title: Effects of pioglitazone and fenofibrate co-administration on bone biomechanics and histomorphometry in ovariectomized rats.
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.
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Rana
authors.initials: R
authors.lastname: Samadfam
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Luc
authors.initials: L
authors.lastname: Chouinard
authors.affiliation: Charles River Laboratories, Montreal, Canada.
authors.forename: Malaika
authors.initials: M
authors.lastname: Awori
authors.affiliation: DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Agnes
authors.initials: A
authors.lastname: Bénardeau
authors.affiliation: Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: Frieder
authors.initials: F
authors.lastname: Bauss
authors.affiliation: Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
authors.affiliation: DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.affiliation: DTA Cardiovascular and Metabolism, pRED Pharma Research and Early Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland. matthew.wright@roche.com.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D001842:Bone and Bones / Q000473:pathology* / Q000503:physiopathology*; D019245:Compressive Strength / Q000187:drug effects; D003720:Densitometry; D018483:Diaphyses / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005272:Femur Neck / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011345:Fenofibrate / Q000008:administration & dosage* / Q000494:pharmacology*; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D010052:Ovariectomy; D000077205:Pioglitazone; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology*; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014057:Tomography, X-Ray Computed
chemical_list: D045162:Thiazolidinediones; D011345:Fenofibrate; D000077205:Pioglitazone
keywords: Fenofibrate; Histomorphometry; PPAR-α agonist; PPAR-γ agonist; Pioglitazone