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Calcified Tissue International

, Volume 92, Issue 6, pp 501–508 | Cite as

High Serum Total Bilirubin as a Protective Factor Against Hip Bone Loss in Healthy Middle-Aged Men

  • Beom-Jun Kim
  • Jung-Min KohEmail author
  • Seong Hee Ahn
  • Seung Hun Lee
  • Eun Hee Kim
  • Sung Jin Bae
  • Hong-Kyu Kim
  • Jae Won Choe
  • Ghi Su Kim
Original Research
  • 370 Downloads

Abstract

Bilirubin is known to have a physiologic role as an antioxidant that efficiently scavenges peroxyl radicals and suppresses oxidation, and oxidative stress has detrimental effects on bone metabolism. In the present study, we performed a 3-year longitudinal study of healthy middle-aged men, investigating the association between serum total bilirubin concentrations and annualized changes in bone mineral density (BMD). The study enrolled a total of 917 Korean men aged 40 years or older who had undergone comprehensive routine health examinations with an average follow-up interval of 3 years. BMD at proximal femur sites was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The overall mean annualized rates of bone loss at the total femur, femoral neck, and trochanter were −0.25 %/year, −0.34 %/year, and −0.44 %/year, respectively. After adjustment for potential confounders, the rates of bone loss at all proximal femur sites were significantly attenuated in a dose–response fashion across increasing bilirubin concentrations (P = 0.006–0.046). Moreover, compared to subjects in the lowest bilirubin quartile category, those in the highest bilirubin quartile category showed significantly less bone loss at all proximal femur sites after adjustment for confounding factors (P = 0.010–0.048). This study provides the first clinical evidence that serum total bilirubin could be a protective marker against future bone loss, especially in subjects without liver diseases.

Keywords

Bilirubin Bone loss Antioxidant Bone density 

Notes

Acknowledgments

This study was supported by grants from the Korea Health Technology R&D Project and the National Project for Personalized Genomic Medicine, Ministry of Health & Welfare, Republic of Korea (projects A110536 and A111218-GM03, respectively).

