The cyclooxygenase-2 selective inhibitor NS-398 does not influence trabecular or cortical bone gain resulting from repeated mechanical loading in female mice

Abstract

A single injection of the cyclooxygenase-2 (COX-2) selective inhibitor NS-398 reduces bone's osteogenic response to a single period of mechanical loading in female rats, while women taking COX-2 selective inhibitors do not have lower bone mass. We show that daily NS-398 injection does not influence bone gain from repeated loading in female mice.

Introduction: Prostaglandins are mediators of bone cells' early response to mechanical stimulation. COX-2 expression is up-regulated by exposure of these cells to mechanical strain or fluid flow, and the osteogenic response to a single loading period is reduced by COX-2 inhibition. This study determined, in female mice in vivo, the effect of longer term COX-2 inhibition on adaptive (re)modelling of cortical and trabecular bone in response to repeated loading.

Methods: Nineteen-week-old female C57BL/6 mice were injected with vehicle or NS-398 (5 mg/kg/day) 5 days a week for 2 weeks. On three alternate days each week, the right tibiae/fibulae were axially loaded [40 cycles (7 min)/day] three hours after injection. Left limbs acted as internal controls. Changes in three-dimensional bone architecture were analysed by high-resolution micro-computed tomography.

Results: In control limbs NS-398 was associated with reduced trabecular number but had no influence on cortical bone. In loaded limbs trabecular thickness and cortical periosteally enclosed volume increased. NS-398 showed no effect on this response.

Conclusion: Pharmacological inhibition of COX-2 by NS-398 does not affect trabecular or cortical bone's response to repeated mechanical loading in female mice and thus would not be expected to impair the functional adaptation of bone to physical activity in women.

Fig. 1

a Representative transverse μCT images of the left control and right loaded trabecular (0.5 mm distal to the growth plate) and cortical (37% site of the bone’s longitudinal length from its proximal end) bone in the tibiae and cortical bone (50% site of the bone’s longitudinal length from its proximal end) in the fibulae in 21-week-old female C57BL/6 mice treated with vehicle or NS-398 (5 mg/kg/day, 5 days/week) for 2 weeks. Note that woven bone formation is observed in cortical bone of the right loaded proximal/middle tibia, but not of the right loaded middle fibula. b Mechanical loading-related changes [(right loaded − left control)/left control] in polar moment of inertia, a parameter of structural bone strength, in 21-week-old female C57BL/6 mice treated with vehicle or NS-398 (5 mg/kg/day, 5 days/week) for 2 weeks. Values are presented as the means and SEM (n = 8 in each group). No significant difference was detected between vehicle and NS-398 groups by one-way ANOVA