Proton pump inhibitor use and fracture risk - effect modification by histamine H1 receptor blockade. Observational case-control study using National Prescription Data.

It remains unknown why proton pump inhibitor (PPI) use may be associated with risk of osteoporotic fractures; evidence of direct effects on calcium absorption or on the osteoclast in humans is weak or absent. However, the ensuing increased gastrin levels may cause histamine production through hypertrophy of gastric enterochromaffin like cells, which could lead to bone loss. We speculated that H1 receptor antagonists (H1RA) used for allergies would then reduce the effect of PPI on bone. We therefore conducted a register-based case-control study comprising 124,655 patients with hospital treated fractures, who were matched 3:1 with non fracture control subjects of the same age and gender. Use of prescription medications was retrieved from the National Prescription Database and data was analyzed using conditional logistic regression analysis. We observed a significant interaction between PPI and H1RA use on fracture risk in general (adjusted OR 0.92, 95% CI 0.87-0.98) though not on hip fracture risk (adjusted OR 0.99, 95% CI 0.85-1.16). There was a significant modification of the interaction by age (p<0.05 for both fracture categories). As previously shown, fracture risk was higher in PPI users both for fractures in general and for hip fractures. Irrespective of PPI use, H1RA users had lower risk of hip fractures than non-users (adjusted OR 0.86, 95% CI 0.79-0.93). This short report suggests that the effects of PPI on bone could be driven by in part by increased histamine release as the increased fracture risk can be modified by H1RA.