Animal study indicates heartburn medication may increase osteoporosis and anemia risk — Evidence Review

A new animal study suggests that long-term use of proton pump inhibitors (PPIs)—common heartburn medications—may disrupt mineral balance, potentially increasing the risk of anemia and bone loss. These findings from the Federal University of São Paulo align with several prior studies that have raised concerns about nutrient deficiencies and adverse effects from prolonged PPI use.

• Numerous clinical reports and systematic reviews have linked chronic PPI use to iron deficiency anemia and, in some cases, bone health issues, echoing the new study's findings of altered mineral metabolism and hematological changes 2 3 4 6 10 12.
• Observational and pharmacovigilance studies indicate a higher risk of osteoporosis-related events and fractures among long-term PPI users, especially in older adults and women, supporting the new study’s concerns about bone health 10 12.
• While some studies highlight the association between iron deficiency and bone loss, others note that increasing dietary calcium alone may not effectively prevent osteoporosis, suggesting the interplay of multiple nutrients and factors in bone health 6 7 8.

Study Overview and Key Findings

Proton pump inhibitors are among the most widely used medications for treating acid-related gastrointestinal conditions. Their over-the-counter availability and frequent long-term use, often without medical supervision, have raised concerns about potential side effects beyond the digestive tract. This study is timely as it addresses the less obvious systemic effects of chronic PPI use, particularly at a time when regulatory changes—such as Brazil’s recent decision to allow non-prescription sales of certain PPIs—may increase unsupervised consumption. Notably, the research takes a comprehensive approach by examining not just one, but multiple essential minerals and their distribution throughout the body, as well as immune system impacts.

Property	Value
Study Year	2025
Organization	Federal University of São Paulo (UNIFESP), ABC Medical School (FMABC)
Journal Name	ACS Omega
Authors	Andréa Santana de Brito, Angerson Nogueira do Nascimento, Fernando Luiz Affonso Fonseca, Alexandre Minami Fioroto, Giuliana Petri, Rafaela Garcia Vidigal do Nascimento
Population	Adult rats
Methods	Animal Study
Outcome	Nutrient absorption, immune system changes
Results	Calcium increased while iron decreased, indicating osteoporosis and anemia risk.

Literature Review: Related Studies

To assess how this study fits within the broader scientific landscape, we searched the Consensus database, which contains over 200 million research papers. The following search queries were used:

1. heartburn medication anemia risk
2. calcium iron bone loss connection
3. osteoporosis heartburn drug effects

Below, key themes are summarized in a table, followed by a deeper discussion of each topic.

Topic	Key Findings
What are the long-term effects of PPI/heartburn drug use on anemia risk?	- Multiple case reports and reviews describe iron deficiency and anemia in patients on long-term PPIs, often without other obvious causes 2 3 4. - Anemia is more frequent in high-risk populations (e.g., cardiovascular disease, elderly, hemodialysis) using PPIs, and may be linked to PPI-induced changes in the gut or nutrient absorption 2 3 4 5.
How does PPI use affect bone health and osteoporosis risk?	- Observational and pharmacovigilance studies consistently report a higher incidence of osteoporosis-related adverse events and fractures in long-term PPI users, especially women and older adults 10 12. - The association is hypothesized to result from impaired absorption of minerals (e.g., calcium, magnesium), but direct effects on bone mineral density remain under debate 10 12.
What is the connection between iron deficiency, calcium, and bone health?	- Iron deficiency and iron deficiency anemia are increasingly recognized as potential contributors to bone loss and osteoporosis, through effects on bone cell function and metabolism 6 8. - Some studies suggest that simply increasing dietary calcium does not reliably prevent osteoporosis or bone loss, particularly in men, indicating the need to consider multiple nutrient interactions 7 8.
What are the adverse reactions and drug interactions of osteoporosis treatments and PPIs?	- Osteoporosis treatments are generally safe but may carry rare, serious adverse reactions; the risk-benefit balance should be considered 9 11. - PPI-induced changes in mineral metabolism may interact with osteoporosis treatments, but evidence of clinically significant interactions is limited and often only seen with prolonged use or in high-risk patients 9 11.

What are the long-term effects of PPI/heartburn drug use on anemia risk?

The new animal study's findings of decreased iron levels and anemia risk with prolonged PPI use are echoed in clinical case reports, systematic reviews, and observational studies. These sources describe iron deficiency anemia developing in patients on chronic PPIs, even in the absence of gastrointestinal bleeding or other apparent causes, raising concern for at-risk populations such as the elderly and those with coexisting health conditions.

