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Combination Treatment with Pioglitazone and Fenofibrate 179 Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats Rana Samadfam, Malaika Awori, Agnes Be´nardeau1, Frieder Bauss2, Elena Sebokova1, Matthew Wright1 and Susan Y Smith Charles River Laboratories, 22022 Transcanadienne, Senneville, Montre´al, Que´bec, Canada H9X 3R3 1F. Hoffmann-La Roche AG, Basel, CH-4070 Switzerland 2Roche Diagnostics GmbH, Penzberg, DE-82377 Germany (Correspondence should be addressed to S Y Smith; Email: [email protected]) Abstract Peroxisome proliferator-activated receptor (PPAR) g ago- mineral content (w45%) and bone mineral density (BMD; nists, such as pioglitazone (Pio), improve glycemia and lipid w60%) at the lumbar spine. Similar effects of treatments were profile but are associated with bone loss and fracture risk. Data observed at the femur, most notably at sites rich in trabecular regarding bone effects of PPARa agonists (including bone. At the proximal tibial metaphysis, concomitant fenofibrate (Feno)) are limited, although animal studies treatment with PioCFeno prevented Pio exacerbation of suggest that Feno may increase bone mass. This study ovariectomy-induced loss of trabecular bone, resulting in investigated the effects of a 13-week oral combination BMD values in the PioCFeno group comparable to OVX treatment with Pio (10 mg/kg per day)CFeno (25 mg/kg controls. Discontinuation of Pio or Feno treatment of per day) on body composition and bone mass parameters OVX rats was associated with partial reversal of effects on compared with Pio or Feno alone in adult ovariectomized bone loss or bone mass gain, respectively, while values in the (OVX) rats, with a 4-week bone depletion period, followed PioCFeno group remained comparable to OVX controls. by a 6-week treatment-free period. Treatment of OVX rats These data suggest that concurrent/dual agonism of PPARg with PioCFeno resulted in w50% lower fat mass gain and PPARa may reduce the negative effects of PPARg compared with Pio treatment alone. Combination treatment agonism on bone mass. with PioCFeno partially prevented Pio-induced loss of bone Journal of Endocrinology (2012) 212, 179–186 Introduction selectivity/agonistic effects on PPAR subtypes. Thiazolidine- diones (TZDs) work predominantly through the activation of Bone is a highly specialized and dynamic tissue that undergoes PPARg and have been shown to improve insulin sensitivity constant remodeling by balancing bone formation and and glucose homeostasis in type 2 diabetes mellitus resorption (Clarke 2008, Eriksen 2010), processes that are (Spiegelman 1998, Lalloyer & Staels 2010), while fibrates regulated by osteoblasts and osteoclasts respectively (Clarke activate PPARa, with the primary effect of improving plasma 2008, Eriksen 2010). Osteoblastogenesis, osteoclastogenesis, lipids (Sierra et al. 2007, Lalloyer & Staels 2010). Accumulating and activity of the resultant cell types are controlled by a evidence from animal studies as well as clinical trials indicates variety of hormonal and humoral factors such as estrogen that activation of PPARg results in loss of bone mass and/or (Manolagas et al. 2002), thyroid hormones (Eriksen 2010), strength (Kahn et al. 2006, Glintborg et al. 2008, Schwartz growth factors (Eriksen 2010), and cytokines (Clarke 2008, 2008) via effects on bone formation and resorption (Sottile Eriksen 2010), the actions of which are mediated via specific et al. 2004, Grey et al. 2007), underlying the increased risk of receptors, including nuclear receptors (Boyce et al. 2009, fractures observed clinically with these agents (Kahn et al. Eriksen 2010). 2006, Glintborg et al. 2008). The role of PPARa (and the third The peroxisome proliferator-activated receptors (PPARs) member of the PPAR family, PPARd) in regulating bone are a group of ligand-activated nuclear receptors that play a key health is much less understood although, recently,fibrates were role in the regulation of lipid and carbohydrate metabolism, as reported to increase bone mass and strength in normal rats well as inflammation, immunomodulation, and cellular (Syversen et al. 2009) and in an animal model of osteoporosis, differentiation (Karpe & Ehrenborg 2009, Lalloyer & Staels the ovariectomized (OVX) rat (Stunes et al. 2011). 