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PubMed2001

Effect of physicians opinion on patients' choice of treatment.

BACKGROUND: While it is obvious that patients should be involved in the decision making process, questions arise as to whether it is feasible to inform them objectively. OBJECTIVE: To assess the impact of the physician's opinion, on the choice of treatment, to the patient. SETTING: We imagined a hypothetical case of a 55-years-old woman with a high risk of osteoporosis. Two patient information letters were written, containing valid scientific information, but reflecting two diverging physicians' opinions, giving the choice between two available medications for osteoporosis prevention: hormone replacement therapy (HRT) and a selective estrogen receptor modulator (SERM), raloxifene. SUBJECTS: We submitted one of the letters (by lottery) to 58 nurses. They were asked to act as this potential patient, and to choose which treatment they preferred to have prescribed. RESULTS: 23/30 women receiving the version favouring the use of HRT, preferred HRT, 26/28 receiving the version favouring SERM preferred this treatment (Chi-Square Pearson 37.3; P<0.001). CONCLUSION: The content of the information provided and its wording have a great influence on the patients' decision.

Estrogen Replacement Therapy↗
PubMed2000

Drugs for the gynecologist to prescribe in the prevention of breast cancer: current status and future trends.

Tamoxifen was approved for breast cancer prevention in October 1998. Thus, for the first time, we as gynecologists are being asked to prescribe this drug to healthy women. In the past each one of us has cared for women with breast cancer who have been treated with tamoxifen by oncologists or breast surgeons for the malignancy. Effects of tamoxifen on the uterus resulting in carcinomas, hyperplasia, and polyps are well known. Furthermore, tamoxifen has estrogenic properties in the venous system, increasing the incidence of deep vein thrombosis and pulmonary emboli. A new SERM (selective estrogen receptor modulator), raloxifene, has been approved for prevention and treatment of osteoporosis in postmenopausal women. It does not have stimulatory effects on the endometrium; however, it is estrogenic in the venous system. Preclinical data, as well as the breast cancer incidence reported in studies of the skeleton, seem to indicate that its effects in the breast are similar to those of tamoxifen. This article reviews tamoxifen and the new SERM, raloxifene, in an attempt to help gynecologists better understand each compound and what data are currently known, what we hope to learn from future studies, and what currently makes sense for clinical practice.

Breast Neoplasms↗
PubMed2001

A review of cancer chemopreventive agents.

In the late 20(th) century, the treatment of cancer began to include its prevention. Today, compounds exist that will lower the risk of developing certain types of cancer. This has been demonstrated in studies where chemically induced tumor growth has been slowed or reversed. Anti-inflammatory compounds having chemopreventive activity are piroxicam, sulindac, aspirin, celecoxib and curcumin. The selective estrogen receptor modulators, tamoxifen and raloxifene, are beneficial in the prevention of estrogen dependent tumors. Retinoids, vitamin A derivatives, such as targretin and fenretinide are useful in the prevention of tumors. Compounds containing sulfur, such as sulforaphane and oltipraz, are even useful as radioprotective agents. The steroid dehydroepiandosterone can inhibit experimental carcinogenesis. All of these chemical classes provide a start for the medicinal chemist to design more effective chemopreventive agents. The biomarkers used to determine the chemopreventive activity of new compounds are quite often activities of enzymes. The identification of those individuals at high risk is still in its infancy and presents a troubling dilemma.

Animals↗
PubMed2003

Prevention of breast cancer using SERMs and aromatase inhibitors.

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.

Aromatase Inhibitors↗
PubMed2003

SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GM-CSF.

