Advanced Glycation Endproduct Accumulation Linked to Decreased Bone Material Strength in Type 2 Diabetes

Commentary by Mishaela Rubin, MD and Matthew Drake, MD, PhD

Increased accumulation of advanced glycation endproducts (AGEs) was linked to impaired bone mineral properties in postmenopausal women with type 2 diabetes, according to a cross-sectional study published online ahead of print in the Journal of Clinical Endocrinology and Metabolism.

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"The findings suggest that skeletal deterioration is yet another diabetic complication and that there may be accumulation of AGEs that impact bone just as in other tissues, which may lead to altered function of bone," said lead author Mishaela Rubin, MD, Associate Professor of Medicine at CUMC, Columbia University College of Physicians and Surgeons, New York, NY. "This may explain why patients with type 2 diabetes are prone to fracturing at normal or increased bone mineral density, because the tissue has been compromised by chronic hyperglycemia and AGEs."

"AGEs accumulate when amino groups on collagen are exposed to extracellular sugars for prolonged time," Dr. Rubin explained. "These irreversible endproducts form nonenzymatic crosslinks in collagen that may decrease bone toughness and impair bone remodeling."

"These findings add to our growing understanding that patients with long-standing and poorly controlled diabetes have worsened bone quality, which predisposes them to increased fracture risk," commented Matthew Drake, MD, PhD, Associate Professor, Mayo Clinic College of Medicine, Rochester, MN.

Study Rationale
Previous studies have shown accumulation of AGEs in some tissues of patients with type 2 diabetes. However, the potential effects of AGE accumulation on bone health in this population was previously unknown.

The present study was designed to resolve whether AGE accumulation determined by skin autofluorescence (SAF) is associated with bone material strength index (BMSi) measured by in vivo reference point indentation (RPI). The study included 16 postmenopausal women with type 2 diabetes and 19 matched controls.

BMSi was significantly lower in the postmenopausal diabetes group than in the control group (63.69 vs. 70.12; P=0.02), even after adjusting for the presence of diabetes-related complications, and was inversely correlated with the duration of type 2 diabetes (r=-0.68, P=0.004).

SAF was considerably higher in the diabetes group than the control group (2.8 vs 2.2; P<0.001). In the diabetes group, increased SAF was significantly associated with reduced BMSi (r=-0.65, P=0.006) and lower bone formation marker procollagen type 1 amino-terminal propeptide (r=-0.63, P=0.01). These associations were not found in the control group. In an age-controlled analysis, SAF was linked to 26% of the variance in BMSi in the diabetes group (P=0.03).

SAF was not significantly correlated with hemoglobin A1C in the diabetes or control group individually, but was correlated with A1C values in the overall group (r=0.53, P<0.001)

These findings confirm a recent study performed at Mayo Clinic by Dr. Drake and colleagues, showing a decrease in bone material strength in patients with type 2 diabetes.

In addition, "the results examining skin AGEs suggest that this noninvasive method may be a simple surrogate for estimating the accumulation of AGEs that occur in bone tissue," Dr. Drake said. "While care providers are used to thinking about the effects of glycemic control/diabetes on organs such as the vasculature, kidneys, peripheral nerves, and eyes, these data add support to our growing understanding that bone should be considered a diabetes target organ as well."

Reference Point Indentation (RPI) May Be A Valuable Tool For Assessing Bone Quality in Diabetes
"RPI is, at present, a research tool about which we continue to learn. Advantages of RPI are that it appears to be very safe and well-tolerated, is inexpensive, is fairly easy to perform, and gives providers rapid quantifiable data," Dr. Drake said. "While it is a potentially valuable tool for future use and provides information, which is different than DXA [dual-energy X-ray absorptiometry], whether it will eventually be integrated into clinical practice for the assessment of skeletal health in patients with diabetes will require additional work, including its assessment in much larger patient populations than those currently described, as well as our gaining a firm understanding of the relationship between RPI measurements and fracture outcomes," Dr. Drake continued.

"Further longitudinal research is first needed to determine whether RPI predicts fracture risk in type 2 diabetes," Dr. Rubin concluded. "Data also are needed to investigate RPI use in premenopausal women and men."

Good Glycemic Control May Maintain Bone Strength
"The findings suggest that good glycemic control, which would be expected to be associated with lower levels of AGEs, is of paramount importance for maintaining bone strength in patients with diabetes," Dr. Drake told EndocrineWeb. "It is important to note, however, that the described results are from a fairly small patient population, do not include any longitudinal data to assess for changes in bone material strength over time related to glycemic control, and do not include longitudinal fracture data. As such, it would be fair to say that these results support the importance of good glycemic control for maintaining bone strength, but must be followed by other studies, which include these additional endpoints prior to drawing any definitive conclusions."      

May 20, 2016

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