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Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats

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Abstract

Pioglitazone, the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist is an effective therapy for type 2 diabetes, but has been associated with increased risk for bone fracture. Preclinical studies suggest that PPAR-α agonists (e.g., fenofibrate) increase bone mineral density/content, although clinical data on bone effects of fibrates are lacking. We investigated the effects of pioglitazone (10 mg/kg/day) and fenofibrate (25 mg/kg/day) on bone strength and bone histomorphometric parameters in osteopenic ovariectomized (OVX) rats. An additional group of rats received a combination of pioglitazone + fenofibrate to mimic the effects of a dual PPAR-α/γ agonist. The study consisted of a 13-week treatment phase followed by a 6-week treatment-free recovery period. Pioglitazone significantly reduced biomechanical strength at the lumbar spine and femoral neck compared with rats administered fenofibrate. Co-treatment with pioglitazone + fenofibrate had no significant effect on bone strength in comparison with OVX vehicle controls. Histomorphometric analysis of the proximal tibia revealed that pioglitazone suppressed bone formation and increased bone resorption at both cancellous and cortical bone sites relative to OVX vehicle controls. In contrast, fenofibrate did not affect bone resorption and only slightly suppressed bone formation. Discontinuation of pioglitazone treatment, both in the monotherapy and in the combination therapy arms, resulted in restoration of bone formation and resorption rates, demonstrating reversibility of effects. The above data support the concept that dual activation of PPAR-γ and PPAR-α attenuates the negative effects of PPAR-γ agonism on bone strength.

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Acknowledgments

The authors wish to thank the imaging, histomorphometry and biomechanics technical teams for their excellent work (Charles River Laboratories, Canada). Editorial support for the development of this manuscript was provided by Moh Tadayyon (MediTech Media, UK) and was funded by F. Hoffmann-La Roche Ltd.

Conflict of interest

A. Bénardeau, E. Sebokova and M. Wright are employees of F. Hoffmann La-Roche, Switzerland. F. Bauss is employed by Roche Diagnostics GmbH, Germany. S. Y. Smith, R. Samadfam, L. Chouinard and M. Awori are employees of Charles River Laboratories, Canada. R. E. Guldberg is a consultant for Charles River Laboratories, Canada. This study was performed at Charles River Laboratories, funded by F. Hoffmann-La Roche AG, Switzerland.

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Authors and Affiliations

  1. Charles River Laboratories, Montreal, Canada

    Susan Y. Smith, Rana Samadfam, Luc Chouinard & Malaika Awori

  2. DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland

    Agnes Bénardeau, Elena Sebokova & Matthew B. Wright

  3. Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany

    Frieder Bauss

  4. Georgia Institute of Technology, Atlanta, GA, USA

    Robert E. Guldberg

Authors
  1. Susan Y. Smith
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  2. Rana Samadfam
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  3. Luc Chouinard
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  4. Malaika Awori
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  5. Agnes Bénardeau
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  6. Frieder Bauss
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  7. Robert E. Guldberg
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  8. Elena Sebokova
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  9. Matthew B. Wright
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Correspondence to Matthew B. Wright.

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Smith, S.Y., Samadfam, R., Chouinard, L. et al. Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats. J Bone Miner Metab 33, 625–641 (2015). https://doi.org/10.1007/s00774-014-0632-4

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  • DOI: https://doi.org/10.1007/s00774-014-0632-4

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