From the Guidelines
Chronic use of Proton Pump Inhibitors (PPIs) is associated with several adverse effects, including increased risk of vitamin and mineral deficiencies, particularly vitamin B12, magnesium, calcium, and iron, as well as potential links to osteoporosis, fractures, and other conditions, as reported in a 2021 study 1. The adverse effects of chronic PPI therapy can be categorized into several key areas, including:
- Nutrient deficiencies: Long-term PPI use has been linked to decreased absorption of essential nutrients like vitamin B12, magnesium, calcium, and iron, which can lead to anemia, neurological symptoms, or osteoporosis with increased fracture risk over time 1.
- Increased risk of infections: PPIs may increase the risk of Clostridium difficile infections and other enteric infections by altering gut microbiota and reducing the stomach's natural acid barrier against pathogens 1.
- Kidney problems: Chronic PPI use has been associated with an increased risk of kidney problems, including acute interstitial nephritis and chronic kidney disease 1.
- Other potential risks: Some studies suggest associations between PPI use and dementia, cardiovascular events, and community-acquired pneumonia, although these connections remain controversial 1. It is essential to weigh these potential risks against the benefits of PPI therapy and to use the lowest effective dose for the shortest duration necessary, with periodic reassessment of the need for continued therapy 1. Key considerations for clinicians and patients include:
- Monitoring for signs of nutrient deficiencies and addressing them promptly
- Being aware of the potential increased risk of infections and taking steps to mitigate this risk
- Regularly reviewing the need for continued PPI therapy and adjusting the treatment plan as necessary
- Considering alternative treatments or therapies when possible to minimize the risks associated with long-term PPI use.
From the FDA Drug Label
3 Clostridium difficile-Associated Diarrhea Published observational studies suggest that PPI therapy like pantoprazole sodium may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. 5. 4 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. 5. 5 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. 5.6 Cyanocobalamin (Vitamin B-12) Deficiency Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. 5. 7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. 5. 8 Tumorigenicity Due to the chronic nature of GERD, there may be a potential for prolonged administration of pantoprazole sodium. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. 5. 9 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.
The adverse effects of chronic Proton Pump Inhibitor (PPI) therapy include:
- Increased risk of Clostridium difficile-associated diarrhea
- Increased risk of osteoporosis-related fractures
- Cutaneous and systemic lupus erythematosus
- Cyanocobalamin (Vitamin B-12) deficiency
- Hypomagnesemia
- Potential for tumorigenicity
- Increased risk of fundic gland polyps 2 2
From the Research
Adverse Effects of Chronic PPI Therapy
The adverse effects of chronic Proton Pump Inhibitor (PPI) therapy include:
- Increased risk of pneumonia, with a 27-39% increase in short-term use 3
- Association with Clostridium difficile infections, with an odds ratio of 2.15 (95% CI: 1.81-2.55; p < 0.00001) 3
- Impaired magnesium absorption, with the US FDA issuing a warning regarding fractures associated with PPI use 3
- Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis, and acute interstitial nephritis have also been reported with PPI use 3
- Nutritional deficiencies, including B12 and magnesium deficiencies 4
- Rebound acid hypersecretion, acute interstitial nephritis, gastric carcinoid tumor, and cardiovascular risk with clopidogrel and PPI coprescription 4
- Bone fractures, particularly in susceptible populations 4, 5
- Enteric infections, including Clostridium difficile and pneumonia 5
- Acute and chronic kidney disease, gastrointestinal infections, and deficiencies in vitamin B12 and magnesium 5
- Increased risk of coronavirus disease 2019 and respiratory infections 5
Specific Adverse Effects
Some specific adverse effects of chronic PPI therapy include:
- Bone fracture: consistently reported in studies, albeit mostly in low-quality data 5
- Acute and chronic kidney disease: associated with PPI use, although the evidence is mostly based on observational studies 5
- Gastrointestinal infections: increased risk with PPI use, particularly in studies involving low-quality data 5, 6
- Magnesium deficiency: consistently reported in studies, although the evidence is mostly based on observational studies 5
- Vitamin B12 deficiency: associated with PPI use, although the evidence is mostly based on observational studies 5
Clinical Relevance
The clinical relevance of these adverse effects is still being debated, with some studies suggesting a high probability of causality for certain effects, such as increased risk of gastrointestinal infections and rebound acid hypersecretion 6. However, other studies have failed to demonstrate supportive clinical relevance for certain effects, such as acute interstitial nephritis, nutritional deficiencies, and gastric carcinoid 4.