The Increased Risk of Osteoporotic Fractures with PPI and H2RA Combination Therapy

Please check the names of the medications you are taking to see if they include a PPI or H2RA. If you are taking both together, make sure to review this with your doctor.

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Recent Study Findings: PPI and H2RA Combination Increases Fracture Risk

A recent study (Oh DJ, et al., 2024) analyzed data from the Korean National Health Insurance Service (2014–2020) and found that the combination of PPI (proton pump inhibitors) and H2RA (histamine H2 receptor antagonists) is associated with an increased risk of osteoporotic fractures.

📌 Key Findings from the Study:

• PPI alone increased the risk of osteoporotic fractures (HR 1.31, p < 0.001)
• H2RA alone also increased the risk (HR 1.44, p < 0.001)
• PPI + H2RA combination further elevated the risk (HR 1.58, p = 0.010)
• PPI + H2RA + MPA (mucoprotective agent) combination had the highest risk (HR 1.71, p = 0.001)

This study highlights that combining PPI and H2RA poses a greater risk than using either agent alone. But why was this study conducted when PPI and H2RA are rarely prescribed together and are often not covered by insurance?

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Why Study PPI + H2RA Combination When It’s Rarely Prescribed?

In clinical practice, PPI and H2RA are generally not prescribed together, and health insurance in many countries does not cover their combined use. However, real-world prescription data indicate that intentional or unintentional dual therapy still occurs.

🔹 Possible Reasons for PPI + H2RA Combination:

1️⃣ Unintentional Duplicate Prescriptions from Different Physicians

• Patients who visit multiple healthcare providers might receive PPI from one doctor and H2RA from another, leading to unintentional combination therapy.

2️⃣ Off-Label, Non-Reimbursed Prescriptions for Nighttime Acid Breakthrough (NAB)

• Some physicians add an H2RA at bedtime in patients experiencing nighttime acid rebound despite PPI therapy.

3️⃣ Transitional Use When Switching from PPI to H2RA

• A patient switching from a PPI to an H2RA may have a brief overlap of both medications during the transition period.

By investigating real-world prescription patterns, this study aimed to assess the clinical consequences of dual therapy, particularly regarding fracture risk.

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How Do PPI and H2RA Increase Fracture Risk?

Although PPI and H2RA suppress gastric acid, long-term use may impair calcium absorption and bone metabolism, increasing fracture risk.

1. How PPI Increases Fracture Risk

🔹 Reduced Calcium Absorption

• Calcium needs gastric acid to dissolve and ionize (Ca²⁺) for absorption.
• PPIs reduce gastric acid, impairing calcium solubility and absorption.

🔹 Increased Parathyroid Hormone (PTH) Activation

• Low calcium levels trigger PTH release, which stimulates bone resorption, leading to bone loss.

🔹 Inhibition of Osteoblast Function

• Some studies suggest that PPI use can directly suppress osteoblast activity, reducing bone formation.

2. How H2RA Increases Fracture Risk

🔹 Similar Reduction in Calcium Absorption (Same mechanism as PPI)
🔹 Possible Vitamin B12 Deficiency

• Long-term H2RA use may lead to B12 deficiency, which has been linked to reduced bone density.

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Why PPI Works Best During the Day and H2RA at Night

The key difference between PPI and H2RA is their mechanism of action, leading to different effectiveness based on the time of day.

1. PPI: Most Effective During the Day

• PPIs irreversibly inhibit proton pumps (H⁺/K⁺ ATPase) in gastric parietal cells, but they must be activated by gastric acid.
• PPIs work best after meals when acid production is highest.
• However, new proton pumps regenerate overnight, leading to reduced nighttime acid suppression.

2. H2RA: More Effective at Night

• H2RA blocks histamine from stimulating acid production via H2 receptors.
• Nighttime acid production is driven primarily by histamine, making H2RA more effective at suppressing nocturnal acid secretion.

🛑 Due to these differences, past studies suggested nighttime H2RA use with daytime PPI to control 24-hour acid secretion. However, this combination is now discouraged due to increased fracture risk.

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Clinical Implications – The Importance of Medication Review

This study serves as a warning against unnecessary combination therapy of PPI and H2RA.

✅ Patients should review their medications carefully to avoid unintentional dual therapy.
✅ Elderly patients and those with chronic conditions should be monitored for polypharmacy risks.
✅ If PPI or H2RA therapy is necessary, single-agent therapy should be optimized rather than combining both.

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Common PPI and H2RA Medications in the U.S.

🔵 Commonly Used PPIs in the U.S.

Active Ingredient	Brand Name(s)
Esomeprazole	Nexium
Omeprazole	Prilosec
Lansoprazole	Prevacid
Pantoprazole	Protonix
Rabeprazole	AcipHex
Dexlansoprazole	Dexilant

🟢 Commonly Used H2RAs in the U.S.

Active Ingredient	Brand Name(s)
Famotidine	Pepcid
Ranitidine (withdrawn due to NDMA contamination)	Zantac (discontinued)
Nizatidine	Axid
Cimetidine	Tagamet (rarely used due to side effects)

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Conclusion – Check Your Medications!

💊 If you are taking a PPI (e.g., Nexium, Prilosec, Protonix) and an H2RA (e.g., Pepcid, Axid), review your prescriptions with your doctor.
💊 PPI and H2RA combination therapy is not generally recommended and can increase fracture risk.
💊 Long-term acid suppressant use should be periodically reassessed, especially in elderly patients at risk for osteoporosis.

🔹 Reference: Oh DJ, et al. The Korean Journal of Internal Medicine 2024;39:228-237.