In contrast to tibolone and estrogens (±progestogen), SERMs do not treat climacteric complaints, whilst estrogen plus progestogen treatments cause a high incidence of bleeding. Estrogen plus progestogen combinations have compromising effects on the breast. Tibolone and SERMs do not stimulate the breast or endometrium. Unlike SERMs, tibolone does not posses antagonistic biological effects via the ER in these tissues. Estrogenic stimulation in these tissues is prevented by local metabolism and inhibition of steroid metabolizing enzymes by tibolone and its metabolites. SERMs and estrogen (±progestogen) treatments increase the risk of venous thromboembolism (VTE), whilst estrogen (±progestogen) combinations have unwanted effects on cardiovascular events. So far, no detrimental effects of tibolone have been observed with respect to VTE or cardiovascular events. The clinical profile of tibolone therefore has advantages over those of other treatment modalities. It is also clear that tibolone is a unique compound with a specific mode of action and that it belongs to a separate class of compounds that can best be described as selective, tissue estrogenic activity regulators (STEARs).     

Identification of selective estrogen receptor modulators by their gene expression fingerprints

Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in postmenopausal women. However, long term estrogen treatment also increases the risk of endometrial and breast cancer. The selective estrogen receptor (ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and agonistic responses when bound to the ER. Their predominantly antagonistic actions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like effects in bone and the cardiovascular system make them candidates for ERT regimens. Of these two SERMs, raloxifene is preferred because it has markedly less uterine-stimulatory activity than either estrogen or tamoxifen. To identify additional SERMs, a method to classify compounds based on differential gene expression modulation was developed. By analysis of 24 different combinations of genes and cells, a selected set of assays that permitted discrimination between estrogen, tamoxifen, raloxifene, and the pure ER antagonist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtained for each compound were used to classify all compounds into eight groups. The compound's GEF predicted its uterine-stimulatory activity. One group of compounds was evaluated for activity in attenuating bone loss in ovariectomized rats. Most compounds with similar GEFs had similar in vivo activities, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.     

Selective estrogen receptor modulators (SERMS) and their roles in breast cancer prevention

Tamoxifen has not only proved to be a valuable treatment for estrogen receptor (ER)-positive breast cancer, but is also a pioneering medicine for chemoprevention in high-risk pre- and postmenopausal women. Insights into the pharmacology and toxicology of tamoxifen have led to the recognition of selective ER modulators (SERMs) with estrogen-like actions in maintaining bone density and in lowering circulating cholesterol, but antiestrogenic actions in the breast. Raloxifene, a related SERM, is now available to treat osteoporosis and is also being tested as a preventive for breast cancer and coronary heart disease. Emerging knowledge about the action of SERMs will provide clues for the design of mechanism-based medicines.     

Four decades of discovery in breast cancer research and treatment--an interview with V. Craig Jordan. Interview by Marc Poirot

V. Craig Jordan is a pioneer in the molecular pharmacology and therapeutics of breast cancer. As a teenager, he wanted to develop drugs to treat cancer, but at the time in the 1960s, this was unfashionable. Nevertheless, he saw an opportunity and through his mentors, trained himself to re-invent a failed "morning-after pill" to become tamoxifen, the gold standard for the treatment and prevention of breast cancer. It is estimated that at least a million women worldwide are alive today because of the clinical application of Jordan's laboratory research. Throughout his career, he has always looked at "the good, the bad and the ugly" of tamoxifen. He was the first to raise concerns about the possibility of tamoxifen increasing endometrial cancer. He described selective estrogen receptor modulation (SERM) and he was the first to describe both the bone protective effects and the breast chemopreventive effects of raloxifene. Raloxifene did not increase endometrial cancer and is now used to prevent breast cancer and osteoporosis.The scientific strategy he introduced of using long term therapy for treatment and prevention caused him to study acquired drug resistance to SERMs. He made the paradoxical discovery that physiological estrogen can be used to treat and to prevent breast cancer once exhaustive anti-hormone resistance develops. His philosophy for his four decades of discovery has been to use the conversation between the laboratory and the clinic to improve women's health.     

Vascular effects of aromatase inhibitors: data from clinical trials

Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer.     

选择性雌激素受体调节剂

雌激素替代疗法（estrogen replacement therapy,ERT）是治疗绝经后综合征的首选治疗方案,但是长期应用导致子宫内膜增生、乳腺癌等。选择性雌激素受体调节剂主要通过ER亚型、共调节子、靶启动子、雌激素受体相关受体等机制实现其组织选择性,在发挥骨骼、心血管保护作用的同时,减少了对乳腺及生殖系统的副作用。目前,选择性雌激素受体调节剂的种类、作用的组织特异性及其临床应用在医学界引起广泛关注,具有广阔的发展前景。     

Effects of SERM (selective estrogen receptor modulator) treatment on growth and proliferation in the rat uterus

Background  

Selective estrogen receptor modulators (SERMs) have been developed in order to create means to control estrogenic effects on different tissues. A major drawback in treatment of estrogen receptor (ER) positive breast cancer with the antagonist tamoxifen (TAM) is its agonistic effect in the endometrium. Raloxifene (RAL) is the next generation of SERMs where the agonistic effect on the endometrium has been reduced.     

