Association of bone metabolism markers with coronary atherosclerosis and coronary artery disease in postmenopausal women

Abstract

This study aimed to evaluate the association of bone metabolism markers with coronary atherosclerosis and coronary artery disease (CAD) in postmenopausal women. Based on the findings of coronary angiography, 111 women with CAD and 116 women without CAD were recruited. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), osteocalcin, N-terminal propeptide of type I procollagen (P1NP) and C-terminal cross-linked telopeptide of type I collagen (CTX) were measured. The Gensini score was used to assess the severity of coronary atherosclerosis. Compared with women with serum calcium ≤2.29 mmol/L, women with serum calcium >2.29 mmol/L had a 2.63-fold increased risk of CAD after adjusting for multiple cardiovascular risks, PTH and 25OHD [odds ratio (OR) = 2.91, 95% confidence interval (CI) 1.35–6.28]. In the fully adjusted model plus PTH and 25OHD, the risk of CAD increased 1.87-fold with every 1-SD increment of serum calcium (OR = 1.87, 95% CI 1.21–2.88). To further analyze the potential strong confounding effect of albumin, the absolute levels of calcium were replaced by their albumin-corrected values in the regression model. Compared with women with albumin-corrected calcium ≤2.27 mmol/L, women with albumin-corrected calcium >2.27 mmol/L had a 2.36-fold increased risk of CAD in the fully adjusted model plus PTH and 25OHD (OR = 2.36, 95% CI 1.13–4.92). The risk of coronary atherosclerosis as defined by Gensini score >0 increased 1.73-fold with every 1-SD increment of serum calcium in the fully adjusted model plus PTH and 25OHD (OR = 1.73, 95% CI 1.09–2.73). However, albumin-corrected calcium was not associated with coronary atherosclerosis either as a categorical variable or as a continuous variable in all models. No significant association of PTH, 25OHD, osteocalcin, CTX and P1NP with CAD or coronary atherosclerosis was found in this study. Higher serum calcium levels were independently associated with CAD in postmenopausal women.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Giachelli CM (2004) Vascular calcification mechanisms. J Am Soc Nephrol 15:2959–2964

    Article  PubMed  Google Scholar 

  2. 2.

    Shin S, Kim KJ, Chang HJ, Cho I, Kim YJ, Choi BW, Rhee Y, Lim SK, Yang WI, Shim CY, Ha JW, Jang Y, Chung N (2012) Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography. Eur Heart J 33:2873–2881

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Kwak SM, Kim JS, Choi Y, Chang Y, Kwon MJ, Jung JG, Jeong C, Ahn J, Kim HS, Shin H, Ryu S (2014) Dietary intake of calcium and phosphorus and serum concentration in relation to the risk of coronary artery calcification in asymptomatic adults. Arterioscler Thromb Vasc Biol 34:1763–1769

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kim WS, Lee DH, Youn HJ (2013) Calcium-phosphorus product concentration is a risk factor of coronary artery disease in metabolic syndrome. Atherosclerosis 229:253–257

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Jorde R, Schirmer H, Njolstad I, Lochen ML, Bogeberg Mathiesen E, Kamycheva E, Figenschau Y, Grimnes G (2013) Serum calcium and the calcium-sensing receptor polymorphism rs17251221 in relation to coronary heart disease, type 2 diabetes, cancer and mortality: the Tromso Study. Eur J Epidemiol 28:569–578

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Lutsey PL, Alonso A, Michos ED, Loehr LR, Astor BC, Coresh J, Folsom AR (2014) Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 100:756–764

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Grandi NC, Brenner H, Hahmann H, Wusten B, Marz W, Rothenbacher D, Breitling LP (2012) Calcium, phosphate and the risk of cardiovascular events and all-cause mortality in a population with stable coronary heart disease. Heart 98:926–933

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Williams DM, Fraser A, Lawlor DA (2011) Associations of vitamin D, parathyroid hormone and calcium with cardiovascular risk factors in US adolescents. Heart 97:315–320

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Gallo L, Faniello MC, Canino G, Tripolino C, Gnasso A, Cuda G, Costanzo FS, Irace C (2016) Serum calcium increase correlates with worsening of lipid profile: an observational study on a large cohort from south Italy. Medicine (Baltimore) 95:e2774

    CAS  Article  Google Scholar 

  10. 10.

    Bergwitz C, Juppner H (2010) Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 61:91–104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Liew JY, Sasha SR, Ngu PJ, Warren JL, Wark J, Dart AM, Shaw JA (2015) Circulating vitamin D levels are associated with the presence and severity of coronary artery disease but not peripheral arterial disease in patients undergoing coronary angiography. Nutr Metab Cardiovasc Dis 25:274–279

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Verdoia M, Schaffer A, Barbieri L, Di Giovine G, Marino P, Suryapranata H, De Luca G, Novara Atherosclerosis Study Group (2015) Impact of gender difference on vitamin D status and its relationship with the extent of coronary artery disease. Nutr Metab Cardiovasc Dis 25:464–470

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bosworth C, Sachs MC, Duprez D, Hoofnagle AN, Ix JH, Jacobs DR Jr, Peralta CA, Siscovick DS, Kestenbaum B, de Boer IH (2013) Parathyroid hormone and arterial dysfunction in the multi-ethnic study of atherosclerosis. Clin Endocrinol (Oxf) 79:429–436

    CAS  Article  Google Scholar 

  14. 14.

