What are the potential side effects of Alendronate (bisphosphonate) in postmenopausal women and older adults with osteoporosis, particularly those with a history of kidney disease or gastrointestinal disorders?

Alendronate Side Effects in Postmenopausal Women and Older Adults

Alendronate is generally well tolerated with most adverse events being transient gastrointestinal symptoms, but patients must be counseled on proper administration technique to minimize esophageal complications, and treatment should be limited to 5 years due to rare but serious long-term risks including osteonecrosis of the jaw and atypical femoral fractures. 1, 2

Common Gastrointestinal Side Effects

The most frequent adverse events are upper GI symptoms that occur at similar rates to placebo when the medication is taken correctly 3:

• Abdominal pain (3.7-6.6% vs 3.0-4.8% placebo), dyspepsia (2.7-3.6% vs 2.2-3.5% placebo), and acid regurgitation (1.9-2.0% vs 2.4-4.3% placebo) are the most common complaints 3
• Nausea (1.9-3.6%), constipation (0.8-3.1%), diarrhea (0.6-3.1%), and flatulence (0.4-2.6%) occur at low frequencies 3
• Esophageal ulceration and esophagitis can occur if proper administration instructions are not followed 1, 3

Critical Administration Instructions to Minimize GI Risk

Patients must take alendronate with a full glass of water (6-8 ounces), remain upright for at least 30 minutes, and avoid food/drink during this period to minimize esophageal risk 2, 3. Oral bisphosphonates should be avoided in patients with esophageal emptying disorders and those who cannot sit upright 4.

Musculoskeletal Side Effects

• Musculoskeletal pain (bone, muscle, or joint pain) occurs in 2.9-4.1% of patients vs 2.5-3.2% with placebo 3
• Muscle cramps are uncommon (0.2% vs 1.0% placebo) 3
• These symptoms are generally transient 5, 6

Rare but Serious Long-Term Adverse Events

Osteonecrosis of the Jaw (ONJ)

• Incidence is very rare at <1 case per 100,000 person-years with osteoporosis dosing 1, 2
• Risk increases with duration of therapy beyond 5 years 1, 2
• The most consistent risk factor is recent dental surgery or tooth extraction 2
• Ensure dental work is completed before initiating or continuing bisphosphonate therapy 2, 4

Atypical Femoral Fractures

• Incidence ranges from 3.0 to 9.8 cases per 100,000 patient-years 1, 2
• Risk begins to increase significantly after 5 years of treatment, escalating sharply beyond 8 years 2
• Asian patients face up to 8 times higher risk (595 vs 109 per 100,000 person-years in White patients) 2
• If an atypical femur fracture occurs, stopping bisphosphonates can reduce contralateral fracture risk from 25% 2

Atrial Fibrillation

• Some trials have reported associations, though the USPSTF analysis found no clear evidence of causality 1
• Evidence remains insufficient to establish a definitive link 1

Laboratory Abnormalities

• Asymptomatic, mild, and transient decreases in serum calcium occur in approximately 18% of patients (vs 12% placebo) 3
• Serum phosphate decreases occur in approximately 10% (vs 3% placebo) 3
• Clinically significant hypocalcemia (calcium <8.0 mg/dL) occurs at similar rates to placebo 3
• Vitamin D deficiency should be corrected prior to bisphosphonate initiation, particularly for IV therapy, as deficiency may increase risk of bisphosphonate-related hypocalcemia 2

Special Population Considerations

Patients with Kidney Disease

• Alendronate is contraindicated if creatinine clearance <35 mL/min 2
• Consider switching to denosumab for patients with CrCl <60 mL/min, as it does not require renal dose adjustment 1, 2
• IV bisphosphonates require renal monitoring and dose reductions for renal impairment 1

Patients with Gastrointestinal Disorders

• In clinical trials, 49-54% of patients had a history of GI disorders at baseline, and 54-89% used NSAIDs or aspirin concurrently 3
• Real-world data shows elderly alendronate users or those concurrently taking NSAIDs have significantly higher risk of acid-related upper GI disorders (relative risk 1.7) 7
• Women using alendronate had 28.5 ARD encounters per 100 person-years vs 17.6 in non-users 7
• Gastric and duodenal ulcers have been reported in post-marketing surveillance, though controlled trials showed no increased risk vs placebo 3

Overall Safety Profile

• Serious adverse events occur at similar rates to placebo (30.9% vs 30.7%) 3
• Treatment discontinuation due to adverse events occurs in 8.9% of alendronate patients vs 9.5% placebo 3
• All-cause mortality is identical between groups (1.8% vs 1.8% placebo) 3

Optimal Treatment Duration to Balance Benefits and Risks

The American College of Physicians strongly recommends 5 years as the standard treatment duration 1, 2. Evidence shows that increasing duration beyond 5 years probably reduces vertebral fractures but not other fractures, while increasing long-term harm risk 2. Clinicians should consider stopping bisphosphonate treatment after 5 years unless strong indications for continuation exist (previous hip/vertebral fractures, T-score ≤-2.5, age >80, ongoing glucocorticoid use) 1, 2.