In control bones which received no more than normal functional mechanical loading, NS-398 slightly but significantly decreased trabecular BV/TV of the proximal tibiae. This would be compatible with a small

reduction in bone mass of COX-2 deficient mice [11]. In bones that had been artificially loaded, COX-2 inhibition had no discernible effect on the loading-related lamellar or woven bone response in either trabecular or cortical compartments. As a result, NS-398 showed no influence on the loading-related increase in polar moment of inertia, a parameter of structural bone strength. Although there may be a potential small inhibitory effect of NS-398 on bone’s response to mechanical loading that could Protease Inhibitor Library cell line be detected only by histomorphometry, such an effect would not alter the conclusion of the present study. The present data are consistent with the evidence from female mice lacking COX-2 [11], showing that bone adaptation to two consecutive days of mechanical loading does not require a functional COX-2 gene. The authors [11] suggested a compensatory effect of COX-1 in vivo, though this enzyme does not appear to be important for bone cells’ response to a single period of fluid

flow in vitro [20]. If such compensation exists, it does not seem to be immediately available since in female Ibrutinib datasheet rats a single injection of NS-398 reduces the cortical response to a single period of mechanical Bortezomib loading [9, 10]. The data we present here suggest that compensation for the pharmacological inhibition of COX-2 function does exist and can occur sufficiently swiftly to ensure that adaptive (re)modelling of trabecular and cortical bone to artificial mechanical loading over a 2-week period is not

impaired. The relevance of the present experiment in female mice to the human condition must take into account a number of differences in the two situations. Importantly, however, our experimental data of three-dimensional bone architecture analysed by high-resolution μCT are compatible with clinical evidence that women taking COX-2 selective inhibitors such as celecoxib and rofecoxib do not have lower hip areal BMD [13]. In contrast to women, the use of the COX-2 selective inhibitors is associated with lower hip areal BMD in men [13]. It remains to be elucidated whether there are sex differences in the effects of COX-2 inhibition on bone’s response to mechanical loading. In conclusion, our present data demonstrate that in female mice pharmacological inhibition of COX-2 using daily NS-398 injection does not affect trabecular or cortical bone gain engendered by repeated periods of mechanical loading over a 2-week period.