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PubMed2001

Rationale and overview of the Raloxifene Use for the Heart (RUTH) trial.

Raloxifene is a selective estrogen receptor modulator (SERM) that has beneficial effects on several cardiovascular risk factors and has also been associated with a reduced risk of breast cancer in osteoporosis prevention trials. The Raloxifene Use for the Heart (RUTH) study was designed to test the hypothesis that, compared to placebo, raloxifene at 60 mg/day (1) lowers the risk of the combined end point of coronary death, nonfatal myocardial infarction (MI), and hospitalized acute coronary syndromes other than MI and (2) reduces the risk of invasive breast cancer (coprimary end point) in women at high risk for major coronary events based on established cardiovascular disease (CVD) or multiple risk factors. RUTH is a double-blind, placebo-controlled, randomized, clinical trial of 10,101 women aged 55 years or older from 26 countries and is expected to be completed in approximately 5 years.

Adenocarcinoma↗
PubMed2002

Tamoxifen, raloxifene and the prevention of breast cancer.

The recognition of a new group of drugs, now named selective estrogen receptor modulators (SERMs) has revolutionized prospects for the prevention of breast cancer. New agents will continue to be tested against tamoxifen, the first SERM and an established treatment of ER positive breast cancer. Raloxifene a related SERM is used to treat and prevent osteoporosis with the potential beneficial side effect of preventing breast cancer. The Study of Tamoxifen and Raloxifene (STAR) trial will establish whether raloxifene is an improvement over tamoxifen. Most importantly, emerging information about the molecular pharmacology of SERMs will be used to decipher the mechanism of action at specific target sites around a woman's body. This knowledge can be used to design new SERMs and advance the prospects for multifunctional medicine to prevent breast cancer, osteoporosis and coronary heart disease.

Adult↗
PubMed2005

[Effects of raloxifene on bone biomarkers in postmenopausal women on maintenance haemodialysis].

Postmenopausal women on maintenance haemodialysis (MHD) has considerably higher risk of bone fracture than general population with combination of postmenopausal osteoporosis and renal osteodystrophy. However, the treatment of osteoporosis on MHD has not been established. Evidence indicates raloxifene (RLX), a selective estrogen receptor modulator, is effective for a protection of bone fracture without increasing of breast cancer and endometrial cancer. We hereby report short-term use experience of RLX for the postmenopausal MHD patients. Fifteen postmenopausal MHD patients with less than 80% of YAM bone density in DEXA administrated 60 mg RLX on every HD days (3 days/week). Serum NTX level significantly decreased after 6 months (180 +/- 18 vs. 95 +/- 12 nmol/BCE/L, p< 0.05), however, i-PTH did not have the significant difference. (115 +/- 23 vs. 157 +/- 29 pg/mL). RLX is effective for bone biomarker improvement in postmenopausal MHD patients. Further evaluation for the effectiveness and safety of RLX is necessary in the long term.

Aged↗
PubMed2006

Controversies in adjuvant endocrine treatment of premenopausal women.

For patients with hormone receptor-positive breast cancer, some form of endocrine therapy is central to the management of their disease. For premenopausal patients in whom estrogen synthesis occurs primarily in the ovaries, current treatment options include ovarian ablation or suppression and selective estrogen receptor modulators such as tamoxifen and toremifene. Ovarian ablation and tamoxifen have demonstrated their effectiveness in the adjuvant setting, reducing the risk of recurrence and death. However, although some studies suggest ovarian ablation results in an equivalent outcome to chemotherapy alone, studies examining the combination have not demonstrated a clear benefit with the addition of ovarian suppression to standard chemotherapy. Results from trials combining ovarian suppression with tamoxifen have also been inconclusive. Finally, although aromatase inhibitors cannot be used as monotherapy in premenopausal patients, the reduction in the risk of recurrence observed with the integration of these agents into adjuvant regimens in postmenopausal patients when compared with the standard 5 years of tamoxifen has stimulated interest in evaluating the combination of ovarian suppression with an aromatase inhibitor in premenopausal women. Several ongoing trials will investigate these combinations as well as ovarian suppression plus tamoxifen.

