Diabetes and Its Effect on Bone and Fracture Healing

Abstract

Diabetes mellitus is a metabolic disorder that increases fracture risk, interferes with bone formation, and impairs fracture healing. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) both increase fracture risk and have several common features that affect the bone including hyperglycemia and increased advanced glycation end product (AGE) formation, reactive oxygen species (ROS) generation, and inflammation. These factors affect both osteoblasts and osteoclasts leading to increased osteoclasts and reduced numbers of osteoblasts and bone formation. In addition to fracture healing, T1DM and T2DM impair bone formation under conditions of perturbation such as bacteria-induced periodontal bone loss by increasing osteoblast apoptosis and reducing expression of factors that stimulate osteoblasts such as BMPs and growth factors.

Figure1. Mechanisms of diabetes-increased osteoclastogenesis

Diabetes leads to hyperglycemia, enhanced and prolonged inflammation, formation of AGEs and generation of ROS. This dysregulation as well as reduced insulin signaling may lead to increased osteoclast formation, particularly when bone is challenged by wounding, bacteria induced inflammation or other events that disrupt homeostasis. This dysregulation may lead to an increased RANKL/OPG ratio or affect osteoblasts through other mechanisms to increase bone resorption.

Figure2

Mechanisms of diabetes-reduced bone formation. Diabetes leads to hyperglycemia, enhanced and prolonged inflammation, formation of AGEs and generation of ROS. This dysregulation as well as reduced insulin signaling may adversely affect osteoblasts and reduce bone formation particularly when bone is challenged by wounding, bacteria induced inflammation or other events that disrupt homeostasis. The effect of dysregulation may lead to a reduction in BMPs, Runx2 or Fra1, an increase in PPARγ or other mechanisms to reduce bone formation or bone quality.