When should alendronate (70 mg orally once weekly) be restarted after a 5‑year drug holiday?

When to Restart Alendronate After a 5-Year Drug Holiday

Restart alendronate immediately if any of the following high-risk criteria develop during the drug holiday: new fracture, T-score decline to ≤ -2.5 at the spine or hip, significant BMD loss exceeding the least-significant change of your DXA instrument, or FRAX-calculated hip fracture probability ≥ 3% or major osteoporotic fracture probability ≥ 20%. 1, 2

Risk Stratification During the Drug Holiday

After completing 5 years of alendronate, the decision to restart therapy depends on systematic reassessment of fracture risk every 2–4 years while off treatment. 1, 2

Immediate Restart Criteria (High-Risk Features)

Restart alendronate if any of the following develop:

• New fracture of any type during the holiday period 2
• T-score ≤ -2.5 at the lumbar spine or hip on follow-up DXA 1, 2
• Significant BMD decline beyond the least-significant change (typically 4–5% at spine or hip) 1, 2
• FRAX scores showing hip fracture probability ≥ 3% or major osteoporotic fracture probability ≥ 20% 2
• Recent fracture within the past 2 years (these patients should never have started a holiday) 1

Continue Holiday Criteria (Low-to-Moderate Risk)

The drug holiday may be extended beyond 5 years if:

• T-score remains > -2.5 at all sites 1, 2
• No new fractures have occurred 1, 2
• BMD remains stable or shows only minimal decline within measurement error 2
• FRAX scores remain below treatment thresholds 2

Evidence Supporting the 5-Year Holiday Duration

The FLEX trial demonstrated that discontinuing alendronate after 5 years resulted in moderate BMD decline (-2.4% at total hip, -3.7% at spine) but no increased risk of non-vertebral fractures compared to continuing therapy for 10 years total. 3 However, there was a significantly higher risk of clinical vertebral fractures in those who stopped (5.3% vs 2.4%; RR 0.45), suggesting that women at very high risk of vertebral fractures benefit from continuing beyond 5 years. 3

The Endocrine Society guidelines explicitly state that a bisphosphonate holiday is "operationally defined as a temporary discontinuation of bisphosphonate for up to 5 years," which may be extended depending on BMD and clinical circumstances. 1 This recommendation is based on randomized extension trials showing residual anti-fracture effects after alendronate discontinuation. 1

Monitoring Schedule During the Holiday

Reassess fracture risk every 2–4 years using: 1, 2

• DXA scan at lumbar spine and hip 1
• FRAX calculation incorporating current BMD and clinical risk factors 2
• Clinical assessment for new fractures, falls, or changes in risk factors 2
• Optional bone turnover markers (serum CTX or P1NP) to detect accelerated bone loss, though this is not universally recommended 1

Maximum Holiday Duration

While the operational definition allows up to 5 years, fracture risk rises after more than 2 years off therapy, particularly in patients with T-scores ≤ -2.5. 2 The holiday may be extended beyond 5 years only if BMD remains stable and clinical circumstances permit, but this requires closer monitoring. 1, 2

Common Pitfalls to Avoid

• Do not extend holidays indefinitely without reassessment—fracture risk increases progressively after 2 years off therapy, especially with low baseline T-scores 2
• Do not ignore new fractures—any incident fracture during a holiday mandates immediate resumption of therapy 2
• Do not apply drug holiday concepts to non-bisphosphonate agents (denosumab, raloxifene, teriparatide)—these lack the residual bone binding that permits safe interruption 1, 2
• Do not continue holidays in patients who were never appropriate candidates—those with T-scores ≤ -2.5, prior vertebral fractures, or very high FRAX scores should not have started a holiday 1, 2

Strength of Evidence

The evidence for drug holidays is stronger for alendronate and zoledronic acid than for other bisphosphonates like risedronate, based on randomized extension trials. 1, 2 High-certainty evidence shows that bisphosphonates reduce hip, clinical vertebral, and any clinical fracture when used for ≥ 36 months. 2, 4 The safety profile remains favorable, with no difference in serious adverse events compared to placebo after ≥ 3 years of use. 4