Use of gastrointestinal proton pump inhibitors to regulate osteoclast-mediated resorption of calcium phosphate cements in vivo.

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.

Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth.

Calcium phosphate (CAP) rods and pastes based on dicalcium and tetracalcium phosphate chemistry were modified with a specific osteoclast proton pump inhibitor, Bafilomycin A(1), and implanted in the distal femurs of young male Wistar rats for 7, 10, and 14 days. The extent of osteoclastic resorption of these materials and the amount of regenerative bone formed were qualitatively evaluated. Resorptive activity similar to the remodeling process of natural bone was observed in the controls. In contrast, the resorption of materials containing Bafilomycin A(1) was considerably lower, even though tartrate-resistant acid phosphatase-positive osteoclasts were present at the tissue/material interface. A greater amount of newly formed bone consistently surrounded the CAP rods and pastes containing Bafilomycin A(1) in comparison to the control specimens, which indicated that this reparative bone was not resorbed as quickly as the new bone surrounding the controls. Increased local bone mass around the Bafilomycin A(1)-modified materials resulted from the diffusion of the proton pump inhibitor into the biological tissue at the defect site. Thus, through inhibition of the osteoclast proton pump, Bafilomycin A(1) slowed down not only the resorption of the implant material but also the resorption of the newly formed reparative bone, which resulted in an increased local bone mass.