Restarting Bisphosphonates After a Drug Holiday
Yes, patients can restart bisphosphonates after a drug holiday if their fracture risk increases, new fractures occur, or bone mineral density declines significantly during the holiday period. 1, 2
When to Restart Bisphosphonates
The decision to restart therapy depends on specific clinical triggers that emerge during the drug holiday:
New fracture occurrence: Any new fracture during the holiday period warrants immediate resumption of bisphosphonate therapy 2
Significant BMD decline: If femoral neck T-score drops to ≤ -2.5 or shows significant decline (≥10% per year), restart therapy 2, 3
Increased fracture risk profile: Development of new risk factors such as initiation of high-dose glucocorticoids (≥7.5 mg prednisone daily), multiple falls, or other conditions that substantially elevate fracture risk 2
High-risk features present: Patients with previous hip or vertebral fractures, multiple non-spine fractures, or T-score ≤ -2.5 at baseline should have shorter holidays (1-2 years maximum) and lower threshold for restarting 1, 4
Duration of Drug Holiday Before Restarting
The appropriate holiday length varies by bisphosphonate type due to different bone retention characteristics:
Alendronate: Drug holidays can safely extend up to 5 years in low-risk patients 5, 4
Zoledronic acid: Drug holidays should not exceed 3 years 5, 4
Risedronate: Drug holidays should be limited to 1 year due to shorter bone retention 5, 6
Critical pitfall: The American College of Physicians explicitly states that bisphosphonates should only be continued beyond 10 years (6 years if parenteral) in patients at very high risk of fracture 4. This means even after restarting, total cumulative exposure matters.
Monitoring During the Drug Holiday
Regular reassessment is mandatory to determine when restarting is appropriate:
Clinical monitoring: Assess for new fractures, falls, and changes in risk factors every 1-3 years 3, 4
BMD monitoring: Check bone mineral density periodically, particularly at the femoral neck, though the American College of Physicians does not recommend routine BMD monitoring during initial treatment 2
Risk stratification: Recalculate FRAX score if ≥40 years old to quantify current fracture risk 2
Alternative Considerations When Restarting
Not all patients should simply restart the same bisphosphonate:
Very high-risk patients: Those who fracture after ≥18 months of bisphosphonate therapy or experience significant bone loss (≥10% per year) despite prior bisphosphonate therapy should switch to anabolic agents (teriparatide, romosozumab) rather than restart bisphosphonates 2
Renal impairment: Patients with creatinine clearance <60 ml/min should switch to denosumab rather than restart bisphosphonates 2
Treatment failure: If a patient had inadequate response to the initial bisphosphonate course, consider switching to a different medication class rather than restarting the same agent 2
Special Precautions When Restarting
Before resuming bisphosphonate therapy, address these critical safety considerations:
Dental evaluation: Complete any pending dental work before restarting, as osteonecrosis of the jaw risk increases with cumulative exposure, particularly beyond 5 years total treatment 1, 7, 2
Vitamin D status: Correct vitamin D deficiency prior to restarting, especially for IV bisphosphonates, as deficiency increases risk of bisphosphonate-related hypocalcemia 2
Calcium supplementation: Ensure adequate calcium (1000-1200 mg/day) and vitamin D (800 IU/day) intake 2
Total cumulative exposure: Track total years of bisphosphonate exposure across all treatment periods, as atypical femoral fracture risk escalates sharply beyond 8 years of cumulative use 2
Major pitfall to avoid: Never restart denosumab after a drug holiday without immediately transitioning to bisphosphonates within 6 months, as denosumab discontinuation causes rebound vertebral fractures 1, 2. This is the opposite scenario—if a patient was on denosumab and stopped, they need bisphosphonates, not a holiday.
Risk-Benefit Context for Restarting
The decision to restart must weigh ongoing fracture prevention against cumulative harm risk:
Fracture prevention benefit: An estimated 162 osteoporosis-related fractures are prevented for every one atypical femoral fracture associated with bisphosphonate treatment 2
Harm reduction with holidays: The risk of atypical femoral fractures falls rapidly after bisphosphonates are discontinued 4
Limited additional benefit beyond 5 years: Extending treatment beyond 5 years reduces vertebral fractures but NOT other fracture types 1, 7