Skip to main content

Advertisement

SpringerLink
Log in

Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health In Men Study

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

In older men, both lower and higher total osteocalcin levels predict increased all-cause mortality, with comparable associations for cardiovascular and non-cardiovascular deaths. Differences in osteocalcin levels might influence glucose metabolism and thereby cardiovascular risk, or reflect changes in bone turnover thus representing a marker for poorer health outcomes.

Introduction

Reduced levels of total osteocalcin (TOC) are associated with adiposity, insulin resistance and type 2 diabetes, implying this bone-derived peptide might modulate cardiovascular risk. However, there are few longitudinal data relating TOC levels to survival. We examined associations of TOC level with all-cause and cardiovascular mortality in older men.

Methods

We conducted a prospective cohort study of community-dwelling men aged 70–89 years. Aliquots of plasma collected at baseline (2001–2004) were assayed for TOC. Incidence and causes of death to 31 December 2008 were ascertained using data linkage. Cox regression analyses were performed with adjustment for conventional cardiovascular risk factors.

Results

From 3,542 men followed for median 5.2 years there were 572 deaths (16.1%). Mortality was lowest in men with TOC levels in the second quintile (12.6%). In multivariate analyses, men with TOC in the lowest and highest quintiles of values had increased all-cause mortality (Q1 vs Q2: hazard ratio [HR], 1.36; 95% confidence interval 1.02–1.80 and Q5 vs Q2: HR, 1.53, 95% CI 1.18–1.98). Men with low TOC levels had similar HR for cardiovascular and non-cardiovascular deaths (Q1 vs Q2: HR, 1.35 and 1.30 respectively). Higher TOC levels predicted cardiovascular disease (CVD)-related mortality (Q5 vs Q2, HR, 1.69, 95% CI 1.09–2.64).

Conclusions

TOC predicts all-cause and CVD-related mortality in community-dwelling older men. However, the relationship is U shaped with men at both ends of the distribution at increased risk. Further investigation is required to clarify whether the underlying mechanisms involve altered bone turnover or relate specifically to the biological activity of osteocalcin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047

    PubMed  CAS  Google Scholar 

  2. Gundberg CM, Nieman SD, Abrams S, Rosen H (1998) Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–3266

    Article  PubMed  CAS  Google Scholar 

  3. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469

    Article  PubMed  CAS  Google Scholar 

  4. Ferron M, Hinoi E, Karsenty G, Ducy P (2008) Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci 105:5266–5270

    Article  PubMed  CAS  Google Scholar 

  5. Shea MK, Gundberg CM, Meigs JB, Dallal GE, Saltzman E, Yoshida M, Jacques P, Booth SL (2009) γ-Carboxylation of osteocalcin and insulin resistance in older men and women. Am J Clin Nutr 90:1230–1235

    Article  PubMed  CAS  Google Scholar 

  6. HwangY-C JI-K, Ahn KJ, Chung HY (2009) The uncarboxylated form of osteocalcin is associated with improved glucose tolerance and enhanced β-cell function in middle-aged male subjects. Diabetes Metab Res Rev 25:768–772

    Article  Google Scholar 

  7. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2009) Adiponectin is associated with changes in bone markers during glycemic control in Type 2 diabetes mellitus. J Clin Endocrinol Metab 94:3031–3037

    Article  PubMed  CAS  Google Scholar 

  8. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2010) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int. doi:10.1007/s00198-010-1184-7

    Google Scholar 

  9. Levinger I, Zebaze R, Jerums G, Hare DL, Selig S, Seeman E (2010) The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporos Int. doi:10.1007/s00198-010-1370-7

    PubMed  Google Scholar 

  10. Im J-A, Yu B-P, Jeon JY, Kim S-H (2008) Relationship between osteocalcin and glucose metabolism. Clin Chim Acta 396:66–69

    Article  PubMed  CAS  Google Scholar 

  11. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellstrom D (2009) Plasma osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner Res 24:785–791

