Abstract
BackgroundActivation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.MethodsFifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.ResultsWhole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.ConclusionsThe PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.
Highlights
Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects
The significance of PPARa and its agonists in bone metabolism remains poorly elucidated, we have demonstrated that administration of the PPARa agonist fenofibrate, increases femoral bone mineral density (BMD) and reduces medullary area in intact female rats [12,13], suggesting a positive impact on skeletal homeostasis
In order to better characterize the role of PPARa in bone, we examined the long-term skeletal effects of the PPARa agonists fenofibrate and Wyeth 14643 in ovariectomized rats, and compared the effects to those of the PPARg agonist pioglitazone
Summary
Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats. Endogenous ligands for PPARs include eicosanoids, fatty acids and fatty acid derivatives [3]. Because of their metabolic actions, PPARs (as yet preferentially PPARa and g) have become major drug targets [6]. Thiazolidinediones/glitazones are synthetic PPARg agonists used for treatment of type 2 diabetes mellitus (T2DM) [2,3,10]
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