When to consider a drug holiday for patients on osteoporosis therapy, such as bisphosphonates (e.g. alendronate or zoledronic acid), to minimize the risk of atypical fractures?

Drug Holiday Considerations for Bisphosphonate Therapy in Osteoporosis

When to Consider a Drug Holiday

After 3-5 years of bisphosphonate therapy, patients at low-to-moderate fracture risk should be considered for a drug holiday, while high-risk patients should continue treatment for up to 10 years (oral) or 6 years (intravenous) before reassessment. 1, 2

Risk Stratification After Initial Treatment Period

High-Risk Patients Who Should Continue Treatment

Continue bisphosphonate therapy beyond the initial 3-5 years in patients with:

• Hip T-score ≤ -2.5 (or between -2.0 and -2.5 with additional risk factors) 3
• Age >74 years 2
• History of major osteoporotic fracture (especially vertebral or hip fracture) 3
• Fracture occurring while on bisphosphonate therapy 2
• Multiple prior osteoporotic fractures 2
• Very high FRAX scores 2

These patients should continue treatment for up to 10 years with oral bisphosphonates (alendronate/risedronate) or 6 years with intravenous zoledronic acid, with periodic reassessment 3, 2.

Low-to-Moderate Risk Patients Eligible for Drug Holiday

Consider a drug holiday of 2-3 years after 3-5 years of bisphosphonate therapy in patients who:

• Do not meet high-risk criteria above 3
• Have stable or improved bone mineral density 4
• Have not experienced fractures during treatment 4
• Have hip T-score > -2.5 3

Duration of Drug Holiday

• Low-risk patients: May remain off therapy as long as bone mineral density remains stable and no fractures occur 4
• Moderate-risk patients: Drug holiday should not exceed 2-3 years, with close monitoring 3, 5
• High-risk patients: If drug holiday is considered, limit to 1-2 years maximum and consider transitioning to non-bisphosphonate therapy during this period 4

Rationale for Drug Holidays

Bisphosphonates accumulate in bone and continue to provide residual antifracture efficacy for 1-2 years after discontinuation due to slow release from the bone reservoir 4, 3. This pharmacologic property allows for temporary cessation in appropriate patients while maintaining some protective effect.

The primary concern driving drug holidays is the time-dependent increase in risk of atypical femoral fractures with prolonged bisphosphonate use 6, 7. However, this risk remains extremely low—approximately 162 typical osteoporotic fractures are prevented for every 1 atypical femoral fracture associated with bisphosphonate therapy 7.

Monitoring During Drug Holiday

During the drug holiday period:

• Reassess fracture risk periodically (annually or biannually) 1
• Monitor bone mineral density to detect significant bone loss 4
• Evaluate for new fractures clinically 1
• Assess for new risk factors that might warrant treatment resumption 3

Critical Safety Considerations

Atypical Femoral Fractures

• Risk increases with duration of bisphosphonate therapy beyond 5 years 6, 7
• Patients may experience prodromal thigh or groin pain weeks to months before fracture 6
• Evaluate any patient with thigh/groin pain for possible atypical fracture, even during drug holiday 6
• Fractures are often bilateral—examine contralateral femur if atypical fracture occurs 6

Osteonecrosis of the Jaw (ONJ)

• Risk increases with duration of bisphosphonate exposure 6
• Perform preventive dental examination before initiating bisphosphonates 6
• Avoid invasive dental procedures during active treatment when possible 6

Agent-Specific Considerations

Alendronate and zoledronic acid have demonstrated residual bone effects that persist after discontinuation, making them suitable for drug holidays 7, 4.

Other bisphosphonates (such as ibandronate) without demonstrated residual effects typically do not warrant drug holidays 7.

When to Resume Treatment After Drug Holiday

Restart bisphosphonate therapy if:

• Significant decline in bone mineral density occurs during holiday 4
• New fracture occurs during holiday 4
• New high-risk factors develop 3
• Drug holiday exceeds 2-3 years in moderate-risk patients 3

Common Pitfalls to Avoid

• Do not discontinue bisphosphonates in high-risk patients simply because they have reached 5 years of treatment—these patients benefit from continued therapy 3, 2
• Do not implement drug holidays without risk stratification—fracture risk must be reassessed before discontinuation 1, 3
• Do not confuse denosumab with bisphosphonates—denosumab causes severe rebound bone loss and multiple vertebral fractures upon discontinuation and should NOT have drug holidays 1, 2
• Do not ignore prodromal symptoms—thigh or groin pain warrants immediate evaluation for atypical fracture 6