The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice

Abstract

To explore the skeletal effects and the potential underlying mechanisms of treatment with two thiazolidinediones (rosiglitazone and pioglitazone) or metformin in insulin-resistant mice, 24 female, 12-week-old C57BL6J ob/ob mice were evaluated according to the following treatment groups for 6 weeks: placebo group, pioglitazone group (Pio), rosiglitazone group (Rosi), and metformin group (Met). Bone mineral density (BMD), bone microarchitecture, bone histomorphometry, and expression of three phenotype-specific gene markers, including bone morphogenetic protein 2 (Bmp2), runt-related transcription factor 2 (Runx2), and fatty acid-binding protein 4 (Fabp4), were compared across the four groups. At the femur, the Met group had the highest BMD (0.084 ± 0.001 g/cm(2)) and trabecular bone volume/total volume (0.644 ± 0.018 %) and the lowest trabecular spacing (Tb.Sp.) (0.143 ± 0.008 μm), whereas the Rosi group had lower BMD (0.076 ± 0.003 g/cm(2)) and a relatively higher degree of Tb.Sp. (0.173 ± 0.024 μm). A histomorphometric analysis revealed that in the Rosi group the number of adipocytes was fourfold higher than in the placebo group and fivefold higher than in the Met group, whereas the highest osteoid width and mineral apposition rate were found in the Met group (49.88 ± 48.53 μm and 4.46 ± 1.72 μm/day). Furthermore, the Rosi group displayed the highest level of Fabp4 gene expression, which was accompanied by normal expression levels of Bmp2 and Runx2. Seemingly, metformin is a bone-friendly antidiabetic drug. Rosiglitazone had adverse effects on the skeleton at the trabecular bone even in insulin-resistant mice, whereas no evidence of adverse effects was found for pioglitazone.