Calcified Tissue International

, Volume 59, Supplement 1, pp S2–S9 | Cite as

New developments in biochemical markers for osteoporosis

  • P. Garnero
  • P. D. Delmas
Diagnostics: The Correlation Of Bone Mineral Density And Biochemical Markers To Fracture Risk—Where Do We Go From Here?


The noninvasive assessment of bone turnover has markedly improved in the past few years with the development of sensitive and specific markers of bone formation and bone resorption. Markers of bone formation in serum include total and bone-specific alkaline phosphatase, osteocalcin, and type I collagen carboxyterminal extension peptide. Assessment of bone resorption can be achieved by measuring plasma tartrate-resistant acid phosphate and the urinary excretion (and possibly serum levels) of bone type I collagen degradation products: hydroxyproline, hydroxylysine glycosides, and, more recently, the pyridinium crosslinks (pyridinoline and deoxypyridinoline) and associated peptides. The immunoassay of human osteocalcin and bone alkaline phosphatase for formation and the pyridinoline crosslinks measured by high-pressure liquid chromatography or by immunoassay for bone resorption are currently the most sensitive and specific markers of bone turnover for the clinical assessment of osteoporosis. Using these new markers, several studies have shown that bone turnover increases after the menopause and remains elevated in late postmenopausal and elderly women. An increased bone turnover rate is related to a high rate of bone loss in postmenopausal women and to a decreased bone mass in elderly women. Recent data suggest that some of the new immunoassays for pyridinoline crosslinks could predict the subsequent risk of hip fracture in elderly women. Thus, bone markers might be used in combination with bone mass measurement to improve the prognostic assessment of postmenopausal women, i.e., their risk of developing osteoporosis and ultimately fractures. Treatment of postmenopausal women with antiresorptive drugs such as estrogens, bisphosphonates, and calcitonin induces a rapid decrease in the levels of bone markers that is correlated with the long-term effect of such treatments on bone mass. Thus, bone markers should be very useful in monitoring treatment efficacy in patients with osteoporosis.


Bone Mass Bone Resorption Bone Turnover Osteocalcin Pyridinoline 
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.
    Crilly RG, Jones MM, Horsman A, et al. (1980) Rise in plasma alkaline phosphatase at the menopause. Clin Sei 53: 341–342Google Scholar
  2. 2.
    Brown JP, Delmas PD, Arlot M, et al. (1987) Active bone turnover of the cortico-endosteal envelope in postmenopausal osteoporosis. J Clin Endocrinol Metab 64:954–959PubMedGoogle Scholar
  3. 3.
    Podenphant J, Johansen JS, Thomsen K, et al. (1987) Bone turnover in spinal osteoporosis. J Bone Miner Res 2:497–503PubMedGoogle Scholar
  4. 4.
    Moss DVV (1982) Alkaline phosphatase isoenzymes. Clin Chem 28:2007–2016PubMedGoogle Scholar
  5. 5.
    Farley JR, Chesnut CJ, Baylink DJ (1981) Improved method for quantitative determination in serum alkaline phosphatase of skeletal origin. Clin Chem 27:2002–2007PubMedGoogle Scholar
  6. 6.
    Duda RJ, O’Brien JF, Katzmann JA, et al. (1988) Concurrent assays of circulating bone gla-protein and bone alkaline phosphatase: effects of sex. ase, and metabolic bone disease. J Clin Endocrinol Metab 66:951–957PubMedGoogle Scholar
  7. 7.
    Hill CS, Wolfen RL (1986) The preparation of monoclonal antibodies which react preferentially with human bone alkaline phosphatase and not liver alkaline phosphatase. Clin Chem Acta 186:315–320CrossRefGoogle Scholar
  8. 8.
    Garnero P, Delmas PD (1993) Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometrie assay in patients with metabolic bone disease. J Clin Endocrinol Metab 77(4): 1046–1053PubMedCrossRefGoogle Scholar
  9. 9.
