When is a drug holiday from bisphosphonates (e.g. risedronate) considered?

Bisphosphonate Drug Holiday: When and Why

A drug holiday from bisphosphonates like risedronate should be considered after 5 years of treatment in patients without high fracture risk, as continued therapy beyond this point increases risk for rare but serious adverse events (atypical femoral fractures and osteonecrosis of the jaw) while providing limited additional benefit beyond vertebral fracture reduction. 1

Primary Rationale for Drug Holidays

Balance of Benefits vs. Harms After 5 Years

• Bisphosphonates accumulate in bone and continue to provide anti-fracture protection for months to years after discontinuation, making temporary cessation feasible without immediate loss of benefit 2, 3
• Evidence demonstrates that extending bisphosphonate therapy beyond 3-5 years reduces vertebral fractures but does not reduce hip or other non-vertebral fractures, while increasing long-term harm risk 1
• The FDA label for risedronate explicitly states: "For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use" 4

Rare Adverse Events Drive the Decision

• Atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) are causally linked to bisphosphonate use, particularly with >5 years of therapy 5, 6
• The risk of AFF falls rapidly after bisphosphonates are discontinued, supporting the protective effect of drug holidays 6
• ONJ incidence increases with longer treatment duration (11 cases with 5-year treatment vs. 5 cases with 2-year treatment in the SUCCESS A trial) 7

Who Should Take a Drug Holiday

Eligible Patients (Low-to-Moderate Risk)

• Patients with no previous hip or vertebral fractures during treatment AND hip BMD T-score >-2.5 after 5 years of oral bisphosphonates (or 3 years of IV zoledronic acid) 7, 5, 6
• Patients without multiple non-spine fractures during treatment 7, 6

Patients Who Should Continue Treatment (High Risk)

• Previous hip or vertebral fractures (before or during treatment) 7, 5
• Hip BMD T-score ≤-2.5 despite treatment 7, 5
• Multiple non-spine fractures 7, 6
• Very high ongoing fracture risk factors: age >80 years, ongoing glucocorticoid use, multiple risk factors 7

Duration of Drug Holiday by Agent

Agent-Specific Recommendations Based on Half-Life

• Risedronate: 1-2 years drug holiday duration 8, 5
• Alendronate: 3-5 years drug holiday duration 8, 5
• Zoledronic acid: 3-6 years drug holiday duration 5
• These durations reflect the different bone retention and half-lives of each bisphosphonate 1

Critical Decision-Making Framework

The Individualization Factors

The decision for drug holiday duration must be based on four key factors: 1

1. Baseline fracture risk (bone density, fracture history, age, comorbidities)
2. Type of bisphosphonate and its half-life in bone (risedronate has shorter retention than alendronate or zoledronic acid)
3. Total duration of bisphosphonate exposure (5 years oral vs. 3 years IV)
4. Balance of benefits (continued vertebral fracture reduction) vs. harms (AFF, ONJ risk)

Monitoring During Drug Holiday

What to Assess

• Reassess fracture risk regularly during the holiday period 7, 5
• Monitor for new fractures clinically 7, 5
• Do NOT perform routine BMD monitoring during the initial 5-year treatment period, as fracture reduction occurs even without BMD increases 7
• During the holiday, BMD changes (particularly femoral neck T-score) should be monitored 7, 5

When to Resume Treatment

Resume bisphosphonate therapy if: 7, 5

• A new fracture occurs during the drug holiday
• Fracture risk increases significantly (new risk factors emerge)
• BMD remains low or declines (femoral neck T-score ≤-2.5)

Critical Pitfalls to Avoid

Denosumab Exception

• NEVER implement a drug holiday with denosumab without immediately transitioning to bisphosphonate therapy 7, 5
• Denosumab discontinuation causes rebound osteolysis and multiple vertebral fractures 7
• If denosumab must be stopped, initiate bisphosphonate therapy within 6 months 7

Anabolic Agent Transition

• 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, 7

Dental Considerations

• Ensure all necessary dental work is completed before initiating or continuing bisphosphonate therapy to reduce ONJ risk 7
• Recent dental surgery or tooth extraction is the most consistent risk factor for ONJ 7