Pantoprazole impairs fracture healing in aged mice

Maximilian M Menger,Tina Histing,Philipp Bremer,Steven C Herath,Marcel Orth,Mika F Rollmann,Claudia Scheuer,Tim Pohlemann,Benedikt J Braun,Thomas Später,Michael D Menger

doi:10.1038/s41598-020-79605-3

Maximilian M Menger, Tina Histing + Show 9 more

Open Access

https://doi.org/10.1038/s41598-020-79605-3

Copy DOI

Journal: Scientific Reports	Publication Date: Dec 1, 2020
Citations: 9	License type: open-access

Affiliation: Saarland University, University of Tübingen

Abstract

Proton pump inhibitors (PPIs) belong to the most common medication in geriatric medicine. They are known to reduce osteoclast activity and to delay fracture healing in young adult mice. Because differentiation and proliferation in fracture healing as well as pharmacologic actions of drugs markedly differ in the elderly compared to the young, we herein studied the effect of the PPI pantoprazole on bone healing in aged mice using a murine fracture model. Bone healing was analyzed by biomechanical, histomorphometric, radiological and protein biochemical analyses. The biomechanical analysis revealed a significantly reduced bending stiffness in pantoprazole-treated animals when compared to controls. This was associated with a decreased amount of bone tissue within the callus, a reduced trabecular thickness and a higher amount of fibrous tissue. Furthermore, the number of osteoclasts in pantoprazole-treated animals was significantly increased at 2 weeks and decreased at 5 weeks after fracture, indicating an acceleration of bone turnover. Western blot analysis showed a lower expression of the bone morphogenetic protein-4 (BMP-4), whereas the expression of the pro-angiogenic parameters was higher when compared to controls. Thus, pantoprazole impairs fracture healing in aged mice by affecting angiogenic and osteogenic growth factor expression, osteoclast activity and bone formation.

Highlights

Proton pump inhibitors (PPIs) belong to the most common medication in geriatric medicine
We found in pantoprazoletreated animals slightly lower ratios of bone morphogenetic protein (BMP)-2/vascular endothelial growth factor (VEGF) (p = 0.162) and bone morphogenetic protein-2 (BMP-2)/Cyr 61 (p = 0.310), but markedly lower ratios of bone morphogenetic protein-4 (BMP-4)/VEGF (p = 0.016) and BMP-4/Cyr 61 (p = 0.095) (Table 1)
The impaired fracture repair was associated with a lower expression of the bone formation marker BMP-4, and a disturbed ratio of pro-angiogenic proteins to osteogenic growth factors

Summary

Introduction

Proton pump inhibitors (PPIs) belong to the most common medication in geriatric medicine They are known to reduce osteoclast activity and to delay fracture healing in young adult mice. Because differentiation and proliferation in fracture healing as well as pharmacologic actions of drugs markedly differ in the elderly compared to the young, we studied the effect of the PPI pantoprazole on bone healing in aged mice using a murine fracture model. Aging involves a progressive decline in the functional reserve of multiple organs, such as hepatic clearance and renal extraction[27] These physiological changes do affect drug pharmacokinetics and metabolism, but may alter the mode of action of specific drugs, including PPIs. Of interest, there is a complete lack of information about the effects of PPIs on bone healing and regeneration in the elderly. We studied in aged mice the effects of pantoprazole on fracture healing using a standardized femur fracture model

Objectives

Methods

Conclusion