title: Pantoprazole, a proton pump inhibitor, delays fracture healing in mice.
abstract: Proton pump inhibitors (PPIs), which are widely used in the treatment of dyspeptic problems, have been shown to reduce osteoclast activity. There is no information, however, on whether PPIs affect fracture healing. We therefore studied the effect of the PPI pantoprazole on callus formation and biomechanics during fracture repair. Bone healing was analyzed in a murine fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analyses at 2 and 5 weeks after fracture. Twenty-one mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls (n = 21) received equivalent amounts of vehicle. In pantoprazole-treated animals biomechanical analysis revealed a significantly reduced bending stiffness at 5 weeks after fracture compared to controls. This was associated with a significantly lower amount of bony tissue within the callus and higher amounts of cartilaginous and fibrous tissue. Western blot analysis showed reduced expression of the bone formation markers bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich protein (CYR61). In addition, significantly lower expression of proliferating cell nuclear antigen indicated reduced cell proliferation after pantoprazole treatment. Of interest, the reduced expression of bone formation markers was associated with a significantly diminished expression of RANKL, indicating osteoclast inhibition. Pantoprazole delays fracture healing by affecting both bone formation and bone remodeling.
authors.affiliation: Department of Trauma, Hand, and Reconstructive Surgery, University of Saarland, 66421, Homburg/Saar, Germany. tina.histing@uks.eu
authors.forename: T
authors.initials: T
authors.lastname: Histing
authors.forename: D
authors.initials: D
authors.lastname: Stenger
authors.forename: C
authors.initials: C
authors.lastname: Scheuer
authors.forename: W
authors.initials: W
authors.lastname: Metzger
authors.forename: P
authors.initials: P
authors.lastname: Garcia
authors.forename: J H
authors.initials: JH
authors.lastname: Holstein
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.forename: T
authors.initials: T
authors.lastname: Pohlemann
authors.forename: M D
authors.initials: MD
authors.lastname: Menger
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002146:Bony Callus / Q000378:metabolism / Q000473:pathology; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D054328:Proton Pump Inhibitors; D053245:RANK Ligand; D000077402:Pantoprazole