What is the role of alendronate (bisphosphonate) in treating osteoporosis in men?

Alendronate for Osteoporosis in Men

Primary Recommendation

Oral bisphosphonates, specifically alendronate 70 mg once weekly or risedronate 35 mg once weekly, are the first-line pharmacologic treatment for men with clinically recognized osteoporosis to reduce vertebral fracture risk. 1, 2

Evidence Base and Treatment Efficacy

The 2024 Nature Reviews Rheumatology guideline provides the most comprehensive and recent evidence supporting alendronate use in men:

• Alendronate monotherapy increases bone mineral density (BMD) at the lumbar spine by 5.2% (95% CI 2.76–7.64), total hip by 2.34% (95% CI 1.66–3.03), and femoral neck by 2.53% (95% CI 1.76–3.31) based on systematic review and meta-analysis. 1

• Vertebral fracture reduction is established: In the landmark 2-year trial of 241 men, alendronate 10 mg daily reduced vertebral fracture incidence from 7.1% to 0.8% (P=0.02), representing an 89% relative risk reduction. 3

• The BMD improvements exceed surrogate threshold effects for fracture reduction: The 2.34% improvement at total hip surpasses the 1.42% threshold for vertebral fractures and approaches the 2.13% threshold for non-vertebral fractures. 1

Treatment Regimen

Prescribe alendronate 70 mg orally once weekly with the following specific instructions to minimize gastrointestinal adverse effects: 2, 4

• Take upon arising for the day with a full glass (6-8 oz) of plain water only
• Remain upright (sitting or standing) for at least 30 minutes after administration
• Do not eat, drink, or take other medications for at least 30 minutes after the dose
• Do not take at bedtime or before arising for the day

Essential Concurrent Therapy

All men over 65 years require calcium 1000-1200 mg daily and vitamin D 800-1000 IU daily as baseline supplementation, which is necessary for bisphosphonates to work effectively. 1, 2

Treatment Duration and Monitoring

Plan initial treatment for 5 years, then reassess fracture risk to determine whether to continue therapy or initiate a drug holiday. 1, 2 The American College of Physicians recommends against routine BMD monitoring during the 5-year treatment period. 1

Monitor adherence using bone turnover markers at baseline and 3 months: expect reductions >38% for P1NP and >56% for CTX to confirm therapeutic response. 1

Alternative Bisphosphonates

If alendronate is not tolerated or contraindicated:

• Risedronate 35 mg once weekly provides comparable efficacy with lumbar spine BMD increases of 4.39% (95% CI 3.46–5.31) and total hip increases of 2.46% (95% CI 1.71–3.22). 1

• Zoledronic acid 5 mg intravenously annually is second-line therapy, particularly useful when oral medication adherence is problematic, with demonstrated vertebral fracture reduction (RR 0.33; 95% CI 0.16–0.7). 1, 2

• Denosumab 60 mg subcutaneously every 6 months is another second-line option if bisphosphonates are contraindicated. 1, 2

Special Populations Requiring Different Approach

For men at very high fracture risk (recent vertebral or hip fracture, T-score ≤-2.5 with multiple fractures), consider starting with an anabolic agent (teriparatide, abaloparatide, or romosozumab) followed by bisphosphonate consolidation therapy rather than bisphosphonates alone. 1, 2

Pre-Treatment Assessment

Before initiating therapy:

• Calculate 10-year fracture probability using FRAX (Fracture Risk Assessment Tool) to confirm treatment indication. 1, 2

• Measure serum total testosterone as part of pre-treatment assessment; if borderline or low, check free testosterone and consider testosterone supplementation in hypogonadal men. 1, 2

• Ensure adequate renal function (alendronate is not recommended if creatinine clearance <35 mL/min). 4

Safety Profile and Common Pitfalls

Alendronate is generally well tolerated in men with safety profiles comparable to women. 4, 3 The most common adverse effects are mild upper gastrointestinal symptoms including dyspepsia (2.7%), acid regurgitation (1.9%), and abdominal pain (3.7%). 4

Critical pitfall to avoid: Failure to follow proper administration instructions increases risk of esophageal adverse events. The drug must be taken with plain water only (not coffee, juice, or mineral water) and patients must remain upright for 30 minutes. 4

Rare but serious adverse effects include atypical subtrochanteric fractures and osteonecrosis of the jaw, though these remain uncommon even with long-term use. 1

Evidence Quality Considerations

While the evidence base for alendronate in men is less extensive than in postmenopausal women, the 2024 Nature Reviews Rheumatology guideline provides strong recommendations based on "bridging studies" that demonstrate comparable BMD responses between men and women at similar fracture risk. 1 The American College of Physicians 2017 guideline rates this as a weak recommendation with low-quality evidence specifically for men, but emphasizes that bisphosphonates reduce vertebral fracture risk. 1

The most robust male-specific data comes from the 2000 New England Journal of Medicine trial demonstrating both BMD improvements and vertebral fracture reduction. 3 This remains the highest quality fracture outcome data available for men, though subsequent meta-analyses incorporating Bayesian methods and prior knowledge from women's trials support vertebral fracture reduction (OR 0.44; 95% CI 0.23,0.83). 5