Raloxifene (SERM): Med

Raloxifene, marketed under the brand name Evista and others, is a drug used for the prevention and treatment of osteoporosis in postmenopausal women and individuals taking glucocorticoids. For osteoporosis, it is less favored compared to bisphosphonates. Additionally, it is used to lower the risk of breast cancer in those with a high risk. It is administered orally.

Typical side effects are hot flashes, leg cramps, swelling, and joint pain. Serious side effects can include blood clots and stroke. Using it during pregnancy might harm the baby. The drug may exacerbate menstrual symptoms. Raloxifene is a selective estrogen receptor modulator (SERM), acting as both an agonist and an antagonist of the estrogen receptor (ER). It exhibits estrogenic effects in the bone and antiestrogenic effects in the breasts and uterus.

Raloxifene was approved for medical use in the United States in 1997 and is available as a generic medication. In 2020, it ranked as the 292nd most commonly prescribed medication in the United States, with over 1 million prescriptions.

Medical uses

Raloxifene is utilized for both the treatment and prevention of osteoporosis in postmenopausal women, administered at a dosage of 60 mg/day. For either prevention or treatment of osteoporosis, additional calcium and vitamin D should be included in the diet if daily intake is insufficient.

Raloxifene is also used to lower the risk of breast cancer in postmenopausal women, with a dosage of 60 mg/day for this purpose. In the Multiple Outcomes of Raloxifene (MORE) clinical trial, raloxifene reduced the risk of all types of breast cancer by 62%, invasive breast cancer by 72%, and invasive estrogen receptor-positive breast cancer by 84%. However, it does not decrease the risk of estrogen receptor-negative breast cancer.

In the MORE trial, there were no significant differences in the effectiveness of raloxifene for breast cancer prevention between a dosage of 60 mg/m2/day and 120 mg/m2/day. In the Study of Tamoxifen and Raloxifene (STAR) trial, 60 mg/day raloxifene was found to be 78% as effective as 20 mg/day tamoxifen in preventing non-invasive breast cancer. Women with undetectable estradiol levels (<2.7 pg/mL) naturally have a low risk of breast cancer and, unlike women with detectable estradiol levels, do not gain significant benefit from raloxifene in reducing breast cancer risk.

Contraindications

Raloxifene is contraindicated for lactating women or those who are or may become pregnant. It is also a concern for women with an active or past history of venous thromboembolic events, such as deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.

Side effects

Common side effects of raloxifene include hot flashes (25–28% vs. 18–21% for placebo), vaginal dryness, and leg cramps (generally mild; 5.5% vs. 1.9% for placebo). Raloxifene does not cause breast tenderness, endometrial hyperplasia, menstrual bleeding, or endometrial cancer. It does not seem to affect cognition or memory. Raloxifene is a teratogen; meaning it can cause developmental issues like birth defects.

Raloxifene may rarely lead to serious blood clots forming in the legs, lungs, or eyes. Other symptoms include leg swelling/pain, difficulty breathing, chest pain, and vision changes. In 2007, black box warnings were added to raloxifene's label regarding the increased risk of death from stroke in postmenopausal women with documented coronary heart disease or at high risk for major coronary events, as well as a higher risk of deep vein thrombosis and pulmonary embolism.

The risk of venous thromboembolism with raloxifene is increased several-fold in postmenopausal women (RRTooltip relative risk = 3.1). However, raloxifene has a lower risk of thromboembolism compared to tamoxifen. In the MORE trial, raloxifene reduced the risk of cardiovascular events by 40% in women at higher risk for coronary artery disease, though there was no reduction in cardiovascular events for the group overall.

A September 2009 report from the Health and Human Services' Agency for Healthcare Research and Quality indicates that tamoxifen and raloxifene, used for breast cancer treatment, significantly lower invasive breast cancer in midlife and older women, but also raise the risk of adverse side effects.

