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Raloxifene – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Raloxifene is a selective estrogen receptor modulator that acts as both an estrogen agonist and antagonist via differential effects on the tissue-specific estrogen receptors. Based on the findings of competitive binding assays, raloxifene displays a binding affinity that is similar to that of [estradiol], the predominant circulating estrogen. Estrogens play variable roles in different tissues in females, including the bone, breasts, uterus, and liver, by binding to the steroid nuclear hormone receptors, Estrogen Receptor alpha (ERα) or Estrogen Receptor beta (ERβ). These receptors are normally bound to the Heat Shock Protein 90 (Hsp90) when unbound to the ligand. Ligand binding induces a conformational change in the receptor that promotes dissociation of the receptor from Hsp90, dimerization, and translocation into the nucleus. This movement into the nucleus allows the receptor to bind to genomic locations based on sequence recognition of the DNA binding domain, also known as the Estrogen Response Elements (EREs). In bones, endogenous estrogens normally modulate multiple DNA response elements, including the gene-encoding transforming growth factor-β3 (TGF-β3), which is a cytokine embedded in the bone matrix. TGF-β3 plays an important role in bone remodeling by working with other cytokines to induce the production of osteoblasts, such as IL-6, and attenuate the activity of osteoclasts. Estrogens typically maintain bone integrity by inhibiting the cytokines that recruit osteoclasts and oppose the bone-resorbing, Ca2+-mobilizing action of parathyroid hormone. In contrast, estrogens promote osteoblast proliferation, augment the production of TGF-β3 and bone morphogenic proteins, and inhibit apoptosis. Mimicking the action of endogenous estrogen in bone tissues, raloxifene binds to the estrogen receptor to influence gene transcription through interactions with the estrogen response element (ERE) and a distinct DNA target, the raloxifene response element (RRE). It occupies the same ER ligand binding site as estrogen. Upon binding, raloxifene induces a conformational change of the receptor, allowing mediation of direct binding to transcriptional elements by accessory proteins. Increased expression of bone matrix proteins, such as alkaline phosphatase, osteonectin, osteocalcin, and collagen may be seen. The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promotors. In breast tissues, raloxifene acts as an estrogen receptor antagonist to attenuate the estrogen-dependent proliferative effects of epithelial cell expansion. In addition to the antiproliferative effects, raloxifene prevents the production of cytokines and the recruitment of macrophages and lymphocytes into the tumor mass.

or

Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affect bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in postmenopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate, and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition, we found that Pyk2-KO OBs cultured in the presence of either 17beta-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor a (ERa), but not estrogen receptor beta (ERbeta). As a consequence, E2 signaling via ERbeta was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERalpha and ERbeta signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, maybe a novel strategy for the prevention and/or treatment of bone loss diseases.

Indications

  • Indicated for the prevention and treatment of osteoporosis in postmenopausal women, as well as prevention and treatment of corticosteroid-induced bone loss. Indicated for the reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women with a high risk for invasive breast cancer.
  • Optruma is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of Optruma or other therapies, including estrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5. 1).
  • Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of Evista or other therapies, including estrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits.
  • Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated. When determining the choice of raloxifene or other therapies, including estrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits. It has a role as a bone density conservation agent, an estrogen antagonist, and an estrogen receptor modulator. It contains raloxifene(1+).

FDA-approved Indications

  • Raloxifene is an FDA-approved second-generation selective estrogen receptor modulator (SERM), a drug with an estrogen-agonistic effect on bone, increasing bone mineral density and mass by decreasing bone resorption. It is indicated in the treatment and prevention of postmenopausal osteoporosis.
  • Raloxifene is also indicated for the risk reduction of invasive breast cancer in postmenopausal women, demonstrating a high risk for invasive breast cancer or women with osteoporosis. The definition of high breast cancer risk is one or more first-degree relatives with breast cancer, or at least one breast biopsy showing lobular carcinoma in situ (LCIS), or atypical hyperplasia, or a 5-year predicted breast cancer risk of more than 1.66%.
  • Studies are underway on raloxifene as an adjuvant treatment for postmenopausal women with schizophrenia. It shows particularly promising results in mild presentations of schizophrenia.

Use in Cancer

  • Raloxifene hydrochloride is approved to prevent: Breast cancer. It is used to decrease the chance of invasive breast cancer in postmenopausal women who have a high risk of developing the disease or who have osteoporosis.
  • Raloxifene hydrochloride is also approved to prevent and treat: Osteoporosis in postmenopausal women.
  • Raloxifene hydrochloride is also being studied in the treatment of other types of cancer.

