Raloxifene: Recommended Use and Management
Primary Recommendation
Raloxifene 60 mg daily should be discussed as a first-line option for postmenopausal women ≥35 years who have both osteoporosis (or low bone density) AND elevated breast cancer risk (5-year risk ≥1.66% by Gail model or LCIS), providing dual protection against vertebral fractures and invasive ER-positive breast cancer. 1, 2
FDA-Approved Indications
Raloxifene is FDA-approved for three specific indications in postmenopausal women: 3
- Treatment and prevention of osteoporosis 3
- Reduction of invasive breast cancer risk in women with osteoporosis 3
- Reduction of invasive breast cancer risk in high-risk women (defined as ≥1.66% 5-year risk by Gail model, LCIS, or atypical hyperplasia) 3
Clinical Decision Algorithm
Step 1: Assess Eligibility
Screen for absolute contraindications first: 1, 3
- Active or history of venous thromboembolism (DVT, PE, retinal vein thrombosis)
- History of stroke or transient ischemic attack
- Premenopausal status
- Pregnancy or potential pregnancy
- Prolonged immobilization anticipated
Step 2: Identify Ideal Candidates
Best candidates are postmenopausal women with BOTH conditions: 2
- Osteoporosis or low bone density requiring treatment
- Elevated breast cancer risk (5-year risk ≥1.66% by Gail model, LCIS, or atypical hyperplasia) 1, 3
Step 3: Consider Relative Positioning
When raloxifene is preferred over alternatives:
- Women seeking dual osteoporosis and breast cancer risk reduction 2
- Women who cannot tolerate or prefer to avoid tamoxifen (raloxifene has lower rates of thromboembolic events, endometrial cancer, cataracts, and benign uterine complaints compared to tamoxifen) 1, 4
When raloxifene is NOT preferred:
- Primary osteoporosis treatment alone: Bisphosphonates are superior for comprehensive fracture prevention, as raloxifene does NOT reduce non-vertebral or hip fracture risk 2, 5
- Women with established breast cancer: Raloxifene should NOT be used in women with prior breast cancer for osteoporosis management due to concerns about cross-resistance and potential tumor stimulation 6
- Premenopausal women: Raloxifene is contraindicated and ineffective 1, 3
Dosing and Duration
Standard dosing: 60 mg orally once daily, taken any time of day with or without food 1, 3
- For breast cancer risk reduction alone: 5 years is the standard recommendation 1, 4
- For osteoporosis with breast cancer risk reduction as secondary benefit: May be used beyond 5 years, with 8-year safety data supporting extended use 1, 4
- The American Society of Clinical Oncology explicitly supports extended use beyond 5 years when osteoporosis treatment is the primary indication 4
Efficacy Profile
Breast Cancer Risk Reduction
- 72% reduction in invasive breast cancer after 4 years (RR 0.28,95% CI 0.17-0.46) 7
- 84% reduction in ER-positive invasive breast cancer (RR 0.16,95% CI 0.09-0.30) 1, 2
- NO effect on ER-negative breast cancers 2
- Number needed to treat: 93 women for 4 years to prevent one invasive breast cancer 2, 7
- Important limitation: Raloxifene is less effective than tamoxifen for preventing noninvasive breast cancer 1
Osteoporosis Management
- Reduces vertebral fracture risk by 30-50% in women with osteoporosis 5
- Increases bone mineral density: lumbar spine 1.6-3.4%, femoral neck 0.9-2.3%, total hip 1.0-1.6% 5
- Does NOT reduce non-vertebral or hip fracture risk, making it less potent than bisphosphonates for comprehensive fracture prevention 2, 5, 8
Critical Safety Considerations
Boxed Warnings (FDA Black Box)
Increased risk of venous thromboembolism and death from stroke: 3
- Deep vein thrombosis and pulmonary embolism risk increased (RR 3.1 vs placebo) 5
- Increased risk of death from stroke in women with documented coronary heart disease or at high risk for coronary events 3
- Discontinue raloxifene 72 hours before and during prolonged immobilization 4, 3
Common Adverse Effects
Occurring in >2% and more common than placebo: 3, 8
- Hot flashes (particularly problematic in early menopause) 2
- Leg cramps 2, 3
- Peripheral edema 2, 3
- Flu-like symptoms 2
- Arthralgia 3
Monitoring Requirements
- Monitor for signs of venous thromboembolism, especially during first 4 months of therapy 4
- Continue regular breast exams and mammograms before starting and throughout treatment 3
- Monitor serum triglycerides if prior estrogen therapy caused hypertriglyceridemia 3
- Monitor prothrombin time when starting or stopping raloxifene in women on warfarin 3
Important Clinical Caveats
What Raloxifene Does NOT Do
- Does NOT treat established breast cancer or reduce recurrence risk 1, 3
- Does NOT reduce noninvasive breast cancer risk (not FDA-approved for this indication) 3
- Does NOT prevent or treat cardiovascular disease 3
- Does NOT eliminate breast cancer risk entirely 3
- No data on effectiveness in BRCA1/BRCA2 mutation carriers 3
Drug Interactions
- Cholestyramine: Not recommended with raloxifene (reduces absorption and enterohepatic cycling) 3
- Warfarin: Requires prothrombin time monitoring 3
- Highly protein-bound drugs (diazepam, diazoxide, lidocaine): Use with caution 3
- Systemic estrogens: Concomitant use not recommended 3
Special Populations
- Hepatic impairment: Use with caution 3
- Women with history of breast cancer on tamoxifen: Raloxifene is NOT recommended following tamoxifen due to cross-resistance concerns 6
Shared Decision-Making Requirements
Before prescribing, discuss in detail: 1
- Risks and benefits of raloxifene versus alternatives (tamoxifen, exemestane, bisphosphonates)
- Thromboembolic risk and stroke mortality risk
- Lack of effect on noninvasive breast cancer
- Lack of effect on non-vertebral fractures
- Impact on quality of life (hot flashes, leg cramps)
- Duration of therapy and long-term effects
The most favorable risk-benefit profile exists in women at greatest risk of developing breast cancer who also have osteoporosis. 1