    Price PA (1987) Vitamin K-dependent bone proteins. In: Conn DV, Martin TJ, Meunier PJ (eds) Calcium regulation and bone metabolism. Basic and clinical aspects, vol 9. Elsevier Science Publishers, New York, pp 419–426Google Scholar
  10. 10.
    Price PA, Parthemore JG, Deftos JL (1980) New biochemical marker for bone metabolism. J Clin Invest 66:878–883PubMedCrossRefGoogle Scholar
  11. 11.
    Price PA, Williamson MK, Lothringer JW (1981) Origin of vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone. J Biol Chem 256:12760–12766PubMedGoogle Scholar
  12. 12.
    Lian JB, Gundberg CM ( 1988) Osteocalcin: biochemical considerations and clinical applications. Clin Orthop 226:267–291PubMedGoogle Scholar
  13. 13.
    Delmas PD, Stenner D, Wanner HW, et al. (1983) Serum bone gla-protein increases with aging in normal women: implications for the mechanism of age-related bone loss. J Clin Invest 71:1316–1321PubMedCrossRefGoogle Scholar
  14. 14.
    Thiede MA, Smock SL, Petersen DN, et al. (1994) Presence of messenger of ribonucleic acid encoding osteocalcin, a marker of bone turnover, in bone marrow megakaryocytes and peripheral blood platelets. Endocrinology 135:929–937PubMedCrossRefGoogle Scholar
  15. 15.
    Delmas PD, Wilson DM, Mann KGT et al. (1983) Effect of renal function on plasma levels of bone gla-protein. J Clin Endocrinol Metab 57:1028–1030PubMedGoogle Scholar
  16. 16.
    Delmas PD (1990) Biochemical markers of bone turnover for the clinical assessment of metabolic disease. Endocrinol Metab Clin North Am 19 (1): 1–18PubMedGoogle Scholar
  17. 17.
    Brown JP, Delmas PD, Malaval L, et al. (1984) Serum bone gla-protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet i: 1091–1093CrossRefGoogle Scholar
  18. 18.
    Charles P, Poser JW, Mosekilde L. et al. (1985) Estimation of bone turnover evaluated by 47 calcium kinetics: efficiency of serum bone gamma-carboxyglutamic acid containing protein, serum alkaline phosphatase and urinary hydroxyproline excretion. J Clin Invest 76:2254–2258PubMedCrossRefGoogle Scholar
  19. 19.
    Delmas PD, Malaval L, Arlot ME, et al. (1985) Serum bone gla-protein compared to bone histomorphometry in endocrine diseases. Bone 6:329–341CrossRefGoogle Scholar
  20. 20.
    Delmas PD, Demiaux B, Malaval L, et al. (1986) Serum bone gla-protein (osteocalcin) in primary hyperparathyroidism and in malignant hypercalcemias: comparison with bone histomorphometry. J Clin Invest 77:985–991PubMedCrossRefGoogle Scholar
  21. 21.
    Bataille R, Delmas P, Sany J (1987) Serum bone gla-protein in multiple myeloma. Cancer 59:329–334PubMedCrossRefGoogle Scholar
  22. 22.
    Gundberg C, Weinstein RS. Multiple immunoreactive forms in uremic serum (1986) J Clin Invest 77:1762–1767PubMedCrossRefGoogle Scholar
  23. 23.
    Tracy RP, Andrianorivo A, Riggs BL, et al. (1990) Comparison of monoclonal and polyclonal antibody-based immunoassays for osteocalcin: a study of sources of variation in assay results. J Bone Miner Res 5:451–461PubMedGoogle Scholar
  24. 24.
    Taylor AK, Linkart S, Mohan S, et al. (1990) Multiple osteocalcin fragments in human urine and serum as detected by a midmoiecule osteocalcin radioimmunoassay. J Clin Endocrinol Metab 70:467–472PubMedGoogle Scholar
  25. 25.
    Garnero P, Grimaux M, Seguin P, et al. (1994) Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro. J Bone Miner Res 9(2):255–264PubMedGoogle Scholar
  26. 26.
    Delmas PD, Christiansen C, Mann KG, et al. (1990) Bone gla-protein (osteocalcin) assay standardization report. J Bone Miner Res 1:5–11Google Scholar
  27. 27.
