Insights into the Effects of Type 2 Diabetes on Bone Health

Abstract: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.