Dose-effect and evidence of escape of inhibition after indomethacin treatment in a synchronized model of bone resorption.

Abstract

We previously showed that cyclooxygenase inhibition by indomethacin (7.5 mg/kg/d) prevented resorption in a model of synchronized remodeling. In the present paper, we (i) tested the effectiveness of three doses of indomethacin (2, 4, 7.5 mg/kg/d) in this model, and (ii) verified whether indomethacin action was sustained in time. For that purpose, on day 6 after induction, untreated controls were compared with a group treated for six days with indomethacin (7.5 mg/kg/d), and an interrupted treatment group (4 days indomethacin + 2 days free). Indomethacin inhibited resorption and total number of osteoclasts in a dose-dependent manner. In the second experiment in the discontinued group, the resorption and total number of osteoclasts were similar to sham-treated animals. Indomethacin was still effective in the continuous treatment group; however, resorption was distinctly higher than in the rats treated for four days. These data indicate that despite cyclooxygenase inhibition, another metabolic pathway started resorption. The stoppage of prostanoid inhibition permitted the rapid and complete restoration of resorption.