What is the role of bisphosphonates (e.g. alendronate, risedronate) in primary prevention of fractures in patients without a history of osteoporosis or fractures?

Bisphosphonates for Primary Prevention of Fractures

Bisphosphonates should NOT be used for primary prevention in patients without osteoporosis or prior fractures. The term "primary prevention" in osteoporosis guidelines refers to preventing fractures in patients who already have osteoporosis but no prior fractures—not preventing osteoporosis itself in healthy individuals. 1

Key Distinction: Primary vs. True Primary Prevention

The evidence base defines "primary prevention" as treatment of patients with:

• Low bone mineral density (BMD T-score ≤ -2.5) but no previous fractures, OR
• Trials excluding patients with prior vertebral/osteoporotic fractures 1

This is fundamentally different from treating patients with normal bone density or no osteoporosis diagnosis.

Evidence-Based Recommendations by Population

Postmenopausal Women WITH Diagnosed Osteoporosis (No Prior Fractures)

Bisphosphonates are strongly recommended as first-line therapy to reduce fracture risk in this population. 1

• Alendronate, risedronate, and zoledronic acid reduce vertebral fractures by 47-48% (RR 0.66,95% CI 0.50-0.89) 1
• Hip fracture reduction demonstrated in the Fracture Intervention Trial, but only in women with femoral neck T-scores < -2.5 1, 2
• Nonvertebral fracture reduction shows a trend but is not consistently statistically significant (RR 0.83, CI 0.64-1.08) 1
• Benefits appear within 6-12 months of starting therapy 3, 4

Women Over 65 WITH Low Bone Mass (Osteopenia, T-score -1.0 to -2.5)

An individualized approach is recommended—treatment is NOT automatically indicated. 1

The American College of Physicians suggests weighing:

• Baseline fracture risk using FRAX or similar tools 1
• Additional risk factors (age, prior falls, family history, medications) 1
• Cost considerations (bisphosphonates are inexpensive as generics but still represent treatment burden) 1

Evidence is limited: Only one trial (zoledronic acid) showed reduction in clinical vertebral fractures in osteopenic women, with very uncertain evidence for hip fractures. 1

Practical threshold: Consider treatment if 10-year FRAX hip fracture risk ≥3% or major osteoporotic fracture risk ≥20%, though guidelines do not mandate specific cutoffs. 1

Men WITH Diagnosed Primary Osteoporosis (No Prior Fractures)

Bisphosphonates are conditionally recommended as first-line therapy, though evidence is extrapolated from women. 1

• No primary prevention trials exist specifically in men 1
• Radiographic vertebral fractures probably reduced (140 fewer per 1000 treated), but clinical fractures not significantly reduced 1
• FDA approval based on BMD improvements rather than fracture outcomes 1
• Denosumab recommended as second-line if bisphosphonates contraindicated 1

Patients WITHOUT Osteoporosis or Low Bone Mass

No role for bisphosphonate therapy. 1

• No controlled studies evaluate screening or treatment in normal BMD populations 1
• Potential harms (false-positives, unnecessary treatment, patient anxiety) outweigh unproven benefits 1
• Focus should be on lifestyle measures: weight-bearing exercise, calcium 1000-1200 mg/day, vitamin D 600-800 IU/day 1

Treatment Duration and Drug Holidays

Bisphosphonates should be stopped after 3-5 years in low-risk patients due to bone accumulation and persistent antifracture effects. 1

• Continued therapy beyond 5 years probably reduces vertebral fractures but not other fractures, with increased long-term harm risk 1
• Residual antifracture efficacy persists 1-2 years after discontinuation 4, 5
• High-risk patients (prior fracture on therapy, very low BMD, new fractures during holiday) may continue 10 years 4

Reassess fracture risk annually during drug holidays using BMD monitoring and clinical evaluation. 1, 4

Important Safety Considerations

Bisphosphonates have favorable short-term safety but rare long-term risks:

• Osteonecrosis of the jaw: Higher risk with longer duration, particularly beyond 5 years 1, 4
• Atypical femoral fractures: Rare but increased risk with prolonged use 1, 4
• Esophageal irritation: Common with oral formulations; take with full glass of water, remain upright 30 minutes 3, 4
• Acute phase response: Fever, myalgias with IV zoledronic acid 4

No increased risk of serious adverse events, atrial fibrillation, or treatment withdrawal in primary prevention trials. 1

Common Pitfalls to Avoid

• Do not treat based on age alone without BMD testing or fracture risk assessment 1
• Do not continue bisphosphonates indefinitely without reassessing need at 3-5 years 1, 4
• Do not use expensive anabolic agents (teriparatide, romosozumab) for primary prevention—these are reserved only for very high fracture risk patients 1, 6
• Do not forget calcium and vitamin D supplementation as foundational therapy 1