Advertisement

Hip Fracture Risk Is Strongly Related to Circulating Levels of the Advanced Glycation End Product Carboxy-Methyl Lysine (CML)

  • Joshua Barzilay
  • Petra Bůžková
  • Kenneth J. Mukamal
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)

Abstract

Advanced glycation end products (AGEs) are markers of oxidative stress, the process whereby the body is unable to neutralize the effects of oxygen radicals generated during the process of metabolism. Oxidative stress is believed to underlie (in part) the biological process of aging. In this chapter we describe how one particular AGE – carboxymethyl-lysine (CML) – is related to hip fracture risk in a cohort of over 3,000 older adults (mean age 78 years). Hip fractures are an age-related disorder with a high degree of morbidity and mortality and are costly to national health care systems.

The study found that for every one standard deviation increase in serum CML level the hazard ratio for hip fracture increased 27% (HR 1.27, 95% CI 1.16–1.40; p < 0.001). With adjustment for risk factors strongly associated with osteoporotic fractures (advanced age, low body mass index, white or Asian race, and low bone mineral density), as well as other factors (such as kidney function, alcohol use, and energy consumption), the risk remained significant (HR 1.17, 95% CI 1.05–1.31; p = 0.006).

It is concluded that serum CML levels are strongly associated with hip fracture risk independent of other risk factors for hip fracture. These findings suggest that serum CML levels may be a useful tool for gauging hip fracture risk.

Keywords

Hip fracture Bone quality Carboxymethyl-lysine (CML) Oxidative stress Advanced glycation end products (AGEs) 

