Rosiglitazone Decreases Plasma Levels of Osteoprotegerin in a Randomized Clinical Trial with Type 2 Diabetes Patients

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin/placebo or rosiglitazone/placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA1c at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA1c (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA1c improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p = 0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA1c. Alteration in the OPG/RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.