Bone metabolism requires tightly coupled activities exhibited by two unique cell populations, the bone-resorbing osteoclasts and the bone-forming osteoblasts. Imbalance in the function of these two cell types can result in osteoporosis, a condition characterized by loss in bone integrity and of bone mass. We developed a human bone cell culture model that allows the in vitro study of bone formation and osteoclastogenesis and employed this bone model for the screening and pharmacological analyses of protein and small molecule therapeutics. The cytokines, interleukin-6 (IL-6) and granulocyte macrophage colony stimulating factor (GM-CSF), play an intricate role in osteoclastogenesis in this system. Neutralizing antibodies to IL-6 and GM-CSF decreased the formation of osteoclast-like cells. SP500263, an early lead compound from a novel class of selective estrogen receptor modulators (SERMs), was more efficacious than estrogen and comparable to raloxifene in blocking cytokine production and formation of osteoclast-like cells. Our research demonstrates the usefulness of the in vitro co-culture model in the dissection of molecular events relevant to bone metabolism and provides greater insight into a potential novel role for cytokines in bone resorption. Furthermore, representatives of the SP500263 family of SERMs may be effective as therapeutics for the treatment of osteoporosis.

Biomarkers↗
PubMed2002

[Antiestrogen therapy in the treatment of breast neoplasms].

During recent years the development of hormone therapy for the treatment breast neoplasms has seen, in addition to classic aspecific antiestrogens (AE) like tamoxifen (TAM) and to a lesser extent toremifen, a major development of new molecules divided into two groups: the first is the so-called selective estrogen receptor modulators (SERMs), the most important of which is Raloxifen, which mediate estrogen-agonist effects in some tissues and estrogen-antagonist effects in others; the second group includes the aromatase inhibitors (AI), important enzymes for peripheral estrogen conversion. Some studies compare or associate classic AE with the new SERMs and AI, both in adjuvant therapy and in treatment for advanced forms. Other trials assess the anti-osteoporotic activity of some SERMs which present concomitant inhibitory activity on the breast and endometrium.

Adult↗
PubMed2001

[Hormone therapy and breast cancer: a review].

PURPOSE: Tamoxifen as adjuvant hormonal therapy after hormonosensitive-breast cancer surgery is well established nowadays, as well as its efficacy in first-line therapy of advanced hormonosensitive breast cancers. Research of drugs which could be effective, with little toxicity, and having a positive impact on cardiovascular disease or bone is an important issue. CURRENT KNOWLEDGE AND KEY POINTS: New drugs are in development or will soon be on the market to permit second or third lines of treatment with respect to effectiveness and quality of life, such as new anti-estrogens or selective estrogen receptors modulators or aromatase inhibitors. Their principal characteristics are reviewed through recent data. FUTURE PROSPECTS AND PROJECTS: Prevention of breast cancer is a pertinent question and major publications are presented. Finally, the controversy about the possible reintroduction of replacement hormonal therapy after breast cancer will be questioned through trials.

Adolescent↗
PubMed2005

Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin.

OBJECTIVES: In different tissues, estrogens, selective estrogen receptor modulators (SERMs), and anti-estrogens exert different biologic activities. For the endometrium, estradiol and tamoxifen induce proliferation, and because of this, tamoxifen treatment of breast cancer patients results in a two- to sevenfold increased risk for development of endometrial cancer. Use of raloxifene, or the anti-estrogen ICI182780, does not result in such an increased risk. The objective of the current study was to generate and analyze gene expression profiles that reflect the transcriptional response of the human endometrium to estradiol, SERMs like tamoxifen and raloxifene, and anti-estrogens like ICI182780. METHODS: Transient transfections were performed to analyze the transcriptional response of ECC-1 cells to estradiol, tamoxifen, raloxifene, and ICI182780. Subsequently, to reveal the molecular mechanism of action, gene expression profiles were generated and some of the observed regulated genes were confirmed by Northern blotting. Biostatistical methods were employed to analyze the expression profile results further, and amphiregulin effects on ECC-1 cell signaling were investigated using Northern and Western blotting, and 3H-thymidine incorporation. RESULTS: Analysis of the profiles revealed that estradiol, tamoxifen, raloxifene, and ICI182780 influence the same biologic processes, but they do so via regulation of different sets of genes. Upon construction of a genetic network it was observed that the largest possible network centered on epidermal growth factor (EGF) receptor signaling. Furthermore, the EGF receptor ligand amphiregulin was differentially regulated by all four ligands. Next it was shown that amphiregulin indeed could stimulate EGF receptor signaling in ECC-1 cells. Based on these results, it was hypothesized that EGF receptor signaling could differentially be affected by estrogen, tamoxifen, raloxifene, and ICI182780 because these four compounds differentially regulate the EGF receptor ligand amphiregulin. CONCLUSIONS: Regulation of amphiregulin coincides with the described in vivo effect of the four ligands on the endometrium. Therefore, it is possible that modulation of EGF receptor signaling is a significant player in estrogen-agonistic growth of the endometrium and needs to be investigated further.

