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Effects of Glucose on Bone Markers: Overview of Current Knowledge with Focus on Diabetes, Glucose, and Bone Markers

  • Jakob Starup-LindeEmail author
  • Sidse Westberg-RasmussenEmail author
  • Simon LykkeboeEmail author
  • Peter VestergaardEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)

Abstract

Diabetes mellitus is associated with an increased risk of fracture. However, in patients with diabetes the bone mineral density does not explain this. Bone turnover markers give information on bone formation and bone resorption and may explain the decreased bone material competence in patients with diabetes. Diabetes mellitus is characterized by the lack of a fasting condition, which also may affect the general bone turnover and be reflected in the bone turnover markers. This chapter focuses on the relation between bone turnover markers and plasma glucose, and bone turnover markers in diabetes subjects. In clinical trials, an oral glucose tolerance test (OGTT) decreased bone resorption markers in both patients with type 2 diabetes and healthy individuals. During an OGTT, bone formation markers were decreased in healthy individuals, but the markers were not investigated in patients with diabetes. An intravenous glucose tolerance test decreases the bone resorption marker C-terminal cross-linked telopeptide of type-I collagen (CTX) but not as much as the OGTT. Therefore a gastrointestinal interaction may affect the relation between glucose and bone turnover markers. In patients with diabetes, both CTX and the bone formation marker osteocalcin were decreased compared to controls. However, heterogeneity was present in the markers, which may be due to differences in glycemic status. In vitro studies show direct effects of glucose on the bone cells: osteoblasts, osteoclasts, and osteocytes. Hyperglycemia had detrimental effects on osteoblasts and osteoclasts and increased the sclerostin production in osteocytes; thus both bone resorption and formation seemed to decrease during hyperglycemia. However, in the mild hyperglycemia with a glucose level of 11–15 mmol/l, the osteoblasts increased the mineralization. Thus, hyperglycemia may hypermineralize the bone, so the bone mineral density is increased relatively to the bone material competence due to a relative decrease in non-mineralized matrix, e.g., collagen.

Further, investigations are needed to determine if the glucose bone turnover marker interaction may be a prognostic marker of fracture in patients with diabetes.

Keywords

Glucose Hyperglycemia Bone turnover markers Bone turnover Diabetes mellitus Osteoblasts Osteoclasts Osteocytes Hypermineralization 

