Effects of the Histamine 1 Receptor Antagonist Cetirizine on the Osteoporotic Phenotype in H⁺/K⁺ATPase Beta Subunit KO Mice

Abstract

Epidemiological studies suggest increased fracture risk in patients using proton pump inhibitors (PPIs). We have previously shown that the H(+) /K(+) ATPase beta subunit knockout (KO) mouse, which is a model of PPI-use, have lower bone mineral density (BMD) and impaired bone quality compared to wild type (WT) mice. Like PPI users, these KO mice display elevated gastric pH and hypergastrinemia, which in turn stimulates gastric histamine release. Previous studies have suggested a negative effect of histamine on bone, thus, we wanted to study whether a histamine 1 receptor (H1R) antagonist could improve bone quality in KO mice. Female KO and WT mice aged 8 weeks received either an H1R antagonist (cetirizine) or polyethylene glycol (PEG) for 6 months. At the end of the study, KO mice displayed elevated plasma histamine levels compared to WT. As demonstrated previously, the KO mice also exhibited lower whole body BMD, reduced mechanical bone strength, and impaired bone quality assessed by μCT. No significant differences, however, were found between the KO groups receiving cetirizine or PEG for any of the measured bone parameters. In vitro gene expression analyses of histamine receptors revealed the presence of H1R and H2R both in osteoblasts and osteoclasts, and H3R in late stage osteoblasts. In conclusion, administration of the H1R antagonist cetirizine in a concentration of 3 mg/kg did not rescue the osteoporotic phenotype in H(+) /K(+) ATPase beta subunit KO mice. It can, however, not be ruled out that histamine may influence bone via other receptors. J. Cell. Biochem. 117: 2089-2096, 2016. © 2016 Wiley Periodicals, Inc.

Long-term administration of fenspiride has no negative impact on bone mineral density and bone turnover in young growing rats

“…29 Treatment with cetirizine (a 2 nd generation H1-antihistamine) did not have any impact on BMD values or bone tissue properties in H(+)/K(+) ATPase β subunit knockout (KO) mice, which are genetically modified to have high histamine levels leading to secondary decreases in BMD. 11,31 Recently, Folwarczna et al 14 administered loratadine (a 2 nd generation H1-antihistamine) to ovariectomized and non-ovariectomized rats with bone metabolism disorders. Short-term loratadine administration significantly improved bone metabolism and biomechanical bone properties in the non-ovariectomized rats.…”

“…[8][9][10] The presence of H1-histamine receptors on both osteoblasts and osteoclasts has been confirmed. 11 Pro-inflammatory cytokines, e.g., interleukin-1, interleukin-6 and TNF-α, increase osteoclast activity through the RANK/RANKL/OPG pathway and inhibit osteoblast activity. Prostaglandins may stimulate both bone formation and bone resorption.…”

“…13 These findings suggest that fenspiride may influence bone metabolism and BMD. The impact of different antagonists of H1-receptors (e.g., loratadine, cetirizine, pheniramine maleate) on bone metabolism has been studied, 11,14,15 but to the best of our knowledge, the action of fenspiride on bone metabolism has not been investigated.…”

Does Allergy Break Bones? Osteoporosis and Its Connection to Allergy

“…Furthermore loratadine, often prescribed to allergic children, is able to slightly but significantly affect at high dose the development of the skeletal system in rapidly growing rats [56]. However, Aasarød et al found increased levels of histamine in an animal model of gastric hypoacidity and hypergastrinemia associated with reduced bone quality and mechanical bone strength while the H1R antagonist cetirizine did not show to be beneficial on bone parameters [57][58][59][60].…”

<p>Effects of loratadine, a histamine H₁ receptor antagonist, on the skeletal system of young male rats</p>

“…In vitro and in vivo experimental studies demonstrated that histamine is involved in the regulation of bone metabolism 8–13. Expression of histamine H 1 and H 2 receptors in bone cells (osteoblasts and osteoclasts) is well documented,8–10,14 and histamine is synthesized in osteoclast precursors 8. Histamine increases bone resorption both directly, acting on osteoclast precursors and osteoclasts, and indirectly, by stimulation of the RANKL expression in osteoblasts 8–10.…”