What are the side effects and risks of Fosamax (alendronate) in postmenopausal women and older adults with a history of gastrointestinal disorders or impaired renal function?

Fosamax Side Effects and Risks

Fosamax (alendronate) carries common gastrointestinal side effects and rare but serious long-term risks including osteonecrosis of the jaw and atypical femoral fractures, with treatment duration limited to 5 years to optimize the benefit-risk ratio. 1

Common Side Effects

Gastrointestinal Effects

The most frequent adverse effects involve the upper GI tract and occur at similar rates to placebo in controlled trials 2:

• Abdominal pain affects 3.7-6.6% of patients (versus 3.0-4.8% with placebo) 2
• Dyspepsia occurs in 2.7-3.6% of patients (versus 2.2-3.5% with placebo) 2
• Acid regurgitation affects 1.9-2.0% of patients (versus 2.4-4.3% with placebo) 2
• Nausea occurs in 1.9-3.6% of patients (versus 2.4-4.0% with placebo) 2
• Constipation, diarrhea, and flatulence are reported but generally transient 2

Musculoskeletal Effects

• Bone, muscle, or joint pain affects 2.9-4.1% of patients (versus 2.5-3.2% with placebo) 2
• Muscle cramps occur in approximately 0.2-1.0% of patients 2

Laboratory Abnormalities

• Asymptomatic, mild, and transient decreases in serum calcium occur in approximately 18% of patients (versus 12% with placebo) 2
• Decreases in serum phosphate occur in approximately 10% of patients (versus 3% with placebo) 2

Serious Long-Term Risks

Osteonecrosis of the Jaw (ONJ)

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

Atypical Femoral Fractures

• Incidence ranges from 3.0 to 9.8 cases per 100,000 patient-years 1
• Risk begins to increase significantly after 5 years of treatment, escalating sharply beyond 8 years of continuous use 1
• Risk increases from 1.78 per 100,000 person-years to 113 per 100,000 person-years with exposure greater than 8 years 1
• Asian patients face up to 8 times higher risk than White patients (595 versus 109 per 100,000 person-years) 1
• If an atypical femur fracture occurs, stopping bisphosphonates can reduce contralateral fracture risk, which is otherwise 25% 1

Esophageal Complications

• Esophageal ulcers and esophagitis have been reported, particularly when dosing instructions are not followed 2
• Gastric and duodenal ulcers have been reported in post-marketing surveillance, though controlled trials showed no increased risk compared to placebo 1

Special Population Considerations

Patients with Gastrointestinal Disorders

• Alendronate is contraindicated in patients with abnormalities of the esophagus that delay esophageal emptying 3
• Patients with a history of upper GI disease do not have increased risk of upper GI events when taking alendronate according to proper dosing instructions 4
• 49-54% of trial participants had a history of gastrointestinal disorders at baseline, and tolerability was not affected 2

Patients with Impaired Renal Function

• Alendronate is contraindicated in patients with creatinine clearance <35 mL/min 1, 3
• Consider switching to denosumab for patients with CrCl <60 mL/min, as it does not require renal dose adjustment 1
• IV bisphosphonates require renal monitoring and dose reductions for renal impairment 1

Critical Administration Requirements to Minimize Risk

Proper Dosing Instructions

• Take alendronate with a full glass of water (6-8 ounces) 1
• Remain upright for at least 30 minutes after taking the medication 1
• Avoid food and drink during this 30-minute period 1
• Take after an overnight fast to improve bioavailability 5
• Improper administration may explain lack of response and increased risk of esophageal complications 1

Essential Concurrent Supplementation

• Ensure adequate calcium intake (1000-1200 mg/day) throughout treatment 1, 3
• Ensure adequate vitamin D intake (800 IU/day) throughout treatment 1, 3
• Check serum 25(OH)D levels before starting bisphosphonates and correct vitamin D deficiency to prevent hypocalcemia 3
• Vitamin D deficiency may attenuate efficacy and increase risk of bisphosphonate-related hypocalcemia 1

Optimal Treatment Duration to Balance Benefits and Risks

Standard Duration

• The American College of Physicians strongly recommends 5 years as the standard treatment duration 1
• Evidence shows that increasing duration beyond 5 years probably reduces vertebral fractures but not other fractures, while increasing long-term harm risk 1

Risk-Benefit Context

• An estimated 162 osteoporosis-related fractures are prevented for every one atypical femoral fracture that may be associated with antiresorptive medication treatment 1
• Treatment benefit reduces after 5 years while atypical femoral fracture risk increases 1

Drug Holiday Considerations

• Clinicians should consider stopping bisphosphonate treatment after 5 years unless strong indications for continuation exist 1
• Patients without high-risk features (previous hip or vertebral fractures, T-score ≤ -2.5, age >80, ongoing glucocorticoid use) can discontinue and be monitored 1

Withdrawal Rates and Overall Tolerability

• Discontinuation due to adverse events occurred in 8.9% of alendronate patients versus 9.5% of placebo patients in major trials 2
• The incidence of serious adverse events was 30.9% in the alendronate group versus 30.7% in the placebo group 2
• All-cause mortality was 1.8% in both the alendronate and placebo groups 2