What are the potential side effects of prolonged use of proton pump inhibitors (PPIs) in older adults with a history of osteoporosis or those taking corticosteroids?

Potential Side Effects of Prolonged PPI Use in Older Adults with Osteoporosis or on Corticosteroids

In older adults with osteoporosis or those taking corticosteroids, prolonged PPI use increases fracture risk by approximately 20% and should be avoided unless there is a compelling gastroprotective indication, with the 2019 AGS Beers Criteria specifically recommending avoidance of PPIs beyond 8 weeks in high-risk patients unless treating high-risk conditions like NSAID/corticosteroid-induced ulcer prevention. 1

Fracture Risk: The Primary Concern in This Population

Evidence Quality and Magnitude of Risk

• Meta-analysis of 24 observational studies demonstrates a 20% increased risk of hip fracture with PPI use (RR: 1.20; 95% CI: 1.14,1.28), with the association strongest in patients with pre-existing risk factors including diabetes, CKD, and arthritis, particularly with ≥2 years of use 2
• Prospective cohort data in older Australian women showed PPI users had 29% increased fracture risk (SHR=1.29, CI=1.08-1.55), with evidence of dose-response effect: <400 defined daily doses showed SHR=1.23, while ≥400 DDD showed SHR=1.39 3
• Critical caveat: Large RCTs including the COMPASS trial found no differences in fracture rates between PPI and placebo groups, suggesting observational studies may be confounded by underlying frailty and comorbidities 2

Specific Concerns for Osteoporosis Patients

• In older women, PPI use was associated with 28% increased risk of subsequent osteoporosis medication initiation (SHR=1.28; 95% CI=1.13-1.44), indicating clinically significant bone density deterioration 3
• Osteopenia was observed in 52% and osteoporosis in 19% of patients on long-term PPIs, with predictive factors including age ≥50 years, menopause, calcium intake ≤550mg/day, and PPI duration ≥30 months 4

Established Adverse Effects with Strong Evidence

Gastrointestinal Infections

• PPIs increase susceptibility to Clostridium difficile infection and gastroenteritis due to reduced gastric acid barrier 2
• Community-acquired pneumonia risk is elevated, though hospital-acquired pneumonia risk is not 2

Micronutrient Deficiencies

• Vitamin B12 deficiency: While large 5-year RCTs showed no significant differences in serum B12 levels, these studies had methodological limitations; the FDA includes precautionary notices regarding anemia risk 2, 5
• Iron deficiency: Dose-dependent associations exist with continuous PPI use, particularly after ≥1 year, as reduced gastric acid impairs non-heme iron absorption 2
• Hypomagnesemia: Meta-analysis shows 71% higher risk (adjusted OR: 1.71; 95% CI: 1.33,2.19), typically occurring after ≥3 months but most commonly after 1 year of therapy 2

Rebound Acid Hypersecretion

• Common after discontinuation of long-term PPI therapy, lasting 2-6 months, representing a physiological response to secondary hypergastrinemia that may trap patients in continued PPI use 2

Clinical Decision Algorithm for This Population

When PPIs MUST Continue (Do Not Discontinue)

The American Gastroenterological Association identifies absolute indications where discontinuation would cause more harm than potential adverse effects: 2

• Barrett's esophagus
• Severe erosive esophagitis
• Secondary prevention of gastric/duodenal ulcers in patients on NSAIDs/corticosteroids
• High-risk NSAID/aspirin users requiring gastroprotection
• Eosinophilic esophagitis with PPI response
• Idiopathic pulmonary fibrosis

When to Aggressively De-prescribe

• All patients without definitive indication for chronic PPI should be considered for trial of de-prescribing 2
• Most patients on twice-daily dosing should be stepped down to once-daily PPI 2
• The 2019 AGS Beers Criteria specifically flags PPIs as potentially inappropriate in older adults when used >8 weeks without high-risk indication 1

Risk Mitigation Strategies for Patients Who Must Continue PPIs

• Use the lowest effective dose, as dose-response relationship exists for fractures (higher doses = higher risk) 2, 3
• Ensure adequate calcium intake (>550mg/day) and vitamin D supplementation 4
• Consider periodic monitoring of magnesium levels, especially after 3-12 months of therapy 2
• Assess B12 status in high-risk patients (elderly, those with additional malabsorption risk factors) 5
• Monitor for iron deficiency, particularly in patients with baseline anemia or after ≥1 year of use 2

Type-Specific Considerations

• Esomeprazole (the most commonly prescribed PPI at 22.9%) showed increased risk for both osteoporosis medication use (SHR=1.48) and fractures 3
• Rabeprazole demonstrated the highest fracture risk (SHR=2.06, CI=1.37-3.10) in older women 3
• Users of multiple types of PPIs had increased risks for both osteoporosis medication use and fractures 3

Critical Pitfall to Avoid

Discontinuing PPIs in patients with definite indications (particularly those on corticosteroids requiring gastroprotection) based on concerns about unproven risks may lead to recurrent symptoms and serious complications, including upper GI bleeding 2. Poor compliance with gastroprotective agents increases relative risk of adverse events 4-6 times 2.

The Evidence Paradox

The divergence between observational studies (showing harm) and RCTs (showing no harm) likely reflects that sicker, frailer patients with multiple comorbidities are prescribed PPIs more frequently, creating residual confounding that observational studies cannot fully eliminate 2. However, in the specific context of older adults with pre-existing osteoporosis or on corticosteroids, the observational data showing dose-response relationships and specific risk factor interactions suggests real biological plausibility for harm 4, 3.