What is the role of Raloxifene (Selective Estrogen Receptor Modulator) in the prevention and treatment of osteoporosis in postmenopausal women, particularly those with a history of osteoporosis or increased risk of breast cancer?

Raloxifene in Postmenopausal Women

Raloxifene 60 mg daily is FDA-approved and recommended for both osteoporosis treatment/prevention and invasive breast cancer risk reduction in postmenopausal women, with the dual benefit making it particularly valuable for women at increased risk of both conditions. 1

FDA-Approved Indications

Raloxifene is approved for three specific indications in postmenopausal women 1:

• Treatment and prevention of osteoporosis in postmenopausal women 1
• Reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis 1
• Reduction in risk of invasive breast cancer in postmenopausal women at high risk (defined as ≥1.66% 5-year risk by Gail model, LCIS, or atypical hyperplasia) 1

Dosing and Duration

• Standard dose: 60 mg orally once daily, taken at any time without regard to meals 1
• For breast cancer risk reduction alone: 5 years is the standard recommendation 2
• For osteoporosis with breast cancer risk reduction as secondary benefit: may be used beyond 5 years, with 8-year safety data supporting extended use 3, 2
• Supplemental calcium (1500 mg/day) and vitamin D should be added if dietary intake is inadequate 1

Efficacy Profile

Osteoporosis Benefits

Raloxifene is less potent than bisphosphonates but provides meaningful skeletal protection 2:

• Reduces vertebral fracture risk by 30-55% depending on baseline fracture status 2, 4
• Does NOT reduce hip or non-vertebral fracture risk in randomized trials 2
• Increases bone mineral density by 2.1-2.6% at femoral neck and 2.6-2.7% at spine over 3 years 4

Breast Cancer Risk Reduction

Raloxifene reduces invasive ER-positive breast cancer risk by 66-84% 2, 5:

• Number needed to treat: 93 osteoporotic women for 4 years to prevent one invasive breast cancer 5
• No effect on ER-negative breast cancers 2
• Not indicated for noninvasive breast cancer, treatment of established breast cancer, or prevention of recurrence 1

Absolute Contraindications

Do not use raloxifene in women with 1:

• Active or past history of venous thromboembolism (DVT, PE, retinal vein thrombosis) 1
• History of stroke or transient ischemic attack 2
• Premenopausal status (raloxifene decreases BMD in premenopausal women) 2
• Pregnancy or potential for pregnancy 1
• Prolonged immobilization (discontinue 72 hours before and during) 1

Serious Adverse Events

Venous Thromboembolism (VTE)

Raloxifene increases VTE risk 3-fold 4:

• Hazard ratio 1.44 for VTE (absolute risk increase 1.3/1000) 2
• Higher rate of DVT (38 vs 5 cases) and PE (17 vs 3 cases) compared to placebo in MORE trial 4
• Discontinue 72 hours before and during prolonged immobilization 1

Fatal Stroke Risk

Increased risk of death from stroke in women with coronary heart disease or cardiovascular risk factors 1:

• Hazard ratio 1.49 for fatal stroke (absolute risk increase 0.7/1000) in RUTH trial 2
• Consider risk-benefit balance carefully in women at risk for stroke 1

Cardiovascular Disease

Raloxifene should NOT be used for primary or secondary prevention of cardiovascular disease 1:

• Unlike estrogen, raloxifene is not associated with increased myocardial infarction risk 2
• No overall benefit for coronary events 1

Common Side Effects

More frequent with raloxifene than placebo 2, 1:

• Hot flashes (may be accentuated in early menopause) 2
• Leg cramps 2, 1
• Peripheral edema 2, 1
• Gallbladder disease 2
• Flu syndrome, arthralgia, sweating 1

Special Clinical Considerations

Comparison to Tamoxifen

Raloxifene has a more favorable safety profile than tamoxifen 3:

• Lower risk of thromboembolic disease, benign uterine complaints, and cataracts compared to tamoxifen 3
• Lower risk of endometrial cancer compared to tamoxifen 3
• However, tamoxifen may be slightly more effective for breast cancer risk reduction 2

Use in Breast Cancer Patients

For women with a history of breast cancer, bisphosphonates are preferred over raloxifene for osteoporosis treatment 2:

• Do not combine raloxifene with aromatase inhibitors outside clinical trials (ATAC trial showed decreased efficacy with SERM + AI combination) 2
• Raloxifene is not indicated for breast cancer treatment or recurrence prevention 1

Drug Interactions

• Cholestyramine: not recommended (reduces raloxifene absorption and enterohepatic cycling) 1
• Warfarin: monitor prothrombin time when starting or stopping raloxifene 1
• Highly protein-bound drugs: use with caution (diazepam, diazoxide, lidocaine) as raloxifene is >95% protein-bound 1
• Do not combine with systemic estrogens 1

Monitoring Requirements

• Breast exams and mammograms before starting and continued regularly during treatment 1
• Monitor for signs of VTE, particularly during first 4 months of therapy 3
• Monitor serum triglycerides if previous estrogen treatment caused hypertriglyceridemia 1
• Use with caution in hepatic impairment 1

Clinical Decision Algorithm

Choose raloxifene when:

• Postmenopausal woman with osteoporosis OR at high breast cancer risk (≥1.66% 5-year risk) 2
• AND no history of VTE, stroke, or TIA 2
• AND not at high risk for stroke 1
• AND vertebral fracture prevention is the primary skeletal concern (not hip fractures) 2

Choose bisphosphonates instead when:

• History of breast cancer requiring osteoporosis treatment 2
• Hip or non-vertebral fracture prevention is the primary concern 2
• History of VTE or stroke 2

Ideal candidate for raloxifene:

• Postmenopausal woman at increased risk of both vertebral fractures and invasive breast cancer 6
• No contraindications to SERM therapy 6