What are the risks of taking proton pump inhibitors (PPIs) long-term, especially in older adults or those with a history of osteoporosis?

Risks of Long-Term PPI Use

Long-term PPI use is generally safe when clinically indicated, with randomized controlled trials consistently showing no increased adverse events compared to placebo, though observational studies have suggested associations with several complications that remain unproven as causal relationships. 1, 2

Evidence Quality: Critical Context

• All studies reporting associations between PPIs and serious adverse events (dementia, fractures, kidney disease, cardiovascular events) have been observational and cannot establish causality. 1, 2
• Large randomized controlled trials comparing PPIs with placebo have consistently shown no higher rate of any adverse events among PPI users. 1, 2
• Many reported associations lack plausible mechanisms and are likely explained by residual confounding and analytic biases. 2

Established Risks with Higher Probability of Causality

Gastrointestinal Infections

• PPIs increase susceptibility to Clostridium difficile colitis and bacterial gastroenteritis due to reduced gastric acid barrier, though the magnitude of risk is slight. 3, 2
• Community-acquired pneumonia risk may be increased, particularly early in therapy. 2

Rebound Acid Hypersecretion

• Common physiologic phenomenon occurring after discontinuation of long-term PPI therapy, lasting 2-6 months. 3, 2
• Results from hypergastrinemia-induced parietal cell proliferation during PPI therapy. 3
• Patients should be warned about potential transient upper GI symptoms when stopping PPIs. 3, 1

Hypomagnesemia

• Reported in patients treated with PPIs for at least 3 months, most commonly after 1 year of therapy. 2
• Meta-analysis shows 71% higher risk (adjusted OR: 1.71; 95% CI: 1.33,2.19). 2
• Both symptomatic and asymptomatic cases occur. 2

Associations with Weaker or Conflicting Evidence

Bone Health and Fractures

• Observational studies suggest increased fracture risk, but large RCTs have not confirmed this association. 2
• Meta-analysis of 24 observational studies found 20% greater risk of hip fracture (RR: 1.20; 95% CI: 1.14,1.28). 2
• However, the COMPASS trial and other large RCTs found no differences in fracture rates between PPI and placebo groups. 2
• The association appears strongest in patients with pre-existing risk factors (diabetes, CKD, arthritis) and ≥2 years of use. 2
• Long-term PPI use may affect bone mineral density, particularly in the femoral neck, though clinical significance remains uncertain. 4, 5, 6

Micronutrient Deficiencies

• Vitamin B12 deficiency: Large RCTs have not shown significant differences in serum B12 levels at 5 years, though methodological limitations exist. 2
• Iron deficiency: Dose-dependent associations exist, particularly after ≥1 year of continuous use, due to impaired non-heme iron absorption. 2
• Calcium absorption: Reduced gastric acid may impair calcium absorption, though clinical fracture risk remains unproven in RCTs. 3

Cardiovascular Risk

• Long-term PPI use has been associated with increased cardiovascular disease risk in some observational studies, but these associations have not been confirmed in randomized controlled trials. 2

Cancer Risk

• No causal relationship established in RCTs. 2
• Japanese population-based data suggest possible association with gastric cancer, though rates are similar between PPIs and H2-receptor antagonists. 2

Enterochromaffin-Like (ECL) Cell Hyperplasia

• Demonstrated in up to 50% of patients receiving PPIs for >2.5 years, though considered a benign histologic change. 2
• Five-year RCT comparing vonoprazan and lansoprazole found infrequent and comparable proportions developing ECL hyperplasia. 2

Clinical Management Principles

When PPIs Should NOT Be Discontinued

Patients with the following definitive indications should continue long-term PPI therapy regardless of potential risks: 1, 2

• Barrett's esophagus (reduces esophageal adenocarcinoma risk) 1
• Severe erosive esophagitis (Los Angeles Classification grade C/D) 1
• History of upper GI bleeding, especially with ongoing anticoagulant/antiplatelet therapy 3, 1
• High-risk NSAID/aspirin users requiring gastroprotection 1
• Secondary prevention of gastric/duodenal ulcers 1
• Eosinophilic esophagitis with PPI response 1
• Idiopathic pulmonary fibrosis (for prevention of progression) 3, 1

When to Consider De-prescribing

• All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing. 1, 2
• Patients should be assessed for upper GI bleeding risk using an evidence-based strategy before de-prescribing. 3
• Most patients on twice-daily dosing should be stepped down to once-daily PPI. 1, 2

Risk Assessment Before De-prescribing

Patients at high risk for upper GI bleeding should NOT be considered for PPI de-prescribing: 3

• History of upper GI bleeding 3
• Taking multiple antithrombotics (anticoagulants plus antiplatelet agents) 3
• Taking aspirin or NSAID with additional risk factors: age >60 years, severe medical comorbidity, concurrent antithrombotic, or oral corticosteroid 3

Special Considerations for Older Adults and Osteoporosis

Older Adults with Osteoporosis Risk

• The 2008 AGA guideline found insufficient evidence to mandate bone density studies, calcium supplementation, or any routine precaution specifically because of PPI use. 3
• However, it is good medical practice to screen and treat the elderly for osteoporosis irrespective of PPI use. 3
• Patients over 65 years taking NSAIDs should continue PPI therapy, as the combination is considered appropriate. 7
• The substantial risk reduction from PPIs for GI bleeding in high-risk elderly patients outweighs any theoretical risks from observational studies. 1

Practical Approach for High-Risk Patients

• Use the lowest effective dose for patients requiring long-term therapy. 1, 7
• Step down from twice-daily to once-daily dosing when appropriate. 1
• Regularly review ongoing indications with documentation of the specific reason for continued use. 1

Critical Pitfalls to Avoid

• Do not discontinue PPIs solely due to concern about potential adverse events when a valid indication exists. 1, 2
• Discontinuing PPIs in patients with definite indications based on concerns about unproven risks may lead to recurrent symptoms and serious complications, including upper GI bleeding. 2
• Do not ignore "hidden" risk factors for upper GI bleeding (such as over-the-counter aspirin use) when considering de-prescribing. 3
• Poor adherence to PPI therapy in high-risk patients increases the risk of NSAID-induced upper GI adverse events 4-6 fold. 2