Background: Fracture risk is increased in individuals with type 2 diabetes (T2D). The pathophysiological mechanisms accentuating fracture risk in T2D are convoluted, incorporating factors such as hyperglycaemia, insulinopenia, and antidiabetic drugs. The objectives of this study were to assess whether different insulin regimens, metformin and rosiglitazone influence bone metabolism. We explored if the concentration of metformin and rosiglitazone in blood or improved glycaemic control altered bone turnover. Methods: Two-year clinical trial designed to investigate effects of antidiabetic treatment in 371 T2D patients. Participants were randomized to short or long-acting human insulin (non-blinded) and then further randomized to metformin + placebo, rosiglitazone + placebo, metformin + rosiglitazone or placebo + placebo (blinded). Fasting bone turnover markers (BTM) representing bone resorption (CTX) and formation (PINP) including HbA1c were measured at baseline and after 3, 12 and 24 months. Trough steady-state plasma concentrations of metformin and rosiglitazone were measured after 3, 6 and 9 months of treatment. Associations between treatments and BTMs during the follow-up of the trial were analysed in mixed-effects models that included adjustments for age, gender, BMI, renal function and repeated measures of HbA1c. Results: BTMs increased from baseline to month 12 and remained higher at month 24, with CTX and PINP increasing 28.5% and 23.0% (all: p < 0.001), respectively. Allocation of insulin regimens was not associated with different levels of BTMs. Metformin and metformin + rosiglitazone but not rosiglitazone alone were associated with lower bone formation (PINP). Neither metformin nor rosiglitazone plasma concentrations was associated with BTMs. HbA1c was inversely associated with CTX but not P1NP. Conclusions: The choice of insulin treatment is not influencing BTMs, metformin treatment may decrease BTMs, and improvement of glycaemic control may influence bone resorption activity.