Amphiregulin↗
PubMedDate not supplied

Estrogen receptor profiles: changes in mouse and rat mammary tumors by treatment with selective estrogen receptor modifiers.

OBJECTIVE: The aim of this work was to analyze the effect of estradiol (E(2)), medroxyprogesterone and the two selective estrogen receptor modulators (SERMs) (tamoxifen (Tam) and raloxifene (Ral)) on the estrogen receptor (ER) conformers profile performed by size exclusion HPLC in relation to hormone dependence of mammary tumors. MATERIALS AND METHODS: Two types of mammary tumors were studied: tumors transplanted in BALB/c mice that are medroxyprogesterone acetate (MPA)-dependent for growth, and tumors induced in Sprague-Dawley rats by intraperitoneal injection of N-nitroso-N-methylurea (NMU). Tumors from mice treated with MPA, E(2), Tam or Ral and NMU-treated rats were analyzed and compared to that of control. RESULTS: The tumor conformer profiles were as follows: control and MPA-treated mice showed only one peak (oligomeric form); E(2)-treated mice also showed only one peak (dimer); Tam-treated mice showed one peak corresponding to a possible proteolytic fragment, and Ral-treated mice showed two peaks (oligomeric and a possible proteolytic fragment). On the other hand, NMU-induced mammary tumors from rats showed three peaks (oligomeric, monomeric and proteolytic). CONCLUSION: Our findings may indicate that SERMs affect the aggregation state of ER and thereby its ability to modulate genomic transcription mechanisms related to growth rate.

Animals↗
PubMed2004

[Which is the better choice, estrogen or SERMs in postmenopausal women?].

Hormone replacement therapy (HRT) increases the bone mineral density (BMD) and reduces the risk of vertebral and hip fractures in postmenopausal women. But, long term HRT slightly increases the risk of breast cancer. Raloxifene is a selective estrogen receptor modulator that has estrogen agonist effects in the skeleton and cardiovascular system and estrogen antagonist effects in the uterus and breast. Raloxifene effectively prevents bone loss and significantly, increases lumbar spine, hip, and total body bone mineral density, raloxifene reduces the risk of vertebral fracture. Raloxifene treatment leads to no increase in vaginal bleeding or mastaigia and to greater than 70% reduction in risk for invasive breast cancer. But raloxifene increases the hot flashes in postmenopausal women. In conclusion, HRT is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women with menopausal symptoms, raloxifene is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women without menopausal symptoms.

Breast Neoplasms↗
PubMed2005

[SERMs: an update for clinicians].

With the successful manipulation by molecular pharmacological technology of the estrogenic properties of selective estrogen receptor modulators (SERMs) that are highly organ- and tissue-specific, SERMs have now become available for the management of osteoporosis, as they did for breast cancer earlier. This presentation focuses on raloxifene (RLX), a second-generation SERM and an agent of interest to clinicians engaged in the management of osteoporosis on a day-to-day basis. RLX is a unique agent, in that it exhibits similar but distinct effects on bone metabolism from those of estrogen. RLX also appears to exert milder inhibitory effects on bone resorption than bisphosphonates (BPs), another class of antiresorptive agents, while ample evidence suggests that RLX compares favorably with BPs in preventing a variety of non-traumatic fractures.

Animals↗
PubMed2001

Preventing and treating osteoporosis: strategies at the millennium.

