Reviewed by MedNext Clinical Team
Proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and pantoprazole are among the most widely prescribed drugs globally. They are highly effective for acid-related conditions — gastro-oesophageal reflux disease (GORD), peptic ulcer disease, and gastroprotection in NSAID users — but their widespread, often long-term use has raised important safety concerns that require careful consideration at every prescription review [1].
Mechanism and Indications
PPIs irreversibly inhibit the H⁺/K⁺-ATPase proton pump on the luminal surface of gastric parietal cells, producing profound and prolonged acid suppression. Standard indications include: confirmed GORD with erosive oesophagitis; peptic ulcer disease (healing and prevention of relapse); gastroprotection in patients on long-term NSAIDs or anticoagulants; Helicobacter pylori eradication regimens; and Zollinger-Ellison syndrome.
PPIs are frequently initiated for symptomatic dyspepsia without objective confirmation of acid-related disease, and many patients continue therapy indefinitely without periodic reassessment — a pattern that contributes to both the scale of use and the associated risks [1].
Long-Term Safety Concerns
Fracture Risk
Long-term PPI use has been associated with a modest increase in hip, wrist, and spine fracture risk, attributed to reduced calcium absorption in a hypochlorhydric environment (gastric acid solubilises calcium salts for absorption) and possible direct effects on osteoclast function. A meta-analysis of observational studies found approximately a 25% increase in hip fracture risk with long-term PPI use, though the absolute risk increase is small [1].
Clostridium difficile Infection
Gastric acid is an important first-line defence against ingested pathogens. PPI-induced hypochlorhydria allows Clostridioides difficile spores to survive passage through the stomach, increasing colonisation risk. Multiple meta-analyses have demonstrated a significant association between PPI use and C. difficile infection, with odds ratios typically in the range of 1.5–2.0 [1]. This risk is especially relevant in hospitalised or recently hospitalised patients.
Hypomagnesaemia
Long-term PPI use impairs active magnesium absorption in the intestine, causing hypomagnesaemia in a small but clinically important proportion of patients. Severe hypomagnesaemia can present with tetany, cardiac arrhythmias, and seizures — and importantly, it does not respond to magnesium supplementation while the PPI is continued. Checking magnesium in patients on long-term PPIs who develop unexplained symptoms is important [1].
Vitamin B12 and Iron Deficiency
Gastric acid is required for the release of dietary B12 from food proteins (though not for absorption of supplemental B12). Long-term PPI use can therefore contribute to B12 deficiency in susceptible individuals. Acid also enhances non-haem iron absorption; PPI-induced hypochlorhydria may worsen iron deficiency in predisposed patients.
Deprescribing PPIs
For patients without a continuing indication — such as those started on PPIs during a hospital admission without ongoing risk factors — a structured deprescribing approach is appropriate. Step-down to the lowest effective dose, or a trial of stopping with on-demand use for symptoms, should be offered. Rebound acid hypersecretion can cause temporary symptom flare on stopping PPIs, and patients should be counselled about this to prevent unnecessary re-initiation [1].
References
- Vaezi MF, Yang Y-X, Howden CW. Complications of proton pump inhibitor therapy. Gastroenterology. 2017;153(1):35-48.