A human case report from July 2016 suggests that raloxifene may, at some point, actually stimulate breast cancer growth, leading to a reduction of advanced breast cancer disease upon discontinuation of the drug.

Unlike other SERMs, such as tamoxifen, raloxifene does not carry a risk of uterine hyperplasia or endometrial cancer (RRTooltip relative risk = 0.8).

Raloxifene does not increase the incidence of breast pain or tenderness in postmenopausal women.

Overdose

Raloxifene has been tested in clinical trials at dosages ranging from 30 to 600 mg/day, and all dosages were well-tolerated.

Pharmacodynamics

Mechanism of action

Raloxifene is a selective estrogen receptor modulator (SERM), acting as a mixed agonist and antagonist of the estrogen receptor (ER) in different tissues. It exhibits estrogenic effects in some tissues, like bone and the liver, and antiestrogenic effects in others, such as the breasts and uterus. Its affinity (Kd) for the ERα is about 50 pM, similar to estradiol. Compared to estradiol, raloxifene has been shown to have 8 to 34% of the affinity for ERα and 0.5 to 76% for ERβ. Raloxifene functions as a partial agonist for ERα and a pure antagonist for ERβ. Unlike classical ERs, raloxifene acts as an agonist of the G protein-coupled estrogen receptor (GPER) (EC50Tooltip half-maximal effective concentration = 10–100 nM), a membrane estrogen receptor.

Clinical effects

Raloxifene shows antiestrogenic properties in the mammary glands in preclinical studies. Consequently, raloxifene decreases breast density in postmenopausal women, which is a known risk factor for breast cancer. It does not stimulate the uterus in postmenopausal women, and does not increase the risk of endometrial thickening, vaginal bleeding, endometrial hyperplasia, or endometrial cancer. Additionally, raloxifene has minimal antiestrogenic impact on the uterus in premenopausal women, possibly due to insufficient exposure of the uterus to raloxifene in these estrogen-rich individuals.

In premenopausal women, raloxifene raises levels of follicle-stimulating hormone (FSH) and estradiol. Conversely, in postmenopausal women, raloxifene has been observed to lower levels of gonadotropins, including luteinizing hormone (LH) and FSH, without affecting estradiol levels. Raloxifene also reduces prolactin levels in postmenopausal women. In men, raloxifene has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis), thereby increasing total testosterone levels. However, due to the simultaneous rise in sex hormone-binding globulin (SHBG) levels, free testosterone levels often remain unchanged in men during raloxifene therapy.

Raloxifene exhibits estrogen-like effects on liver protein synthesis. It elevates SHBG levels in both pre- and postmenopausal women as well as in men. The drug reduces levels of total and low-density lipoprotein (LDL) cholesterol, C-reactive protein, apolipoprotein B, and homocysteine. However, it has minimal impact on levels of triglycerides and high-density lipoprotein (HDL).

Raloxifene has been found to prevent the oxidation of LDL cholesterol in vitro. The drug has been shown to lower insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men. Additionally, it has been observed to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women. Due to activation of estrogen receptors in the liver, raloxifene has procoagulatory effects, such as reducing levels of fibrinogen and affecting levels of other coagulation factors. For these reasons, raloxifene raises the risk of thrombosis.

Raloxifene enhances bone mineral density in postmenopausal women but reduces it in premenopausal women. In the MORE trial, the risk of vertebral fractures was reduced by 30%, and bone mineral density increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg). It has been found to have estrogenic effects in adipose tissue in postmenopausal women, encouraging a shift from an android fat distribution to a gynoid fat distribution.

The drug has been found to elevate levels of leptin, an adipokine.

Pharmacokinetics

Absorption

The absorption of raloxifene is about 60%. However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is merely 2.0%. Raloxifene is quickly absorbed from the intestines after oral administration. Peak plasma levels of raloxifene are reached 0.5 to 6 hours following an oral dose. In healthy postmenopausal women treated with 60 mg/day raloxifene, peak circulating raloxifene levels normalized by dose and body weight were 0.50 ng/mL (500 pg/mL) after a single dose and 1.36 ng/mL (1,360 pg/mL) after multiple doses.