The Most Common

  • hot flashes (more common in the first 6 months of raloxifene therapy)
  • leg cramps
  • swelling of the hands, feet, ankles, or lower legs
  • flu-like syndrome
  • joint pain
  • sweating
  • difficulty falling asleep or staying asleep
  • Hot flashes, including sudden sweating and feelings of warmth (especially common during the first 6 months of treatment)
  • increased white vaginal discharge
  • joint or muscle pain
  • mental depression
  • problems of stomach or intestines, including passing of gas, upset stomach, or vomiting
  • swollen joints
  • trouble in sleeping
  • weight gain (unexplained)

More common

  • Bloody or cloudy urine
  • chest pain
  • difficult, burning, or painful urination
  • fever
  • frequent urge to urinate
  • infection, including body aches or pain, congestion in throat, cough, dryness or soreness of throat, runny nose, and loss of voice
  • leg cramping
  • skin rash
  • swelling of hands, ankles, or feet
  • vaginal itching

Rare

  • Abdominal pain (severe)
  • aching body pains
  • congestion in lungs
  • decreased vision or other changes in vision
  • diarrhea
  • difficulty in breathing
  • hoarseness
  • loss of appetite
  • nausea
  • trouble in swallowing
  • weakness

Pregnancy and Lactation

Pregnancy

Raloxifene Hydrochloride Tablets are contraindicated for use in pregnant women and are not indicated for use in females of reproductive potential. Based on the mechanism of action, Raloxifene Hydrochloride Tablets may block the important functions that estrogen has during all stages of pregnancy. Limited data on Raloxifene Hydrochloride Tablets used in pregnant women are insufficient to inform any drug-associated risks for birth defects or miscarriage.

Lactation

Raloxifene Hydrochloride Tablets are not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breastfed child, or the effects on milk production. However, based on the mechanism of action, Raloxifene Hydrochloride Tablets may block the important functions that estrogen has in mammary tissue during lactation

How should this medicine be used?

Raloxifene comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take raloxifene at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take raloxifene exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor. Continue to take raloxifene even if you feel well. Do not stop taking raloxifene without talking to your doctor.

What special precautions should I follow?

Before taking raloxifene,

  • tell your doctor and pharmacist if you are allergic to raloxifene, any other medications, or any of the ingredients in raloxifene tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners) such as warfarin (Coumadin, Jantoven), cholestyramine (Prevalite), colestipol (Colestid), diazepam (Valium), diazoxide (Proglycem), medications that contain estrogen such as hormone replacement therapy (ERT or HRT), and lidocaine (Akten, Lidoderm, Xylocaine). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have any type of cancer and if you have or have ever had breast lumps or breast cancer; heart failure; kidney disease; or liver disease. If you have ever taken estrogen, tell your doctor if your triglycerides increased during your treatment.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. Do not become pregnant while taking raloxifene. If you become pregnant while taking raloxifene, call your doctor immediately. Raloxifene may harm the fetus.
  • you should know that raloxifene has not been found to cause spotting or menstrual-like bleeding nor to increase the risk of cancer of the lining of the uterus. Tell your doctor if you develop vaginal bleeding or spotting. Your doctor will need to examine you or order tests to find the cause of the bleeding.
  • you should know that although raloxifene decreases the chance that you will develop invasive breast cancer, there is still a risk that you will develop this condition. You will still need regularly scheduled breast exams and mammograms before you start taking raloxifene and during your treatment with raloxifene. Call your doctor if you notice tenderness, enlargement, lumps, or any other changes in your breasts.
  • if you are taking raloxifene to treat osteoporosis, talk to your doctor about other things you can do to prevent osteoporosis from developing or worsening. Your doctor will probably tell you to avoid smoking and drinking large amounts of alcohol and to follow a regular program of weight-bearing exercise.

What special dietary instructions should I follow?

  • You should eat and drink plenty of foods and drinks that are rich in calcium and vitamin D while you are taking raloxifene. Your doctor will tell you which foods and drinks are good sources of these nutrients and how many servings you need each day. If you find it difficult to eat enough of these foods or if you have a condition that makes it difficult for your body to absorb the nutrients that you eat, tell your doctor. In that case, your doctor can prescribe or recommend a supplement.

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