What is the evidence for postmenopausal hormone replacement therapy (HRT) in treating osteoporosis?

Postmenopausal Hormone Replacement Therapy for Osteoporosis

Hormone replacement therapy (HRT) effectively increases bone mineral density and reduces fracture risk in postmenopausal women, but should NOT be used routinely for osteoporosis prevention or treatment due to significant risks that outweigh benefits, including increased breast cancer, cardiovascular disease, stroke, and venous thromboembolism. 1

Evidence for Efficacy

Bone Density Improvements

• HRT increases bone mineral density at the hip, lumbar spine, and peripheral sites in postmenopausal women 1
• Bone density decreases by approximately 2% annually during the first 5 years after menopause, followed by 1% annual loss thereafter, which HRT can prevent during active treatment 2
• When HRT is discontinued, bone mass declines at rates comparable to the immediate postmenopausal period, meaning protective effects do not persist long-term 3

Fracture Reduction Data

• Meta-analysis of 22 trials: 27% reduction in nonvertebral fractures (RR 0.73,95% CI 0.56-0.94) 1

• Observational studies showed reductions in:

  • Vertebral fractures: RR 0.6 (95% CI 0.36-0.99) for ever-users 1
  • Wrist fractures: RR 0.39 (95% CI 0.24-0.64) for current users 1
  • Hip fractures: RR 0.64 (95% CI 0.32-1.04) for current users 1

• Women's Health Initiative (WHI): Significant 24% reduction in total fracture risk (RH 0.76,95% CI 0.63-0.92) among healthy women taking combined estrogen/progestin 1

• WHI also showed 34% reductions in hip and vertebral fractures, though these did not achieve statistical significance in adjusted analyses 1

Contradictory Evidence

• HERS and HERS II trials: Found NO reduction in hip, wrist, vertebral, or total fractures with hormone therapy (RH 1.04,95% CI 0.87-1.25) 1
• This discrepancy likely reflects that HERS studied women with existing cardiovascular disease (secondary prevention population), not healthy postmenopausal women 1

Critical Harms That Preclude Routine Use

Cardiovascular Risks

• Coronary heart disease: 29% increased risk (RH 1.29,95% CI 1.02-1.63) with 7 additional CHD events per 10,000 women-years 3
• Stroke: 41% increased risk (RH 1.41,95% CI 1.07-1.85) with 8 additional strokes per 10,000 women-years 1, 3
• Venous thromboembolism: 113% increased risk (RH 2.13,95% CI 1.39-3.25) with 8 additional PEs per 10,000 women-years 3
• Risks appear within the first 1-2 years of therapy 1

Cancer Risks

• Breast cancer: 26% increased risk (RH 1.26,95% CI 1.00-1.59) with 8 additional cases per 10,000 women-years 1, 3
• Risk increases with longer-term use (>5 years) 1
• Endometrial cancer: Increased risk unless progestin is co-administered for at least 10 days per cycle 3, 4

Official Guideline Recommendations

The U.S. Preventive Services Task Force recommends AGAINST using HRT routinely for the specific purpose of preventing chronic disease, including osteoporosis, in postmenopausal women. 1

Rationale for Recommendation

• The absolute excess risk in the "global index" was 19 additional adverse events per 10,000 women-years 3
• While HRT reduces fractures by 5 per 10,000 women-years, it causes 7 additional CHD events, 8 additional strokes, 8 additional PEs, and 8 additional breast cancers per 10,000 women-years 3
• Alternative medications (bisphosphonates, selective estrogen receptor modulators) provide comparable fracture reduction without cardiovascular and cancer risks 1

When HRT May Be Considered

FDA-Approved Indication

• Estradiol is FDA-approved for prevention of postmenopausal osteoporosis, but only for women at significant risk where non-estrogen medications are not appropriate 3
• Should use the lowest effective dose for the shortest duration consistent with treatment goals 3
• Patients should be reevaluated at 3-6 month intervals to determine if treatment is still necessary 3

Clinical Context for Use

• HRT should be considered primarily for women requiring treatment of moderate-to-severe menopausal vasomotor symptoms who also have osteoporosis risk 1
• For women using HRT for menopausal symptoms, bone protection is a secondary benefit, not the primary indication 1
• Women should be informed of all risks and use the lowest effective dose for the shortest possible time 1

Critical Pitfalls to Avoid

• Do not prescribe HRT solely for osteoporosis prevention or treatment when safer alternatives exist (bisphosphonates, denosumab, selective estrogen receptor modulators) 1
• Do not assume bone benefits persist after discontinuation—bone loss resumes at menopausal rates when HRT stops 3
• Do not use HRT in women with intact uterus without progestin—this dramatically increases endometrial cancer risk 3
• Do not prescribe without discussing cardiovascular and breast cancer risks, particularly in women over 60 or more than 10 years post-menopause 1
• Do not rely on evidence from conjugated equine estrogen/medroxyprogesterone acetate trials to justify other HRT regimens—most evidence comes from this specific formulation 1