Impact of Proton Pump Inhibitor Therapy on Bone Mineral Density: An Updated Systematic Review

Proton pump inhibitors (PPIs) are often prescribed for acid-related disorders, but while chronic use may harm bone health, a clear link to changes in bone mineral density (BMD) remains unestablished. Therefore, this systematic review aims to evaluate the association between prolonged PPI therapy and changes in BMD across skeletal sites. Following PROSPERO registration (ID: CRD420250651077), a comprehensive search of PubMed/MEDLINE, Cochrane CENTRAL, Web of Science, and Scopus databases (January 2005-September 2025) identified original research studies assessing changes in BMD among adults (≥18 years) using PPIs for ≥6 months. Two reviewers independently extracted the data for qualitative data synthesis. Risk-of-bias was assessed using the ROBINS-E tool. A total of 14 studies (11 cohort, two cross-sectional, one case-control), with participants ranging from 40 to >6,000, were included. Most studies (13 out of 14; 92.9%) assessed BMD changes in the hip, femoral neck, and lumbar spine. Ten studies (71%) found significant BMD reductions among PPI users, particularly at the hip and femoral neck, and also in the mandible. Findings for lumbar spine BMD were inconsistent. Longer PPI therapy (>1 year) and higher doses were associated with greater BMD reductions. Esomeprazole and lansoprazole were linked to more significant BMD loss than omeprazole, with older adults, males, and postmenopausal women being more affected. Proposed mechanisms include impaired calcium absorption, osteoclast-mediated trabecular bone reduction, altered plasma metabolites, and inhibition of bone-specific enzymes. Prolonged PPI use ≥6 months is linked with a modest overall reduction in BMD, especially in the hip and femoral neck, which may contribute to fracture risk. Clinicians should use the lowest effective dose and duration, and regularly monitor BMD in high-risk patients using PPIs.