What is the role of Raloxifene in the prevention and treatment of osteoporosis in postmenopausal women?

Raloxifene in Postmenopausal Osteoporosis

Raloxifene is FDA-approved for prevention and treatment of osteoporosis in postmenopausal women at 60 mg daily, but it is a second-line agent because it only reduces vertebral fractures—not hip or nonvertebral fractures—making bisphosphonates the preferred first-line therapy for most patients. 1, 2

Efficacy Profile: Vertebral Fractures Only

Raloxifene reduces vertebral fracture risk by 30-55% but does not reduce hip or nonvertebral fractures, which is a critical limitation when prioritizing morbidity and mortality outcomes 2, 3. In the landmark MORE trial of 7,705 postmenopausal women with osteoporosis:

• Vertebral fracture reduction: 30% in women with prevalent fractures and 55% in women without baseline fractures over 36 months 2, 3
• Nonvertebral fractures: No significant reduction (RR 0.9; 95% CI 0.8-1.1) 3
• Hip fractures: No demonstrated benefit 2

This contrasts sharply with bisphosphonates (alendronate and risedronate), which are the only agents proven to significantly reduce nonvertebral and hip fractures—the fractures that cause the greatest mortality and morbidity 2.

Bone Mineral Density Effects

Raloxifene increases BMD modestly at 60 mg daily 4, 5:

• Lumbar spine: 2.1-2.6% increase over 36 months
• Femoral neck: 2.1-2.4% increase over 36 months
• Total hip: 1.0-1.6% increase 5, 3

These increases are less robust than those achieved with bisphosphonates 2.

Serious Safety Concerns That Impact Mortality

Increased Stroke Mortality Risk

The FDA black box warning specifically highlights increased risk of death from stroke 1. In the RUTH trial of postmenopausal women with coronary heart disease or cardiovascular risk factors:

• Fatal stroke: HR 1.49 (absolute risk increase 0.7/1000) 2
• This finding mandates careful risk-benefit assessment in women with stroke risk factors 1

Venous Thromboembolism

Raloxifene increases venous thromboembolism risk 3-fold (RR 3.1; 95% CI 1.5-6.2), including deep vein thrombosis and pulmonary embolism 2, 1, 3. Women with active or past history of venous thromboembolism should not receive raloxifene 1.

Clinical Positioning: When to Use Raloxifene

Appropriate Candidates

Raloxifene should be reserved for postmenopausal women who meet all of the following criteria 2, 6:

• Primary concern is vertebral fracture prevention (not hip fracture)
• Increased breast cancer risk where dual benefit is desired (raloxifene reduces invasive breast cancer risk by 65-76%) 4, 5, 3
• Cannot tolerate bisphosphonates due to gastrointestinal side effects
• No history of venous thromboembolism
• Low stroke risk (no coronary artery disease, cardiovascular risk factors)

Absolute Contraindications

Do not use raloxifene in 2, 7, 1:

• Premenopausal women: Raloxifene actually decreases BMD in premenopausal women 2, 7
• After tamoxifen therapy: Cross-resistance limits efficacy 2
• Active or history of venous thromboembolism 1
• Women requiring hip fracture prevention: No proven benefit 2

Dosing and Administration

Standard dose: 60 mg orally once daily, taken any time of day without regard to meals 1. All women should receive:

• Calcium 1,200 mg daily
• Vitamin D 400-800 IU daily 2

The 120 mg dose offers no additional vertebral fracture benefit over 60 mg 3.

Common Adverse Effects

Expect these tolerability issues 2, 1, 5:

• Hot flashes: Very common, may be accentuated in early menopause 2
• Leg cramps: Common
• Peripheral edema: More common than placebo 2

Critical advantage: Unlike estrogen, raloxifene does not cause vaginal bleeding or breast tenderness and has no stimulatory effects on the endometrium 5, 3.

Why Bisphosphonates Are Preferred First-Line

For women with a history of breast cancer or those requiring comprehensive fracture protection, bisphosphonates are the superior choice 2. The NCCN Task Force explicitly states: "For women with a history of breast cancer, bisphosphonates are probably the best choice for preventing bone loss or treating established osteoporosis" 2.

Bisphosphonates (alendronate, risedronate, zoledronic acid) provide:

• Hip fracture reduction: Proven benefit 2
• Nonvertebral fracture reduction: Significant reduction 2
• No increased stroke mortality risk
• No breast cancer concerns

Duration of Therapy

The optimal duration of raloxifene treatment is unknown 1. The MORE trial followed patients for 36 months, and the breast cancer risk reduction trial had a median follow-up of only 4.3 years with just 27% of participants receiving drug for 5 years 1.