Do long-term Proton Pump Inhibitors (PPIs) cause osteoporosis?

From the Guidelines

Long-term use of Proton Pump Inhibitors (PPIs) does not definitively cause osteoporosis in all users, and the current evidence suggests that the risk of osteoporosis is not significantly increased with PPI use, as stated by the American Gastroenterological Association in 2008 1. The mechanism behind the potential association between PPIs and osteoporosis involves reduced calcium absorption due to decreased stomach acid production. However, the available data show no worrisome safety signals with PPIs, and the American College of Physicians updated clinical practice guideline in 2017 does not list PPIs as a risk factor for osteoporotic fracture 1. Some key points to consider:

• The American Gastroenterological Association states that there is insufficient evidence to recommend for or against routine bone density studies, calcium supplementation, or H pylori screening in patients taking PPIs 1.
• The American College of Physicians guideline update lists risk factors for osteoporotic fracture, but does not include long-term PPI use as a significant risk factor 1.
• Patients on long-term PPI therapy should still consider calcium citrate supplements and adequate vitamin D intake to support bone health.
• Risk mitigation strategies include using the lowest effective PPI dose and implementing lifestyle modifications such as weight-bearing exercise and smoking cessation. It is essential to note that the evidence is not strong enough to support a definitive causal relationship between long-term PPI use and osteoporosis, and the benefits of PPI therapy often outweigh the potential risks. Therefore, PPIs should be used as clinically indicated, and patients should be monitored and managed according to their individual risk factors for osteoporosis.

From the FDA Drug Label

1. 4 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer)

There is no evidence that long-term Proton Pump Inhibitors (PPIs) do not cause osteoporosis. In fact, 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, particularly with high-dose and long-term use 2. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. Key points to consider:

• Increased risk of fractures with long-term PPI use
• High-dose PPI therapy may increase the risk of fractures
• Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines It is essential to weigh the benefits and risks of long-term PPI use and to consider alternative treatments or osteoporosis prevention strategies for patients at risk of fractures 2.

From the Research

Evidence on Long-Term PPI Use and Osteoporosis

• There is evidence suggesting that long-term use of Proton Pump Inhibitors (PPIs) may be associated with an increased risk of osteoporosis and fractures 3, 4, 5.
• A study published in 2015 found that PPI use was associated with an increased risk of subsequent use of osteoporosis medication and fractures in older Australian women 3.
• Another study published in 2016 found that new studies have further strengthened existing evidence linking use of PPIs to osteoporosis, and that short-term use does not appear to pose a lower risk than long-term use 4.
• A 2022 study found that long-term PPI users had a greater risk of osteoporosis, with a hazard ratio of 1.62 compared to non-PPI users 5.

Dose-Response Effect and Type of PPI

• Some evidence suggests a dose-response effect, with higher doses of PPIs associated with an increased risk of osteoporosis and fractures 3.
• Certain types of PPIs, such as esomeprazole and rabeprazole, may be associated with a higher risk of osteoporosis and fractures compared to other types of PPIs 3.

Global Trends and Practices

• A 2023 systematic review found that nearly one-quarter of adults use a PPI, and that 25% of users continue PPIs for more than 1 year, and 28% continue for more than 3 years 6.
• The review also found that 63% of PPI users were less than 65 years old, and that 56% of users were female 6.

Deprescribing and Alternative Therapies

• Deprescribing, or reducing the dose or discontinuing PPIs, should be considered for many PPI users, especially older adults 7.
• Alternative therapies, such as histamine-2-receptor antagonists, may be associated with reduced risks of osteoporosis and fractures compared to PPIs 7.