Skeletal effects of a gastrin receptor antagonist in H+/K+ATPase beta subunit KO mice

Abstract

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H + /K + ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1 year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by threepoint bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Threepoint bending test also showed higher Young's modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

“…Furthermore, the skeletal changes in CCKB receptor-deficient mice could be reversed by calcium supplementation [79], suggesting a mechanism somehow related to impaired calcium handling and uptake in the gastrointestinal tract. H + K + ATPase beta subunit-deficient mice are also hypoacidic, hypergastrinemic, display an elevated parathyroid hormone [80], and have reduced BMD and bone quality [80,81], which only slightly improved by administration of a gastrin receptor antagonist. Patients with chronic atrophic gastritis, a condition that may be analogous to long-term high-dose PPI use with respect to hypoacidity, hypergastrinemia, and absorption of micronutrients, have an increased risk of fractures [82,83], reduced BMD [84], and reduced calcium carbonate absorption in fasting state [85].…”

Proton pump inhibitors and fracture risk. The HUNT study, Norway

“…The effect could be due to gastric hypoacidity, causing reduced calcium absorption with subsequent secondary hyperparathyroidism [2,8,[16][17][18]. However, recent studies have not been able to show reduced calcium absorption in humans [12,14,19], Hypoacidity also induces hypergastrinemia that has been proposed to have a negative effect on bone both directly and indirectly via the parathyroid hormone [8,17,18,20].…”

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

“…The H + /K + ATPase beta subunit KO mouse is a model of long-term PPI use, gastric hypoacidity and secondary hypergastrinemia [20][21][22]. KO mice develop marked hyperplasia of the oxyntic mucosa with intramucosal cystic changes and ECL cell hyperplasia, but only a few develop gastric carcinoma [21].…”