What is Raloxifene?

What is Raloxifene?

Raloxifene is a selective estrogen receptor modulator (SERM) that acts as an estrogen agonist in bone and lipid metabolism while functioning as an estrogen antagonist in breast and endometrial tissue. 1

Drug Classification and Mechanism

• Raloxifene hydrochloride is a benzothiophene compound with the molecular formula C28H27NO4S•HCl and molecular weight of 510.05 1
• The medication works by binding to estrogen receptors, resulting in tissue-selective activation or blockade of estrogenic pathways depending on recruitment of coactivators and corepressors at target gene promoters 1
• In bone tissue, raloxifene acts as an estrogen agonist, decreasing bone resorption and turnover while increasing bone mineral density 1
• In breast and uterine tissues, raloxifene functions as an estrogen antagonist, lacking estrogen-like stimulatory effects 1

FDA-Approved Indications

Raloxifene has three primary FDA-approved uses 2:

• Treatment and prevention of osteoporosis in postmenopausal women
• Reduction of invasive breast cancer risk in postmenopausal women with osteoporosis
• Reduction of invasive breast cancer risk in postmenopausal women at high risk for breast cancer

Clinical Use for Breast Cancer Risk Reduction

Raloxifene 60 mg daily for 5 years should be offered to postmenopausal women aged ≥35 years with a 5-year projected breast cancer risk ≥1.66% (by NCI Breast Cancer Risk Assessment Tool) or with lobular carcinoma in situ (LCIS). 2

• Raloxifene specifically reduces the risk of estrogen receptor-positive invasive breast cancer by approximately 76-90%, but does not affect estrogen receptor-negative breast cancer risk 2, 3
• The medication may be used longer than 5 years in women with osteoporosis, where breast cancer risk reduction becomes a secondary benefit 2
• Raloxifene is not indicated for premenopausal women for breast cancer risk reduction 2

Clinical Use for Osteoporosis

• The standard dose is 60 mg orally once daily 2
• Raloxifene increases bone mineral density at the lumbar spine by 2.1-2.6% and at the femoral neck by 2.1-2.4% compared to placebo over 36 months 4
• The medication reduces vertebral fracture risk by 30-55% in postmenopausal women with osteoporosis 4, 5
• Raloxifene does not significantly reduce non-vertebral or hip fracture risk 2, 5

Absolute Contraindications

Raloxifene must not be used in women with 2:

• History of deep vein thrombosis (DVT)
• History of pulmonary embolism (PE)
• History of stroke or transient ischemic attack
• Anticipated prolonged immobilization
• Pregnancy or potential for pregnancy
• Premenopausal status (for breast cancer risk reduction indication)

Common Side Effects

The most frequently reported adverse effects include 2, 6:

• Hot flashes and vasomotor symptoms (particularly problematic in early menopause)
• Leg cramps
• Peripheral edema
• Influenza-like syndromes
• Endometrial cavity fluid (without endometrial hyperplasia)

Serious Adverse Events

• Venous thromboembolism risk is increased 3.1-fold compared to placebo, with absolute risk increases of 0.7/1000 for DVT and 1.3/1000 for PE 2, 3
• Fatal stroke risk is increased (hazard ratio 1.49, absolute risk increase 0.7/1000) in postmenopausal women with cardiovascular risk factors 2
• Raloxifene does not increase endometrial cancer risk 3

Important Clinical Considerations

• Raloxifene should not be combined with tamoxifen, as these are alternative agents, not complementary therapies 7
• The medication should not be used concurrently with hormone replacement therapy 2
• Use with caution in patients with moderate to severe renal or hepatic impairment 1
• Hot flashes may be accentuated in women with early menopause, making raloxifene less suitable for symptomatic perimenopausal women 2, 6

Comparative Efficacy

• Compared to bisphosphonates, raloxifene has a lesser impact on bone mineral density and no demonstrated effect on non-vertebral fractures 5
• Raloxifene has a more favorable side effect profile than tamoxifen, with lower risks of thromboembolic disease, benign uterine complaints, and cataracts 7
• Unlike estrogen therapy, raloxifene does not increase myocardial infarction risk and reduces breast cancer incidence 2