    Yao L, Folsom AR, Pankow JS, Selvin E, Michos ED, Alonso A, Tang W, Lutsey PL (2016) Parathyroid hormone and the risk of incident hypertension: the Atherosclerosis Risk in Communities study. J Hypertens 34:196–203

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Soares AA, Freitas WM, Japiassu AV, Quaglia LA, Santos SN, Pereira AC, Nadruz Junior W, Sposito AC (2015) Enhanced parathyroid hormone levels are associated with left ventricle hypertrophy in very elderly men and women. J Am Soc Hypertens 9:697–704

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Bansal N, Zelnick L, Robinson-Cohen C, Hoofnagle AN, Ix JH, Lima JA, Shoben AB, Peralta CA, Siscovick DS, Kestenbaum B, de Boer IH (2014) Serum parathyroid hormone and 25-hydroxyvitamin D concentrations and risk of incident heart failure: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 3:e001278

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Hagstrom E, Michaelsson K, Melhus H, Hansen T, Ahlstrom H, Johansson L, Ingelsson E, Sundstrom J, Lind L, Arnlov J (2014) Plasma-parathyroid hormone is associated with subclinical and clinical atherosclerotic disease in 2 community-based cohorts. Arterioscler Thromb Vasc Biol 34:1567–1573

    Article  PubMed  Google Scholar 

  18. 18.

    Wolf G (1996) Function of the bone protein osteocalcin: definitive evidence. Nutr Rev 54:332–333

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Price PA, Parthemore JG, Deftos LJ (1980) New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease. J Clin Invest 66:878–883

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ivaska KK, Hentunen TA, Vaaraniemi J, Ylipahkala H, Pettersson K, Vaananen HK (2004) Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro. J Biol Chem 279:18361–18369

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Yang R, Ma X, Dou J, Wang F, Luo Y, Li D, Zhu J, Bao Y, Jia W (2013) Relationship between serum osteocalcin levels and carotid intima-media thickness in Chinese postmenopausal women. Menopause 20:1194–1199

    Article  PubMed  Google Scholar 

  22. 22.

    Ogawa-Furuya N, Yamaguchi T, Yamamoto M, Kanazawa I, Sugimoto T (2013) Serum osteocalcin levels are inversely associated with abdominal aortic calcification in men with type 2 diabetes mellitus. Osteoporos Int 24:2223–2230

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Zhang Y, Qi L, Gu W, Yan Q, Dai M, Shi J, Zhai Y, Chen Y, Liu J, Wang W, Ning G, Hong J (2010) Relation of serum osteocalcin level to risk of coronary heart disease in Chinese adults. Am J Cardiol 106:1461–1465

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Kim KM, Lim S, Moon JH, Jin H, Jung KY, Shin CS, Park KS, Jang HC, Choi SH (2016) Lower uncarboxylated osteocalcin and higher sclerostin levels are significantly associated with coronary artery disease. Bone 83:178–183

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bao Y, Zhou M, Lu Z, Li H, Wang Y, Sun L, Gao M, Wei M, Jia W (2011) Serum levels of osteocalcin are inversely associated with the metabolic syndrome and the severity of coronary artery disease in Chinese men. Clin Endocrinol (Oxf) 75:196–201

    CAS  Article  Google Scholar 

  26. 26.

    Gossl M, Modder UI, Atkinson EJ, Lerman A, Khosla S (2008) Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol 52:1314–1325

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Flammer AJ, Gossl M, Widmer RJ, Reriani M, Lennon R, Loeffler D, Shonyo S, Simari RD, Lerman LO, Khosla S, Lerman A (2012) Osteocalcin positive CD133+/CD34/KDR+ progenitor cells as an independent marker for unstable atherosclerosis. Eur Heart J 33:2963–2969

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Leli C, Pasqualini L, Vaudo G, Gaggioli S, Scarponi AM, Mannarino E (2010) Carotid intima-media thickness and bone turnover: the role of C-terminal telopeptide of type I collagen. Intern Emerg Med 5:127–134

    Article  PubMed  Google Scholar 

  29. 29.

    Yeap BB, Alfonso H, Chubb SA, Byrnes E, Beilby JP, Ebeling PR, Allan CA, Schultz C, Hankey GJ, Golledge J, Flicker L, Norman PE (2015) Proportion of undercarboxylated osteocalcin and serum P1NP predict incidence of myocardial infarction in older men. J Clin Endocrinol Metab 100:3934–3942

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Stevens LA, Coresh J, Greene T, Levey AS (2006) Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 354:2473–2483

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Dhingra R, Sullivan LM, Fox CS, Wang TJ, D’Agostino RB Sr, Gaziano JM, Vasan RS (2007) Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med 167:879–885

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Mizobuchi M, Towler D, Slatopolsky E (2009) Vascular calcification: the killer of patients with chronic kidney disease. J Am Soc Nephrol 20:1453–1464

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Jorde R, Sundsfjord J, Bonaa KH (2001) Determinants of serum calcium in men and women. The Tromso Study. Eur J Epidemiol 17:1117–1123

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Heeneman S, Cleutjens JP, Faber BC, Creemers EE, van Suylen RJ, Lutgens E, Cleutjens KB, Daemen MJ (2003) The dynamic extracellular matrix: intervention strategies during heart failure and atherosclerosis. J Pathol 200:516–525

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW (1995) A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92:1355–1374

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Barascuk N, Skjot-Arkil H, Register TC, Larsen L, Byrjalsen I, Christiansen C, Karsdal MA (2010) Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes. BMC Cardiovasc Disord 10:19

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM (2003) Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol 23:489–494

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Xin Gao.

Ethics declarations

Conflict of interest

All authors have no conflicts of interest.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ling, Y., Wang, Z., Wu, B. et al. Association of bone metabolism markers with coronary atherosclerosis and coronary artery disease in postmenopausal women. J Bone Miner Metab 36, 352–363 (2018). https://doi.org/10.1007/s00774-017-0841-8

Download citation

Keywords

  • Bone metabolism marker
  • Serum calcium
  • Coronary atherosclerosis
  • Coronary artery disease