What is the adverse effect of long-term use of omeprazole (proton pump inhibitor)?

Long-Term Omeprazole Use and Adverse Effects

The most clinically significant adverse effects of long-term omeprazole use are increased risk of bone fractures (particularly hip and vertebral), gastrointestinal infections, and hypomagnesemia—not diarrhea as the most common complication, and the fracture risk is approximately 20% increased (not 10-fold) based on the highest quality evidence.

Established Adverse Effects with Strong Evidence

Bone Health and Fracture Risk

• Meta-analysis of 24 observational studies demonstrates a 20% increased risk of hip fracture with long-term PPI use (RR: 1.20; 95% CI: 1.14,1.28), not a 10-fold increase as suggested in the question 1
• The FDA drug label specifically warns that patients taking multiple daily doses of PPIs for ≥1 year may have increased risk of fractures of the hip, wrist, or spine 2
• Prospective data show omeprazole use independently predicts vertebral fractures in postmenopausal women (RR = 3.50,95% CI 1.14-8.44), with age-adjusted fracture rates of 1.89 versus 0.60 per 100 person-years for users versus non-users 3
• However, large randomized controlled trials including the COMPASS trial found no differences in fracture rates between PPI and placebo groups, suggesting observational studies may be confounded 1, 4
• The association appears strongest in patients with pre-existing risk factors (diabetes, CKD, arthritis) and ≥2 years of continuous use 1
• PPIs lower gastric acid, decreasing calcium absorption and potentially increasing fracture risk through this mechanism 5

Gastrointestinal Infections

• PPIs increase susceptibility to gastroenteritis and other enteric infections due to reduced gastric acid barrier 1, 4
• The FDA label warns that omeprazole may increase risk of severe diarrhea caused by Clostridium difficile infection in the intestines 2
• PPIs increase the risk of community-acquired pneumonia (but not hospital-acquired pneumonia), particularly in vulnerable populations 1, 4

Electrolyte and Micronutrient Deficiencies

• Meta-analysis shows 71% higher risk of hypomagnesemia with PPI use (adjusted OR: 1.71; 95% CI: 1.33,2.19) after ≥3 months of therapy 1, 4
• Dose-dependent associations exist between continuous PPI use and iron deficiency, particularly after ≥1 year of use, with the FDA including precautionary notices regarding anemia risk 1
• Clinical data demonstrate significant reductions in serum ferritin, vitamin D3, and calcium levels with prolonged omeprazole use 6
• Reduced gastric acid impairs absorption of non-heme iron specifically 1

Renal Effects

• The FDA label warns of tubulointerstitial nephritis that can occur at any time during treatment, manifesting as decreased urine output or blood in urine 2
• Clinical studies show significantly increased creatinine and blood urea nitrogen levels in long-term omeprazole users 6

Other Established Effects

• Rebound acid hypersecretion is common after discontinuation, lasting 2-6 months as a physiological response to secondary hypergastrinemia 1, 4
• Enterochromaffin-like (ECL) cell hyperplasia occurs in up to 50% of patients receiving PPIs for >2.5 years, though this is considered a benign histologic change 1, 4

Associations with Weaker or Conflicting Evidence

Cardiovascular Risk

• Some observational studies suggest increased cardiovascular disease risk with long-term PPI use, but large RCTs including COMPASS found no differences in cardiovascular event rates between PPI and placebo groups 1, 4

Metabolic Effects

• Long-term omeprazole use significantly elevates cholesterol (p<0.001), triglycerides (p<0.001), and LDL (p<0.01) without affecting HDL 6
• Liver enzymes (alkaline phosphatase and AST) are elevated in long-term users 6

Hematological Effects

• Diarrhea is NOT the most common complication—hematological changes are more consistently documented 6
• Prolonged use results in significant reductions in RBC count and indices, potentially leading to anemia 6

Critical Management Principles

When to Continue Long-Term PPI Therapy

• Do not discontinue PPIs in patients with definitive indications: Barrett's esophagus, severe erosive esophagitis, eosinophilic esophagitis with PPI response, idiopathic pulmonary fibrosis, high-risk NSAID/aspirin users requiring gastroprotection, and secondary prevention of gastric/duodenal ulcers 1, 4
• Discontinuing PPIs based on concerns about unproven risks may lead to recurrent symptoms and serious complications including upper GI bleeding 1

When to Consider De-prescribing

• All patients without definitive indication for chronic PPI should be considered for trial of de-prescribing 1, 4
• Most patients on twice-daily dosing should be stepped down to once-daily PPI 1

Monitoring Recommendations

• Check magnesium levels before starting and periodically during long-term therapy 4
• Monitor for signs of renal deterioration (decreased urine output, elevated creatinine) 4, 2
• Assess vitamin B12 status after 3+ years of continuous use 4
• Consider iron studies in patients with anemia symptoms 4
• Monitor for bone health in patients with pre-existing fracture risk factors 1

Key Clinical Pitfall

• The question's assertion that omeprazole carries a "10 times risk of osteoporosis" is incorrect—the actual increased risk is approximately 20% for hip fractures based on observational data, and large RCTs show no increased fracture risk 1, 4
• Diarrhea is not the most common complication—it is one of several potential adverse effects, with bone health concerns, electrolyte disturbances, and infection risk being more consistently documented 1, 2, 6