2010). PPAR agonists are a diverse group of compounds Combined (dual) activation of PPARa and PPARg has and, although often grouped together, exhibit different been pursued for over a decade due to the expectation of Journal of Endocrinology (2012) 212, 179–186 DOI: 10.1530/JOE-11-0356 0022–0795/12/0212–179 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/27/2021 03:55:21PM via free access 180 R SAMADFAM and others . Effects of PPARa and g activation on bone mass better control of cardiovascular risk factors vs solo activation was discontinued in the remaining ten animals from each of one of the PPARs, as both diabetic dyslipidemia and of these groups for 6 weeks (i.e. end of the study at week 19). glucose control/insulin sensitivity are targeted (Lalloyer & Body weight and food consumption were measured Staels 2010). Several combined (dual) PPARa/g agonists weekly, starting from the last week of the acclimation period have reached phase III trials – muraglitazar (Kendall et al. and extending through the treatment and treatment-free 2006), tesaglitazar (Bays et al. 2007), and aleglitazar (Henry periods. In addition, body weight was measured at et al. 2009) – and although the development of muraglitazar randomization and on the day of termination (as an overnight and tesaglitazar was terminated because of safety concerns, the fasted body weight). therapeutic potential of PPARa/g agonists remains of high clinical interest. To our knowledge, the effect of combined Laboratory analysis activation of PPARg and PPARa on bone biology has not been investigated previously. At the end of the bone depletion period, blood was collected The objective of this study was to investigate the effects of from overnight fasted animals at weeks 5 or 6 and 12 or 13 of combination treatment with an agonist of PPARa (fenofi- the treatment period and at week 19 (i.e. end of the brate (Feno)) and PPARg (pioglitazone (Pio)) on bone mass, treatment-free period). Plasma was analyzed for assessment of bone density, and markers of bone turnover compared with triglyceride (TG), insulin, and biomarkers of bone turnover the effect of Pio and Feno alone in OVX rats. In addition, the (serum osteocalcin (bone formation) and urinary effect of discontinuation of treatment was investigated to C-telopeptide of type I collagen (CTx; bone resorption)). evaluate the reversibility of observed effects. TG was measured by an enzymatic colorimetric assay (GPO-PAP, Roche Diagnostics GmbH), while insulin and osteocalcin were measured using rat RIA kits (LINCO Research, Billerica, MA, USA and Biomedical Technologies, Materials and Methods Inc., Stoughton, MA, USA respectively). CTx was assessed with a rat ELISA (Immunodiagnostic Systems, Tyneand Wear, Animals UK). Adiponectin was measured by a colorimetric ELISA The study was conducted in accordance with Standard assay (B-Bridge International, Inc., Cupertino, CA, USA). Operating Procedures of Charles River Laboratories, Montreal, and F. Hoffmann-La Roche AG and the protocol Bone densitometry measurements was approved by the Institutional Animal Care and Use Committee. Animals were appropriately housed and experi- Bone densitometry was evaluated by dual-energy X-ray mental procedures were performed in accordance with absorptiometry (DXA) and peripheral quantitative computed guidelines of the Association for the Assessment and tomography (pQCT). Animals were anesthetized using iso- Accreditation of Laboratory and Animal Care and appropriate flurane and were maintained under the effect during the scans. federal, state, or local guidelines. Scans were acquired once prior to surgery,at the end of the bone At the beginning of treatment, animals were w7 months of depletion period, during weeks 5/6 and 12/13 of the treatment age and ranged in weight from 318 to 454 g. Animals had free period, and at the end of the treatment-free period at week 19. access to purified water and standard laboratory diet (PMI Certified rodent 5002, PMI Nutrition International, Inc., Dual-energy X-ray absorptiometry Saint Paul, MN, USA) throughout the study, except where indicated. The overall average temperature and relative DXA was used to measure area (cm2), bone mineral content humidity during the study were 21.9 8C and 50% respectively. (BMC (g)), and bone mineral density (BMD (g/cm2)) using a After a minimum acclimation period of 3 weeks, animals Hologic Discovery A densitometer (Hologic, Inc., Bedford, underwent surgical procedure (sham operation or ovari- MA, USA) with small animal hi-res software version 12.3. ectomy). Prior to surgery, baseline bone densitometry and The percent coefficient of variation for rat BMD at the spine body weight measurements were obtained from all animals. and femur was 1.1–1.5%. In addition, lean mass and fat mass Using a randomization procedure stratified according to body were reported from whole-body DXA scans. Bone densito- weight, animals were assigned to one of the following metry measurements of the whole body, lumbar spine (L1– treatment groups: 1) sham vehicle control, 2) OVX vehicle L4), and whole and regionalized right femur were acquired control, 3) OVX Pio (10 mg/kg per day),
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