List of Abbreviations

AGEs

Advanced glycation end products

BMD

Bone mineral density

BMI

Body mass index

CEL

Nε-carboxyethyl-lysine

CHS

Cardiovascular Health Study

CI

Confidence interval

CML

Carboxymethyl-lysine

DM

Diabetes mellitus

DXA

DEXA

eGFR

Estimated glomerular filtration rate

ELISA

Enzyme-linked immunosorbent assay

HR

Hazard ratio

ICD-9

International Classification of Diseases

IL1

Interleukin 1

IL6

Interleukin 6

IQ

Interquartile

NF kB

Nuclear factor kappa B

RAGE

Receptor for advanced glycation end product

TNF-alpha

Tumor necrosis factor alpha

References

  1. Barzilay JI, Blaum C, Moore T, et al. Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study. Arch Intern Med. 2007;167(7):635–41.CrossRefPubMedGoogle Scholar
  2. Barzilay JI, Bůžková P, Zieman SJ, et al. Circulating levels of carboxy-methyl-lysine (CML) are associated with hip fracture risk: the Cardiovascular Health Study. J Bone Miner Res. 2014;29(5):1061–6.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Boehm BO, Schilling S, Rosinger S, et al. Elevated serum levels of N ϵ-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema. Diabetologia. 2004;47(8):1376–9.CrossRefPubMedGoogle Scholar
  4. Bůžková P, Barzilay JI, Fink HA, et al. Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. J Clin Endocrinol Metab. 2014;99(11):4116–23.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a “glycoxidation-centric” point of view. Nutr Metab Cardiovasc Dis. 2013;23(10):913–9.CrossRefPubMedGoogle Scholar
  6. Compston J. Monitoring osteoporosis treatment. Best Pract Res Clin Rheumatol. 2009;23(6):781–8.CrossRefPubMedGoogle Scholar
  7. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol. 1991;1(3):263–76.CrossRefPubMedGoogle Scholar
  8. Gineyts E, Munoz F, Bertholon C, et al. Urinary levels of pentosidine and the risk of fracture in postmenopausal women: the OFELY study. Osteoporos Int. 2010;21(2):243–50.CrossRefPubMedGoogle Scholar
  9. Health Quality Ontario. Utilization of DXA bone mineral densitometry in Ontario: an evidence-based analysis. Ont Health Technol Assess Ser. 2006;6(20):1–180.Google Scholar
  10. Hein E. Glycation endproducts in osteoporosis – is there a pathophysiologic importance? Clin Chim Acta. 2006;371(1–2):32–6.CrossRefPubMedGoogle Scholar
  11. Holvik K, Gjesdal CG, Tell GS, et al. Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study. Osteoporos Int. 2014;25(11):2545–54.CrossRefPubMedGoogle Scholar
  12. Jomova K, Vondrakova D, Lawson M, et al. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem. 2010;345(1–2):91–104.CrossRefPubMedGoogle Scholar
  13. Jono T, Nagai R, Lin X, et al. N epsilon-(carboxymethyl)lysine and 3-DG-imidazolone are major AGE structures in protein modification by 3-deoxyglucosone. J Biochem (Tokyo). 2004;136(3):351–8.CrossRefGoogle Scholar
  14. Kandarakis SA, Piperi C, Topouzis F, et al. Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases. Prog Retin Eye Res. 2014;42:85–102.CrossRefPubMedGoogle Scholar
  15. Kong Y, Trabucco SE, Zhang H. Oxidative stress, mitochondrial dysfunction and the mitochondria theory of aging. Interdiscip Top Gerontol. 2014;39:86–107.CrossRefPubMedGoogle Scholar
  16. Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507(7492):323–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Li G, Xu J, Li Z. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling. Biochem Biophys Res Commun. 2012;423(4):684–9.CrossRefPubMedGoogle Scholar
  18. Lipscombe LL, Jamal SA, Booth GL, et al. The risk of hip fractures in older individuals with diabetes: a population-based study. Diabetes Care. 2007;30(4):835–41.CrossRefPubMedGoogle Scholar
  19. Loidl-Stahlhofen A, Hannemann K, Spitteler G. Generation of alpha-hydroxyaldehydic compounds in the course of lipid peroxidation. Biochim Biophys Acta. 1994;1213(2):140–8.CrossRefPubMedGoogle Scholar
  20. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312(7041):1254–9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Odetti P, Rossi S, Monacelli F, et al. Advanced glycation end products and bone loss during aging. Ann N Y Acad Sci. 2005;1043:710–7.CrossRefPubMedGoogle Scholar
  22. Online Document. American Diabetes Association. http://www.diabetes.org/diabetes-basics/statistics. Accessed 6 Mar 2015.
  23. Online Document. Centers for Disease Control. http://www.cdc.gov/HomeandRecreationalSafety/Falls/adulthipfx.html. Accessed 6 Mar 2015.
  24. Prasad K, Dhar I. Oxidative stress as a mechanism of added sugar-induced cardiovascular disease. Int J Angiol. 2014;23(4):217–26.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Ramasamy R, Vannucci SJ, Yan SS, et al. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology. 2005;15(7):16R–28R.CrossRefPubMedGoogle Scholar
  26. Reddy S, Bichler J, Wells Knecht KJ, et al. N-epsilon-(carboxymethyl) lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry. 1995;34(34):10872–8.CrossRefPubMedGoogle Scholar
  27. Roncero-Ramos I, Niquet-Léridon C, Strauch C, et al. An advanced glycation end product (AGE)-rich diet promotes Nε-carboxymethyl-lysine accumulation in the cardiac tissue and tendons of rats. J Agric Food Chem. 2014;62(25):6001–6.CrossRefPubMedGoogle Scholar
  28. Saito M, Kida Y, Marumo K. Diabetes, collagen, and bone quality. Curr Osteoporos Rep. 2014;12(2):181–8.CrossRefPubMedGoogle Scholar
  29. Sanguineti R, Puddu A, Mach F, et al. Advanced glycation end products play adverse proinflammatory activities in osteoporosis. Mediators Inflamm. 2014;2014:975872. doi: 10.1155/2014/975872.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Schwartz AV, Garnero P, Hillier TA, et al. Pentosidine and increased fracture risk in older adults with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(7):2380–6.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Shiraki M, Kuroda T, Tanaka S, et al. Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J Bone Miner Metab. 2008;26(1):93–100.CrossRefPubMedGoogle Scholar
  32. Sun LL, Li BL, Xie HL, et al. Associations between the dietary intake of antioxidant nutrients and the risk of hip fracture in elderly Chinese: a case–control study. Br J Nutr. 2014;112(10):1706–14.CrossRefPubMedGoogle Scholar
  33. Tanaka S, Kuroda T, Saito M, et al. Urinary pentosidine improves risk classification using fracture risk assessment. J Bone Miner Res. 2011;26(11):2778–84.CrossRefPubMedGoogle Scholar
  34. Uribarri J, Woodruff S, Goodman S, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010;110(6):911–6.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Vashisth D. Advanced glycation end products and bone fracture. IBMS Bonekey. 2009;6:268–78.CrossRefGoogle Scholar
  36. Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes – a meta-analysis. Osteoporos Int. 2007;18(4):427–44.CrossRefPubMedGoogle Scholar
  37. Vistoli G, de Maddis D, Cipak A, et al. Advanced glycation and lipoxidation end products (AGEs and ALEs): an overview of their mechanism of formation. Free Radic Res. 2013;47 Suppl 1:3–27.CrossRefPubMedGoogle Scholar
  38. Viteri G, Carrard G, Birlouez-Aragón I, et al. Age-dependent protein modifications and declining proteasome activity in the human lens. Arch Biochem Biophys. 2004;427(2):197–203.CrossRefPubMedGoogle Scholar
  39. Weintroub S, Eisenberg D, Tardiman R, et al. Is diabetic osteoporosis due to microangiopathy? Lancet. 1980;ii:983.Google Scholar
  40. Yamamoto M, Yamaguchi T, Yamauchi M, et al. Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab. 2008;93(3):1013–9.CrossRefPubMedGoogle Scholar
  41. Yang S, Feskanich D, Willett WC, et al. Association between global biomarkers of oxidative stress and hip fracture in postmenopausal women: a prospective study. J Bone Miner Res. 2014;29(12):2577–83.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Zhang X, Frischmann M, Kientsch-Engel R, et al. Two immunochemical assays to measure advanced glycation end-products in serum from dialysis patients. Clin Chem Lab Med. 2005;43(5):503–11.CrossRefPubMedGoogle Scholar
  43. Zhang J, Munger RG, West NA, et al. Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status. Am J Epidemiol. 2006;163(1):9–17.CrossRefPubMedGoogle Scholar
  44. Zhou Z, Immel D, Xi CX, et al. Regulation of osteoclast function and bone mass by RAGE. J Exp Med. 2006;203(4):1067–80.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens. 2007;25(3):577–83.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Kaiser Permanente of GeorgiaDuluthUSA
  2. 2.Division of EndocrinologyEmory University School of MedicineAtlantaUSA
  3. 3.Department of BiostatisticsUniversity of WashingtonSeattleUSA
  4. 4.Department of General MedicineBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations