Is a drug holiday typically taken after 5 years of bisphosphonate (e.g. alendronate or risedronate) therapy and then 3 years of intravenous (IV) therapy?

No, That Is Not the Correct Sequence for Bisphosphonate Drug Holidays

The standard approach is to take a drug holiday AFTER 5 years of oral bisphosphonates (like alendronate or risedronate) OR after 3 years of IV bisphosphonates (like zoledronic acid)—not to switch from oral to IV therapy before the holiday. There is no evidence supporting sequential therapy with oral followed by IV bisphosphonates before initiating a drug holiday 1, 2.

The Evidence-Based Approach to Bisphosphonate Drug Holidays

Initial Treatment Duration

• Oral bisphosphonates (alendronate, risedronate): Treat for 5 years before considering a drug holiday 1, 3, 2
• IV bisphosphonates (zoledronic acid): Treat for 3 years before considering a drug holiday 1, 2
• The FDA label for risedronate explicitly states: "For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use" 3

Who Should Get a Drug Holiday After Initial Treatment

Low-to-moderate risk patients should be offered a drug holiday if they meet ALL of these criteria:

• No hip or vertebral fractures during treatment 1, 4, 2
• Hip BMD T-score > -2.5 after treatment 1, 4, 2
• No multiple non-spine fractures 4, 2

High-risk patients should continue treatment beyond 5-10 years WITHOUT a drug holiday if they have:

• Previous hip or vertebral fracture 1, 2
• Hip BMD T-score ≤ -2.5 despite treatment 1, 2
• Multiple non-spine fractures 4, 2
• Age 70 or older (independent risk factor) 1

Duration of Drug Holiday

• Standard drug holiday duration: 2-3 years for most patients 5, 4, 2
• Can extend up to 5 years in very low-risk patients with stable BMD and no new fractures 1, 4
• The FLEX trial showed continued vertebral fracture protection for at least 5 years after stopping alendronate 2

Why Not Switch to IV Therapy Before a Holiday?

There is no evidence supporting switching from oral to IV bisphosphonates as a bridge to drug holiday:

• The SWOG S0307 trial found no efficacy differences among zoledronic acid, clodronate, and ibandronate (5-year DFS: 88.3% vs 87.6% vs 87.4%, P=0.49), indicating no advantage to switching between bisphosphonates 1
• Guidelines explicitly state that administration beyond 5 years has not been evaluated in trials and is not supported by current evidence 6, 1
• The SUCCESS A trial demonstrated that 2 years of zoledronic acid was as effective as 5 years with significantly less toxicity (all adverse events: 46.2% with 5-year treatment vs 27.2% with 2-year treatment, P=0.001) 1

Critical Pitfalls to Avoid

• Do NOT automatically continue bisphosphonates beyond 5 years without reassessing fracture risk, as this exposes patients to unnecessary rare adverse events (atypical femoral fractures, osteonecrosis of the jaw) without proven additional benefit in low-risk individuals 1, 2
• Do NOT perform routine BMD monitoring during the initial 5-year treatment period, as fracture reduction occurs even without BMD increases 1
• Do NOT switch to denosumab during or after bisphosphonate therapy without careful consideration—denosumab is not recommended as adjuvant therapy and carries risk of rebound fractures upon discontinuation 1
• Ensure dental work is completed before initiating or continuing bisphosphonate therapy to reduce osteonecrosis of the jaw risk, particularly with longer treatment durations 1, 7

Monitoring During Drug Holiday

• Reassess patients regularly for new fractures, changes in fracture risk profile, and BMD changes (particularly femoral neck T-score) 1, 4
• 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) 1, 4
• The risk of atypical femoral fractures falls rapidly after bisphosphonates are discontinued 4, 2