Skip to main content

Advertisement

SpringerLink
Log in

Association of Bone Mineral Density, Bone Turnover Markers, and Vertebral Fractures with All-Cause Mortality in Type 2 Diabetes Mellitus

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fracture. However, the association between diabetes-related osteoporosis and mortality in T2DM remains unknown. This historical cohort study assessed the endpoint of all-cause mortality in patients with T2DM. According to our hospital record, bone parameters were examined in 797 patients from 1997 to 2009. We excluded 78 because of diseases affecting bone metabolism and could not follow-up 308 patients. Finally, in 411 patients, the associations of bone turnover markers, bone mineral density (BMD), and the prevalence of vertebral fractures with mortality were investigated by Cox regression analyses adjusted for confounding factors. Of 411 patients, 56 died during the follow-up period of almost 7 years. Cox regression analyses showed that reduced BMD at the lumbar spine (LS) and femoral neck (FN) (T-score ≤ −2.5) and severe vertebral fractures were associated with higher mortality (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.48–7.16, p = 0.003 for LS-T score ≤ −2.5; HR 5.19, 95% CI 1.83–14.75, p = 0.002 for FN-T score ≤ −2.5; HR 2.93, 95% CI 1.42–6.02, p = 0.004 for multiple vertebral fractures; HR 7.64, 95% CI 2.13–27.42, p = 0.002 for grade 3 vertebral fracture). Separate analysis in men and women showed that decreased serum osteocalcin was associated with mortality in women (HR 3.82, 95% CI 1.01–14.46 per SD decrease, p = 0.048). The present study is the first to show the association of reduced BMD and severe vertebral fractures with increased all-cause mortality in patients with T2DM. Moreover, higher serum osteocalcin was significantly associated with decreased mortality in women with T2DM.

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
Fig. 3

Similar content being viewed by others

Abbreviations

T2DM:

Type 2 diabetes mellitus

BMD:

Bone mineral density

CTX:

Carboxyterminal telopeptide of type 1 collagen

P1NP:

Aminoterminal propeptide of type 1 collagen

BAP:

Bone-specific alkaline phosphatase

uNTX:

Urinary N-terminal cross-linked telopeptide of type-I collagen

CV:

Coefficients of variation

HbA1c:

Hemoglobin A1c

LS:

Lumbar spine

FN:

Femoral neck

1/3R:

One-third of the radius

SD:

Standard deviation

HR:

Hazard ratio

95% CI:

95% confidence interval

BMI:

Body mass index

References

  1. Matheus AS, Tannus LR, Cobas RA, Palma CC, Negrato CA, Gomes MB (2013) Impact of diabetes on cardiovascular disease: an update. Int J Hypertens 2013:653789

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fisher-Hoch SP, Mathews CE, McCormick JB (2013) Obesity, diabetes and pneumonia: the menacing interface of non-communicable and infectious diseases. Trop Med Int Health 18:1510–1519

    Article  PubMed  Google Scholar 

  3. Gallagher EJ, LeRoith D (2015) Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol Rev 95:727–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Almdal T, Scharling H, Jensen JS, Vestergaad H (2004) The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 164:1422–1426

    Article  PubMed  Google Scholar 

  5. Barret-Connor E, Holbrook TL (1992) Sex differences in osteoporosis in older adults with non-insulin-dependent diabetes mellitus. JAMA 268:3333–3337

    Article  Google Scholar 

  6. Vestergaard P (2007) Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta-analysis. Osteoporos Int 18:427–444

    Article  CAS  PubMed  Google Scholar 

  7. Yamamoto M, Yamaguchi T, Yamauchi M, Kaji H, Sugimoto T (2009) Diabetic patients have an increased risk of vertebral fractures independent of bone mineral density or diabetic complications. J Bone Miner Res 24:702–709

    Article  CAS  PubMed  Google Scholar 

  8. Haentjens P, Magaziner J, Colon-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, Boonen S (2010) Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 152:380–390

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ensrund KE, Thompson DE, Cauley JA, Nevitt MC, Kado DM, Hochberg MC, Santora AC 2nd, Black DM (2009) Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. J Am Geriatr Soc 48:241–249

    Article  Google Scholar 

  10. 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 

  11. Lerchbaum E, Schwetx V, Pilz S, Grammer TB, Look M, Boehm BO, Obermayer-Pietsch B, März W (2012) Association of bone turnover markers with mortality in men referred to coronary angiography. Osteoporos Int 24:1321–1332

    Article  PubMed  Google Scholar 

  12. Lerchbaum E, Schwetz V, Pilz S, Boehm BO, März W (2014) Association of bone turnover markers with mortality in women referred to coronary angiography: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Osteoporos Int 25:455–465

    Article  CAS  PubMed  Google Scholar 

  13. Gulin T, Kruljac I, Kirigin L, Merc M, Pavic M, Trcin MT, Bokulic A, Megla ZB, Kastelan D (2016) Advanced age, high & #x03B2;-CTX levels, and impaired renal function are independent risk factors for all-cause one-year mortality in hip fracture patients. Calcif Tissue Int 98:67–75

    Article  CAS  PubMed  Google Scholar 

  14. Yeap BB, Chubb SA, Flicker L, McCaul KA, Ebeling PR, Hankey GJ, Beilby JP, Norman PE (2012) Associations of total osteocalcin with all-cause and cardiovascular mortality in older men: the Health In Men Study. Osteoporos Int 23:599–606

    Article  CAS  PubMed  Google Scholar 

  15. Saito M, Fujii K, Mori Y, Marumo K (2006) Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int 17:1514–1523

    Article  CAS  PubMed  Google Scholar 

  16. Liu C, Wo J, Zhao Q, Wang Y, Wang B, Zhao W (2015) Association between serum total osteocalcin level and type 2 diabetes mellitus: a systematic review and meta-analysis. Horm Metab Res 47:813–819

    Article  CAS  PubMed  Google Scholar 

  17. 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  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pi M, Quarles LD (2012) Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153:2062–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jung CH, Lee WJ, Hwang JY, Lee MJ, Seol SM, Kim YM, Lee YL, Park JY (2013) The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway. Metabolism 62:1250–1257

    Article  CAS  PubMed  Google Scholar 

  20. Zhou B, Li H, Liu J, Xu L, Zang W, Wu S, Sun H (2013) Intermittent injections of osteocalcin reverse autophagic dysfunction and endoplasmic reticulum stress resulting from diet-induced obesity in the vascular tissue via the NFκB-p65-dependent mechanism. Cell Cycle 12:1901–1903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kanazawa I, Yamaguchi T, Tada Y, Yamauchi M, Yano S, Sugimoto T (2011) Serum osteocalcin level is positively associated with insulin sensitivity and secretion in patients with type 2 diabetes. Bone 48:720–725

    Article  CAS  PubMed  Google Scholar 

  22. 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 mellitus. J Clin Endocrinol Metab 94:45–49

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. Kanazawa I, Yamaguchi T, Yamauchi M, Yamamoto M, Kurioka S, Yano S, Sugimoto T (2011) Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus. Osteoporos Int 22:187–194

    Article  CAS  PubMed  Google Scholar 

  25. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, 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  CAS  PubMed  Google Scholar 

  26. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T (2009) Relationships between serum adiponectin levels versus bone mineral density, bone metabolic markers, and vertebral fractures in type 2 diabetes mellitus. Eur J Endocrinol 160:265–273

    Article  CAS  PubMed  Google Scholar 

  27. Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148

    Article  CAS  PubMed  Google Scholar 

  28. Report of a WHO Study Group (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 843:1–129

    Google Scholar 

  29. Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Karsenty G, Oury F (2014) Regulation of male fertility by the bone-derived hormone osteocalcin. Mol Cell Endocrinol 382:521–526

    Article  CAS  PubMed  Google Scholar 

  31. Richards JB, Valdes AM, Burling K, Perks UC, Spector TD (2007) Serum adiponectin and bone mineral density in women. J Clin Endocrinol Metab 92:1517–1523

    Article  CAS  PubMed  Google Scholar 

  32. Oh KW, Lee WY, Rhee EJ, Baek KH, Yoon KH, Kang MI, Yun EJ, Park CY, Ihm SH, Choi MG, Yoo HJ, Park SW (2005) The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. Clin Endocrinol 63:131–138

    Article  CAS  Google Scholar 

  33. Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocr Rev 26:439–451

    Article  CAS  PubMed  Google Scholar 

  34. Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K, Froguel P, Nagai R, Kadowaki T (2003) Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr Drug Targets Immune Endocr Metabol Disord 3:243–254

    Article  CAS  PubMed  Google Scholar 

  35. Dalamaga M, Diakopoulos KN, Mantzoros CS (2012) The role of adiponectin in cancer: a review of current evidence. Endocr Rev 33:547–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T, Sugimoto T (2013) Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int 24:1115–1119

    Article  CAS  PubMed  Google Scholar 

  37. De Almeida Pereira Coutinho M, Bandeira E, de Almeida JM, Godoi ET, Vasconcelos G, Bandeira F (2013) Low bone mass is associated with increased carotid intima media thickness in men with type 2 diabetes mellitus. Clin Med Insights Endocrinol Diabetes 6:1–6

    PubMed  PubMed Central  Google Scholar 

  38. Kanis JA, McCloskey EV, Johansson H, Strom O, Borqstrom F, Oden A, National Osteoporosis Guideline Group (2008) Case finding for the management of osteoporosis with FRAX–assessment and intervention thresholds for the UK. Osteoporos Int 19:1395–1408

    Article  CAS  PubMed  Google Scholar 

  39. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA (1999) Mortality after all major types of osteoporotic fracture in men and women an observational study. Lancet 353:878–882

    Article  CAS  PubMed  Google Scholar 

  40. Klop C, van Staa TP, Cooper C, Harvey NC, de Vries F (2017) The epidemiology of mortality after fracture in England: variation by age, sex, time, geographic location, and ethnicity. Osteoporos Int 28:161–168

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the patients and staff of Shimane University Faculty of Medicine who participated in this study. This study had no funding support. All authors participated in the development and writing of the article and approved the final manuscript for publication. IK takes full responsibility for the content of the article.

Author information

Authors and Affiliations

  1. Department of Internal Medicine 1, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, 693-8501, Japan

    Hitomi Miyake, Ippei Kanazawa & Toshitsugu Sugimoto

Authors
  1. Hitomi Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ippei Kanazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshitsugu Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HM researched data and wrote manuscript. IK researched data and wrote/reviewed/edited manuscript. TS contributed to discussion and reviewed/edited manuscript.

Corresponding author

Correspondence to Ippei Kanazawa.

Ethics declarations

Conflicts of interest

Hitomi Miyake, Ippei Kanazawa, and Toshitsugu Sugimoto declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This study was approved by the institutional review board of Shimane University Faculty of Medicine; the requirement for informed patient consent was waived because no intervention and further examinations were performed.

Additional information

This manuscript has not been published and is not under consideration for publication elsewhere.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyake, H., Kanazawa, I. & Sugimoto, T. Association of Bone Mineral Density, Bone Turnover Markers, and Vertebral Fractures with All-Cause Mortality in Type 2 Diabetes Mellitus. Calcif Tissue Int 102, 1–13 (2018). https://doi.org/10.1007/s00223-017-0324-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-017-0324-x

Keywords

Search

Navigation