• Several case reports and systematic reviews have documented the onset of iron deficiency anemia in patients using PPIs for extended periods, consistent with the new study's results 2 3 4.
• PPI-induced anemia is particularly noted among individuals with cardiovascular disease, those on antiplatelet therapy, and older adults 2 4 5.
• The mechanisms are thought to include reduced gastric acid needed for iron absorption and, possibly, changes in gut microbiota 2 3.
• Not all studies find a direct association, but there is growing support for the need to monitor patients on long-term PPIs for anemia, especially those with other risk factors 2 3 4 5.

How does PPI use affect bone health and osteoporosis risk?

The observed increase in circulating calcium and concern for bone loss in the new study parallels findings from large-scale pharmacovigilance and observational research. These studies associate chronic PPI use with a higher risk of osteoporosis-related adverse events and fractures, though the direct impact on bone mineral density is less clear.

• Pharmacovigilance data highlight that esomeprazole and omeprazole are linked to increased osteoporosis-related adverse events, especially in women and older adults 12.
• Several narrative and systematic reviews report a higher risk of osteoporotic fractures in long-term PPI users, though the underlying mechanism (e.g., impaired mineral absorption, secondary hormonal changes) is debated 10 12.
• Some evidence suggests that the risk increases with duration of PPI use, and is most pronounced in specific subgroups (e.g., elderly, postmenopausal women) 10 12.
• The new study adds to this literature by demonstrating direct alterations in mineral balance in an animal model, supporting biological plausibility for the clinical associations observed 10 12.

What is the connection between iron deficiency, calcium, and bone health?

The interplay between iron, calcium, and bone metabolism is complex. The new study's demonstration of altered iron and calcium levels aligns with research showing that iron deficiency can impair bone health, while excessive calcium intake alone may not be sufficient to prevent bone loss.

• Iron deficiency, with or without anemia, can disrupt the activity of bone-forming and bone-resorbing cells, leading to increased bone loss and osteoporosis risk 6 8.
• In physically active young males, both iron status and vitamin D appear more closely linked to cortical bone health than calcium intake alone 8.
• Intervention studies in men suggest that boosting dietary calcium intake does not significantly alter bone mineral density or slow bone loss, indicating that multifactorial approaches are needed for osteoporosis prevention 7.
• The animal study’s finding of increased serum calcium but reduced iron is consistent with clinical evidence that multiple minerals must be balanced for optimal bone health 6 7 8.

What are the adverse reactions and drug interactions of osteoporosis treatments and PPIs?

Both osteoporosis medications and PPIs are widely used, and their safety profiles are generally favorable, but rare serious adverse reactions and interactions are possible. The new study’s focus on mineral imbalance suggests potential for interaction effects, though clinical evidence for significant drug-drug interactions remains limited.

• Reviews of osteoporosis treatments note generally good safety, with rare but serious side effects such as atypical fractures and osteonecrosis; monitoring is recommended, particularly in high-risk populations 9 11.
• There is limited direct evidence that PPI-induced mineral changes significantly impact the efficacy or safety of osteoporosis medications, though caution is advised for prolonged or unsupervised use 9 11.
• Both drug classes require ongoing evaluation of risks and benefits, especially when used together or in vulnerable individuals 9 11.
• The new findings highlight the importance of physician oversight and individualized assessment when combining treatments or using PPIs long-term 9 11.

Future Research Questions

While the current study provides new insights into the systemic effects of prolonged PPI use, further research is needed to clarify the clinical significance of these findings, especially in humans. Key gaps include understanding the mechanisms underlying nutrient imbalances, the long-term impact on bone and blood health, and how these risks might vary across different populations and treatment durations.

Research Question	Relevance
Do the mineral imbalances seen in animal studies with PPIs also occur in humans?	Translating findings from animal models to humans is critical for assessing real-world risk; existing human studies have shown associations, but direct mechanistic data are limited 2 3 4 10 12.
What is the mechanism linking PPI-induced iron deficiency to bone loss?	Understanding whether PPI-induced changes in iron status directly contribute to bone loss would clarify the causal pathway and inform prevention strategies, given the observed association between iron deficiency and osteoporosis 6 8.
How does duration and dose of PPI use affect anemia and osteoporosis risk?	Risk may be dose- and time-dependent, with some evidence suggesting greater risk with longer and higher-dose use; more precise data would inform clinical guidelines 10 12.
Are certain populations (e.g. elderly, women, patients with comorbidities) at greater risk for PPI-related adverse effects?	Studies suggest that women, older adults, and those with cardiovascular or kidney disease may be more susceptible to anemia and bone complications from PPIs, but further research is needed to define high-risk groups 2 4 5 10 12.
Can nutritional supplementation offset the risks of long-term PPI use?	It remains unclear whether targeted supplementation with iron, calcium, or other nutrients can prevent anemia or bone loss in chronic PPI users; clinical trials are needed to evaluate efficacy and safety 6 7 8.

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This article provides a comprehensive, evidence-based summary of the current understanding of long-term PPI use and its potential risks, integrating new experimental findings with the broader scientific literature.