Background: Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover. Advanced glycation end products (AGEs) have been associated with vascular complications in people with diabetes.
Aims: We tested the hypothesis that circulating AGEs and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and fracture risk in older men.
Participants: 3,384 community-dwelling men aged 70-89 years.
Methods: Plasma N-carboxymethyllisine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Collagen type I C-terminal cross-linked telopeptide (CTX), N-terminal propeptide of type I collagen (P1NP), undercarboxylated osteocalcin (ucOC) and total osteocalcin (TOC) were assayed using immunoassay. Incident hip fractures were ascertained.
Results: Median age 76.3 years (interquartile range, 74.2-79.1) and BMI 26.3kg/m2 (24.2-28.6). Plasma CML was measured in 3,011 men, methygloxal and glyoxal in 766 men and esRAGE in 748 men. Plasma CML, methylglyoxal, glyoxal and esRAGE were similar in men without and with diabetes (log CML mmol/mol 6.70±1.51 vs 6.75±1.45, p=0.537; methylglyoxal nmol/L 528.0±198.3 vs 539.2±215.6, p=0.583; glyoxal nmol/L722.6±336.5 vs 688.4±317.7, p=0.310; esRAGE pg/mL 1647.8±832.6 vs 1500.6±919.9, p=0.088). Log CML was inversely associated with CTX (r=-0.05, p=0.009) and ucOC (r=-0.04, p=0.025). Methylglyoxal and glyoxal were inversely associated with CTX (r=-0.07, p=0.042; r=-0.07, p=0.046, respectively). EsRAGE was positively associated with all bone turnover markers (CTX r=0.13, p<0.001; P1NP r=0.21, p<0.001; ucOC r=0.18, p<0.001; TOC r=0.15, p<0.001). In men with CML results 106 hip fractures occurred during follow-up. Compared to men the lowest quartile, men with CML in the third quartile had reduced incidence of hip fracture (HR 0.53, 95% CI 0.29-0.95, p=0.033).
Concentrations and activity of circulating AGEs are associated with bone turnover and incidence of hip fracture. Further research is needed to determine whether a causal relationship exists and to investigate the potential for therapeutic interventions.