title: Decreased bone mineral density and reduced bone quality in H(+) /K(+) ATPase beta-subunit deficient mice.
abstract: Proton pump inhibitors (PPIs) are widely used against gastroesophageal reflux disease. Recent epidemiological studies suggest that PPI users have an increased risk of fractures, but a causal relationship has been questioned. We have therefore investigated the skeletal phenotype in H(+) /K(+) ATPase beta-subunit knockout (KO) female mice. Skeletal parameters were determined in 6- and 20-month-old KO mice and in wild-type controls (WT). Whole body bone mineral density (BMD) and bone mineral content (BMC) were measured by dual energy X-ray absorptiometry (DXA). Femurs were examined with µCT analyses and break force were examined by a three-point bending test. Plasma levels of gastrin, RANKL, OPG, osteocalcin, leptin, and PTH were analyzed. KO mice had lower whole body BMC at 6 months (0.53 vs. 0.59 g, P = 0.035) and at 20 months (0.49 vs. 0.74 g, P < 0.01) compared to WT as well as lower BMD at 6 months (0.068 vs. 0.072 g/cm(2) , P = 0.026) and 20 months (0.067 vs. 0.077 g/cm(2) , P < 0.01). Mechanical strength was lower in KO mice at the age of 20 months (6.7 vs. 17.9 N, P < 0.01). Cortical thickness at 20 months and trabecular bone volume% at 6 months were significantly reduced in KO mice. Plasma OPG/RANKL ratio and PTH was increased in KO mice compared to controls. H(+) /K(+) ATPase beta subunit KO mice had decreased BMC and BMD, reduced cortical thickness and inferior mechanical bone strength. Whereas the mechanism is uncertain, these findings suggest a causal relationship between long-term PPI use and an increased risk of fractures.
authors: Department of Gastroenterology and Hepatology, St Olav's Hospital, Trondheim, Norway. reidar.fossmark@ntnu.no
authors: Reidar
authors: R
authors: Fossmark
authors: Astrid K
authors: AK
authors: Stunes
authors: Christiane
authors: C
authors: Petzold
authors: Helge L
authors: HL
authors: Waldum
authors: Marina
authors: M
authors: Rubert
authors: Aina-Mari
authors: AM
authors: Lian
authors: Janne E
authors: JE
authors: Reseland
authors: Unni
authors: U
authors: Syversen
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology*; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced; D005755:Gastrins / Q000097:blood; D020738:Leptin / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D025261:Mitochondrial Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics*; D015675:Osteocalcin / Q000097:blood; D053244:Osteoprotegerin / Q000097:blood; D010281:Parathyroid Hormone / Q000097:blood; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D053245:RANK Ligand / Q000097:blood; D012306:Risk
chemical_list: D005755:Gastrins; D020738:Leptin; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D021122:Protein Subunits; D054328:Proton Pump Inhibitors; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D025261:Mitochondrial Proton-Translocating ATPases