Distribution

Raloxifene is extensively distributed throughout the body. There is significant distribution of raloxifene into the liver, serum, lungs, and kidneys. The volume of distribution of raloxifene with a single 30 to 150 mg oral dose is approximately 2348 L/kg, which corresponds to ~170,000 L for a 72 kg person. Both raloxifene and its glucuronide metabolites exhibit high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin. More specifically, raloxifene is 98.2 ± 0.4% bound to plasma proteins.

Metabolism

Raloxifene is metabolized in the liver and undergoes enterohepatic recycling. It is exclusively metabolized through glucuronidation and does not involve the cytochrome P450 system. Less than 1% of the radiolabeled material in plasma is unconjugated raloxifene. The metabolites of raloxifene are several glucuronides.

The elimination half-life of raloxifene after a single dose is 27.7 hours (1.2 days), while at a steady state with a dosage of 60 mg/day, it ranges from 15.8 to 86.6 hours (0.7–3.6 days), averaging 32.5 hours (1.4 days). The prolonged half-life of raloxifene is due to enterohepatic recirculation and its significant plasma protein binding. Raloxifene and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, extending the elimination half-life of raloxifene when taken orally.

The medication is deconjugated into its active form in various tissues, including the liver, lungs, spleen, bone, uterus, and kidneys.

Elimination

Raloxifene is primarily excreted in bile and is eliminated in feces. Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.

Chemistry

See also: List of selective estrogen receptor modulators and Benzothiophene

Raloxifene hydrochloride has the empirical formula C28H27NO4S•HCl, with a molecular weight of 510.05 g/mol. It is an off-white to pale-yellow solid that is slightly soluble in water.

Raloxifene is a benzothiophene derivative and is structurally different from the triphenylethylene SERMs like tamoxifen, clomifene, and toremifene. It is the only benzothiophene SERM that has been marketed. A benzothiophene SERM that was not marketed is arzoxifene (LY-353381). Bazedoxifene (Duavee, Viviant) and pipendoxifene (ERA-923) are structurally related to raloxifene but are technically not benzothiophenes and instead are indoles.

Availability

Raloxifene is widely accessible globally, including in the United States, Canada, the United Kingdom, Ireland, various parts of Europe, Australia, New Zealand, South Africa, Latin America, Southern, Eastern, and Southeastern Asia, as well as in other regions like Israel and Egypt.

Raloxifene is supplied in 60 mg oral tablets.

Controversy

An editorial in Lancet Oncology criticized the dissemination of research concerning the medication's role in breast cancer prevention.

Research

Clinical trials of raloxifene for metastatic breast cancer in women have been conducted, showing limited effectiveness at 60 mg/day in those previously treated with tamoxifen, though some effectiveness was noted at higher doses. Unlike tamoxifen, raloxifene is not approved for breast cancer treatment.

Raloxifene has been researched in men for various purposes, including the treatment of schizophrenia, prostate cancer, and osteoporosis. It has been studied in combination with castration and bicalutamide, a nonsteroidal antiandrogen, for prostate cancer treatment.

Raloxifene has been evaluated as an adjunct in treating schizophrenia in postmenopausal women. A 2017 meta-analysis found it to be safe and effective for this use, although further studies with larger sample sizes are needed for verification. It may be beneficial for women with milder symptoms.

A tissue-selective estrogen-receptor complex (TSEC) of estradiol and raloxifene has been studied in postmenopausal women.

Raloxifene (60 mg/day) was reported to be effective in treating pubertal gynecomastia in adolescent boys in a small retrospective chart review. Other SERMs are also known to be effective in treating gynecomastia.

Raloxifene has been reported to enhance the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs).