Diabetes mellitus (DM) affects a significant portion of the world’s people, and the problem is increasing in magnitude as the population ages and becomes more obese.1 An estimated 347 million people have diabetes.1 In the United States, 26 million (roughly 8% of the population) are affected, making DM a major health issue.2 Given the prevalence of diabetes in the general population, it is not surprising that increasing numbers of fracture patients have DM. Unfortunately, for these patients, many relatively simple fractures can have disastrous outcomes. Infections and wound complications occur in disproportionate numbers, healing time is delayed, and risk for nonunion or malunion is substantially higher.3
It is imperative to understand the pathophysiology of DM to appreciate potential interventions and strategies aimed at decreasing complications and improving outcomes of fractures in patients with the disease. In type 1 DM (T1DM), autoimmune destruction of the insulin-secreting β cells in the pancreas results in a complete absence of insulin. Patients with T1DM are dependent on exogenous insulin, and, despite hyperglycemia, most cells in the body are starved for energy. This leads to a catabolic condition, high lipid and protein metabolism, and, in many cases, ketoacidosis. When insulin resistance develops, the β cells are forced to secrete large amounts of insulin; when they fail to keep up, type 2 DM (T2DM) develops. T2DM is often associated with obesity, as excess adipose tissue leads to insulin resistance. Although exogenous insulin may be necessary to treat advanced T2DM, other medications are commonly used to effectively lower blood glucose: Secretagogues (eg, sulfonylureas) facilitate insulin release from β cells, and sensitizers (eg, metformin) increase insulin sensitivity.4,5
The potential morbidity of fractures in patients with DM can be appreciated with the example of ankle fractures. These typically uncomplicated fractures can have very poor outcomes in the setting of DM. In a prospective study of approximately 1500 patients with ankle fractures treated with open reduction and internal fixation, Wukich and colleagues6 found that 9.5% of patients with DM (vs 2.4% of patients without DM) developed surgical site infections. As defined by Jones and colleagues,7 major complications of treating ankle fractures in patients with DM include infection, malunion, nonunion, Charcot arthropathy, and amputation. The authors reported major complications in 31% and 17% of patients with and without DM, respectively. Highlighting the importance of glycemic control, Wukich and colleagues6 found relative risks of 3.8 for infection, 3.4 for noninfectious complications, and 5.0 for revision in complicated (vs uncomplicated) fractures in patients with DM.
Given the magnitude of problems in the treatment of fractures in patients with DM, we focus our review on the pathobiology of diabetes in terms of bone metabolism and fracture healing, wound healing and vasculopathy, infection, and potential new treatment modalities.
Bone Metabolism and Fracture Healing in Diabetes
Insulin appears to play a role in bone metabolism and fracture healing. Therefore, absence of insulin in T1DM and elevated insulin levels associated with T2DM likely influence these metabolic and fracture-healing processes. Insulin has been hypothesized to have an anabolic effect on bone, and in both human and animal models bone mineral density (BMD) is significantly lower in T1DM. Furthermore, BMD in T2DM has been shown to be normal or even elevated.8 Other metabolic effects of insulin on bone metabolism and growth include slower growth rates and lower BMD in pediatric patients with T1DM versus patients without diabetes, and some animal models show bone microarchitecture altered in the absence of insulin (and reversible with insulin supplementation).9 These factors seem to contradict the markedly elevated risk for osteoporotic fracture in patients with T2DM, but the mechanisms responsible for this have not been elucidated.8
In terms of fracture healing, resorption of cartilage during transition to hard callus appears to be influenced by diabetes. It has been hypothesized that the smaller callus observed in diabetic mice may be secondary to upregulation of osteoclasts. Initial callus size appears not to differ between mice with streptozotocin-induced diabetes, which exhibit a complete absence of insulin, and control mice, but levels of osteoclast and osteoclastogenesis mediators were significantly higher in the diabetic mice.10 Some investigators think that the reduction in cartilage callus size in diabetic mice is caused by altered mRNA expression and collagen production.11 Diabetic mice, in addition to showing increased resorption by osteoclasts, demonstrate increased chondrocyte apoptosis, which is thought to activate cartilage resorption events. Exogenous insulin effectively reverses this cartilage loss to baseline levels.12
Osteoblasts are a crucial component of the fracture-healing cascade, and acute and chronic hyperglycemia, the hallmark of diabetes, has a variety of effects on osteoblasts.13 Genes for cell-signal proteins such as osteocalcin, MMP-13, and vascular endothelial growth factor are downregulated in the presence of chronic hyperglycemia, whereas genes for alkaline phosphate are upregulated. Acute hyperglycemia by way of hyperosmolarity is associated with MMP-13 downregulation. Thus, osteoblasts appear to respond to hyperglycemia through 2 different processes: Hyperosmolarity, through osteoblast cell shrinkage, influences the acute response, and hyperglycemia itself, through pathways such as nonenzymatic glycosylation, protein kinase C (PKC) signaling, and the polyol pathway, is the force behind the chronic response.14 The lineage of osteoblasts from mesenchymal stem cells also can be affected by hyperglycemia, with lower growth rates for mesenchymal stem cells and preferential development toward the adipocyte lineage, while the osteoblast and chondrocyte lineages are downregulated.15