Methods in Bone Biology in Animals: Biochemical Markers

  • Markus Herrmann


Osteoporosis represents a chronic disease, which is usually preceded by an extended period of time during which bone metabolism is already disturbed. In humans this period can last for more than a decade.


Bone Resorption Bone Turnover Strontium Ranelate Bone Resorption Marker Bone Formation Marker 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1.  1.
    Seibel MJ. Biochemical markers of bone remodeling. Endocrinol Metab Clin North Am. 2003;32:83-113.PubMedCrossRefGoogle Scholar
  2.  2.
    Seibel MJ. Biochemical markers of bone turnover: Part I: Biochemistry and variability. Clin Biochem Rev. 2005;26:97-122.PubMedGoogle Scholar
  3.  3.
    Herrmann M, Klitscher D, Georg T, Frank J, Marzi I, Herrmann W. Different kinetics of bone markers in normal and delayed fracture healing of long bones. Clin Chem. 2002;48:2263-2266.PubMedGoogle Scholar
  4.  4.
    Garnero P, Piperno M, Gineyts E, Christgau S, Delmas PD, Vignon E. Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage. Ann Rheum Dis. 2001;60:619-626.PubMedCrossRefGoogle Scholar
  5.  5.
    Berger CE, Kroner A, Kristen KH, Minai-Pour M, Leitha T, Engel A. Spontaneous osteonecrosis of the knee: biochemical markers of bone turnover and pathohistology. Osteoar­thritis Cartilage. 2005;13:716-721.PubMedCrossRefGoogle Scholar
  6.  6.
    Berger CE, Kroner AH, Minai-Pour MB, Ogris E, Engel A. Biochemical markers of bone metabolism in bone marrow edema syndrome of the hip. Bone. 2003;33:346-351.PubMedCrossRefGoogle Scholar
  7.  7.
    Herrmann M, Seibel M. The amino- and carboxyterminal cross-linked telopeptides of collagen type I, NTX-I and CTX-I: a comparative review. Clin Chim Acta. 2008;393:57-75.PubMedCrossRefGoogle Scholar
  8.  8.
    Ott SM. Histomorphometric measurements of bone turnover, mineralization, and volume. Clin J Am Soc Nephrol. 2008;3(Suppl 3):S151-S156.PubMedCrossRefGoogle Scholar
  9.  9.
    Pogoda P, Priemel M, Rueger JM, Amling M. Bone remodeling: new aspects of a key process that controls skeletal maintenance and repair. Osteoporos Int. 2005;16(Suppl 2): S18-S24 (Epub November 16, 2004; S18–S24).PubMedCrossRefGoogle Scholar
  10. 10.
    Seeman E. Bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19:219-233.PubMedGoogle Scholar
  11. 11.
    Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem. 1999;45:1353-1358.PubMedGoogle Scholar
  12. 12.
    Sorensen MG, Henriksen K, Schaller S, Karsdal MA. Biochemical markers in preclinical models of osteoporosis. Biomarkers. 2007;12:266-286.PubMedCrossRefGoogle Scholar
  13. 13.
    Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther. 2008;12:157-170.PubMedGoogle Scholar
  14. 14.
    Stein GS, Lian JB. Molecular mechanisms mediating proliferation/differentiation interrelationships during progressive development of the osteoblast phenotype. Endocr Rev. 1993;14:424-442.PubMedGoogle Scholar
  15. 15.
    Owen TA, Aronow M, Shalhoub V, et al. Progressive development of the rat osteoblast phenotype in vitro: reciprocal relationships in expression of genes associated with osteoblast proliferation and differentiation during formation of the bone extracellular matrix. J Cell Physiol. 1990;143:420-430.PubMedCrossRefGoogle Scholar
  16. 16.
    Lian JB, Stein GS. Concepts of osteoblast growth and differentiation: basis for modulation of bone cell development and tissue formation. Crit Rev Oral Biol Med. 1992;3:269-305.PubMedGoogle Scholar
  17. 17.
    Siggelkow H, Rebenstorff K, Kurre W, et al. Development of the osteoblast phenotype in primary human osteoblasts in culture: comparison with rat calvarial cells in osteoblast differentiation. J Cell Biochem. 1999;75:22-35.PubMedCrossRefGoogle Scholar
  18. 18.
    Leeming DJ, Alexandersen P, Karsdal MA, Qvist P, Schaller S, Tanko LB. An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice. Eur J Clin Pharmacol. 2006;62:781-792.PubMedCrossRefGoogle Scholar
  19. 19.
    Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA. 2008;105:5266-5270.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell. 2007;130:456-469.PubMedCrossRefGoogle Scholar
  21. 21.
    Nesbitt SA, Horton MA. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science. 1997;276:266-269.PubMedCrossRefGoogle Scholar
  22. 22.
    Vaananen HK, Zhao H, Mulari M, Halleen JM. The cell biology of osteoclast function. J Cell Sci. 2000;113:377-381.PubMedGoogle Scholar
  23. 23.
    Vaaraniemi J, Halleen JM, Kaarlonen K, et al. Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res. 2004;19:1432-1440.PubMedCrossRefGoogle Scholar
  24. 24.
    Halleen JM, Alatalo SL, Janckila AJ, Woitge HW, Seibel MJ, Vaananen HK. Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption. Clin Chem. 2001;47:597-600.PubMedGoogle Scholar
  25. 25.
    Halleen JM, Ranta R. Tartrate-resistant acid phosphatase as a serum marker of bone resorption. Am Clin Lab. 2001;20:29-30.PubMedGoogle Scholar
  26. 26.
    Halleen JM. Tartrate-resistant acid phosphatase 5B is a specific and sensitive marker of bone resorption. Anticancer Res. 2003;23:1027-1029.PubMedGoogle Scholar
  27. 27.
    Minkin C. Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int. 1982;34:285-290.PubMedCrossRefGoogle Scholar
  28. 28.
    Chu P, Chao TY, Lin YF, Janckila AJ, Yam LT. Correlation between histomorphometric parameters of bone resorption and serum type 5b tartrate-resistant acid phosphatase in uremic patients on maintenance hemodialysis. Am J Kidney Dis. 2003;41:1052-1059.PubMedCrossRefGoogle Scholar
  29. 29.
    Janckila AJ, Nakasato YR, Neustadt DH, Yam LT. Disease-specific expression of tartrate-resistant acid phosphatase isoforms. J Bone Miner Res. 2003;18:1916-1919.PubMedCrossRefGoogle Scholar
  30. 30.
    Janckila AJ, Takahashi K, Sun SZ, Yam LT. Tartrate-resistant acid phosphatase isoform 5b as serum marker for osteoclastic activity. Clin Chem. 2001;47:74-80.PubMedGoogle Scholar
  31. 31.
    Meier C, Meinhardt U, Greenfield JR, et al. Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget’s disease. Clin Lab. 2006;52:1-10.PubMedGoogle Scholar
  32. 32.
    Fuller K, Lawrence KM, Ross JL, et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone. 2008;42:200-211.PubMedCrossRefGoogle Scholar
  33. 33.
    Skoumal M, Haberhauer G, Kolarz G, Hawa G, Woloszczuk W, Klingler A. Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther. 2005;7:R65-R70.PubMedCrossRefGoogle Scholar
  34. 34.
    Munoz-Torres M, Reyes-Garcia R, Mezquita-Raya P, et al. Serum cathepsin K as a marker of bone metabolism in postmenopausal women treated with alendronate. Maturitas. 2009;64:188-192.PubMedCrossRefGoogle Scholar
  35. 35.
    Saftig P, Hunziker E, Everts V, et al. Functions of cathepsin K in bone resorption: lessons from cathepsin K deficient mice. Adv Exp Med Biol. 2000;477:293-303.PubMedCrossRefGoogle Scholar
  36. 36.
    Gowen M, Lazner F, Dodds R, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res. 1999; 14:1654-1663.PubMedCrossRefGoogle Scholar
  37. 37.
    McCudden CR, Kraus VB. Biochemistry of amino acid racemization and clinical application to musculoskeletal disease. Clin Biochem. 2006;39:1112-1130.PubMedCrossRefGoogle Scholar
  38. 38.
    Garnero P, Ferreras M, Karsdal MA, et al. The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. J Bone Miner Res. 2003;18:859-867.PubMedCrossRefGoogle Scholar
  39. 39.
    Kong QQ, Sun TW, Dou QY, et al. Beta-CTX and ICTP act as indicators of skeletal metastasis status in male patients with non-small cell lung cancer. Int J Biol Markers. 2007;22:214-220.PubMedGoogle Scholar
  40. 40.
    Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L. Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem. 1993; 39:635-640.PubMedGoogle Scholar
  41. 41.
    Risteli J, Risteli L. Analysing connective tissue metabolites in human serum. Biochemical, physiological and methodological aspects. J Hepatol. 1995;22:77-81.PubMedCrossRefGoogle Scholar
  42. 42.
    Risteli L, Risteli J. Biochemical markers of bone metabolism. Ann Med. 1993;25:385-393.PubMedCrossRefGoogle Scholar
  43. 43.
    DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80: 1689S-1696S.PubMedGoogle Scholar
  44. 44.
    Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22: 477-501.PubMedCrossRefGoogle Scholar
  45. 45.
    Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.PubMedCrossRefGoogle Scholar
  46. 46.
    Lepage R, Roy L, Brossard JH, et al. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem. 1998;44:805-809.PubMedGoogle Scholar
  47. 47.
    Solal ME, Sebert JL, Boudailliez B, et al. Comparison of intact, midregion, and carboxy terminal assays of parathyroid hormone for the diagnosis of bone disease in hemodialyzed patients. J Clin Endocrinol Metab. 1991;73:516-524.PubMedCrossRefGoogle Scholar
  48. 48.
    Stability of N-MID osteocalcin in serum, heparin- and EDTA-plasma over a 24 month period at −70°C. 2010. 18-3-2010. Ref Type: Internet Communication.
  49. 49.
    Bais R, Edwards JB. An optimized continuous-monitoring procedure for semiautomated determination of serum acid phosphatase activity. Clin Chem. 1976;22:2025-2028.PubMedGoogle Scholar
  50. 50.
    Tsutsumi H, Katagiri K, Morimoto M, Nasu T, Tanigawa M, Mamba K. Diurnal variation and age-related changes of bone turnover markers in female Gottingen minipigs. Lab Anim. 2004;38:439-446.PubMedCrossRefGoogle Scholar
  51. 51.
    Srivastava AK, Bhattacharyya S, Li X, Mohan S, Baylink DJ. Circadian and longitudinal variation of serum C-telopeptide, osteocalcin, and skeletal alkaline phosphatase in C3H/HeJ mice. Bone. 2001;29:361-367.PubMedCrossRefGoogle Scholar
  52. 52.
    Clowes JA, Hannon RA, Yap TS, Hoyle NR, Blumsohn A, Eastell R. Effect of feeding on bone turnover markers and its impact on biological variability of measurements. Bone. 2002;30:886-890.PubMedCrossRefGoogle Scholar
  53. 53.
    Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int. 2000;11:S30-S44.PubMedCrossRefGoogle Scholar
  54. 54.
    Bernardi D, Zaninotto M, Plebani M. Requirements for improving quality in the measurement of bone markers. Clin Chim Acta. 2004;346:79-86.PubMedCrossRefGoogle Scholar
  55. 55.
    Eriksen EF, Charles P, Melsen F, Mosekilde L, Risteli L, Risteli J. Serum markers of type I collagen formation and degradation in metabolic bone disease: correlation with bone histomorphometry. J Bone Miner Res. 1993;8:127-132.PubMedCrossRefGoogle Scholar
  56. 56.
    Schaller S, Henriksen K, Sveigaard C, et al. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res. 2004;19:1144-1153.PubMedCrossRefGoogle Scholar
  57. 57.
    Visentin L, Dodds RA, Valente M, et al. A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J Clin Invest. 2000;106:309-318.PubMedCrossRefGoogle Scholar
  58. 58.
    Garnero P, Gineyts E, Schaffer AV, Seaman J, Delmas PD. Measurement of urinary excretion of nonisomerized and beta-isomerized forms of type I collagen breakdown products to monitor the effects of the bisphosphonate zoledronate in Paget’s disease. Arthritis Rheum. 1998;41:354-360.PubMedCrossRefGoogle Scholar
  59. 59.
    Chapurlat RD, Garnero P, Breart G, Meunier PJ, Delmas PD. Serum type I collagen breakdown product (serum CTX) predicts hip fracture risk in elderly women: the EPIDOS study. Bone. 2000;27:283-286.PubMedCrossRefGoogle Scholar
  60. 60.
    Hamrick MW, Ding KH, Pennington C, et al. Age-related loss of muscle mass and bone strength in mice is associated with a decline in physical activity and serum leptin. Bone. 2006;39:845-853.PubMedCrossRefGoogle Scholar
  61. 61.
    Corlett SC, Couch M, Care AD, Sykes AR. Measurement of plasma osteocalcin in sheep: assessment of circadian variation, the effects of age and nutritional status and the response to perturbation of the adrenocortical axis. Exp Physiol. 1990;75:515-527.PubMedGoogle Scholar
  62. 62.
    Farrugia W, Fortune CL, Heath J, Caple IW, Wark JD. Osteocalcin as an index of osteoblast function during and after ovine pregnancy. Endocrinology. 1989;125:1705-1710.PubMedCrossRefGoogle Scholar
  63. 63.
    Sigrist IM, Gerhardt C, Alini M, Schneider E, Egermann M. The long-term effects of ovariectomy on bone metabolism in sheep. J Bone Miner Metab. 2007;25:28-35.PubMedCrossRefGoogle Scholar
