Effects of Rosiglitazone vs Metformin on Circulating Osteoclast and Osteogenic Precursor Cells in Postmenopausal Women with Type 2 Diabetes Mellitus

Context: Thiazolidinediones are associated with increased fractures in type 2 diabetes mellitus (T2D). One explanation is that activation of peroxisome proliferator-activated receptor-gamma expression alters bone remodeling cells. Objective: To investigate whether osteoclast and osteogenic precursor cells are altered by rosiglitazone (RSG) treatment in T2D as compared to metformin (MET) treatment. Design: A randomized controlled trial of RSG or MET for 52 weeks, followed by 24 weeks of MET. Setting: Data were generated at a tertiary care center. Patients: Seventy-three T2D postmenopausal women participated. Main Outcome Measures: Peripheral blood mononuclear cells were isolated and cultured with receptor activator of nuclear factor kappa B ligand and stained for tartrate-resistant acid phosphatase to measure circulating osteoclast precursors. Peripheral blood mononuclear cells were also characterized for osteogenic, endothelial, and calcification markers by flow cytometry with the ligands osteocalcin (OCN), CD34, and CD 146. Results: Tartrate-resistant acid phosphatase-positive cells increased between weeks 0 and 52 (RSG, 2.9 +/- 2 to 14.0 +/- 3 U/L, P = .001; MET, 3.3 +/- 2 to 16.7 +/- 2 U/L, P = .001), increasing further in the RSG group after changing to MET (to 26.5 +/- 5 U/L, P = .05 vs wk 52). With RSG, OCN+ cells with CD34 but without CD146 fell from weeks 0 to 52 (20.1 +/- 1% to 15.5 +/- 2%; P = .03), remaining stable through week 76. The OCN + cells lacking both CD34 and CD146 increased from weeks 0 to 52 (67.3 +/- 2 to 74.4 +/- 2%; P = .02), but returned to baseline after switching to MET. Conclusion: In postmenopausal women with T2D, circulating osteoclast precursor cells increase with both RSG and MET, and increase further when switching from RSG to MET. Subpopulations of cells that may be involved in the osteogenic lineage pathway are also altered with RSG. Further work is necessary to elucidate how these changes may relate to fracture risk.