Adult↗
PubMed2006

Effects of raloxifene on platelet functions in patients with postmenopausal osteoporosis.

Many studies have addressed the effects of estrogenic compounds on platelet function. Raloxifene is a selective estrogen receptor modulator (SERM), which is currently used for the treatment of postmenopausal osteoporosis. At present, there are no clinical data about the effects of raloxifene on platelet function. The purpose of this study was to determine if raloxifene at therapeutic doses affects platelet function in patients with postmenopausal osteoporosis. The effects of raloxifene on platelet function were investigated using a commercial platelet function analyzer (PFA-100) with collagen epinephrine and collagen adenosine 5'-diphosphate (ADP) cartridges. We studied platelet function of 30 patients with postmenopausal osteoporosis before and 15 days after initiation of raloxifene 60 mg/daily. Closure times did not differ significantly between samples obtained before (117.8 +/- 20.5 s) and after raloxifene therapy (106.5 +/- 25.4 s) in collagen/epinephrine cartridges (P > 0.05). There was also no statistically significant difference in mean closure times with collagen/ADP cartridges at baseline (86.2 +/- 18.5 s) and after raloxifene therapy (84.4 +/- 13.8 s) (P > 0.05). Platelet counts (278.3 +/- 72.9 vs. 262.4 +/- 56.7 109/L, P > 0.05) and mean platelet volumes (8.9 +/- 1 vs. 9.1 +/- 1 fL, P > 0.05) were not different before and after raloxifene therapy. Although estrogen related compounds do affect platelet function, there is suggestive data in our study that raloxifene in therapeutic dose exhibit no effect on platelet function in patients with postmenopausal osteoporosis.

Aged↗
PubMed2003

Raloxifene causing malabsorption of levothyroxine.

To our knowledge, raloxifene hydrochloride, a selective estrogen receptor modulator, has never been reported to interfere with absorption of levothyroxine. We describe a 79-year-old woman with chronic, treated primary hypothyroidism, presenting with increasing levothyroxine requirement while taking raloxifene at the same time as levothyroxine. For two 6- to 8-week periods, we separated the ingestion of raloxifene and levothyroxine by about 12 hours. In addition, we tested the absorption of 1.0 mg of levothyroxine sodium with and without the coadministration of 60 mg of raloxifene hydrochloride on 2 separate occasions by collecting serial blood samples for 6 hours. Hypothyroidism occurred in a reproducible fashion whenever levothyroxine and raloxifene were administered together and improved whenever they were taken separately. Combined administration of levothyroxine and raloxifene resulted in lower levels of serum thyroxine compared with administration of levothyroxine alone. By a yet unknown mechanism, raloxifene caused malabsorption of levothyroxine in our patient when coadministered.

Absorption↗
PubMed2006

Small optic cup sizes among women using tamoxifen: assessment with scanning laser ophthalmoscopy.

PURPOSE: There is a substantial literature showing that the selective estrogen receptor modulator tamoxifen can block swelling-activated chloride channels, such as those in astrocytes. This study aimed to test the hypothesis that anatomic characteristics consistent with swelling may be measured within the optic nerve head (ONH) of tamoxifen users whose ONH appearance is considered within normal limits. METHODS: Indices of ONH topography were measured using the Heidelberg Retina Tomograph II (HRT) for two populations of women ages 40-69 years: (1) subjects using tamoxifen (20 mg/day) as adjuvant therapy after successful primary treatment for breast cancer and (2) control subjects not using any hormonal medication. All subjects had excellent visual acuity (with 20/20 or better in the test eye), and all appeared to be free of eye disease, as based on conventional photographic assessment. The study design was cross-sectional. The various ONH indices were assessed as functions of the duration of tamoxifen use. RESULTS: The optic cups of short-term tamoxifen users ( 2 years, <or=5 years) were not distinguishable from those of the control subjects. The presence of small cups among short-term users did not depend on subjects' medical histories prior to tamoxifen use. Disk margin indices were not related significantly to the duration of tamoxifen use. CONCLUSIONS: Small cup sizes consistent with localized subclinical swelling are not rare among short-term tamoxifen users. Thus, small cups are not likely to be a manifestation of a cumulative-dose toxicity. Instead, they probably result from other causes, possibly involving the action of tamoxifen on estrogen receptors. Further investigation with longitudinal and interventional methodologies is needed to definitively interpret the results.

