Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

Abstract

Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant's grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08-2.35; p = .02); OR 1.30 (95% CI, 0.89-1.97; p = .20), and OR 1.40 (95% CI, 0.95-2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08-2.64; p = .02), OR 1.74(95% CI, 1.11-2.71; p = .01), and OR 1.73 (95% CI, 1.12-2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04-2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18-2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings.

A Prospective Analysis of Skin and Fingertip Advanced Glycation End-Product Devices in Healthy Volunteers

“…As the excitation light source, the AGE reader utilizes ultraviolet A (UVA) with a peak wavelength at 370 nm that illuminates 4 cm 2 of skin. In general, emission light with a wavelength of 420–600 nm and reflected excitation light of 300–420 nm from the skin are measured and the ratio of excitation light to emitted light is calculated and reported in arbitrary numerical units (AU) [ 2 , 5 , 7 ].…”

“…The heterogeneous group of advanced glycation end products (AGEs) are formed as a result of non-enzymatic attachment of glucose to proteins such as type I collagen, lipids, or nucleic acids through Maillard’s reaction [ 1 , 2 , 3 , 4 ]. Tissues undergo unfavorable structural and functional modifications when AGEs accumulate, and subsequent binding to the receptor for advanced glycation end products (RAGE) occurs [ 3 , 5 ].…”

“…Studies suggest that extracellular matrices made out of long-living proteins such as skeletal muscles, are highly vulnerable to AGE modifications, muscle strength, and muscle mass [ 9 , 10 , 11 , 12 ]. Additionally, cross-sectional studies have demonstrated a destructive effect of AGEs on bone properties and reduced bone material strength index (BMSi), which are potential measures of bone quality [ 2 , 3 , 5 , 13 , 14 ]. However, the role of AGEs in bone metabolism or osteoporosis is not completely understood [ 2 ].…”

“…Additionally, cross-sectional studies have demonstrated a destructive effect of AGEs on bone properties and reduced bone material strength index (BMSi), which are potential measures of bone quality [ 2 , 3 , 5 , 13 , 14 ]. However, the role of AGEs in bone metabolism or osteoporosis is not completely understood [ 2 ].…”

Type 2 Diabetes Mellitus and Vertebral Fracture Risk

“…Levels of advanced glycation end products (AGEs) have been found to be increased in T2DM and might contribute to increased bone fragility through impaired enzymatic cross-linking and/or an increase in non-enzymatic cross-links in bone collagen [41]. In a recent study embedded in the Rotterdam Study, skin autofluorescence (SAF), a non-invasive biomarker of AGEs, was associated positively with prevalent vertebral fractures [42]. In cortical bone, compromised bone remodelling likely leads to accumulation of micro cracks, resulting in increased non-vertebral fracture risk [38][39][40].…”