Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved

Abstract

The number of patients with gastroesophageal problems taking proton pump inhibitors (PPIs) is increasing. Several studies suggested a possible association between PPIs and fracture risk, especially hip fractures, but the relationship remains contentious. This review aimed to investigate the longitudinal studies published in the last five years on the relationship between PPIs and fracture risk. The mechanism underlying this relationship was also explored. Overall, PPIs were positively associated with elevated fracture risk in multiple studies (n = 14), although some studies reported no significant relationship (n = 4). Increased gastrin production and hypochlorhydria are the two main mechanisms that affect bone remodeling, mineral absorption, and muscle strength, contributing to increased fracture risk among PPI users. As a conclusion, there is a potential relationship between PPIs and fracture risks. Therefore, patients on long-term PPI treatment should pay attention to bone health status and consider prophylaxis to decrease fracture risk.

Keywords: bone; compression; omeprazole; osteoporosis; pantoprazole.

Figure 1

Summary of the systemic effects of proton pump inhibitors (PPIs) in elevating fracture risk. Abbreviations: IC HCY, intracellular homocysteine; EC HCY, extracellular homocysteine; ECL cells, enterochromaffin-like cells; Ca, calcium; Mg, magnesium; BMD, bone mineral density; PTHrP, parathyroid hormone-related peptide; PTHLH, parathyroid hormone-like hormone; OB, osteoblast; OC, osteoclast; ↑, increase; ↓, decrease.

Figure 2

Summary of the cellular effects of proton pump inhibitors on bone cells. Abbreviations: PPI, proton pump inhibitor; ALP, alkaline phosphatase; TRAP, tartrate-resistant acid phosphatase; COL 1, collagen type 1; BMP-2, bone morphogenetic protein-2; NFATc1, nuclear factor of activated T-cells; MMP, matrix metalloproteinase 9; CATK, cathepsin K.