    Simon LS, Krane SMK (1983) Procollagen extension peptides as markers of collagen synthesis. In: Frame B, Potts JT Jr (eds) Clinical disorders of bone and mineral metabolism. Excerpta Medica, Amsterdam, the Netherlands, pp 108–111Google Scholar
  28. 28.
    Parfitt AM, Simon LS, Villanueva AR, et al. (1987) Procollagen type I carboxy-terminal extension peptide in scrum as a marker of collagen biosynthesis in bone: correlation with iliac bone formation rates and comparison with total alkaline phosphatase. J Bone Miner Res 2:427–436PubMedCrossRefGoogle Scholar
  29. 29.
    Hassager C, Fabbri-Mabelli G, Christiansen C (1993) The effect of the menopause and hormone-replacement therapy on serum carboxyterminal propeptide of type I collagen. Osteoporos Int 3:50–52PubMedCrossRefGoogle Scholar
  30. 30.
    Smedsrod B, Melkko J, Ristelli L, et al. (1990) Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. Biochem J 271:345–350PubMedGoogle Scholar
  31. 31.
    Prockop OJ, Kivirikko KI (1968) Hydroxyproline and the metabolism of collagen. In: Gould BS (ed) Treatise on collagen. Academic Press, New York, pp 215–246Google Scholar
  32. 32.
    Prockop OJ, Kivirikko KI, Tuderman K, et al. (1979) The biosynthesis of collagen and its disorders. N End J Med 301: 13–23CrossRefGoogle Scholar
  33. 33.
    Krane SM, Kantrowitz FG, Byrne M, et al. (1977) Urinary excretion of hydroxylysine and its glycosides as an index of collagen degradation. J Clin Invest 59:819–827PubMedCrossRefGoogle Scholar
  34. 34.
    Vloro L, Mucelli RSP, Gazzarrini C. et al. (1988) Urinary ß-1-galactosyi-O-hydroxylysine (GH) as a marker of collagen turnover of bone. Calcif Tissue Int 42:87–90CrossRefGoogle Scholar
  35. 35.
    Li CY. Chuda RA, Lam WKW, et al. (1973) Acid phosphatase in human plasma. J Lab Clin Med 82:446–460PubMedGoogle Scholar
  36. 36.
    Minkin C (1982) Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int 34:285–290PubMedCrossRefGoogle Scholar
  37. 37.
    Stepan JJ, Silinkova-Malkova E, Havrenek T, et al. (1983) Relationship of plasma tartrate-resistant acid phosphatase to the bone isoen/yme of serum alkaline phosphatase in hyperparathyroidism. Clin Chim Acta 133:189–200PubMedCrossRefGoogle Scholar
  38. 38.
    Stepan JJ, Pospichal J, Presl J, et al. (1987) Bone loss and biochemical indices of bone remodeling in surgically induced postmenopausal women. Bone 8:279–284PubMedCrossRefGoogle Scholar
  39. 39.
    Piedra C, Torres R, Rapado A, et al. (1989) Serum tartrate-resistant acid phosphatase and bone mineral content in postmenopausal osteoporosis. Calcif Tissue Int 45:58–60PubMedCrossRefGoogle Scholar
  40. 40.
    Kraenzlin M, Lau KHW, Liang L (1990) Development of an immunoassay for human serum osteoclastic tartrate-resistant acid phosphatase. J Clin Endocrinol Metab 71:442–451PubMedGoogle Scholar
  41. 41.
    Cheun CK, Panesar NS, Haines C, et al. (1995) Immunoassay of tartrate-resistant acid phosphatase in serum. Clin Chem 41:679–686Google Scholar
  42. 42.
    Fujimoto D, Morigachi T, Ishida T, et al. (1978) The structure of pyridinoline, a collagen crosslink. Biochem Biophys Res Commun 84:52–57PubMedCrossRefGoogle Scholar
  43. 43.
    Eyre DR (1987) Collagen crosslinking amino-acids. Methods Enzymol 144:115–139PubMedCrossRefGoogle Scholar
  44. 44.