List of Abbreviations

BAP

Bone-specific alkaline phosphatase

BMD

Bone mineral density

BSP

Bone sialoprotein

CA/P

Calcium/phosphate

CTX

C-terminal cross-linked telopeptide of type-I collagen

FGF-23

Fibroblast growth factor-23

FRAX

The fracture risk assessment tool

GIP

Gastric inhibitory peptide

GLP-1

Glucagon-like peptide-1

GLP-2

Glucagon-like peptide-2

HbA1c

Glycated hemoglobin A1c

hMSC

Human mesenchymal stem cells

hMSC-TERT

Human mesenchymal stem cells telomerase-immortalized

IGF-1

Insulin-like growth factor-1

IVGTT

Intravenous glucose tolerance test

NTX

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

OGTT

Oral glucose tolerance test

OPG

Osteoprotegerin

P1NP

Procollagen type 1 N-terminal propeptide

PTH

Parathyroid hormone

RANK

Receptor activator of nuclear factor kappa-B

RANKL

Receptor Activator of Nuclear factor Kappa beta Ligand

Runx2

Runt-related protein 2

TRAP

Tartrate resistant acid phosphatase

References

  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35 Suppl 1:S64–71.CrossRefGoogle Scholar
  2. Balint E, Szabo P, Marshall CF, Sprague SM. Glucose-induced inhibition of in vitro bone mineralization. Bone. 2001;28(1):21–8.CrossRefPubMedGoogle Scholar
  3. Bartolome A, Lopez-Herradon A, Portal-Nunez S, Garcia-Aguilar A, Esbrit P, Benito M, Guillen C. Autophagy impairment aggravates the inhibitory effects of high glucose on osteoblast viability and function. Biochem J. 2013;455(3):329–37.CrossRefPubMedGoogle Scholar
  4. Bjarnason NH, Henriksen EE, Alexandersen P, Christgau S, Henriksen DB, Christiansen C. Mechanism of circadian variation in bone resorption. Bone. 2002;30(1):307–13.CrossRefPubMedGoogle Scholar
  5. Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, Johnson KC, Margolis KL. Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. J Clin Endocrinol Metab. 2006;91(9):3404–10.CrossRefPubMedGoogle Scholar
  6. Boskey AL. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. 2013;2:447.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Botolin S, McCabe LR. Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. J Cell Biochem. 2006;99(2):411–24.CrossRefPubMedGoogle Scholar
  8. Bowsher RR, Sailstad JM. Insights in the application of research-grade diagnostic kits for biomarker assessments in support of clinical drug development: bioanalysis of circulating concentrations of soluble receptor activator of nuclear factor kappaB ligand. J Pharm Biomed Anal. 2008;48(5):1282–9.CrossRefPubMedGoogle Scholar
  9. Chailurkit LO, Chanprasertyothin S, Rajatanavin R, Ongphiphadhanakul B. Reduced attenuation of bone resorption after oral glucose in type 2 diabetes. Clin Endocrinol (Oxf). 2008;68(6):858–62.CrossRefGoogle Scholar
  10. Clowes JA, Robinson RT, Heller SR, Eastell R, Blumsohn A. Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies. J Clin Endocrinol Metab. 2002;87(7):3324–9.CrossRefPubMedGoogle Scholar
  11. Clowes JA, Allen HC, Prentis DM, Eastell R, Blumsohn A. Octreotide abolishes the acute decrease in bone turnover in response to oral glucose. J Clin Endocrinol Metab. 2003;88(10):4867–73.CrossRefPubMedGoogle Scholar
  12. Cunha JS, Ferreira VM, Maquigussa E, Naves MA, Boim MA. Effects of high glucose and high insulin concentrations on osteoblast function in vitro. Cell Tissue Res. 2014;358:249.CrossRefPubMedGoogle Scholar
  13. Dienelt A, zur Nieden NI. Hyperglycemia impairs skeletogenesis from embryonic stem cells by affecting osteoblast and osteoclast differentiation. Stem Cells Dev. 2011;20(3):465–74.CrossRefPubMedGoogle Scholar
  14. Garcia-Hernandez A, Arzate H, Gil-Chavarria I, Rojo R, Moreno-Fierros L. High glucose concentrations alter the biomineralization process in human osteoblastic cells. Bone. 2012;50(1):276–88.CrossRefPubMedGoogle Scholar
  15. Giangregorio LM, Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis JA. FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res. 2012;27(2):301–8.CrossRefPubMedGoogle Scholar
  16. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci. 2006;1092:385–96.CrossRefPubMedGoogle Scholar
  17. Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int. 2000;11 Suppl 6:S30–44.CrossRefPubMedGoogle Scholar