References

  1. 1.
    Vallarta-Ast N, Krueger D, Wrase C, Agrawal S, Binkley N (2007) An evaluation of densitometric vertebral fracture assessment in men. Osteoporos Int 18:1405–1410PubMedCrossRefGoogle Scholar
  2. 2.
    Szulc P, Montella A, Delmas PD (2008) High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study. Ann Rheum Dis 67:1249–1255PubMedCrossRefGoogle Scholar
  3. 3.
    Riggs BL, Melton LJ, Robb RA, Camp JJ, Atkinson EJ, McDaniel L, Amin S, Rouleau PA, Khosla S (2008) A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res 23:205–214PubMedCrossRefGoogle Scholar
  4. 4.
    Bai XC, Lu D, Liu AL, Zhang ZM, Li XM, Zou ZP, Zeng WS, Cheng BL, Luo SQ (2005) Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J Biol Chem 280:17497–17506PubMedCrossRefGoogle Scholar
  5. 5.
    Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, Kim N, Lee SY (2005) A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106:852–859PubMedCrossRefGoogle Scholar
  6. 6.
    Wauquier F, Leotoing L, Coxam V, Guicheux J, Wittrant Y (2009) Oxidative stress in bone remodelling and disease. Trends Mol Med 15:468–477PubMedCrossRefGoogle Scholar
  7. 7.
    Nabipour I, Sambrook PN, Blyth FM, Janu MR, Waite LM, Naganathan V, Handelsman DJ, Le Couteur DG, Cumming RG, Seibel MJ (2011) Serum uric acid is associated with bone health in older men: a cross-sectional population-based study. J Bone Miner Res 26:955–964PubMedCrossRefGoogle Scholar
  8. 8.
    Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046PubMedCrossRefGoogle Scholar
  9. 9.
    Baranano DE, Rao M, Ferris CD, Snyder SH (2002) Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA 99:16093–16098PubMedCrossRefGoogle Scholar
  10. 10.
    Perlstein TS, Pande RL, Beckman JA, Creager MA (2008) Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol 28:166–172PubMedCrossRefGoogle Scholar
  11. 11.
    Perlstein TS, Pande RL, Creager MA, Weuve J, Beckman JA (2008) Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med 121:781–788PubMedCrossRefGoogle Scholar
  12. 12.
    Kimm H, Yun JE, Jo J, Jee SH (2009) Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke 40:3422–3427PubMedCrossRefGoogle Scholar
  13. 13.
    Lin LY, Kuo HK, Hwang JJ, Lai LP, Chiang FT, Tseng CD, Lin JL (2009) Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Atherosclerosis 203:563–568PubMedCrossRefGoogle Scholar
  14. 14.
    Abraham NG, Kushida T, McClung J, Weiss M, Quan S, Lafaro R, Darzynkiewicz Z, Wolin M (2003) Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res 93:507–514PubMedCrossRefGoogle Scholar
  15. 15.
    Kawamura K, Ishikawa K, Wada Y, Kimura S, Matsumoto H, Kohro T, Itabe H, Kodama T, Maruyama Y (2005) Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 25:155–160PubMedGoogle Scholar
  16. 16.
    Koh JM, Khang YH, Jung CH, Bae S, Kim DJ, Chung YE, Kim GS (2005) Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int 16:1263–1271PubMedCrossRefGoogle Scholar
  17. 17.
    Menon KV, Angulo P, Weston S, Dickson ER, Lindor KD (2001) Bone disease in primary biliary cirrhosis: independent indicators and rate of progression. J Hepatol 35:316–323PubMedCrossRefGoogle Scholar
  18. 18.
    Smith DL, Shire NJ, Watts NB, Schmitter T, Szabo G, Zucker SD (2006) Hyperbilirubinemia is not a major contributing factor to altered bone mineral density in patients with chronic liver disease. J Clin Densitom 9:105–113PubMedCrossRefGoogle Scholar
  19. 19.
    Bagur A, Mautalen C, Findor J, Sorda J, Somoza J (1998) Risk factors for the development of vertebral and total skeleton osteoporosis in patients with primary biliary cirrhosis. Calcif Tissue Int 63:385–390PubMedCrossRefGoogle Scholar
  20. 20.
    Roll J, Boyer JL, Barry D, Klatskin G (1983) The prognostic importance of clinical and histologic features in asymptomatic and symptomatic primary biliary cirrhosis. N Engl J Med 308:1–7PubMedCrossRefGoogle Scholar
  21. 21.
    Ruiz-Gaspa S, Martinez-Ferrer A, Guanabens N, Dubreuil M, Peris P, Enjuanes A, Martinez de Osaba MJ, Alvarez L, Monegal A, Combalia A, Pares A (2011) Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases. Hepatology 54:2104–2113PubMedCrossRefGoogle Scholar
  22. 22.
    Kwon KM, Kam JH, Kim MY, Chung CH, Kim JK, Linton JA, Eom A, Koh SB, Kang HT (2011) Inverse association between total bilirubin and metabolic syndrome in rural Korean women. J Womens Health (Larchmt) 20:963–969CrossRefGoogle Scholar
  23. 23.
    Jo J, Yun JE, Lee H, Kimm H, Jee SH (2011) Total, direct, and indirect serum bilirubin concentrations and metabolic syndrome among the Korean population. Endocrine 39:182–189PubMedCrossRefGoogle Scholar
  24. 24.
    Wu TW, Fung KP, Wu J, Yang CC, Weisel RD (1996) Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol 51:859–862PubMedCrossRefGoogle Scholar
  25. 25.
    Rosenthal P, Pincus M, Fink D (1984) Sex- and age-related differences in bilirubin concentrations in serum. Clin Chem 30:1380–1382PubMedGoogle Scholar
  26. 26.
    Masud T, Langley S, Wiltshire P, Doyle DV, Spector TD (1993) Effect of spinal osteophytosis on bone mineral density measurements in vertebral osteoporosis. BMJ 307:172–173PubMedCrossRefGoogle Scholar
  27. 27.
    Orwoll ES, Oviatt SK, Mann T (1990) The impact of osteophytic and vascular calcifications on vertebral mineral density measurements in men. J Clin Endocrinol Metab 70:1202–1207PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Beom-Jun Kim
    • 1
  • Jung-Min Koh
    • 1
    Email author
  • Seong Hee Ahn
    • 1
  • Seung Hun Lee
    • 1
  • Eun Hee Kim
    • 2
  • Sung Jin Bae
    • 2
  • Hong-Kyu Kim
    • 2
  • Jae Won Choe
    • 2
  • Ghi Su Kim
    • 1
  1. 1.Division of Endocrinology and MetabolismAsan Medical Center, University of Ulsan College of MedicineSeoulKorea
  2. 2.Health Promotion CenterAsan Medical Center, University of Ulsan College of MedicineSeoulKorea

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