caa a22 4500 605463050 CHVBK 20210128100251.0 cr unu---uuuuu 210128e20151101xx s 000 0 eng 10.1007/s00774-014-0632-4 doi (NATIONALLICENCE)springer-10.1007/s00774-014-0632-4 Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats [Elektronische Daten] [Susan Smith, Rana Samadfam, Luc Chouinard, Malaika Awori, Agnes Bénardeau, Frieder Bauss, Robert Guldberg, Elena Sebokova, Matthew Wright] 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 (10mg/kg/day) and fenofibrate (25mg/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. The Japanese Society for Bone and Mineral Research and Springer Japan, 2014 Fenofibrate nationallicence PPAR-α agonist nationallicence Pioglitazone nationallicence PPAR-γ agonist nationallicence Histomorphometry nationallicence Smith Susan Charles River Laboratories, Montreal, Canada aut Samadfam Rana Charles River Laboratories, Montreal, Canada aut Chouinard Luc Charles River Laboratories, Montreal, Canada aut Awori Malaika Charles River Laboratories, Montreal, Canada aut Bénardeau Agnes DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Bauss Frieder Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany aut Guldberg Robert Georgia Institute of Technology, Atlanta, GA, USA aut Sebokova Elena DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Wright Matthew DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut Journal of Bone and Mineral Metabolism Springer Japan 33/6(2015-11-01), 625-641 0914-8779 33:6<625 2015 33 774 https://doi.org/10.1007/s00774-014-0632-4 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00774-014-0632-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Smith Susan Charles River Laboratories, Montreal, Canada aut NATIONALLICENCE 700 1- Samadfam Rana Charles River Laboratories, Montreal, Canada aut NATIONALLICENCE 700 1- Chouinard Luc Charles River Laboratories, Montreal, Canada aut NATIONALLICENCE 700 1- Awori Malaika Charles River Laboratories, Montreal, Canada aut NATIONALLICENCE 700 1- Bénardeau Agnes DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Bauss Frieder Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany aut NATIONALLICENCE 700 1- Guldberg Robert Georgia Institute of Technology, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Sebokova Elena DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 700 1- Wright Matthew DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland aut NATIONALLICENCE 773 0- Journal of Bone and Mineral Metabolism Springer Japan 33/6(2015-11-01), 625-641 0914-8779 33:6<625 2015 33 774