Adult↗
PubMed2005

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Aerospace Medicine↗
PubMed2003

Skeletal and nonskeletal effects of raloxifene.

Raloxifene, a selective estrogen receptor modulator, is approved for the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density and suppression of bone turnover markers in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation study was the pivotal treatment trial for raloxifene. It demonstrated significant reduction in the risk for vertebral fractures after 1 and 3 years. Significant reduction of nonvertebral fractures with raloxifene has not yet been demonstrated. In addition to the effects of raloxifene on bone, potentially beneficial effects on the cardiovascular system, breast, and uterus have been described. Most of these nonskeletal effects have been reported as secondary endpoints from large osteoporosis trials with raloxifene. Prospective, randomized, double-blind studies of raloxifene with breast cancer prevention and cardiovascular protection as primary endpoints are now underway.

Aged↗
PubMed1999

Out-patient hysteroscopy in asymptomatic postmenopausal women.

OBJECTIVE: To determine the prevalence of uterine and endometrial abnormalities in normal postmenopausal women and assess the accuracy of subjective hysteroscopic appearances and endometrial histology following 12 weeks of hormonal treatment. DESIGN: A multicentered randomized double-blind placebo-controlled trial in which the volunteers received conjugated equine estrogen 0.625 mg, selective estrogen receptor modulator (in one of two doses) or placebo. SETTING: Out-patient endoscopy unit in a large teaching hospital. METHODS: Out-patient hysteroscopy and endometrial biopsy. RESULTS: Forty-eight women had a hysteroscopy and endometrial biopsy: eight (16.6%; 95% confidence interval, CI 6-27%) women had intrauterine polyps and 38 (79.2%) women had normal hysteroscopies. Thirty-five women had a repeat endometrial assessment with hysteroscopy and, for the detection of proliferative endometrium (prevalence 22.8%), a sensitivity of 87.5%, a specificity of 74%, a negative predictive value of 95% and a positive predictive value of 50% were observed. There was a good proportion of agreement, 0.77 (95% CI 0.63-0.91), but a kappa score of 0.486 revealed only a moderate level of agreement. The likelihood ratios for proliferative endometrium were: LHR+ = 3.38 (fair), and LHR- = 0.17 (moderate). CONCLUSIONS: Hysteroscopic assessment of the uterine cavity is efficient in the detection of pathological intrauterine lesions, but is only moderately successful in determining physiological changes in the endometrium. This study defines a standard of observational statistics for out-patient hysteroscopy in relation to normal endometrial histology in postmenopausal women who may have been ingesting exogenous estrogens.

Ambulatory Care↗
PubMed2002

Hormone replacement therapy in women with a history of breast cancer.

Health care professionals in modern Western societies will meet an increasing number of women surviving breast cancer. How the menopause of these women should be treated is still an open question. Use of hormone replacement therapy (HRT) may, at least in theory, increase the risk for recurrence of cancer, but its categoric refusal is a double-edged sword because it also denies these women all the undisputable health benefits HRT provides. This refusal is not, however, supported by the observational data available so far on this question, because HRT has not increased the risk for breast cancer recurrence. In fact, it is well established that HRT abolishes hot flushes and improves significantly these patients' quality of life. At present, we have no effective nonhormonal alternatives for the control of vasomotor symptoms, and the efficacy of phytoestrogens in the treatment of menopausal symptoms is unproven. Selective estrogen receptor modulators (SERMs) which protect against osteoporosis and perhaps also against breast cancer, and which may have beneficial effects on the cardiovascular system, aggravate hot flushes and are therefore not useful, at least in the first postmenopausal years. In some countries, progestins are often prescribed for the control of such patients' vasomotor symptoms, but their safety has never been assessed in clinical trials, and in theory they can be harmful. Randomized clinical trials (RCT) on the use of HRT in breast cancer survivors are underway, but their completion will take years, and even these may be open to criticism. Tibolone may appear to be an appealing alternative for HRT, but it should also be studied with RCTs in this indication. At present, a patient with a history of breast cancer must be given balanced information as to the possible benefits and risks of HRT, and she herself must make the decision whether or not to start HRT.