Is basic research providing answers if adjuvant anti-estrogen treatment of breast cancer can induce cognitive impairment?

Adjuvant treatment of cancer by chemotherapy is associated with cognitive impairment in some cancer survivors. Breast cancer patients are frequently also receiving endocrine therapy with selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) to suppress the growth of estradiol sensitive breast tumors. Estrogens are well-known, however, to target brain areas involved in the regulation of cognitive behavior. In this review clinical and basic preclinical research is reviewed on the actions of estradiol, SERMs and AIs on brain and cognitive functioning to see if endocrine therapy potentially induces cognitive impairment and in that respect may contribute to the detrimental effects of chemotherapy on cognitive performance in breast cancer patients. Although many clinical studies may be underpowered to detect changes in cognitive function, current basic and clinical reports suggest that there is little evidence that AIs may have a lasting detrimental effect on cognitive performance in breast cancer patients. The clinical data on SERMs are not conclusive, but some studies do suggest that tamoxifen administration may form a risk for cognitive functioning particularly in older women. An explanation may come from basic preclinical research which indicates that tamoxifen often acts agonistic in the absence of estradiol but antagonistic in the presence of endogenous estradiol. It could be hypothesized that the negative effects of tamoxifen in older women is related to the so-called window of opportunity for estrogen. Administration of SERMs beyond this so-called window of opportunity may not be effective or might even have detrimental effects similar to estradiol.     

Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: Estrogen receptor dependent or independent pathways of raloxifene

SERMs bind to both estrogen receptor (ER)α and β, resulting in tissue dependent estrogen agonist or antagonist responses. Both raloxifene and tamoxifen are most frequently used SERMs and exert estrogen agonistic effects on human bone tissues, but the details of their possible direct effects on human bone cells have remained largely unknown. In our present study, we examined the comparative effects of raloxifene, tamoxifen, and native estrogen, estradiol on human osteoblast cell line, hFOB in vitro. Both the cell numbers and the ratio of the cells in S phase fraction were significantly increased by the treatment of raloxifene or tamoxifen as well as estradiol treatments in hFOB. Gene profile patterns following treatment with raloxifene, tamoxifen, and estradiol demonstrated similar patterns in a microarray/hierarchal clustering analysis. We also examined the expression levels of these genes detected by this analysis using quantitative RT-PCR. MAF gene was induced by raloxifene treatment alone. GAS6 gene was induced by raloxifene and tamoxifen as well as estradiol. An estrogen receptor blocker, ICI 18, 286, inhibited an increase of GAS6 gene expression but not the levels of MAF gene mRNA expression. Results of our present study demonstrated that raloxifene exerted direct protective effects on human osteoblasts in both estrogen receptor dependent and independent manners.     

An estrogen receptor basis for raloxifene action in boneProceedings of Xth International Congress on Hormonal Steroids, Quebec, Canada, 17–21 June 1998.

Although controversy remains regarding direct effects of estrogen on bone, in vivo data clearly show that estrogens suppress bone turnover, resulting in decreased bone resorption and formation activity. Selective estrogen receptor modulators (SERMs), such as raloxifene, produce effects on bone which are very similar to those of estrogen. In vitro, both raloxifene and estrogen inhibit mammalian osteoclast differentiation and bone resorption activity, but only in the presence of IL-6. Data from a number of ovariectomized rat model manipulations (i.e. hypophysectomy, low calcium diet and drug combinations) demonstrate a strong parallel between the antiosteopenic effects of raloxifene and estrogen. A characteristic action of estrogens on the skeleton is inhibition of longitudinal bone growth, an effect which is not observed with other resorption inhibitors, including calcitonin and bisphosphonates. Consistent with an estrogen-like mechanism on bone, raloxifene inhibits longitudinal bone growth in growing rats. In addition to the overall similarity of the bone activity profile in animals, estrogen and raloxifene also produce similar effects on various signaling pathways relative to the antiosteopenic effect of these two agents. For example, IL-6, a cytokine involved in high turnover bone resorption following estrogen deficiency in rats, is suppressed by both raloxifene and estrogen. Raloxifene and estrogen also produce a similar activation of TGF-β3 (a cytokine associated with inhibition of osteoclast differentiation and activity) in ovariectomized rats. Like 17β-estradiol, raloxifene binds with high affinity to both estrogen receptor- (ER) and estrogen receptor-β (ERβ). Crystal structure analyses have shown that 17β-estradiol and raloxifene bind to ER with small, but important, differences in three dimensional structure. These subtle differences in the conformation of the ligand:receptor complex are likely the basis for the key pharmacological differences between estrogens and the various SERMs (i.e. raloxifene vs tamoxifen). Raloxifene also produces estrogen-like effects on serum cholesterol metabolism and the vasculature. Thus, while raloxifene exhibits a complete estrogen antagonist in mammary tissue and the uterus, it produces beneficial effects on the cardiovascular system and prevents bone loss via an estrogen receptor mediated mechanism.     

