Raloxifene is an FDA approved second-generation selective estrogen receptor modulator (SERM), a drug with an estrogen-agonistic effect on bone, thereby increasing bone mineral density and mass by decreasing bone resorption. It also has an estrogen-antagonistic effect in the uterus and breast, in contrast with tamoxifen (a first generation selective estrogen receptor modulator), which has an estrogen-agonistic effect over the uterus. Raloxifene modifies markers of cardiovascular risk, by decreasing LDL-C, fibrinogen, lipoprotein A and by increasing HDL2-C, without modifying triglycerides levels.
In post-menopausal osteoporosis, bone turnover dramatically increases. The bone resorption develops at a faster rate than bone formation, leading to a progressive loss of bone mass and mineral density. This disease represents an elevated risk for developing fractures. Raloxifene is capable of inhibiting accelerated bone resorption both short and long term, increasing bone mineral density (BMD) and enhancing bone strength. Other pharmacologic agents for the management of osteoporosis are estrogen, bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone (PTH), and calcium and vitamin D.
Raloxifene is used in the treatment and prevention of post-menopausal osteoporosis. This drug also has a role in prevention, risk reduction of invasive breast cancer in post-menopausal women, demonstrating a high risk for invasive breast cancer. 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. Particularly promising results in mild presentations of schizophrenia.
Raloxifene is available in 60 mg tablets.
The recommended dose for osteoporosis is 60 mg orally each day.
The recommended dose for breast cancer prevention is 60 mg orally each day for 5 years.
Renal failure: Use with caution, safety, and efficacy are not well known.
Liver failure: Safety and efficacy are not well known.
Mechanism of Action
The mechanism of action of raloxifene occurs through binding to estrogen receptors. This binding results in activation of estrogenic pathways (estrogen-agonistic effect) and blockade (estrogen-antagonistic effect) in tissues that express estrogen receptors. These receptors express in two different isoforms, the alpha estrogen receptor (activating effect) and the beta estrogen receptor (inhibiting effect). The expression of these receptors will modify cellular and tissue response to estrogens.
Raloxifene bioavailability is approximately 2%, with an absorption of 60%. The onset of action is 8 weeks, and distribution is mainly protein bound (more than 95%). Metabolism of the drug is in the liver, excreted primarily in the feces (more than 93%), and urine (less than 0.2%).
There are no recommendations for raloxifene use in BRCA1 and BRCA2 positive mutations; there are no reports of apparent effectiveness.
This drug is not intended for use in the treatment of patients with an established diagnosis of breast cancer.
Raloxifene administration is via the oral route. Indications for the drug are the treatment and prevention of post-menopausal osteoporosis. It also has a use as prevention and risk reduction of invasive breast cancer in post-menopausal women demonstrating a high risk for invasive breast cancer. 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%.
Clinical trials had reported some beneficial effects of raloxifene during the menopause, decreasing LDL levels and reducing risk of pelvic organ prolapse and breast cancer. No reports exist of an effect in cognitive mood or sleep disturbances.
Raloxifene is available as 60 mg tablets.
The recommended dose for osteoporosis is 60 mg by mouth daily.
The recommended dose for breast cancer prevention is 60 mg by mouth daily for 5 years.
Most common documented adverse effects of raloxifene are hot flashes, flu-like symptoms, muscle spasm, arthralgia, and infection. Less common effects are insomnia, vomiting, sinusitis, deep venous thrombosis (DVT), bronchitis, pharyngitis, breast pain.
Contraindications to raloxifene include past medical history of deep venous thrombosis, renal vein thrombosis, pulmonary embolism, malignancy, active smoking, or any thrombophilia (factor V Leiden deficiency, prothrombin gene mutation G20210A, antiphospholipid syndrome, deficiency of antithrombin, protein c and s deficiency).
Risk-benefit merits consideration before starting these drugs.
Careful administration is recommended in hospitalized patients, immobilized, unable to walk, or post-surgical recovery, given the high risk for the development of deep vein thrombosis and pulmonary embolism.
Pregnancy and lactation constitute a contraindication to use raloxifene. Fertile women wishing to become pregnant need to avoid or discontinue this drug. Raloxifene is pregnancy category X.
There are reports of an ospemifene and raloxifene interaction; it increases the effect of the other by synergism.
Monitor the following drugs (for interaction with raloxifene) closely: with apalutamide, cholestyramine, famciclovir, levothyroxine.
There is a reported minor interaction of raloxifene with warfarin; it increases the effect of warfarin by plasma protein binding competition.
Monitoring is the recommendation in patients with suggestive symptoms of deep vein thrombosis (DVT), including redness, tenderness, and inflammation of calves and lower limbs. In such instances, patients should proceed immediately to the emergency department. In the emergency department, Doppler ultrasound of lower limbs needs to take place to rule out deep vein thrombosis. If such testing proves positive, admission to the hospital will be essential. In patients exhibiting chest pain, shortness of breath, or hemoptysis, it is vital to rule out pulmonary embolism.
Reports recommend suspending raloxifene 72 hours prior and during an expected immobilization of a patient.
Supplementation of vitamin D and calcium is also a recommendation in conjunction with raloxifene therapy.
Monitor hepatic profile and triglycerides levels, given the agonistic effect of estrogen over triglycerides.
Monitor for any unexpected abnormal uterine bleeding. Patients with abnormal uterine bleeding in the setting of using raloxifene, it is recommended to establish a consultation with OB/GYN and initiate further workup to establish the source of the bleeding. An endometrial biopsy is suggested to rule out endometrial cancer.
Investigations and research have been done to establish the effect of raloxifene on the heart, given its estrogen-agonistic effect in the heart estrogen receptors. Reports indicate that raloxifene does not produce myocardial hypertrophy in postmenopausal women after being treated for 6 months.
There is some documentation of increased risk of deep vein thrombosis, embolic cerebrovascular accident, and pulmonary embolism with the usage of this drug.
Patients developing new-onset vaginal bleeding will need workup, including endometrial biopsy, and OB/GYN consultation.
There are some reports of an increased risk of death due to a cerebrovascular accident in trials of post-menopausal women with coronary heart disease or with high-risk factors for coronary arterial disease.
Enhancing Healthcare Team Outcomes
Raloxifene can be prescribed by primary care physicians, nurse practitioners, PAs, OB/GYNS, and endocrinologists. The drug is useful for the prevention and treatment of osteoporosis and the prevention of breast cancer. However, healthcare workers, including pharmacists, must warn the patient that the drug can cause deep vein thrombosis and how to detect the symptoms and present immediately to the emergency department. Also, the drug can cause hot flashes, flu-like symptoms, muscle spasms. The team should work together to monitor the patient closely for deep vein thrombosis, pulmonary embolism, or embolic cerebrovascular accident. Patient education should include immediate provider notification if shortness of breath, chest pain, arm or leg weakness, calf redness, or pain. Nursing must be vigilant to ask about these symptoms at every followup visit and to alert the prescriber of any concerns. The pharmacist will also need to perform medication reconciliation to avoid drug interactions, and verify all dosing is appropriate. A provider may want these medications stopped before prolonged bed rest, immobility, or surgery.
Prescribing raloxifene and follow-up monitoring requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results and prevent complications. [Level 5]