Clinical Review

The Pathobiology of Diabetes Mellitus in Bone Metabolism, Fracture Healing, and Complications

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Increased osteoblast apoptosis has been associated with diabetes through advanced glycation end-products (AGEs), which modify the structure and function of bioactive compounds through AGE receptors that cross-link and bond to amino groups on bioactive molecules.16 It has been reported that AGEs interfere with osteoblast development and collagen and osteocalcin production.17 A common AGE, carboxymethyl lysine-modified collagen, has been associated with a significant increase in apoptosis through the mitogen-activated protein kinase (MAPK) pathway. Although most of the literature suggests that osteoblast apoptosis is activated by hypoxia, nitric oxide, or integrins, these factors all have the MAPK pathway in common.18

Osteoclasts are also influenced by diabetes. Recent work in T1DM demonstrated that osteoclasts are hyperactive and more sensitive to receptor activator of nuclear factor kB ligand (RANKL) compared with osteoclasts from the population without diabetes. It is also known that osteoclasts are under the control of immunologic mediators like lipopolysaccharide (LPS), a surface component of gram-negative bacteria, and various other proinflammatory cytokines. In patients with diabetes, osteoclasts react differently to LPS and other proinflammatory cytokines, at times with opposing effects, including secretion of RANKL to stimulate resorption by the osteoclast, and precursors preventing progression into osteoclasts. In healthy people, high LPS levels not only prevent precursors from producing more osteoclasts, but promote them to mature into immune-like cells that actually phagocytose bacteria. So, in a state of infection, precursors shift from bone-resorbing osteoclasts to protective immune cells. This phenomenon does not occur in patients with diabetes, in whom the osteoclasts instead resorb more bone and stimulate inflammation by releasing cytokines.19

Interestingly, osteoblasts and osteoclasts are also affected by medications commonly used to treat diabetes. Thiazolidinediones are a class of sensitizers often used to treat patients with T2DM. Thiazolidinediones, particularly rosiglitazone, have been associated with increased bone loss primarily caused by increased bone resorption by osteoclasts.20 In addition, some investigators think that thiazolidinediones induce osteocyte apoptosis, contributing to impaired bone growth.8 Metformin, an insulin sensitizer, appears to have a positive effect on bone growth and fracture risk by enhancing osteoblastogenesis and inhibiting osteoclastogenesis, leading to a protective effect on bone.8

Peripheral neuropathy, which is often associated with diabetes, appears to play a major role in fracture-healing complications, even more so than hyperglycemia does. A recent clinical paper found that patients with diabetic neuropathy had a 44% risk of foot and ankle fracture-healing complications.21 Regardless of the risk, the pathogenesis of diabetic neuropathy can be caused by several mechanisms. Neural tissue does not require insulin for glucose uptake; therefore, in a state of hyperglycemia, aldose reductase shunts glucose to sorbitol while using protective glutathione and generating reactive oxygen species. This oxidative stress results in nerve damage or neuropathy. Microangiopathy, which we discuss in more detail later, also contributes to the development of neuropathy, through compromised flow of blood to neural tissue.22 Another mechanism contributing to diabetic neuropathy involves PKC, which is activated by 1,2-diacylglycerol in the presence of glucose, leading to vascular changes that restrict the flow of blood to peripheral nerves.23 Finally, AGEs may also participate by altering nerve function after binding to neural tissue.

Charcot neuroarthropathy is a complication associated with diabetes, particularly after injury in which chronic inflammation results in damage to the joint through fracture, dislocation, and osteolytic bony destruction. The pathophysiology is attributed to repeated microtrauma caused by loss of protective sensibility and hyperemia caused by dysregulation.24 Sympathetic and sensory nerve fibers are associated with bone, but a few serve as mechanoreceptors and nociceptors, which can activate substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide—neuropeptides all thought to be involved in the inflammatory process, and in the activation of osteoblasts and osteoclasts. In diabetic neuropathy, many of these neuropeptides show a reduced regulation response, which can lead to impaired fracture healing. In particular, osteoclast activity is upregulated, and consequently bone resorption is increased. In addition to the neuropeptides mentioned, RANKL is one mechanism by which this upregulation occurs.25

It is clear that bone metabolism and fracture healing are complex processes. In the patient with diabetes, many factors are affected, including BMD, bone microarchitecture and bone growth, cartilage resorption during callus formation, osteoblast and osteoclast activation through both altered responses to cell signals and pharmacologic interactions, and, finally, peripheral neuropathy. Given the complex interactions described, it is likely that these factors in combination, as well as those yet undiscovered, negatively affect fracture healing.

Wound Healing and Vasculopathy in Diabetes

Bone healing and soft-tissue healing depend on many of the same factors. Therefore, interactions between neuropathy and vasculopathy can have a tremendous influence on wound healing in patients with diabetes. The vascular pathology that occurs in diabetes depends in part on the fact that endothelial cells do not require insulin for glucose uptake and therefore are more susceptible to damage by hyperglycemia. As already discussed, shunting of glucose through the polyol pathway with the resultant oxidative stress is partly responsible for angiopathy in diabetes.

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