    Eyre DR, Koob TJ, Van Ness KP (1984) Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal Biochem 137:380–388PubMedCrossRefGoogle Scholar
  45. 45.
    Eyre DR, Dickson IR, Van Ness KP (1988) Collagen cross-linking in human bone and articular cartilage: age-related changes in the content of mature hydroxypyridinium residues. Biochem J 252:495–500PubMedGoogle Scholar
  46. 46.
    Seibel MJ, Robins SP, Bilezikiau JP (1992) Urinary pyridinium crosslinks of collagen. Trends Endocrinoi Metab 3: 263–270CrossRefGoogle Scholar
  47. 47.
    Black D, Duncan A, Robins SP (1988) Quantitative analysis of the pyridinium crosslinks of collagen in urine using ionpaired reversed-phase high-performance liquid chromatography. Anal Biochem 169:197–203PubMedCrossRefGoogle Scholar
  48. 48.
    Beardsworth LJ, Eyre DR, Dickson IR (1990) Changes with age in the urinary excretion of lysyl and hydroxylysylpyridinoline, two new markers of bone collagen turnover. J Bone Miner Res 5:671–676PubMedCrossRefGoogle Scholar
  49. 49.
    Uebelhart D, Schlemmer A, Johansen J, et al. (1991) Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium crosslinks. J Clin Endocrinol Metab 72:367–373PubMedGoogle Scholar
  50. 50.
    Eastell R, Hampton L, Colwell A (1990b) Urinary collagen crosslinks are highly correlated with radio isotopic measurements of bone resorption. In: Christiansen C, Overgaard K (eds) Proc 3rd Int Symp on Osteoporosis. Osteopress, Aalborg, Denmark, pp 469–470Google Scholar
  51. 51.
    Delmas PD, Schlemmer A, Gineyts E, et al. (1991) Urinary excretion of pyridinoline crosslinks correlates with bone turnover measured on iliac crest biopsy in patients with vertebral osteoporosis. J Bone Miner Res 6:639–644PubMedCrossRefGoogle Scholar
  52. 52.
    Uebelhart D, Gineyts E, Chapuy MC, et al. (1990) Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner Res 8: 87–96CrossRefGoogle Scholar
  53. 53.
    Colwell A, Eastell R, Assiri AMA, et al. (1990) Effect of diet on deoxypyrinoline excretion, vol 2. In: Christiansen C, Overgaard K (eds) Osteoporosis. Osteopress, Aalborg, Denmark, pp 520–591Google Scholar
  54. 54.
    Schlemmer A, Hassager C, Jensen SB, et al. (1992) Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 74: 476–480PubMedCrossRefGoogle Scholar
  55. 55.
    Eastell R, Calvo MS, Burritt MF, et al. (1992) Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab 74:487–494PubMedCrossRefGoogle Scholar
  56. 56.
    Blumsohn A, Herringion K, Harmon RA, et al. (1994) The effect of calcium supplementation on the circadian rhythm of bone resorption. J Clin Endocrinol Metab 79:730–735PubMedCrossRefGoogle Scholar
  57. 57.
    Seyedin S, Zuk R, Kung V, et al. (1993) An immunoassay to urinary pyridinoline: the new marker of bone resorption. J Bone Miner Res 8:635–642PubMedCrossRefGoogle Scholar
  58. 58.
    Robins SP, Woitge H, Hesley R, et al. (1994) Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption. J Bone Miner Res 9:1643–1649PubMedCrossRefGoogle Scholar
  59. 59.
    Hanson DA, Weiss MAE, Bollen AM, et al. (1992) A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J Bone Miner Res 7:1251–1258PubMedCrossRefGoogle Scholar
  60. 60.
    Risteli J, Elomaa I, Niemi S. et al. (1993) Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clm Chem 39:635–640Google Scholar
  61. 61.
    Bonde H, Quist P, Fidelins C, et al. (1994) Immunoassay for quantifying type I collagen degradation products in urine evaluated. Clin Chem 40:2022–2025PubMedGoogle Scholar
  62. 62.