Osteoporosis has been defined as "a progressive systemic disease characterized by low bone density and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture." Osteoporosis and the consequences of compromised bone strength--particularly vertebral and hip fractures--are a significant cause of frailty, and increased morbidity and even mortality and hence are a serious and costly public health problem in the elderly population. However, due to remarkable advances in basic and clinical research and in drug design, development, and testing, a number of efficacious, evidence-based options are available for the prevention and treatment of osteoporosis. These options extend far beyond estrogen/progestin therapy and include lifestyle and dietary changes such as increasing weight-bearing activity, enhancing calcium and vitamin D intake, as well as incorporating pharmacologic agents such as the bisphosphonates and selective estrogen receptor modulators (SERMs) such as raloxifene. In addition to its efficacy in increasing bone mineral density and reducing vertebral fractures by almost 40% in women with osteoporosis, the SERM raloxifene appears to promote a cardioprotective profile and to offer some protection against breast cancer. The potential of raloxifene to prevent or delay the development of a number of chronic diseases of aging such as osteoporosis, cardiovascular disease, and perhaps even Alzheimer's disease has stimulated the development and refinement of subsequent generations of SERMs aimed at maximizing beneficial effects in a wide variety of tissues while eliminating deleterious outcomes and side effects.

Diphosphonates↗
PubMed2003

Postmenopausal osteoporosis in the dialysis patient.

PURPOSE OF REVIEW: Osteoporosis is the most prevalent bone disorder in the general population, particularly in the middle and older age groups. Although more than half of the prevalent dialysis population is within these age groups, little concern has been given to the possible role of estrogen deficiency in the pathogenesis of bone disease in end-stage renal disease. The purpose of this review is to summarize the recent published evidence that supports a potential role of the postmenopausal state in the pathogenesis of bone disease in end-stage renal disease and their implications for treatment. RECENT FINDINGS: Recent studies have shown that although the risk factors for fracture in end-stage renal disease are similar to the general population, the incidence is three to fourfold higher. The high prevalence of older population, the frequently observed premature amenorrhea and early menopause in dialysis patients may play a role. Similarly, the proportion of end-stage renal disease women receiving hormone replacement therapy is at least three times lower than the general population. Recent evidence on the risk of hormone replacement therapy should caution about its use in end-stage renal disease patients. New evidence suggests that selective estrogen receptor modulators may increase bone mass without significant secondary effects. Other alternatives, such as the use of bisphosphonates, should be considered with caution due to the risk of excessive suppression of bone turnover, worsening or favoring the development of adynamic bone disease. SUMMARY: Osteoporosis should be recognized as an important entity that may modify the current conception of renal osteodystrophy in postmenopausal patients with end-stage renal disease. Further clinical studies are needed in order to propose strategies that may reduce the impact of postmenopausal osteoporosis in the dialysis population.

Bone Density↗
PubMed2006

[Molecular mechanism of tissue-specific actions of SERM].

Selective estrogen receptor modulator (SERM) is designated as synthetic ligands for estrogen receptors (ERs), exhibiting tissue-specific agonisitic/antagonisitic activities. Among SERM, raloxifen is a most clinically successful as an anti-oseteoporotic agent. Such tissue-specific actions of SERM are presumed to mediate through unusual structure alteration of liganded ERs coupled with co-regulator recruitments.

Bone Density Conservation Agents↗
PubMedDate not supplied

Osteoporosis management.

About 40% of women who reach the age of 50 are expected to suffer from osteoporosis during their remaining life. The morbidity associated with hip, spinal and wrist fractures, resulting from osteoporosis, and the mortality resulting from hip fractures justify the development of prevention strategies. Optimal management of osteoporosis consists of maximizing peak bone mass in early adulthood and preventing the rapid bone loss that occurs soon after the menopause. Peak bone mass will be reached in most women if adequate nutrition is taken and exercise is encouraged, while major risk factors are avoided. At the menopause, prescription of hormone replacement therapy (HRT) constitutes the primary prevention strategy. There are, however, questions that remain unanswered or debated. What is the optimal dose of HRT, when should it be started, and for how long should it be maintained? In women who do not, or may not, take HRT, and who have osteoporosis, alternative therapeutic options include diphosphonates (e.g., alendronate) and Selective Estrogen Receptor Modulators (such as raloxifene). Other treatments to restore bone strength in women with established disease may also reduce the risk of fractures. Some of them, such as calcitonin, may not be cost effective. Others have produced conflicting data (fluoride) and others are still under evaluation (PTH or strontium). In sunlight-deprived, vitamin D-deficient elderly nursing home residents, dietary supplementation of calcium and vitamin D has been shown to prevent bone loss and fractures. Strategies to avoid falls should also be encouraged for these patients.

