gms | German Medical Science

Questionnaire: Proton pump inhibitors (PPIs) are widely used in the treatment of dyspeptic problems. To avoid stress ulcer development after surgery, they are also applied in combination with analgetics, especially with nonsteroidal anti-inflammatory drugs (NSAIDs). A adverse effect of PPIs a negative calcium balance due to attenuation of the acidic milieu in the stomach, resulting in increased rates of bone loss and a greater risk of fracture. There is no information, however, whether pantoprazole affects fracture healing. We therefore studied in a mouse femur fracture model the influence of pantoprazole on callus formation and biomechanics during fracture healing.

Methods: Bone healing was studied in a murine closed femur fracture model using radiological (x-ray), biomechanical (non-destructive bending test), histomorphometric and protein biochemical analysis at 2 and 5 weeks after fracture. Twenty-four mice received 100 mg/kg body weight pantoprazole i.p. daily. Controls (n=24) received equivalent amounts of vehicle. All data are given as means±SEM. After proving the assumption for normal distribution (Kolmogorov-Smirnov test) and equal variance (F-test), comparison between the two experimental groups was performed by Student´s t-test.

Results and Conclusions: Two weeks after fracture, biomechanical analysis could not show significant differences between the two groups. After 5 weeks, however, the bending stiffness in pantoprazole-treated animals was significantly lower compared to controls (55.7±4.9 N/mm vs. 85.7±10.1 N/mm). Tissue distribution analysis further revealed that after pantoprazole treatment the amount of bony tissue within the callus was slightly lower, while the amount of cartilaginous tissue was still elevated. Western blot analysis showed a reduced expression of the bone formation markers bone morphogenetic protein-4 (BMP-4), collagen I and cysteine-rich protein (CYR61). In addition, reduced cell proliferation was indicated by a significantly reduced expression of proliferating cell nuclear antigen (PCNA) after pantoprazole treatment. Of interest, this reduced expression of bone formation markers was associated with a significantly diminished expression of receptor activator of nuclear factor-κ B ligand (RANKL).

Pantoprazole reduces RANKL expression, most probably by reducing the acidic milieu, which attenuates the activity of osteoclasts. Because RANKL is required during bone remodeling, the reduction of RANKL by pantoprazole results in a delay of the remodeling process during fracture healing. Whether the reduction of the bone formation markers BMP-4, collagen I and CYR61 is a compensatory consequence of the pantoprazole-induced reduction of RANKL or whether pantoprazole acts directly on bone formation marker expression remains to be determined in future studies.