Circulating Levels of Carboxy‐Methyl‐Lysine (CML) Are Associated With Hip Fracture Risk: The Cardiovascular Health Study

Advanced glycation end products (AGE) in bone tissue are associated with impaired biomechanical properties and increased fracture risk. Here we examine whether serum levels of the AGE carboxy‐methyl‐lysine (CML) are associated with risk of hip fracture. We followed 3373 participants from the Cardiovascular Health Study (age 78 years; range, 68–102 years; 39.8% male) for a median of 9.22 years (range, 0.01–12.07 years). Rates of incident hip fracture were calculated by quartiles of baseline CML levels, and hazard ratios were adjusted for covariates associated with hip fracture risk. A subcohort of 1315 participants had bone mineral density (BMD) measurement. There were 348 hip fractures during follow‐up, with incidence rates of hip fracture by CML quartiles of 0.94, 1.34, 1.18, and 1.69 per 100 participant‐years. The unadjusted hazard ratio of hip fracture increased with each 1 SD increase (189 ng/mL) of CML level (hazard ratio, 1.27; 95% confidence interval [CI], 1.16–1.40]; p  < 0.001). Sequential adjustment for age, gender, race/ethnicity, body mass index (BMI), smoking, alcohol consumption, prevalent coronary heart disease (CHD), energy expenditure, and estimated glomerular filtration rate (based on cystatin C), moderately attenuated the hazard ratio for fracture (1.17; 95% CI, 1.05–1.31; p  = 0.006). In the cohort with BMD testing, total hip BMD was not significantly associated with CML levels. We conclude that increasing levels of CML are associated with hip fracture risk in older adults, independent of hip BMD. These results implicate AGE in the pathogenesis of hip fractures. © 2014 American Society for Bone and Mineral Research.