What are the risks of long-term alendronate (bisphosphonate) therapy?

Risks of Long-Term Alendronate Therapy

Long-term alendronate use beyond 5 years carries rare but serious risks including atypical femoral fractures, osteonecrosis of the jaw, and potential esophageal complications, with the optimal treatment duration being 5 years followed by reassessment for drug holidays in most patients. 1, 2

Common Adverse Effects

Upper Gastrointestinal Complications:

• Esophageal irritation, esophagitis, esophageal ulcers and erosions occur with oral bisphosphonates, occasionally with bleeding and rarely progressing to stricture or perforation 3
• Gastric and duodenal ulcers have been reported in post-marketing surveillance, though controlled trials showed no increased risk compared to placebo 1, 3
• Dyspepsia and abdominal pain are common but generally transient 1, 4
• Critical administration requirement: Must be taken with 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 1, 3

Musculoskeletal Effects:

• Severe and occasionally incapacitating bone, joint, and/or muscle pain can occur, with onset ranging from one day to several months after starting treatment 3
• Most patients experience symptom relief after discontinuation, though some have recurrence upon rechallenge 3

Acute Phase Reactions:

• Flu-like symptoms including myalgias, arthralgias, fevers, and headaches occur within first 3 days after therapy, typically resolving within 3-4 days but may persist up to 14 days 1

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 with duration of bisphosphonate exposure 3
• Most consistent risk factor is recent dental surgery or tooth extraction 1
• Other risk factors include cancer diagnosis, concomitant chemotherapy/corticosteroids, poor oral hygiene, and pre-existing dental disease 3
• Critical pitfall to avoid: Complete all dental work and allow adequate healing time before initiating or continuing bisphosphonate therapy 1, 2

Atypical Femoral Fractures:

• Atypical subtrochanteric and diaphyseal femoral fractures are low-energy fractures occurring in the femoral shaft 3
• These fractures are transverse or short oblique without comminution and may be bilateral 3
• Patients often report prodromal dull, aching thigh pain weeks to months before complete fracture 3
• Incidence ranges from 3.0 to 9.8 cases per 100,000 patient-years 1
• Any patient with thigh or groin pain should be evaluated for incomplete femur fracture and assessed for contralateral limb involvement 3
• Interestingly, one large registry study found no dose-response relationship, with similar rates in patients receiving 9 years versus 3 months of treatment, suggesting these may be related to underlying osteoporosis rather than the medication itself 5

Cardiovascular Concerns:

• Atrial fibrillation has been associated with bisphosphonate use in some trials, though insufficient evidence exists to establish causality 1
• The USPSTF analysis found no clear evidence of association between bisphosphonates and atrial fibrillation 1

Esophageal Cancer:

• Association reported in some trials but insufficient evidence to establish causal relationship 1

Bone Quality Concerns:

• Chronic suppression of bone turnover may prevent repair of microdamage to bone architecture, paradoxically predisposing to fracture in some patients 1
• However, 10-year data with alendronate in postmenopausal women showed continued BMD increases without increased fracture risk over time 1

Optimal Treatment Duration and Drug Holidays

Standard Treatment Duration:

• The American College of Physicians strongly recommends treating for 5 years as the standard 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 1
• Some experts recommend discontinuation after 5 years with careful observation given prolonged bisphosphonate effects and uncertainty about long-term safety 1

Who Should Stop After 5 Years:

• Patients with no previous hip or vertebral fractures during treatment AND hip BMD T-score > -2.5 after treatment are candidates for drug holidays 2
• Clinicians should consider stopping bisphosphonate treatment after 5 years unless strong indications for continuation exist 1, 2

Who Should Continue Beyond 5 Years:

• Patients with previous hip or vertebral fractures, multiple non-spine fractures, or hip BMD T-score ≤ -2.5 despite treatment should continue 2
• Among women without prevalent vertebral fracture, continuing alendronate for 10 years reduces nonvertebral fractures only in those with femoral neck T-scores ≤ -2.5 after 5 years of treatment 6

Monitoring During Drug Holidays:

• Do NOT perform routine BMD monitoring during the initial 5-year treatment period, as fracture reduction occurs even without BMD increases 1, 2
• During drug holidays, reassess regularly for new fractures, changes in fracture risk profile, and BMD changes (particularly femoral neck T-score) 2
• Resume therapy if new fracture occurs, fracture risk increases significantly, or BMD remains low (femoral neck T-score ≤ -2.5) 2
• Real-world data from Denmark showed no increased fracture risk in patients discontinuing versus continuing alendronate after 5 years during mean follow-up of 1.84 years 7
• Age and hip BMD at discontinuation predict clinical fractures during subsequent 5 years, while follow-up DXA or bone turnover markers 1-2 years after discontinuation are not associated with fracture risk 8

Special Populations and Precautions

Renal Impairment:

• Alendronate is not recommended for patients with creatinine clearance <35 mL/min 3

Mineral Metabolism:

• Hypocalcemia must be corrected before initiating therapy 3
• Vitamin D deficiency should be corrected prior to bisphosphonate initiation, particularly for IV therapy, as deficiency may attenuate efficacy and increase risk of bisphosphonate-related hypocalcemia 1
• Ensure adequate calcium (800-1000 mg/day) and vitamin D (800 IU/day) intake throughout treatment 1

Glucocorticoid-Induced Osteoporosis:

• Ensuring adequate calcium and vitamin D intake is especially important in patients receiving glucocorticoids, as calcium absorption may be decreased 3
• Small, asymptomatic decreases in serum calcium and phosphate may occur in patients receiving glucocorticoids 3

Critical Contraindications:

• Esophageal abnormalities that delay esophageal emptying (stricture, achalasia) 3
• Inability to stand or sit upright for at least 30 minutes 3
• Hypocalcemia 3