What are the potential side effects of Fosamax (alendronate) in older adults, particularly postmenopausal women, with osteoporosis?

Fosamax (Alendronate) Side Effects in Postmenopausal Women with Osteoporosis

Fosamax is generally well-tolerated with primarily mild, transient upper gastrointestinal symptoms as the most common side effects, while serious adverse events like osteonecrosis of the jaw and atypical femoral fractures remain rare but increase with treatment duration beyond 5 years. 1, 2

Common Side Effects (Occurring in ≥1% of Patients)

Gastrointestinal Effects

The most frequent adverse reactions are upper GI-related and typically transient 2:

• Abdominal pain (6.6% vs 4.8% placebo in daily dosing; 3.7% vs 3.0% placebo in weekly dosing) 2
• Dyspepsia (3.6% vs 3.5% placebo in daily dosing; 2.7% vs 2.2% placebo in weekly dosing) 2
• Acid regurgitation (2.0% vs 4.3% placebo in daily dosing; 1.9% vs 2.4% placebo in weekly dosing) 2
• Nausea (3.6% vs 4.0% placebo in daily dosing; 1.9% vs 2.4% placebo in weekly dosing) 2
• Constipation (3.1% vs 1.8% placebo) 2
• Diarrhea (3.1% vs 1.8% placebo) 2

Musculoskeletal Effects

• Bone, muscle, or joint pain (4.1% vs 2.5% placebo in daily dosing; 2.9% vs 3.2% placebo in weekly dosing) 2
• Muscle cramps (1.0% placebo vs 0% alendronate in some studies) 2

Other Common Effects

• Headache (2.6% vs 1.5% placebo) 2
• Rash and erythema have been reported 2

Serious but Rare Adverse Events

Osteonecrosis of the Jaw (ONJ)

• Incidence: <1 case per 100,000 person-years with osteoporosis dosing, but risk increases with longer duration of use 3
• Incidence range: 0.01-0.3% of users overall 4
• Most consistent risk factor: Recent dental surgery or tooth extraction 3
• Critical pitfall: Ensure dental work is completed before initiating or continuing bisphosphonate therapy 3

Atypical Femoral Fractures (AFF)

• Incidence: 3.0-9.8 cases per 100,000 patient-years 3
• Risk escalates significantly after 5 years of continuous use, with sharp increases beyond 8 years (from 1.78 per 100,000 person-years to 113 per 100,000 person-years) 3
• Asian patients face up to 8 times higher risk (595 vs 109 per 100,000 person-years in White patients) 3
• Risk-benefit context: An estimated 162 osteoporosis-related fractures are prevented for every one AFF associated with treatment 3
• If AFF occurs: Stopping bisphosphonates can reduce contralateral fracture risk, which is otherwise 25% 3

Esophageal Adverse Events

• Esophageal ulcers reported in clinical trials (1.5% vs 0% placebo) 2
• Dysphagia (1.0% vs 0% placebo) 2
• Critical administration requirements to minimize risk: Take with full glass of water (6-8 ounces), remain upright for at least 30 minutes, avoid food/drink during this period 3
• Contraindications: Abnormalities of the esophagus, inability to stand or sit upright for at least 30 minutes 1

Cardiovascular Effects

• Atrial fibrillation: Some trials reported associations, though insufficient evidence exists to establish causality 3
• No clear evidence of association found in USPSTF analysis 3
• Bisphosphonates probably resulted in no differences in risk for atrial fibrillation in RCTs (low certainty evidence) 1

Metabolic Effects

• Hypocalcemia: Reported with zoledronic acid (IV bisphosphonate) 1
• Asymptomatic, mild, transient decreases in serum calcium (18% vs 12% placebo) and phosphate (10% vs 3% placebo) 2
• Vitamin D deficiency should be corrected prior to initiation, particularly for IV therapy, as deficiency may increase risk of bisphosphonate-related hypocalcemia 3

Overall Safety Profile

No Difference in Serious Adverse Events

• High-quality evidence shows bisphosphonates resulted in no differences in risk for serious adverse events compared to placebo in RCTs at 12-36 months 1
• Incidence of all-cause mortality: 1.8% in both placebo and alendronate groups 2
• Incidence of serious adverse events: 30.7% placebo vs 30.9% alendronate 2

Treatment Discontinuation Rates

• Discontinuation due to adverse events: 9.5% placebo vs 8.9% alendronate in treatment studies 2
• Bisphosphonates probably resulted in no differences in withdrawal due to adverse events (moderate certainty evidence) 1

Duration-Related Considerations

Standard 5-Year Treatment Period

• Treatment benefit reduces after 5 years while AFF risk increases 3
• High-certainty evidence demonstrates fracture reduction benefits through 5 years without significant increases in serious adverse events during this timeframe 1, 3
• Patients at low risk for fracture should be considered for drug discontinuation after 3-5 years 1

Beyond 5 Years

• Prolonged use beyond 5 years increases risk of rare but serious adverse events including ONJ and AFF 3
• Chronic suppression of bone turnover has uncertain long-term skeletal consequences 3
• Clinicians should consider stopping bisphosphonate treatment after 5 years unless strong indications for continuation exist 3

Special Population Considerations

Patients with Pre-existing GI Disease

• 49-54% had history of GI disorders at baseline in clinical trials 2
• 54-89% used NSAIDs or aspirin at some time during studies 2
• One patient with history of peptic ulcer disease and gastrectomy taking concomitant aspirin developed anastomotic ulcer with mild hemorrhage (considered drug-related) 2

Renal Considerations

• Contraindication for zoledronic acid: Creatinine clearance <35 mL/min per 1.73 m² and acute renal impairment 1
• Denosumab is preferred in patients with renal impairment (CrCl <60 mL/min) 3

Critical Pitfalls to Avoid

1. Never ignore proper administration instructions - esophageal complications are primarily attributed to noncompliance with manufacturer's recommendations 5
2. Do not automatically continue beyond 5 years without reassessing fracture risk - this exposes patients to unnecessary rare adverse events 3
3. Complete dental work before initiating therapy to reduce ONJ risk 3
4. Ensure adequate calcium (800-1000 mg/day) and vitamin D (800 IU/day) intake throughout treatment 3
5. Correct vitamin D deficiency prior to initiation, particularly for IV therapy 3