Rev Osteoporos Metab Miner. 2012; 4 (1): 5-6
Most of the epidemiological studies carried out in patients with type 2 diabetes have shown an increase in bone mineral density1 in spite of which there is an increased risk of fracture of 1.5 for hip fracture, proximal humerus and distal radius2. In terms of the risk of vertebral fracture, the results are less uniform, although most of the studies also show an increase in risk3,4.
Hyperglycemia exerts both direct effects on bone cells, especially the osteoblasts, and indirect effects through the formation of products deriving from glycation.
In vitro, high levels of glycemia stimulate or inhibit osteoblast proliferation as a function of the phase of the cell cycle. The differentiation of these cells is especially suppressed, which is shown in the decrease in the production of osteocalcin, of the deposit of calcium and in bone mineralisation. The expression of the receptors for parathormone and vitamin D are also reduced. In addition, the hyperglycemia affects the functionality of the osteoblasts through the induction of an osmotic response mediated by its sensitivity to the acid medium induced by the lactate5.
The high levels of AGEs and their accumulation play an essential role in the development of the complications associated with diabetes7. High levels of AGEs have been found in various tissues and have been related to low turnover of tissue in tendons, skin, amyloid plaques and cartilage. Their accumulation in the bone reduces the activity of the osteoblasts by the bonding of the AGE products with specific receptors (RAGE), alters osteoclastogenesis and reduces mineralisation. The collagen in the extracellular matrix modified by the AGEs is more difficult to eliminate by the hydrolytic enzymes, which increases bone fragility. The presence of AGEs also interferes in the interaction between the bone cells and the extracellular matrix5. Therefore, excess glycation may affect the properties of the bone, and this effect is evident above all in the cortex due to the accumulation of AGEs such as pentosidine in the parts of the skeleton with less rotation8.
In addition, acute and chronic hyperglycemia has been shown to suppress the expression of the genes associated with the maturation of the osteoblasts in rats with diabetes5. As a counter to this, Miranda Diaz et al. in an article published in this number have demonstrated that the gene expression of RANKL, RANKL/OPG ratio and Runx2 are found to be altered in cultures of osteoblasts from diabetic patients with hip fracture, this being increased9. The authors postulate that these findings would mean a higher number of less differentiated osteoblasts with a higher expression of RANKL, which means that there would be a greater activation of osteoclastogenesis, a higher rate of remodelling and, therefore, a negative influence on bone resistance. However, histomorphometric studies in patients with diabetes have shown a low recruitment of osteoblasts along with a reduction in the rate of mineral apposition10.
In short, to avoid glycation by controlling of hyperglycemia and the consequent reduction in AGEs should be the most effective tool to delay and minimise bone-related complications in diabetic patients.
1. Janghorbani M, van Dam RM, Willet WC, Hu FB. Systematic review of Type 1 and Type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 2007;166:495-505.
2. Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Scheriner PJ, et al. Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 2001;86:32-8.
3. Vestegaard P, Rejnmark L, Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetolologia 2005;48:1292-9.
4. Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T. Diabetic patients have an increased risk of vertebral fractures independent of BMD or diabetic complications. J Bone Miner Res 2009;24:702-9.
5. Blakytny R, Spraul M, Jude EB. Review: The diabetic bone: a cellular and a molecular perspective. Int J Low Extrem Wounds 2011;10:16-32.
6. Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med 1995;46:223-234.
7. Morales S, García-Salcedo JA, Muñoz-Torres M. Pentosidine: a new biomarker in diabetes mellitus complications. Med Clin (Barc) 2011;136:298-302.
8. Odetti P, Rossi S, Monacelli F, Poggi A, Cirnigliaro M, Federici M, et al. Advanced glycation end products and bone loss during aging. Ann NY Acad Sci 2005;1043:710-7.
9. Miranda Díaz C, Giner García M, Montoya García MJ, Vázquez Gámez MA, Moruno R, Miranda García MJ, et al. Estudio génico (OPG, RANKL, Runx2 y receptores AGE) en cultivos de osteoblastos humanos de pacientes con diabetes mellitus tipo 2 y fractura de cadera. Influencia de los niveles de glucosa y AGEs. Rev Osteoporos Metab Miner 2011 [Epub ahead of print].
10. Goodman WG, Hori MT. Diminished bone formation in experimental diabetes. Relationship to osteoid maturation and mineralization. Diabetes 1984;33:825-31.