    Article  PubMed  CAS  Google Scholar 

  12. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T (2009) Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes. J Clin Endocrinol Metab 94:45–49

    Article  PubMed  CAS  Google Scholar 

  13. Pittas AG, Harris SS, Eliades M, Stark P, Dawson-Hughes B (2009) Association between serum osteocalcin and markers of metabolic phenotype. J Clin Endocrinol Metab 94:827–832

    Article  PubMed  CAS  Google Scholar 

  14. Saleem U, Mosley TH, Kullo IJ (2010) Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol 30:1474–1478

    Article  PubMed  CAS  Google Scholar 

  15. Yeap BB, Chubb SAP, Flicker L, McCaul KA, Ebeling PR, Beilby JP, Norman PE (2010) Reduced serum total osteocalcin is associated with metabolic syndrome in older men through its association with hyperglycemia, waist circumference and serum triglycerides. Eur J Endocrinol 163:265–272

    Article  PubMed  CAS  Google Scholar 

  16. Saely CH, Aczel S, Marte T, Langer P, Hoefle G, Drexel H (2005) The Metabolic Syndrome, insulin resistance, and cardiovascular risk in diabetic and nondiabetic patients. J Clin Endocrinol Metab 90:5698–5703

    Article  PubMed  CAS  Google Scholar 

  17. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Meigs JB, Bonadonna RC, Muggeo M (2007) Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in Caucasian subjects from the general population. Diab Care 30:318–324

    Article  Google Scholar 

  18. Szulc P, Kaufman JM, Delmas PD (2007) Biochemical assessment of bone turnover and bone fragility in men. Osteoporos Int 18:1451–1461

    Article  PubMed  CAS  Google Scholar 

  19. Khosla S, Amin S, Orwoll E (2008) Osteoporosis in men. Endocr Rev 29:441–464

    Article  PubMed  CAS  Google Scholar 

  20. Cornier M-A, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH (2008) The metabolic syndrome. Endocr Rev 29:777–822

    Article  PubMed  CAS  Google Scholar 

  21. Norman PE, Flicker L, Almeida OP, Hankey GJ, Hyde Z, Jamrozik K (2009) Cohort profile: the Health In Men Study (HIMS). Int J Epidemiol 38:48–52

    Article  PubMed  Google Scholar 

  22. The Australian Diabetes, Obesity and Lifestyle Study (2000) Diabesity and associated disorders in Australia 2000. International Diabetes Institute, Melbourne

    Google Scholar 

  23. Holman CD, Bass AJ, Rouse IL, Hobbs MS (1999) Population-based linkage of health records in Western Australia: development of a health services research linked database. Aust N Z J Public Health 23:453–459

    Article  PubMed  CAS  Google Scholar 

  24. Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chr Dis 40:373–383

    Article  CAS  Google Scholar 

  25. Takahashi M, Kushida K, Nagano A, Inoue T (2000) Comparison of the analytical and clinical performance characteristics of an N-MID versus an intact osteocalcin immunoradiometric assay. Clin Chim Acta 294:67–76

    Article  PubMed  CAS  Google Scholar 

  26. Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509

    Article  Google Scholar 

  27. Greenland S (1989) Modeling and variable selection in epidemiologic analysis. Am J Public Health 79:340–349

    Article  PubMed  CAS  Google Scholar 

  28. Fernandez-Real JM, Izquierdo M, Ortega F, Gorostiaga E, Gomez-Ambrosi J, Moreno-Navarrete JM, Fruhbeck G, Martinez C, Idoate F, Salvador J, Forga L, Ricart W, Ibanez J (2009) The relationship of serum osteocalcin to insulin secretion, sensitivity, and disposal with hypocaloric diet and resistance training. J Clin Endocrinol Metab 94:237–245

    Article  PubMed  CAS  Google Scholar 

  29. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB (2005) Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 112:3066–3072

