In this study, researchers assessed whether different insulin regimens, metformin, and rosiglitazone influence bone metabolism. They explored if the concentration of metformin and rosiglitazone in blood or improved glycaemic control altered bone turnover

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 hyperglycemia, insulinopenia, and antidiabetic drugs.

In vitro, hyperglycaemia promotes adipogenesis rather than osteogenesis, impairs osteoblast growth, increases osteoblast apoptosis and inhibits osteoclastogenesis.

Insulin and insulin receptor signalling stimulate osteoblast proliferation and differentiation in human osteoblast-like cells, whereas insulin resistance in bone impairs bone formation and resorption in mice. The sensitivity of osteoblasts and osteoclasts to insulin or hyperglycaemia from individuals with T2D is undetermined.

The 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).

Measurement of bone turnover markers

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 analyzed in mixed-effects models that included adjustments for age, gender, BMI, renal function and repeated measures of HbA1c.

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 the lower bone formation (PINP).

Following a minor decline in CTX but not PINP, corresponding in time to the insulin titration period, both BTMs increased in the study population and remained significantly higher by the end of the study.

Neither metformin nor rosiglitazone plasma concentrations were associated with BTMs. HbA1c was inversely associated with CTX but not P1NP. The choice of insulin treatment is not influencing BTMs, metformin treatment may decrease BTMs, and improvement of glycaemic control may influence bone resorption activity.