Association Between Long-Term Proton Pump Inhibitor Use and the Risk of Osteoporotic Fractures

Proton pump inhibitors (PPIs) are among the most widely prescribed medications and remain a cornerstone in the treatment of acid-related gastrointestinal disorders. Their prolonged use, particularly among older adults, has raised concerns regarding a potential association with osteoporotic fractures. This review examines the current evidence linking long-term PPI therapy with fracture risk in older adults, explores the biological mechanisms proposed to explain this association, and discusses its clinical implications. Available epidemiological evidence, derived mainly from observational studies and meta-analyses, suggests a modest association between prolonged PPI use and increased risks of hip, vertebral, and overall osteoporotic fractures. Several mechanisms have been proposed, including impaired calcium absorption, altered mineral homeostasis, hypergastrinemia, micronutrient deficiencies, changes in bone remodeling and microarchitecture, and increased susceptibility to falls. However, evidence supporting these mechanisms is inconsistent, and causality remains uncertain. Although observational studies suggest an association between PPI use and fracture risk, a causal relationship has not been established. Overall, the relationship between long-term PPI use and fracture risk appears multifactorial and incompletely understood. Current evidence does not support routine discontinuation of PPIs when appropriately indicated, as their benefits generally outweigh potential skeletal risks. Instead, treatment should be individualized through regular reassessment of indication, use of the lowest effective dose, appropriate deprescribing when warranted, and assessment of fracture risk. Further prospective studies are needed to clarify causality, dose–response relationships, differences among individual PPIs, and the potential skeletal benefits of deprescribing.