Widely used acid-suppressing drugs may have hidden effects beyond the stomach.
Researchers in Brazil at the Federal University of São Paulo (UNIFESP) and the ABC Medical School (FMABC) are drawing attention to a less obvious side of proton pump inhibitors (PPIs), a popular group of acid suppressing drugs used for gastric disorders. In their study, extended use was linked to poorer nutrient uptake, raising concerns that taking these medications longer than a physician recommends could contribute to deficiencies such as anemia and may also affect bone health. The work appeared in ACS Omega.
Backed by FAPESP, the team tested what happens when the medication is used continuously in rats, tracking minerals the body relies on for blood, bones, nerves, and immune function: iron, calcium, zinc, magnesium, copper, and potassium. Instead of remaining balanced across tissues, these nutrients shifted in where they accumulated. The researchers reported a buildup in the stomach and uneven levels in the spleen and liver, suggesting the effects were not limited to digestion alone.
Blood tests added to the concern. Calcium rose while iron fell, a combination consistent with greater risk of osteoporosis and anemia. The researchers also detected major changes in immune system cells, an outcome that fits with the idea that mineral balance can influence how the immune system maintains and renews its cell populations.
Study Design and Experimental Timeline
To carry out the experiments, adult rats were separated into two groups: a control group and another group that received omeprazole. Treatments lasted 10, 30, and 60 days, allowing the researchers to model different durations of prolonged use comparable to human exposure.
“The most worrying finding was the significant increase in calcium in the animals’ bloodstream, which may indicate an imbalance with the removal of the mineral from the bones and a future risk of osteoporosis. However, longer studies are needed to confirm this hypothesis,” says Angerson Nogueira do Nascimento, a professor at UNIFESP who coordinated the study in partnership with Fernando Fonseca from FMABC.
Drugs such as omeprazole, pantoprazole, and esomeprazole work by blocking the H+, K+, ATPase enzyme. Often referred to as the proton pump, this enzyme plays a key role in the final step of hydrochloric acid production in the stomach. By reducing acid levels, these medications ease symptoms linked to ulcers, gastritis, and acid reflux. At the same time, lower stomach acidity can limit the absorption of nutrients that require an acidic environment.
Widespread Use and Growing Concerns
Omeprazole has been available for more than three decades and is frequently used, sometimes for extended periods and without medical supervision.
“It isn’t a question of demonizing the drug, which is effective for various gastric conditions. The problem is its trivialized use, even for mild symptoms such as heartburn, and for prolonged periods of months and even years. Its adverse effects shouldn’t be overlooked,” says Andréa Santana de Brito, a researcher at UNIFESP. The study formed the basis of her master’s research.
She also warns that the issue could intensify following a recent decision by the Brazilian Health Regulatory Agency (ANVISA), which authorized the sale of 20mg omeprazole without a prescription in November 2025.
“This ease of access may encourage self-medication and continuous use, disregarding the recommendation to limit treatment to 14 days,” she warns.
ANVISA’s position
ANVISA states that reclassifying omeprazole 20mg as an over-the-counter medication is intended to support safer and more responsible use. The agency describes the decision as “a step forward in rationalizing its use and promoting its safe and responsible use.”
“By limiting treatment to a maximum of 14 days, the message that the drug should only be used to relieve mild and temporary symptoms is reinforced, encouraging patients to seek a medical evaluation if their symptoms persist or recur,” ANVISA said in a statement to the Agência FAPESP newsroom. “Clear guidelines in the package insert and on the label, such as the duration of use, warning signs, and possible drug interactions, help consumers make informed decisions.”
The agency also emphasizes that packages containing more than 14 days’ worth of capsules remain available only with a prescription.
Research with other molecules
The research was conducted with omeprazole; however, the researcher points out that more modern molecules in the same class of drugs, such as pantoprazole and esomeprazole, act through the same mechanism. “In these cases, the effect may be even more intense since these molecules have a more potent and longer-lasting action. Some take more than five days to allow the formation of new proton pumps, while omeprazole takes about one to three days, which can intensify side effects,” she explains.
According to the researchers, the impact of PPIs on nutrient absorption was already known; however, the study broadens this understanding by including magnesium and zinc in the analyses. “We reinforce the importance of the rational use of these drugs and even of assessing the need for supplementation in some cases. However, medical supervision is necessary to evaluate each case individually,” Nogueira says.
Reference: “Evaluation of the Long-Term Administration of Proton Pump Inhibitors (PPIs) in the Mineral Nutrient’s Bioavailability” by Andréa Santana de Brito, Angerson Nogueira do Nascimento, Fernando Luiz Affonso Fonseca, Alexandre Minami Fioroto, Giuliana Petri and Rafaela Garcia Vidigal do Nascimento, 12 November 2025, ACS Omega.
DOI: 10.1021/acsomega.5c07700
Funding: São Paulo Research Foundation
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