Advanced glycation end products and esRAGE are associated with bone turnover and incidence of hip fracture in older men

Background: Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover. Aims: We tested the hypothesis that circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and predict fracture risk in older men. Participants: 3,384 community-dwelling men aged 70-89 years. Methods: Collagen type I C-terminal cross-linked telopeptide (CTX), N-terminal propeptide of type I collagen (P1NP), and total osteocalcin (TOC) were assayed using immunoassay, and undercarboxylated osteocalcin (ucOC) following hydroxyapatite binding. Plasma N-carboxymethyllisine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Incident hip fractures were ascertained. Results: Median age 76.3 years (interquartile range, 74.2-79.1). 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 (all p>0.05). CML was positively associated with fasting glucose (r=0.06, p<0.001) and esRAGE was inversely associated (r=-0.08, p=0.045). EsRAGE was positively associated with bone formation (P1NP r=0.17, p<0.001; ucOC r=0.11, p=0.008; total OC 0.16, p<0.001). Incident hip fractures occurred in 106 men during follow-up. Men with CML in the third quartile of values had reduced incidence of hip fracture compared to men in the lowest quartile (HR 0.49, 95% CI 0.24-0.99, P=0.045). Conclusions: Glycaemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men while CML predicts incidence of hip fracture.