Advanced Glycation End Products and esRAGE Predict Hip Fractures in Older Men

hip fracture
hip fracture
Investigators assess whether circulating advanced glycation end products and esRAGE were associated with bone turnover and risk for fracture.

Circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) are associated with glycemia in older men, according to a study published in the Journal of Clinical Endocrinology & Metabolism. In addition, AGEs and esRAGE differentially modulate bone turnover, and active levels of plasma N-carboxymethyllisine predict risk for hip fracture in this population.

To evaluate the pathogenic effects of circulating AGEs and esRAGE on bone in a population of older men, study investigators examined specific associations between plasma N-carboxymethyllisine (a prominent AGE), methylglyoxal and glyoxal (intermediate glycation products), and esRAGE with diabetes, bone turnover, and risk for hip fracture.

Researchers recruited 3384 men aged 70-89 years from the Health in Men Study, a community cohort from Perth, Western Australia, and identified their incidence of hip fracture via the Western Australian Data Linkage System. They used immunoassays to measure the activity of bone turnover markers, including collagen type I C-terminal cross-linked telopeptide, N-terminal propeptide of type I collagen (P1NP), undercarboxylated osteocalcin (ucOC), and total osteocalcin (OC), as well as glycation markers, including plasma N-carboxymethyllisine and esRAGE. Intermediate products of glycation, methylglyoxal and glyoxal, were assayed using mass spectrometry.

Plasma N-carboxymethyllisine concentrations were measured in a subset of 3011 men, methygloxal and glyoxal were measured in 766 men, and esRAGE was measured in 748 men. In total, 502 men had diabetes; however, they showed no significant difference in circulating AGEs and esRAGE values.

After adjusting for possible confounders, plasma N-carboxymethyllisine was positively associated with fasting serum glucose (r=0.06, P <.001). EsRAGE was inversely associated with fasting serum glucose (r=–0.08, P <.0045) but positively associated with bone turnover, especially bone formation (P1NP r=0.17, P <.001; ucOC r=0.11, P=.008; total OC 0.16, P <.001).  The association between esRAGE and bone turnover markers in men with diabetes was stronger compared with men without diabetes.  No associations were observed for glyoxal and methylglyoxal assays. Of 3011 men with plasma N-carboxymethyllisine, incident hip fractures were reported by 106 men during follow-up. Fracture risk was stratified according to quartiles of plasma N-carboymehtyllisine; men in the third quartile showed the lowest cumulative risk and had fewer hip fractures compared with men in the lowest quartile (hazard ratio 0.49, 95% CI, 0.24-0.99; P =.045).

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Limitations of the study were analyzing a single blood sample at baseline, lack of serial data, and that only a random subset of patients was assessed using assays. Another limitation was including a cohort of only older men; therefore, the results may not be generalized to a younger population or women. Hemoglobin A1c was not analyzed, and fasting glucose levels may be a less accurate maker of glycemia and disease severity. Finally, the nature of an observational study limits inferences of causation.

In older men, glycemia is correlated positively with plasma N-carboxymethyllisine concentrations and inversely with AGE decoy receptors, or esRAGE. In addition, esRAGE was independently associated with markers of bone formation, while a non-linear correlation was observed between plasma N-carboxymethyllisine and incidence of hip fracture, indicating that AGEs affect bone metabolism in a way that increases bone fragility.

This study was funded by the Sylvia and Charles Viertel Charitable Foundation and the National Heart Foundation of Australia. Please refer to reference for a complete list of authors’ disclosures.


Lamb LS, Alfonso H, Norman PE, et al. Advanced glycation end products and esRAGE are associated with bone turnover and incidence of hip fracture in older men [published online August 20, 2018]. J Clin Endocrinol Metab. doi: 10.1210/jc.2018-00674