  64. 64.
    DeLaurier A, Jackson B, Pfeiffer D, Ingham K, Horton MA, Price JS. A comparison of methods for measuring serum and urinary markers of bone metabolism in cats. Res Vet Sci. 2004;77:29-39.PubMedCrossRefGoogle Scholar
  65. 65.
    Ladlow JF, Hoffmann WE, Breur GJ, Richardson DC, Allen MJ. Biological variability in serum and urinary indices of bone formation and resorption in dogs. Calcif Tissue Int. 2002;70:186-193.PubMedCrossRefGoogle Scholar
  66. 66.
    Hoegh-Andersen P, Tanko LB, Andersen TL, et al. Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res Ther. 2004; 6:R169-R180.PubMedCrossRefGoogle Scholar
  67. 67.
    Chavassieux P, Garnero P, Duboeuf F, et al. Effects of a new selective estrogen receptor modulator (MDL 103, 323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study. J Bone Miner Res. 2001;16:89-96.PubMedCrossRefGoogle Scholar
  68. 68.
    Lane NE. An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 2001;27:235-253.PubMedCrossRefGoogle Scholar
  69. 69.
    Tsugeno H, Goto B, Fujita T, et al. Oral glucocorticoid-induced fall in cortical bone volume and density in postmenopausal asthmatic patients. Osteoporos Int. 2001;12:266-270.PubMedCrossRefGoogle Scholar
  70. 70.
    Canalis E. Mechanisms of glucocorticoid-induced osteoporosis. Curr Opin Rheumatol. 2003;15:454-457.PubMedCrossRefGoogle Scholar
  71. 71.
    Schorlemmer S, Gohl C, Iwabu S, Ignatius A, Claes L, Augat P. Glucocorticoid treatment of ovariectomized sheep affects mineral density, structure, and mechanical properties of cancellous bone. J Bone Miner Res. 2003;18:2010-2015.PubMedCrossRefGoogle Scholar
  72. 72.
    Iwamoto J, Seki A, Takeda T, Yamada H, Sato Y, Yeh JK. Effects of alfacalcidol on cancellous and cortical bone mass in rats treated with glucocorticoid: a bone histomorphometry study. J Nutr Sci Vitaminol (Tokyo). 2007;53:191-197.CrossRefGoogle Scholar
  73. 73.
    Kaji H, Yamauchi M, Chihara K, Sugimoto T. Glucocorticoid excess affects cortical bone geometry in premenopausal, but not postmenopausal, women. Calcif Tissue Int. 2008;82:182-190.PubMedCrossRefGoogle Scholar
  74. 74.
    Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102:274-282.PubMedCrossRefGoogle Scholar
  75. 75.
    O’Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology. 2004;145:1835-1841.PubMedCrossRefGoogle Scholar
  76. 76.
    Weinstein RS, Chen JR, Powers CC, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest. 2002;109:1041-1048.PubMedGoogle Scholar
  77. 77.
    King CS, Weir EC, Gundberg CW, Fox J, Insogna KL. Effects of continuous glucocorticoid infusion on bone metabolism in the rat. Calcif Tissue Int. 1996;59:184-191.PubMedCrossRefGoogle Scholar
  78. 78.
    Herrmann M, Henneicke H, Street J, et al. The challenge of continuous exogenous glucocorticoid administration in mice. Steroids. 2009;74:245-249.PubMedCrossRefGoogle Scholar
  79. 79.
    Chavassieux P, Buffet A, Vergnaud P, Garnero P, Meunier PJ. Short-term effects of corticosteroids on trabecular bone remodeling in old ewes. Bone. 1997;20:451-455.PubMedCrossRefGoogle Scholar
  80. 80.
    O’Connell SL, Tresham J, Fortune CL, et al. Effects of prednisolone and deflazacort on osteocalcin metabolism in sheep. Calcif Tissue Int. 1993;53:117-121.PubMedCrossRefGoogle Scholar
  81. 81.
    Karsdal MA, Henriksen K, Sorensen MG, et al. Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol. 2005;166:467-476.PubMedCrossRefGoogle Scholar
  82. 82.
    Ding M, Cheng L, Bollen P, Schwarz P, Overgaard S. Glucocorticoid induced osteopenia in cancellous bone of sheep: validation of large animal model for spine fusion and biomaterial research. Spine (Phila Pa 1976). 2010;35:363-370.CrossRefGoogle Scholar

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© Springer-Verlag London Limited 2011

Authors and Affiliations

  1. 1.Ageing Bone Research Centre, Sydney Medical School – Nepean CampusThe University of SydneyPenrithAustralia

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