Comment on “Evaluation of the Long-Term Administration of Proton Pump Inhibitors (PPIs) in the Mineral Nutrient’s Bioavailability”

Proton pump inhibitors (PPIs), including omeprazole, are widely prescribed for acid-related disorders, with well-established efficacy and safety. A recent rat study published in ACS Omega (de Brito, A. S. ACS Omega 2025, 10, 56085−56095, 10.1021/acsomega.5c07700) reported small hematological and mineral changes after 60-day omeprazole exposure and was publicly interpreted as evidence that PPIs cause anemia, bone disease, or cancer in humans. This Comment argues that such extrapolation is not supported by the data. Key methodological limitations include a subtherapeutic dose (0.68 mg/kg/day) for rodents, the absence of pharmacodynamic confirmation (gastric pH, H+/K+-ATPase activity), and a lack of specific markers for anemia (ferritin, transferrin, hepcidin), bone density, or functional mineral absorption. Substantial interspecies differences in gastric physiology, metabolism, and PPI pharmacokinetics preclude direct translation to humans. Meta-analyses involving millions of participants show a modest fracture risk, heavily confounded by age, frailty, and corticosteroid co-use, with no causal link to bone loss. Iron and vitamin B12 deficiencies, when present, are usually modest, multifactorial, and correctable; hypomagnesemia is rare. The historic gastric cancer signal reflected untreated Helicobacter pylori, not PPI toxicity. The genuine clinical concern is inappropriate, indication-free chronic PPI use, not an intrinsic hazard of omeprazole demonstrated in rodents.