Skeletal fragility in patients with type 2 diabetes is a growing public health issue. The prevalence of diabetes is increasing rapidly, and diabetics have three times greater fracture risk compared to non-diabetics. The causes of diabetic skeletal fragility are not well established, which makes it difficult for clinicians to make decisions regarding fracture prevention in this population. Numerous micro-scale changes may contribute to skeletal health issues in these patients. For instance, changes in bone matrix composition due to accumulation of non-enzymatic chemical crosslinks can lead to poor bone quality and in turn deteriorate bone’s mechanical integrity. These crosslinks can also lead to an increase in the formation of micro-scale damage within bone. Further, some patients have altered bone microarchitecture that could contribute to their increased fracture risk, and these microarchitectural changes may result from altered bone cell behavior. Thus, we aim to investigate the biomolecular and cellular mechanisms of skeletal fragility in diabetes and other major clinical conditions. The ultimate goal of our research is to help improve diagnostic methods for fracture risk assessment and clinical management of patients at risk for fracture.