title: Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo.
abstract: Osteoclasts degrade bone through the creation of an enclosed, acidic extracellular microenvironment adjacent to the bone surface. Membrane bound proton pumps in the osteoclast cell membrane function to create this acidified environment. Accordingly, this H(+) ion transport mechanism provides a potential target for a specific class of drugs, proton pump inhibitors (PPI), with a view to controlling osteoclast mediated bone resorption. Self setting calcium phosphate cements are common bone graft materials that are degraded by osteoclastic activity. We have already shown that incorporation of bafilomycin, a non-regulated PPI, within these cements prevents or delays osteoclast mediated resorption of the cement. We demonstrate here that two regulated proton pump inhibitors, Pantaprazole and Omeprazole, currently used clinically to treat gastroesophageal reflux disorders, are effective in inhibiting osteoclast mediated resorption in-vivo when delivered to a bony defect in self setting calcium phosphate cements. As determined by qualitative histology, Pantaprazole at a dose of 0.5mg/ml produced a delay in osteoclast resorption whilst this effect was not as evident using Omeprazole at an equivalent dose, but higher doses of Omeprazole (40mg/ml) did delay cement resorption. These data demonstrate, for the first time, the functional effect of blocking the H(+)/K(+) ATPase pump in-vivo on the capacity of osteoclasts to resorb bone and the potential of this strategy to modulate osteoclast mediated resorption of calcium phosphate biomaterials.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada.
authors.forename: A R
authors.initials: AR
authors.lastname: Sheraly
authors.forename: D
authors.initials: D
authors.lastname: Lickorish
authors.forename: F
authors.initials: F
authors.lastname: Sarraf
authors.forename: J E
authors.initials: JE
authors.lastname: Davies
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001843:Bone Cements / Q000737:chemistry / Q000378:metabolism*; D001862:Bone Resorption / Q000517:prevention & control*; D002130:Calcium Phosphates / Q000737:chemistry / Q000378:metabolism*; D005269:Femur / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001843:Bone Cements; D002130:Calcium Phosphates; D007527:Isoenzymes; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D009853:Omeprazole