  18. Henriksen DB, Alexandersen P, Bjarnason NH, Vilsboll T, Hartmann B, Henriksen EE, Byrjalsen I, Krarup T, Holst JJ, Christiansen C. Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res. 2003;18(12):2180–9.CrossRefPubMedGoogle Scholar
  19. Holst JJ, Hartmann B, Gottschalck IB, Jeppesen PB, Miholic J, Henriksen DB. Bone resorption is decreased postprandially by intestinal factors and glucagon-like peptide-2 is a possible candidate. Scand J Gastroenterol. 2007;42(7):814–20.CrossRefPubMedGoogle Scholar
  20. International Diabetes Federation. IDF Diabetes Atlas Update 2014. Available from: http://www.idf.org/diabetesatlas/update-2014. 2 Oct 2015.
  21. Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166(5):495–505.CrossRefPubMedGoogle Scholar
  22. Karatzoglou I, Yavropoulou MP, Pikilidou M, Germanidis G, Akriviadis E, Papazisi A, Daniilidis M, Zebekakis P, Yovos JG. Postprandial response of bone turnover markers in patients with Crohn’s disease. World J Gastroenterol: WJG. 2014;20(28):9534–40.PubMedPubMedCentralGoogle Scholar
  23. Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am. 2005;34(4):1015–30, xi.CrossRefPubMedGoogle Scholar
  24. Knudsen ST, Jeppesen P, Poulsen PL, Andersen NH, Bek T, Schmitz O, Mogensen CE, Rasmussen LM. Plasma concentrations of osteoprotegerin during normo- and hyperglycaemic clamping. Scand J Clin Lab Invest. 2007;67(2):135–42.CrossRefPubMedGoogle Scholar
  25. Li YM, Schilling T, Benisch P, Zeck S, Meissner-Weigl J, Schneider D, Limbert C, Seufert J, Kassem M, Schutze N, Jakob F, Ebert R. Effects of high glucose on mesenchymal stem cell proliferation and differentiation. Biochem Biophys Res Commun. 2007;363(1):209–15.CrossRefPubMedGoogle Scholar
  26. Liu Z, Jiang H, Dong K, Liu S, Zhou W, Zhang J, Meng L, Rausch-Fan X, Xu X. Different concentrations of glucose regulate proliferation and osteogenic differentiation of osteoblasts via the PI3 kinase/Akt pathway. Implant Dent. 2015;24(1):83–91.CrossRefPubMedGoogle Scholar
  27. Lopez-Herradon A, Portal-Nunez S, Garcia-Martin A, Lozano D, Perez-Martinez FC, Cena V, Esbrit P. Inhibition of the canonical Wnt pathway by high glucose can be reversed by parathyroid hormone-related protein in osteoblastic cells. J Cell Biochem. 2013;114(8):1908–16.CrossRefPubMedGoogle Scholar
  28. Ma P, Gu B, Xiong W, Tan B, Geng W, Li J, Liu H. Glimepiride promotes osteogenic differentiation in rat osteoblasts via the PI3K/Akt/eNOS pathway in a high glucose microenvironment. PLoS One. 2014;9(11):e112243.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Manavalan JS, Cremers S, Dempster DW, Zhou H, Dworakowski E, Kode A, Kousteni S, Rubin MR. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(9):3240–50.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Meier C, Seibel MJ, Kraenzlin ME. Use of bone turnover markers in the real world: are we there yet? J Bone Miner Res. 2009;24(3):386–8.CrossRefPubMedGoogle Scholar
  31. Nissen A, Christensen M, Knop FK, Vilsboll T, Holst JJ, Hartmann B. Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans. J Clin Endocrinol Metab. 2014;99(11):E2325–9.CrossRefPubMedGoogle Scholar
  32. Paldanius PM, Ivaska KK, Hovi P, Andersson S, Vaananen HK, Kajantie E, Makitie O. The effect of oral glucose tolerance test on serum osteocalcin and bone turnover markers in young adults. Calcif Tissue Int. 2012;90(2):90–5.CrossRefPubMedGoogle Scholar
  33. Schwetz V, Lerchbaum E, Schweighofer N, Hacker N, Trummer O, Borel O, Pieber TR, Chapurlat R, Obermayer-Pietsch B. Osteocalcin levels on oral glucose load in women being investigated for polycystic ovary syndrome. Endocr Pract. 2014;20(1):5–14.CrossRefPubMedGoogle Scholar
  34. Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev/Aust Assoc Clin Biochem. 2005;26(4):97–122.Google Scholar
  35. Seibel MJ, Lang M, Geilenkeuser WJ. Interlaboratory variation of biochemical markers of bone turnover. Clin Chem. 2001;47(8):1443–50.PubMedGoogle Scholar
  36. Shao X, Cao X, Song G, Zhao Y, Shi B. Metformin rescues the MG63 osteoblasts against the effect of high glucose on proliferation. J Diabetes Res. 2014;2014:453940.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Starup-Linde J. Diabetes, biochemical markers of bone turnover, diabetes control, and bone. Front Endocrinol. 2013;4:21.CrossRefGoogle Scholar
