Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes

Abstract

Accumulation of advanced glycation end‐products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non‐fluorescent AGEs. We examined associations of carboxy‐methyl‐lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non‐diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non‐diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24–1.79 per 1‐SD increase in log CML) but not in non‐diabetes (HR 1.03; 95% CI, 0.94–1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin‐C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).

Role of Advanced Glycation End-Products and Oxidative Stress in Type-2-Diabetes-Induced Bone Fragility and Implications on Fracture Risk Stratification

“…As a surrogate of skeletal AGEs, levels of urinary ad serum pentosidine or carboxy-methyl-lysine (a nonfluorescent AGE that accumulates at much higher levels in bone than pentosidine with aging and in diabetes), as well as skin autofluorescence, have been considered in clinical observational studies of large patient cohorts. Of interest, increasing levels of pentosidine (measured in serum or urine) or carboxy-methyl-lysine have been both associated with a higher risk of fractures in T2D patients [ 39 , 40 , 41 , 42 ]. In the largest of these studies, performed in the Health, Aging, and Body Composition prospective cohort of older adults, serum carboxy-methyl-lysine levels were remarkably higher in T2D than non-diabetic patients and were significantly associated with a higher risk of incident clinical fracture only in T2D cases (HR 1.49; 95%CIs, 1.24–1.79, per 1-SD increase in log carboxy-methyl-lysine) [ 42 ].…”

“…Of interest, increasing levels of pentosidine (measured in serum or urine) or carboxy-methyl-lysine have been both associated with a higher risk of fractures in T2D patients [ 39 , 40 , 41 , 42 ]. In the largest of these studies, performed in the Health, Aging, and Body Composition prospective cohort of older adults, serum carboxy-methyl-lysine levels were remarkably higher in T2D than non-diabetic patients and were significantly associated with a higher risk of incident clinical fracture only in T2D cases (HR 1.49; 95%CIs, 1.24–1.79, per 1-SD increase in log carboxy-methyl-lysine) [ 42 ]. Likewise, in a group of postmenopausal women with T2D, the accumulation of AGEs, indirectly assessed with skin autofluorescence, was associated with a decrease in bone material strength index, measured by reference point indentation [ 43 ].…”

Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes

“…Increased urinary excretion of pentosidine was reported to be associated with increased fracture risk in diabetic older subjects ( Schwartz et al, 2009 ). Serum carboxy-methyl-lysine (CML) was shown to be higher in T2DM compared to non-diabetic subjects and associated with incident clinical fracture in elderly diabetics ( Dhaliwal et al, 2021 ). Increased AGEs in skin in post-menopausal women with T2DM was demonstrated by a non-invasive measure of skin autofluorescence (SAF) and was found to be inversely correlated with bone material strength index determined by microindentation ( Furst et al, 2016 ).…”

Techniques for advanced glycation end product measurements for diabetic bone disease: pitfalls and future directions

“…The measurement of circulating CML levels as a biomarker of fracture risk in population-based studies still remains rare. Studies examining circulating levels of CML as a biomarker of hip and diabetic fracture risk – performed by Barzilay et al [55] and Dhaliwal et al [56 ▪▪ ] – revealed that the hazard ratio of hip and diabetic fracture risk increased with increasing CML levels, even after adjustment for risk factors associated with these conditions. Other clinical investigations regarding the contribution of bone, serum, or urine AGEs to fracture risk in diabetes have primarily examined pentosidine, a naturally fluorescent AGE.…”

“…CML is of considerable importance to various oxidative stress-related diseases as in-vivo formation of this AGE is also connected with cellular oxidative/carbonyl metabolism [11,12,13 ▪ ]. This nonfluorescent AGE has been shown to accumulate at high levels in human bone [19] and correlate with bone fracture properties [14,15], hip [55] and diabetic fractures [56 ▪▪ ]. Thomas et al [19] determined that CML in bone is 40–100 times greater than pentosidine, the current most commonly used marker of AGEs in bone.…”