Rosiglitazone disrupts endosteal bone formation during distraction osteogenesis by local adipocytic infiltration.

Rosiglitazone (Rosi) is a drug in the thiazolidinedione class for treatment of type 2 diabetes mellitus (T2DM), which binds and activates PPARγ nuclear receptor in fat cells, sensitizing them to insulin. Despite proven antidiabetic efficacy, Rosi therapy may be associated with trabecular bone loss and an increased risk of fractures. To examine the potential side effects of Rosi treatment on bone formation, we delivered Rosi to mice using a combined model of distraction osteogenesis (DO) and type 2 diabetes mellitus (T2DM). DO provides a unique method to isolate the sequence of intramembranous bone formation, an important component of both fracture healing and bone homeostasis. Four groups of n=6 mice were used to compare the effects of Rosi on bone formation and cellular composition in both diabetic (Avy/a strain) and non-diabetic mice (a/a strain). New bone formation was examined by high resolution radiographs, micro-computed tomography, and histology. Precursor cells in the distraction gap were quantitated using immunohistochemical stains for proliferating cell nuclear antigen. Committed osteoblasts and adipocytes in the gap were identified and quantitated by immunostaining for osteocalcin and FABP4/aP2, respectively. The diabetic model developed obesity, hyperglycemia, hyperinsulinemia and insulin resistance, while the control littermates remained lean, normoglycemic and insulin sensitive. Rosi treatment decreased levels of non-fasted glucose and insulin and improved insulin sensitivity in the A(vy)/a mice, but had no effect in a/a mice, indicating antidiabetic efficacy of Rosi at the tested dose. Despite the diabetic, obese mice having twice the number of fat cells in their marrow than the non-diabetic mice, bone formation using DO was not adversely affected by the diabetes itself. However, Rosi treatment significantly diminished intramembranous endosteal bone formation, while increasing adipogenesis in and adjacent to the distraction gap up to 3.5- to 3.8-fold in both diabetic and non-diabetic models. This effect was independent of the anti-diabetic therapeutic response. These results raise the question of whether osteoblast precursors are inhibited in their development or actually converted to adipocytic phenotypes, possibly via marrow fat PPARγ nuclear receptor.