Should Alendronate Be Restarted After Completing Five Years of Treatment?
No, alendronate should not be routinely restarted after completing five years of treatment for most patients, as the evidence demonstrates that discontinuation does not significantly increase fracture risk except for clinical vertebral fractures in very high-risk individuals. 1, 2, 3
Evidence Supporting Treatment Discontinuation
The FDA label explicitly states that patients at low risk for fracture should be considered for drug discontinuation after 3 to 5 years of use, with periodic re-evaluation of fracture risk for those who discontinue. 2 The landmark FLEX trial demonstrated that women who discontinued alendronate after 5 years had no significant difference in non-vertebral fractures (18.9% vs 19%) or hip fractures compared to those who continued treatment for an additional 5 years. 3 A real-world Danish cohort study of 1,865 discontinuers versus 29,619 continuers found no increased risk of any fracture (IRR 1.06,95% CI 0.92-1.23), hip fracture (IRR 1.04,95% CI 0.75-1.45), or major osteoporotic fracture (IRR 1.05,95% CI 0.88-1.25) after discontinuation. 4
Why Discontinuation Is Safe for Most Patients
Alendronate's effects persist after discontinuation due to its long skeletal half-life. 5 Women who stopped alendronate maintained BMD levels at or above pretreatment levels from 10 years earlier, and bone turnover markers remained somewhat below pretreatment levels despite being off therapy for 5 years. 3 This residual effect provides continued fracture protection during a drug holiday. 1, 5
The One Exception: Very High-Risk Patients
The only clinically important difference with discontinuation was a higher rate of clinical vertebral fractures (5.3% placebo vs 2.4% alendronate; RR 0.45,95% CI 0.24-0.85). 3 Therefore, patients at very high risk for clinical vertebral fractures should continue beyond 5 years. 1, 3 High-risk criteria include: 1
- Previous hip or vertebral fractures during treatment
- Multiple non-spine fractures
- Hip BMD T-score ≤ -2.5 despite treatment
- Age >80 years
- Ongoing glucocorticoid use (≥7.5 mg prednisone equivalent daily)
Risks of Continuing Beyond Five Years
Extending treatment beyond 5 years increases adverse events without proportional benefit. 1 The SUCCESS A trial in breast cancer patients showed that 5-year treatment had significantly more adverse events than 2-year treatment (46.2% vs 27.2%, P=0.001), with more grade 3-4 events (7.6% vs 5.1%, P=0.006), and double the cases of osteonecrosis of the jaw (11 vs 5 cases). 6 Long-term risks include: 1
- Osteonecrosis of the jaw (1.26% with zoledronic acid at 3 years) 6
- Atypical femoral fractures (3.0-9.8 per 100,000 patient-years) 1
- Increased musculoskeletal pain and gastrointestinal symptoms 6
Clinical Algorithm for Decision-Making
Step 1: Assess Fracture Risk After 5 Years
- Low risk (no prior fractures, hip T-score >-2.5, age <80): Discontinue alendronate 1, 2
- High risk (prior hip/vertebral fracture, T-score ≤-2.5, age >80, glucocorticoids): Continue treatment 1, 3
Step 2: During Drug Holiday (for Low-Risk Patients)
- Do NOT perform routine BMD monitoring during the initial 5-year treatment period 1, 7
- Reassess fracture risk periodically (annually or biannually) 2
- Monitor for new fractures or changes in risk factors 1
Step 3: Criteria for Restarting Treatment
Restart alendronate if any of the following occur during the drug holiday: 1
- New fracture occurs
- Femoral neck T-score drops to ≤-2.5
- Development of new high-risk factors (glucocorticoid initiation, significant bone loss)
Critical Pitfalls to Avoid
Never automatically continue bisphosphonates beyond 5 years without reassessing fracture risk, as this exposes patients to unnecessary rare adverse events without proven additional benefit in low-risk individuals. 1
Ensure dental work is completed before continuing therapy to reduce osteonecrosis of the jaw risk, particularly important in older patients. 1, 7
Do not discontinue without ensuring adequate calcium (1000-1200 mg/day) and vitamin D (800 IU/day) supplementation, as this can reduce treatment efficacy and increase fracture risk, especially in elderly patients taking proton pump inhibitors or SSRIs. 7
Never switch to denosumab as a routine alternative after 5 years of alendronate unless there is renal impairment (CrCl <60 mL/min) or cancer-related bone disease, as denosumab carries risk of rebound fractures upon discontinuation and requires bisphosphonate therapy within 6 months if stopped. 1