Aged↗
PubMed2004

National trends in osteoporosis visits and osteoporosis treatment, 1988-2003.

BACKGROUND: Research is limited on physicians' prescribing practices for osteoporosis treatment. We investigated patterns of pharmacotherapy from 1988 to 2003 and the impact of new medications on identification and treatment of patients with osteoporosis. METHODS: We tracked trends from 1988 through 2003 in the frequency of osteoporosis visits and patterns of pharmacotherapy associated with these visits using nationally representative data on prescribing patterns by office-based US physicians from the IMS HEALTH National Disease and Therapeutic Index. RESULTS: The number of physician visits for osteoporosis increased 4-fold between 1994 (1.3 million visits) and 2003 (6.3 million visits), whereas it had remained stable in prior years. This increase coincided with the availability of oral daily bisphosphonates and the selective estrogen receptor modulator raloxifene. The annualized percentage of osteoporosis visits where medications were prescribed increased from 82% in 1988 to 97% by 2003. Prior to 1994, the leading choices for osteoporosis therapy were calcium and estrogens, with lesser roles played by calcitonins and bisphosphonates. Between 1994 and 2003, the percentage of visits where bisphosphonates and raloxifene were prescribed increased from 14% to 73% and from 0% to 12%, respectively, while prescriptions for other medications declined. CONCLUSIONS: New medications for osteoporosis offering improved efficacy and convenient dosing were associated with increased frequency of patient visits and treatment. This finding suggests that new drug therapy contributed to increased disease recognition and treatment.

Adult↗
PubMed2003

Randomized, double-blind, multicenter trial comparing two doses of arzoxifene (LY353381) in hormone-sensitive advanced or metastatic breast cancer patients.

BACKGROUND: This randomized, double-blind, phase II study assessed two doses of the selective estrogen receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics and toxicities were also assessed. PATIENTS AND METHODS: Ninety-two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day. Tumor response was assessed using World Health Organization criteria. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) system. Pharmacokinetic data were analyzed using the NONMEM software program (GloboMax, Hanover, MD, USA). RESULTS: Response rates in the 20 mg arm were numerically higher than the 50-mg arm according to the investigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the 20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus 47.7%). Arzoxifene was well tolerated. There were no study drug-related deaths. Mean observed steady-state plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively. CONCLUSIONS: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene. Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.

Aged↗
PubMed2002

[What can we expect of raloxifene in the treatment of postmenopausal osteoporosis--views of a gynecologist].

OBJECTIVE: Evaluation of positive properties and side effects of raloxifene treatment with respect to its potential use as agent to improve women's health and quality of life in postmenopausal years. DESIGN: A review article. SETTING: Obstetrics and Gynaecology Department, Charles University 2nd Medical Faculty and Teaching Hospital Motol, Prague. SUBJECT: Estrogen use may protect against osteoporosis and cardiovascular disease, but may increase the risk of breast cancer in long-term treated women and also may increase the risk of irregular uterine bleeding (in combination with gestagen in non-hysterectomized women) in perimenopause and postmenopause. Drugs with tissue-specific estrogenic effects are termed selective estrogen receptor modulators (SERM). Tamoxifen is the first SERM successfully used in the prevention and treatment of breast cancer. Another SERM raloxifene is widely used in the prevention and treatment of postmenopausal osteoporosis, especially in women without climacteric complaints. Therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate endometrium and breast. Evaluation of another potential positive effects (reducing size of uterine leiomyomas, etc.) warrants further investigation. CONCLUSION: Raloxifene can be used in postmenopausal women free of climacteric symptoms for the prevention and treatment of postmenopausal osteoporosis with no increased risk of thrombosis and with the advantage of positive side effects during the treatment.

Estrogen Replacement Therapy↗