When should a provider consider a drug holiday for a patient with osteoporosis at average risk of fracture who is taking bisphosphonates?

Bisphosphonate Drug Holiday Timing for Average-Risk Osteoporosis Patients

Providers should consider a drug holiday after 3 to 5 years of bisphosphonate therapy for patients with osteoporosis at average fracture risk. 1

Treatment Duration Before Drug Holiday

Standard Duration Recommendation

• The American College of Physicians explicitly states that patients at low risk for fracture should be considered for drug discontinuation after 3 to 5 years of bisphosphonate use. 1
• The need for continued therapy should be reevaluated periodically throughout treatment. 1
• Five years represents the standard treatment duration for bisphosphonates, after which clinicians should consider stopping unless strong indications for continuation exist. 1, 2

Agent-Specific Considerations

• Oral bisphosphonates (alendronate, risedronate) should be considered for a drug holiday after 5 years of treatment. 2
• Zoledronic acid may be considered for a drug holiday after 3 years based on trial data showing equivalent efficacy with 2 versus 5 years of treatment. 2
• Evidence shows that increasing duration beyond 3-5 years reduces vertebral fractures but not other fractures, while increasing long-term harm risk. 1, 2

Patient Selection Criteria for Drug Holiday

Average-Risk Patients Eligible for Holiday

• Patients with no previous hip or vertebral fractures during treatment AND a hip BMD T-score > -2.5 after treatment are appropriate candidates for a drug holiday. 2
• Patients should have stable bone mineral density and no new fractures during the initial treatment period. 2
• The decision should be based on baseline fracture risk, medication type and half-life, duration of treatment, and balance of benefits versus harms. 1, 2

High-Risk Patients Who Should Continue Beyond 5 Years

• Patients with previous hip or vertebral fractures, multiple non-spine fractures, or a hip BMD T-score ≤ -2.5 despite treatment should continue treatment beyond 5 years. 2
• Very high ongoing fracture risk factors include age >80 years, ongoing glucocorticoid use, or multiple risk factors. 2
• Patients with T-score < -2.5 or prevalent vertebral fractures after 5 years of alendronate or 3 years of zoledronate benefit from continuation. 3

Duration of Drug Holiday

Evidence-Based Holiday Length

• Drug holidays can safely extend up to 5 years with alendronate, 3 years with zoledronic acid, and 1 year with risedronate based on pharmacokinetic data and residual anti-fracture effects. 3
• A drug holiday of 2 to 3 years is recommended for most patients after long-term bisphosphonate therapy. 4
• The FLEX trial demonstrated that women who discontinued alendronate after 5 years had only modest increases in clinical vertebral fractures (5.3% vs 2.4%) but no difference in non-vertebral or hip fractures over the subsequent 5 years. 2

Fracture Risk During Holiday

• Fracture incidence during drug holidays ranges from 3.7% to 9.9% yearly, peaking at 9.9% and 9.8% during years 4 and 5 respectively. 5
• Women undertaking a BP holiday of ≥12 months after ≥3 years of use do not appear at greater risk of osteoporosis-related fragility fractures compared to ongoing users. 6
• Bisphosphonates provide persisting anti-fracture efficacy for at least 1-2 years after treatment is stopped due to bone accumulation. 7

Monitoring During Drug Holiday

Reassessment Parameters

• Reassess patients regularly during the drug holiday for new fractures, changes in fracture risk profile, and BMD changes (particularly femoral neck T-score). 2
• Do NOT perform routine BMD monitoring during the initial 5-year treatment period, but reassessment becomes important during the holiday. 2, 8
• Patients who begin drug holidays at high risk based on BMD, age, or other clinical risk factors warrant close follow-up, especially as duration lengthens. 5

Criteria for Resuming Treatment

• Resume bisphosphonate therapy if a new fracture occurs during the holiday, fracture risk increases significantly, or BMD remains low (femoral neck T-score ≤ -2.5). 2
• Patients with lower femoral neck BMD (0.75 g/cm² vs 0.79 g/cm²) and T-scores (-2.13 vs -1.78) at baseline have higher fracture risk during holidays. 5
• Regular reassessment of bone mineral density and fracture risk should guide the decision to recommence therapy. 3

Critical Pitfalls to Avoid

Denosumab Exception

• Denosumab drug holidays are NOT recommended due to risk of rebound fractures; if discontinued, bisphosphonate therapy must be initiated within 6 months. 2
• Never discontinue denosumab without immediately starting bisphosphonate therapy, as rebound vertebral fractures can occur. 2
• Denosumab discontinuation is associated with multiple vertebral fractures in some patients. 1

Anabolic Agent Considerations

• Patients initially treated with anabolic agents (teriparatide, romosozumab) must be offered an antiresorptive agent after discontinuation to preserve gains and prevent serious rebound vertebral fractures. 1, 2

Pre-Treatment Dental Care

• Ensure dental work is completed before initiating or continuing bisphosphonate therapy to reduce osteonecrosis of the jaw risk. 2
• Osteonecrosis of the jaw incidence is very rare at <1 case per 100,000 person-years with osteoporosis dosing, but risk increases with longer duration. 2