Clinical Review

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

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AGE formation appears to be central to many pathologic processes in diabetes, so it is a logical therapeutic target, particularly for pathologic processes at the vascular tissue level. Aminoguanidine is an anti-AGE agent that was initially used to prevent diabetic retinopathy, but it has also been shown to prevent general vascular complications in diabetic animal models. The terminal amino residue in the compound specifically binds glucose-derived reactive intermediates and prevents cross-linking, which renders them inactive. Disrupting those cross-links is another treatment strategy. N-phenacylthiazolium bromide and 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711 or alagebrium) are compounds that have been shown to break cross-links in a diabetic rat model.16

Another tactic for reducing vascular pathology involves mitigating superoxide radicals, as these radicals are generated from the glycolytic intermediates in hyperglycemic states. It has been reasoned that, if the concentration of these intermediates can be decreased, there would be less substrate available for the pathways that lead to radical formation. One approach is to use transketolase, an enzyme that shunts intermediates to pathways that do not produce superoxide radicals. In the treatment of patients with diabetic retinopathy, early data appear promising with benfotiamine, a thiamine derivative, which upregulates transketolase 250%. An additional tactic involves catalytic antioxidants—namely, superoxide dismutase/catalase mimetic, which has been shown to reduce hyperglycemia-induced superoxides. These interventions are appealing because of their nonstoichiometric reactions, which render them potentially more potent antioxidants.26

Potential neurologic interventions include recombinant human nerve growth factor, neurotrophic factors, and gene therapy, all directed toward preventing or regenerating neuropathic tissues in patients with diabetes. Most of these interventions, however, remain theoretical. Few trials have demonstrated clinically significant improvement. In patients with T1DM, however, the absence of circulating C-peptide is thought to contribute to diabetic neuropathy. Results of trials with subcutaneous C-peptide treatment suggest improvement in both sural sensory and vibration perception after only 12 weeks.40 These novel treatments further emphasize the potential for intervention at the tissue, cellular, and molecular levels.


Whereas most fractures are uncomplicated in healthy patients, they can have devastating consequences in patients with diabetes. In this review, we have highlighted many of the pathologic processes that can influence outcomes of fractures in patients with diabetes. These problems will become more common as the population ages, age-related risks for osteoporosis and fragility fracture increase, and diabetes becomes nearly epidemic in our increasingly obese, sedentary society. Although some progress has been made, a more thorough intervention strategy is needed to improve both bone and soft-tissue outcomes of fractures in patients with diabetes.

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