Why are chronic proton pump inhibitors (PPIs) users at a higher risk for pneumonia and hip fractures?

Why Chronic PPI Users Are at Higher Risk for Pneumonia and Hip Fractures

Hip Fracture Risk

Chronic PPI use increases hip fracture risk by approximately 20% (RR: 1.20; 95% CI: 1.14-1.28), though this association is primarily from observational studies and has not been confirmed in randomized controlled trials, suggesting the relationship may be confounded rather than causal. 1

Proposed Mechanisms for Hip Fractures

The theoretical mechanisms linking PPIs to fractures involve:

• Impaired calcium absorption: PPIs reduce gastric acid, which is necessary for calcium absorption, particularly calcium carbonate 2, 3
• Increased gastrin production: Chronic acid suppression leads to reactive hypergastrinemia, which may theoretically affect bone remodeling 3
• Osteoclast inhibition: PPIs may directly inhibit osteoclastic vacuolar proton pumps, though this mechanism is paradoxically protective 4

Critical Evidence Discordance

The fracture risk story reveals important contradictions:

• Observational studies consistently show increased risk: Meta-analyses demonstrate dose-dependent and duration-dependent associations, with higher doses (>1.5 pills/day) showing greater risk (RR: 2.65 for high-dose long-term use) 4, 5
• RCTs show no increased risk: Large randomized trials including the COMPASS trial found no differences in fracture rates between PPI and placebo groups 1, 2
• Risk appears concentrated in vulnerable populations: The association is strongest in patients with pre-existing risk factors (diabetes, CKD, arthritis) after ≥2 years of use 1

Clinical Implications for Fracture Risk

The American Gastroenterological Association does not recommend routine bone density studies, calcium supplementation, or any special precautions specifically because of PPI use, as the evidence for causality is insufficient. 1, 2

However, standard osteoporosis screening should be performed in elderly patients regardless of PPI use 1

Pneumonia Risk

PPIs may increase susceptibility to community-acquired pneumonia (CAP) and other respiratory infections through reduction of the gastric acid barrier, though the absolute risk increase is modest and primarily occurs in the early stages (<1 month) of PPI use, particularly at high doses. 2, 6

Mechanism for Pneumonia Risk

The proposed mechanism is straightforward:

• Loss of gastric acid barrier: Gastric acid normally kills ingested bacteria; PPIs reduce this protective barrier 2
• Bacterial overgrowth: Hypochlorhydria allows bacterial colonization of the upper GI tract 6
• Microaspiration: Colonizing bacteria can be aspirated into the respiratory tract, causing pneumonia 2

Evidence Quality for Pneumonia

• Meta-analyses of observational studies show a slight increase in CAP risk, particularly in the first month of therapy 6
• The risk appears dose-dependent, with higher doses showing greater association 6
• This association is more convincing than the fracture data because it has a plausible biological mechanism and consistent observational findings 2

Additional Micronutrient-Related Mechanisms

Beyond fractures and pneumonia, chronic PPI use affects multiple micronutrients that could theoretically contribute to these risks:

Magnesium Deficiency

• 71% increased risk of hypomagnesemia (adjusted OR: 1.71; 95% CI: 1.33,2.19), particularly in patients with GFR<60, using diuretics, or over 65 years 1, 2, 6
• Hypomagnesemia can affect muscle strength and bone health, potentially contributing to fall risk 2

Iron Deficiency

• Dose-dependent associations after ≥1 year of continuous use, with ≥2 years showing adjusted OR: 2.49 (95% CI: 2.35,2.64) for higher doses 1
• Reduced gastric acid impairs absorption of non-heme iron 2

Vitamin B12 Deficiency

• Dose-dependent association, with >1.5 pills/day showing OR: 1.95 (95% CI: 1.77,2.15) after ≥2 years 1
• However, large RCTs at 5 years showed no significant differences in serum B12 levels, though these studies had methodological limitations 2

Critical Clinical Pitfalls

The most important pitfall is discontinuing PPIs in patients with valid indications based on concerns about unproven risks—this may lead to recurrent symptoms and serious complications including upper GI bleeding. 2

When NOT to Discontinue PPIs

Patients with the following should continue therapy 2, 7:

• Barrett's esophagus
• Severe erosive esophagitis (LA grade C/D)
• Gastroprotection in high-risk NSAID/aspirin users
• Secondary prevention of gastric/duodenal ulcers
• Zollinger-Ellison syndrome

When to Consider De-prescribing

All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing, and most patients on twice-daily dosing should be stepped down to once-daily PPI. 2, 7

Bottom Line on Risk Assessment

The American Gastroenterological Association notes that all studies reporting specific associations between PPIs and serious adverse events have been observational and cannot establish causality, while RCTs comparing PPIs with placebo have consistently shown no higher rate of adverse events among PPI users. 2

Many reported associations likely reflect residual confounding and analytic biases rather than true causal relationships 2. The FDA includes precautionary notices regarding these risks, but routine screening or supplementation is not recommended 1, 2.