    Article  PubMed  CAS  Google Scholar 

  30. Ferron M, Wei J, Yoshizawa T, Del Fattore A, DePinho RA, Teti A, Ducy P, Karsenty G (2010) Insulin signalling in osteoblasts integrates bone remodelling and energy metabolism. Cell 142:296–308

    Article  PubMed  CAS  Google Scholar 

  31. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere M-C, Aja S, Hussain MA, Bruning JC, Clemens TL (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319

    Article  PubMed  CAS  Google Scholar 

  32. Sambrook PN, Chen CJ, March L, Cameron ID, Cumming RG, Lord SR, Simpson JM, Seibel MJ (2006) High bone turnover is an independent predictor of mortality in the frail elderly. J Bone Miner Res 21:549–555

    Article  PubMed  Google Scholar 

  33. Chen JS, Sambrook PN, March L, Cameron ID, Cumming RG, Simpson JM, Seibel MJ (2008) Hypovitaminosis D and parathyroid hormone response in the elderly: effects on bone turnover and mortality. Clin Endocrinol 68:290–298

    CAS  Google Scholar 

  34. Kado DM, Browner WS, Blackwell T, Gore R, Cummings SR (2000) Rate of bone loss is associated with mortality in older women: a prospective study. J Bone Miner Res 15:1974–1980

    Article  PubMed  CAS  Google Scholar 

  35. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, on behalf of the INTERHEART Study Investigators (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364:937–952

    Article  Google Scholar 

  36. Barr ELM, Tonkin AM, Welborn TA, Shaw JE (2009) Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab study. Intern Med J 39:49–53

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. George Koumantakis of Roche Diagnostics Australia for facilitating supply of assay reagents, Johnson Setoh and Seamus Duffy for technical assistance, staff of Shenton Park Hospital and all the participants in the Western Australian Abdominal Aortic Aneurysm Program and the Health In Men Study. We also acknowledge assistance received from the Data Linkage Unit of the Health Department of Western Australia.

Hormone assays were funded by research grants from the Fremantle Hospital Medical Research Foundation, Fremantle Hospital, WA, Australia and the Ada Bartholomew Medical Research Trust, University of Western Australia. The Health In Men Study was funded by Project Grants 279408, 379600, 403963 and 513823 from the National Health and Medical Research Council of Australia (NHMRC). BBY is recipient of a Clinical Investigator Award from the Sylvia and Charles Viertel Charitable Foundation, NSW, Australia. PEN is supported by NHMRC Practitioner Fellowship 458505.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

    B. B. Yeap, S.A. P. Chubb, L. Flicker & G. J. Hankey

  2. Department of Endocrinology and Diabetes, Fremantle Hospital, Fremantle, WA, Australia

    B. B. Yeap

  3. PathWest Laboratory Medicine, Fremantle and Sir Charles Gairdner Hospitals, Perth, WA, Australia

    S.A. P. Chubb & J. P. Beilby

  4. WA Centre for Health and Ageing, Centre for Medical Research, University of Western Australia, Perth, WA, Australia

    L. Flicker & K. A. McCaul

  5. Northwest Academic Centre, Western Hospital, University of Melbourne, Melbourne, VIC, Australia

    P. R. Ebeling

  6. School of Surgery, University of Western Australia, Perth, WA, Australia

    P. E. Norman

  7. School of Medicine and Pharmacology, Level 2, T Block, Fremantle Hospital, Alma Street, Fremantle, WA, 6160, Australia

    B. B. Yeap

Authors
  1. B. B. Yeap
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S.A. P. Chubb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Flicker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. A. McCaul
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. R. Ebeling
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. J. Hankey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. P. Beilby
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P. E. Norman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. B. Yeap.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yeap, B.B., Chubb, S.P., Flicker, L. et al. Associations of total osteocalcin with all-cause and cardiovascular mortality in older men. The Health In Men Study. Osteoporos Int 23, 599–606 (2012). https://doi.org/10.1007/s00198-011-1586-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-011-1586-1

Keywords

Search

Navigation