Breast Neoplasms↗
PubMedDate not supplied

Management of primary osteoporosis.

Although there is a great need for better therapeutic approaches to the patient who presents with a fracture, osteoporotic fractures will remain a condition that is more amenable to prevention than treatment. Hormone replacement therapy (HRT) is still considered by many the mainstay for the prevention and the treatment of posrmenopausal osteoporosis. However, there are several controversies regarding HRT, especially the duration of treatment and the risks/benefits ratio. Recent studies have challenged the assumption that HRT conveys real long-term beneficial effects. Raloxifene or other "selective estrogen receptor modulators" (SERMs) should progressively replace HRT in elderly women. Bisphosphonates have demonstrated a clearcut efficacy in the treatment of osteoporosis. Alendronate and risedronate have been the most extensively studied bisphosphonates under randomized controlled trials conditions. Both agents can reduce the risk of vertebral and hip fractures by one-fourth to one-half. However, oral bisphosphonates are not without gastro-intestinal toxicity and strict adherence to constraining therapeutic schemes is mandatory. Intermittent treatments are already in use. Weekly alendronate is as efficient as daily therapy and improves treatment compliance. Newer more potent bisphosphonates, such as oral ibandronate or intravenous zoledronic acid, will allow much less frequent administration. The anti-fracture efficacy of yearly zoledronic acid infusions is thus currently tested. On the other hand, bone-forming agents, such as daily subcutaneous injections of teriparatide (rhPTH 1-34) offer exciting perspectives for the treatment of severe osteoporosis despite the complexity of such therapy.

Absorptiometry, Photon↗
PubMed2003

Mortality and morbidity associated with osteoporosis drug treatment following hip fracture.

This study examined post-fracture osteoporosis drug treatment in hip fracture patients and the association of treatment with mortality and morbidity. Pre- and post-fracture demographic/health information was collected on a cohort of hip fracture patients aged 65+ years. Post-fracture administrative data on prescription drug use and health care utilization was linked to the cohort data. Five classes of osteoporosis drugs were available during the study period: hormone replacement therapy (HRT), bisphosphonates (BSP), calcitonin, selective estrogen receptor modulators (SERMs) and vitamin D(3) (Rocaltrol). Pre-fracture, 38 of 449 patients (8%) were on osteoporosis medications. Post-fracture, 81 of 356 patients (23%) were treated; 63 of these patients were untreated prior to fracture. Both treated and untreated patients had similar rates of subsequent hip fracture (6% and 4%, respectively) and Colles fracture (2%). Regardless of treatment status, patients were also equally likely to be hospitalized, both in the short-term (28% in treated, 27% in untreated) and in the long-term (43% versus 37%). However, mortality was significantly lower in the treated group. The lower mortality in the treated group, combined with the knowledge that antiresorptive drugs reduce fractures and increase bone density, merit undertaking a randomized trial to confirm our findings that antiresorptive therapy should be considered in all patients post-hip fracture.

Aged↗
PubMedDate not supplied

Sequencing of hormonal therapy in breast cancer.

Hormonal therapy plays an integral role in the management of the majority of women with breast cancer who can be considered to have hormone-dependent breast cancer because of the presence of the molecular predictive markers, estrogen receptor and progesterone receptor. Numerous hormonal agents are available from multiple classes of drugs, including selective estrogen receptor modulators, aromatase inhibitors, progestins, androgens, and luteinizing hormone-releasing hormone analogues. Multiple clinical trials involving these agents have been conducted which permit an evidence-based approach to the development of a sequencing strategy for treatment of women with breast cancer.

