What to do for a postmenopausal woman with persistent osteoporosis after 5 years of alendronic acid (bisphosphonate) therapy?

Management After 5 Years of Alendronic Acid with Persistent Osteoporosis

Reassess fracture risk and consider either continuing alendronate, switching to denosumab, or initiating a drug holiday based on specific high-risk features rather than automatically changing therapy. 1, 2

Risk Stratification After 5 Years

After completing 5 years of alendronate therapy, the critical decision point depends on whether the patient has very high-risk features for fracture: 2

Very high-risk features include:

• Previous hip or vertebral fractures during treatment 2
• Multiple non-spine fractures 2
• Hip BMD T-score ≤ -2.5 despite treatment 2
• Age >80 years 2
• Ongoing glucocorticoid use (≥7.5 mg prednisone daily) 2
• Significant bone loss (≥10% per year) despite bisphosphonate therapy 2

Treatment Options Based on Risk Profile

For Very High-Risk Patients

Continue alendronate beyond 5 years for patients with the high-risk features listed above, as the benefits of continued fracture reduction outweigh the increasing risks of rare adverse events. 2 The evidence shows that extending treatment beyond 5 years reduces vertebral fractures (though not other fracture types), which is particularly important for patients who remain at very high risk. 2

Alternative: Switch to denosumab if the patient has demonstrated treatment failure (new fractures or continued bone loss despite alendronate), renal impairment (creatinine clearance <60 mL/min), or cancer-related bone disease. 2, 3 Denosumab works through a different mechanism (RANK ligand inhibition) and may overcome resistance to bisphosphonate therapy. 3

For Patients Without High-Risk Features

Consider a drug holiday after 5 years for patients who have: 2

• No previous hip or vertebral fractures during treatment
• Hip BMD T-score > -2.5 after treatment
• No multiple non-spine fractures

The FLEX trial demonstrated that women who discontinued alendronate after 5 years had only a modest increase in clinical vertebral fractures (5.3% vs 2.4%) but no difference in non-vertebral or hip fractures over the subsequent 5 years. 2 This supports the safety of drug holidays in appropriately selected patients.

Critical Considerations Before Any Decision

Complete a dental evaluation before continuing or switching bisphosphonate therapy, as osteonecrosis of the jaw risk increases with cumulative exposure, particularly beyond 5 years of total treatment. 2

Ensure adequate supplementation with calcium (1000-1200 mg/day) and vitamin D (800 IU/day) regardless of which treatment path is chosen. 2

Do NOT routinely monitor BMD during the initial 5-year treatment period, as fracture reduction occurs even without BMD increases. 1 However, after 5 years when making continuation decisions, reassessing BMD (particularly femoral neck T-score) can help guide risk stratification. 2

Specific Warnings About Denosumab

If denosumab is initiated, never discontinue it without immediately starting bisphosphonate therapy within 6 months, as denosumab discontinuation causes rebound vertebral fractures. 2, 3 This is a critical safety consideration that makes denosumab a less flexible option than continuing alendronate or taking a drug holiday.

Monitoring During Drug Holidays

For patients who take a drug holiday: 2

• Reassess regularly for new fractures clinically
• Monitor for changes in fracture risk profile
• Consider checking BMD if clinical concern arises
• Resume bisphosphonate therapy if new fracture occurs, fracture risk increases significantly, or BMD remains low (femoral neck T-score ≤ -2.5)

Long-Term Risks to Discuss

Risks increase with duration beyond 5 years: 2

• Osteonecrosis of the jaw: <1 case per 100,000 person-years with standard dosing, but increases with duration
• Atypical femoral fractures: 3.0-9.8 cases per 100,000 patient-years, with risk escalating sharply beyond 8 years
• Asian patients face up to 8 times higher risk for atypical femoral fractures than White patients 2

However, the benefit-risk ratio remains favorable: An estimated 162 osteoporosis-related fractures are prevented for every one atypical femoral fracture associated with antiresorptive medication treatment. 2

Common Pitfalls to Avoid

Do not 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. 2

Do not switch to raloxifene or estrogen therapy, as the American College of Physicians strongly recommends against using these agents for osteoporosis treatment. 1

Do not overlook secondary causes of osteoporosis that may impair response to therapy, such as vitamin D deficiency, hyperparathyroidism, or malabsorption. 3