Synthesis and biological evaluation of 4,6-diaryl-2-pyrimidinamine derivatives as anti-breast cancer agents

Breast cancer is the most frequently diagnosed cancers and the leading causes of cancer death among females worldwide. Estrogen receptor positive has been identified as the predominant internal reasons, involving in more than 70% breast cancer patients and SERMs which competes with estradiol for the binding to ERα in breast tissue are widely used in the treatment of ER+ breast cancer, such as tamoxifen, raloxifene. However, many SERMs may cause negative side effects due to their estrogenic activity in other tissues and approximate 50% of patients with ER-positive tumors either initially do not respond or become resistant to these drugs. Here, a series of designed 4,6-diaryl-2-pyrimidinamine derivatives had been synthesized to treat estrogen receptor positive breast cancer by simultaneously antagonizing ER and inhibiting VEGFR-2. Bioactivity evaluation showed that these compounds could significantly inhibit the proliferation of MCF-7, HUVEC and Ishikawa cells. Further studies identified compound III-3A could antagonize against estrogen action and inhibit the phosphorylation of VEGFR-2 as well as inhibit angiogenesis in vivo. The results indicated designed 4,6-diaryl-2-pyrimidinamine derivatives can be used to further study as anti-breast cancer drugs.     

Tissue selectivity of ospemifene: Pharmacologic profile and clinical implications

The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with approximately equal affinities. In preclinical models, ospemifene increased vaginal and uterine epithelial thickness and mucification to the same extent as estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; there also was no stimulatory effect on endometrial cells. In rat and human mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on estrogen-induced cell responses and cell proliferation, supporting an antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry in preclinical models, consistent with improvements in markers of bone resorption and formation in postmenopausal women. Based on the preclinical evidence, ospemifene has beneficial estrogen-like effects on the vaginal epithelium, preliminary evidence to support a neutral endometrial profile, antiproliferative effects in breast, and estrogenic effects in bone. Taken together, especially regarding estrogen-like effects on the vaginal epithelium, ospemifene presents a profile of tissue-specific effects that appear novel among available SERMs and well-suited for the treatment of VVA.     

Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations

Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E₂ or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival.     

Progress in the prevention of breast cancer: concept to reality

In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention.     

Selective oestrogen receptor modulators

Selective oestrogen receptor modulators (SERMs) are compounds which act like oestrogens in some target tissues but which antagonise their effects in others. The first example of a SERM (referred to as a first-generation compound) was tamoxifen, for which oestrogen-like agonist activity on bone was seen to occur simultaneously with oestrogen antagonist activity on the breast. An unwanted effect of tamoxifen was its oestrogen-like action on the endometrium. Second-generation compounds have since been developed, most notably raloxifene, which has oestrogen-like actions on bone, lipids and the coagulation system, and oestrogen antagonist effects on the breast and uterus. Raloxifene has undergone very extensive, prospective, placebo-controlled, randomised trial evaluation, in which anti-fracture efficacy (to date only for vertebral fracture) has been accompanied by a major reduction in the incidence of new breast cancer. The compound is similar to placebo in its uterine effects, and similar to oestrogen in causing a two- to threefold increase in the risk of venous thromboembolism. Its lipid effects are similar to those of oestrogen, except for a relatively small effect on high-density lipoprotein cholesterol, and no significant effect on triglycerides. Data on cardiovascular event rates are not yet available; data on cognitive function are preliminary and, to date, reassuring. The mechanisms by which the same compound can exert oestrogen agonist effects on one target and antagonist effects on another are still being clarified. Important aspects include the fact that the oestrogen receptor undergoes different conformational changes according to the ligand. Thus the crystal structure of oestradiol bound to the oestrogen receptor differs from that of raloxifene bound to the same receptor. The existence of two oestrogen receptor subtypes may also be relevant. Mechanisms include differing interactions with various domains of the oestrogen receptor, and tissue-specific recruitment of steroid receptor co-activators and co-repressors may underlie some of the tissue-specific effects. The SERMs may be the prototype for other selective steroid receptor modulators, for example the androgen and progesterone receptors. The development of tissue target-specific agents is an exciting advance in endocrine pharmacology and can be extended to agents, such as tibolone, which exert some of their tissue specificity through their metabolites.     

Targeted anti-estrogens to treat and prevent diseases in women

The estrogen receptor has been successfully targeted with the anti-estrogen tamoxifen to treat all stages of breast cancer. Because tamoxifen is a partial agonist, it exhibits target-site specificity: it acts as an anti-estrogen in the breast to inhibit tumor growth, while exhibiting estrogenic effects on bones and lipid metabolism. Therefore, tamoxifen has the added benefit of maintaining bone density and reducing the risk of myocardial infarction in postmenopausal women.However, undesirable side effects of tamoxifen preclude its use as a hormone replacement therapy for otherwise healthy women. New anti-estrogens are currently being developed that may prevent osteoporosis, breast and endometrial cancer, and reduce the risk of myocardial infarction.     

Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus

To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.