  38. Starup-Linde J. Investigations of diabetic bone disease: literature, registry, and clinical studies. Diss. Videnbasen for Aalborg UniversitetVBN, Aalborg UniversitetAalborg University, Det Sundhedsvidenskabelige Fakultet, The Faculty of Medicine, Klinisk InstitutDepartment of Clinical Medicine. 2015.Google Scholar
  39. Starup-Linde J, Vestergaard P. Biochemical bone turnover markers in diabetes mellitus- a systematic review. Bone. 2015;82:69.CrossRefPubMedGoogle Scholar
  40. Starup-Linde J, Eriksen SA, Lykkeboe S, Handberg A, Vestergaard P. Biochemical markers of bone turnover in diabetes patients – a meta-analysis, and a methodological study on the effects of glucose on bone markers. Osteoporos Int. 2014;25(6):1697–708.CrossRefPubMedGoogle Scholar
  41. Tanaka K, Yamaguchi T, Kanazawa I, Sugimoto T. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun. 2015;461(2):193–9.CrossRefPubMedGoogle Scholar
  42. Terada M, Inaba M, Yano Y, Hasuma T, Nishizawa Y, Morii H, Otani S. Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells. Bone. 1998;22(1):17–23.CrossRefPubMedGoogle Scholar
  43. Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T, Wahl DA, Cooper C, Kanis JA, IOF-IFCC Bone Marker Standards Working Group. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22(2):391–420.CrossRefPubMedGoogle Scholar
  44. 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
  45. Vestergaard P, Rejnmark L, Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia. 2005;48(7):1292–9.CrossRefPubMedGoogle Scholar
  46. Viljakainen H, Ivaska KK, Paldanius P, Lipsanen-Nyman M, Saukkonen T, Pietilainen KH, Andersson S, Laitinen K, Makitie O. Suppressed bone turnover in obesity: a link to energy metabolism? A case–control study. J Clin Endocrinol Metab. 2014;99(6):2155–63.CrossRefPubMedGoogle Scholar
  47. White GH. Metrological traceability in clinical biochemistry. Ann Clin Biochem. 2011;48(Pt 5):393–409.CrossRefPubMedGoogle Scholar
  48. Whitham KM, Milford-Ward A. External quality assessment of bone metabolism marker assays. Initial experiences in a UK NEQAS programme. Clin Chem Lab Med: CCLM/FESCC. 2000;38(11):1121–4.CrossRefGoogle Scholar
  49. Wittrant Y, Gorin Y, Woodruff K, Horn D, Abboud HE, Mohan S, Abboud-Werner SL. High d(+)glucose concentration inhibits RANKL-induced osteoclastogenesis. Bone. 2008;42(6):1122–30.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Wu YY, Yu T, Zhang XH, Liu YS, Li F, Wang YY, Wang YY, Gong P. 1,25(OH)2D3 inhibits the deleterious effects induced by high glucose on osteoblasts through undercarboxylated osteocalcin and insulin signaling. J Steroid Biochem Mol Biol. 2012;132(1–2):112–9.CrossRefPubMedGoogle Scholar
  51. Xu F, Ye YP, Dong YH, Guo FJ, Chen AM, Huang SL. Inhibitory effects of high glucose/insulin environment on osteoclast formation and resorption in vitro. J Huazhong Univ Sci Technolog Med Sci = Hua zhong ke ji da xue xue baoYi xue Ying De wen ban = Huazhong keji daxue xuebaoYixue Yingdewen ban. 2013;33(2):244–9.CrossRefPubMedGoogle Scholar
  52. Xu J, Yue F, Wang J, Chen L, Qi W. High glucose inhibits receptor activator of nuclear factorkappaB ligand-induced osteoclast differentiation via downregulation of vATPase V0 subunit d2 and dendritic cellspecific transmembrane protein. Mol Med Rep. 2015;11(2):865–70.PubMedGoogle Scholar
  53. Zayzafoon M, Stell C, Irwin R, McCabe LR. Extracellular glucose influences osteoblast differentiation and c-Jun expression. J Cell Biochem. 2000;79(2):301–10.CrossRefPubMedGoogle Scholar
  54. Zhen D, Chen Y, Tang X. Metformin reverses the deleterious effects of high glucose on osteoblast function. J Diabetes Complications. 2010;24(5):334–44.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of Endocrinology and Internal MedicineAarhus University HospitalAarhus CDenmark
  2. 2.Department of Clinical BiochemistryAalborg University HospitalAalborgDenmark
  3. 3.Department of EndocrinologyAalborg University HospitalAalborgDenmark

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