Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

Abstract

Peroxisome proliferator-activated receptor (PPAR) g agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARa agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)CFeno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with PioCFeno resulted in w50% lower fat mass gain compared with Pio treatment alone. Combination treatment with PioCFeno partially prevented Pio-induced loss of bone mineral content (w45%) and bone mineral density (BMD; w60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with PioCFeno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the PioCFeno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the PioCFeno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARg and PPARa may reduce the negative effects of PPARg agonism on bone mass.

The Effect of Rosiglitazone on Bone Mass and Fragility Is Reversible and Can Be Attenuated With Alendronate

“…Studies in rodent models have suggested effects on both bone resorption and formation via an impact on osteoclasts and osteoblasts. Treatment of 6‐month‐old mice with RSG decreased bone mineral density (BMD) at 7 weeks but not at 4 weeks, with similar observations seen with pioglitazone in the rat . In these and other studies, loss of BMD appeared to result from a reduction in osteoblast number and/or activity, leading to changes in bone marrow composition and bone microarchitecture .…”

“…Treatment of 6-month-old mice with RSG decreased bone mineral density (BMD) at 7 weeks but not at 4 weeks, (10) with similar observations seen with pioglitazone in the rat. (11) In these and other studies, loss of BMD appeared to result from a reduction in osteoblast number and/or activity, leading to changes in bone marrow composition and bone microarchitecture. (10,12,13) These effects on bone formation are supported by in vitro studies in which PPAR-g agonists affected mesenchymal stem cell differentiation into adipocytes, often at the expense of osteoblasts.…”

“…Indeed, in trabecular bone, ovariectomy consistently increased fat tissue and fat marrow volume, an effect exacerbated by treatment with RSG. Interestingly, it has been recently reported that concomitant treatment with fenofibrate, a PPAR‐α‐agonist, can attenuate the negative effects of pioglitazone, a PPAR‐γ‐agonist …”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…These effects have been reversible in certain studies with discontinuation of treatment. Interestingly, when pioglitazone treatment has been combined with fenofibrate (a PPARα agonist) administration, the negative effects on bone were either unaffected or attenuated …”

Acute Effect of Metformin on Postprandial Hypertriglyceridemia through Delayed Gastric Emptying

“…It has been reported that combination therapy of fenofibrate with metformin reduced TG to a greater extent than fenofibrate monotherapy [13]. In contrast, pioglitazone had no additional TG-lowering effect when combined with fenofibrate [14]. These reports suggest that metformin may reduce plasma TG by mechanisms independent of improved insulin sensitivity.…”