Aged↗
PubMed2006

[Present development of new drugs for osteoporosis].

Bisphosphonates are widely used, though gastrointestinal tolerance is a problem on daily administration. Alendronate 35 mg administered once weekly is as effective at increasing bone mineral density (BMD) as 5 mg/day in the treatment of osteoporosis. Once weekly regimen will be soon available in Japan and can reduce adverse events. Injection therapies may also circumvent this, although this introduces the smaller problem of acute phase reactions. New generation bisphosphonates (milodronate, ibandronate and zoledronate) along with anti-receptor activator of nuclear factor-kappaB ligand (RANKL) antibody are promising and eagerly developed for the treatment of osteoporosis. Raloxifene appears to have a superior safety profile to hormone replacement therapy (HRT), though its efficacy on bone may be limited, so that various new generation of selective estrogen receptor modulator (SERMs) is now underdeveloped. Anabolic agents such as teriparatide and strontium ranelate have marked effects on BMD and subsequent reduction on fracture risk. While none of these options is suitable for everyone, the range of future available therapies does mean that most patients can find an intervention that is effective and acceptable.

Antibodies↗
PubMed2003

Administration of raloxifene does not influence 24-hour ambulatory blood pressure of postmenopausal women with osteopenia: a double-blind placebo-controlled study.

OBJECTIVE: Because estrogens may decrease 24-hour blood pressure of postmenopausal women, we tested the effect of the selective estrogen receptor modulator raloxifene on ambulatory blood pressure. STUDY DESIGN: Postmenopausal women with osteopenia who were otherwise healthy were assigned randomly in a double blind-fashion to receive placebo (n = 16 women) or raloxifene (60 mg/d, n = 16 women). Before and after 4 months, the blood pressure of each woman was monitored every 30 minutes for 41 hours with the use of an ambulatory device. RESULTS: Similar to the placebo outcome, the raloxifene administration did not modify 24-hour daytime (7 AM -11 PM) and nighttime (11 PM -7 AM) blood pressure and heart rate values. Day-night differences and the 24-hour rhythmic variation of mean blood pressure, which was evaluated by cosinor analysis, were also not affected by placebo or by raloxifene. CONCLUSION: Raloxifene does not influence 24-hour blood pressure of postmenopausal women. These data are reassuring for the cardiovascular safety of the long-term raloxifene administration.

Blood Pressure↗
PubMedDate not supplied

Chemoprevention of breast cancer: tamoxifen, raloxifene, and beyond.

Breast cancer is the most common cancer and the second most common cause of cancer death among women in the United States. While nonrandomized studies have reported that prophylactic mastectomy or oophorectomy can significantly reduce the risk of breast cancer, these approaches are unacceptable to the majority of women. Chemoprevention, which is defined as the prevention of cancer by pharmacological agents that inhibit or reverse the process of carcinogenesis, has thus increasingly become the focus of breast cancer prevention efforts. The first-generation selective estrogen receptor modulator (SERM) tamoxifen is the only US Food and Drug Administration- approved drug for breast cancer prevention and reduces the risk of breast cancer by as much as 50% in high-risk women. Raloxifene, a second-generation SERM, also has demonstrated efficacy for breast cancer prevention and is being compared with tamoxifen in a large randomized trial that has recently completed accrual. The aromatase inhibitors (AIs) decrease the incidence of contralateral breast cancer when used in the adjuvant setting and are being evaluated in ongoing primary prevention studies. In addition, a number of novel agents, including antiinflammatory drugs and retinoid derivatives, which appear to be of promise based on preclinical and epidemiological data, are under investigation. Several important challenges remain, including determination of the appropriate dose and duration of treatment when used in the primary prevention setting and development of new research models using surrogate end points for breast cancer incidence and mortality to permit more rapid clinical application of promising new agents.

Antineoplastic Agents, Hormonal↗
PubMed2005

Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis.

Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.

Arthritis, Rheumatoid↗