    Delmas PD, Gineyts E, Bertholin A, et al. (1993) Immunoassay of pyridinoline crosslink excretion in normal adults and in Paget’s disease. J Bone Miner Res 5:643–648CrossRefGoogle Scholar
  63. 63.
    Garnero P, Gineyts E, Riou JP, et al. (1994) Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease. J Clin Endocrinol Metab 3:780–785CrossRefGoogle Scholar
  64. 64.
    Hassager C, Risteli J, Risteli L, et al. (1992) Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res 7:1307–1311PubMedCrossRefGoogle Scholar
  65. 65.
    Hassager C, Jensen LT, Podenphant J, et al. (1994) The carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen in serum as a marker of bone resorption: the effect of nandrolone decanoate and hormone replacement therapy. Calcif Tissue Int 54:30–33PubMedCrossRefGoogle Scholar
  66. 66.
    Garnero P, Gineyts E, Arbault P, et al. (1995) Different effects of bisphosphonate and estrogen therapy on free and peptidebound crosslinks excretion. J Bone Miner Res 10:641–649PubMedCrossRefGoogle Scholar
  67. 67.
    Eastell R, Delmas PD, Hodgson SF, et al. (1988) Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics and biochemical markers. J Clin Endocrinol Metab 67:741–748PubMedCrossRefGoogle Scholar
  68. 68.
    Garnero P, Sornay-Rendu E, Delmas PD, et al. (1996) Increased bone turnover in late postmenopausal women is a major risk of osteoporosis. J Bone Miner Res 11:337–349PubMedCrossRefGoogle Scholar
  69. 69.
    Slemenda C, Hui SL, Longcope C, et al. (1987) Sex steroids and bone mass: a study of changes about the time of menopause. J Clin Invest 80:1261–1269PubMedCrossRefGoogle Scholar
  70. 70.
    Johansen JS, Riis BJ, Delmas PD, et al. (1988) Plasma BGP: an indicator of spontaneous bone loss and effect of estrogen treatment in postmenopausal women. Eur J Clin Invest 18: 191–195PubMedGoogle Scholar
  71. 71.
    Hansen MA, Overgaard K, Riis BJ, et al. (1991) Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 years study. BMJ 303:961–964PubMedCrossRefGoogle Scholar
  72. 72.
    Riis BJ, Hansen MA, Jensen K, et al. (1996) Low bone mass and fast rate of bone loss at menopause—equal risk factors for future fracture: a 15-year follow-up study. Bone 19:9–12PubMedCrossRefGoogle Scholar
  73. 73.
    Thompson SP, White DA, Hosking DJ. et al. (1980) Changes in osteocalcin alter femoral neck fracture. Ann Clin Biochem 26:487–491Google Scholar
  74. 74.
    Delmi M, Rapin CH, Bengoa JM, et al. (1990) Dietary supplementation in elderly patients with fractured neck of femur. Lancet 335:1013–1016PubMedCrossRefGoogle Scholar
  75. 75.
    Akesson K, Vergnaud P, Gineyts E, et al. (1993) Impairment of bone turnover in elderly women with hip fracture. Calcif Tissue Int 53:162–169PubMedCrossRefGoogle Scholar
  76. 76.
    Garnero P, Hausher E, Chapuy MC, et al. (1996) Markers of bone resorption predict hip fracture in elderly women: The EPIDOS prospective study. J Bone Miner Res (in press)Google Scholar
  77. 77.
    Civitelli R, Gonnelli S, Zacchei F, et al. (1988) Bone turnover in postmenopausal osteoporosis. Effect of calcitonin treatment. J Clin Invest 82:1268–1274PubMedCrossRefGoogle Scholar
  78. 78.
    Garnero P, Shih WJ, Gineyts E, et al. (1994) Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79:1693–1700PubMedCrossRefGoogle Scholar
  79. 79.
    Harris ET, Gertz BJ, Genant HK, et al. (1993) The effect of short-term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab 76(6): 1399–1403PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • P. Garnero
    • 1
  • P. D. Delmas
    • 1
  1. 1.INSERM Research Unit 403Hôpital E. HerriotLyonFrance

Personalised recommendations