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Bone turnover markers: use in osteoporosis

Nature Reviews Rheumatology volume 8, pages 379–389 (2012)Cite this article

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Abstract

Biochemical markers of bone turnover (bone turnover markers, BTMs) can be used to study changes in bone remodelling in osteoporosis. Investigators and clinicians should be aware of the appropriate sample collection and storage conditions for optimum measurements of these markers. Improvements in the variability of BTM measurements have resulted from the development of assays for automated analysers, and from international consensus regarding their use. Appropriate reference intervals should be used for the optimum interpretation of results. BTMs can provide information that is useful for the management of patients with osteoporosis, for both the initial clinical assessment and for guiding and monitoring of treatment. BTMs are clinically useful to determine possible causes of secondary osteoporosis by identifying patients with high bone turnover and rapid bone loss. In the follow-up of treatment response, BTM levels respond rapidly to both anabolic and antiresorptive treatments. BTM changes can also be used for understanding the mechanism of action of drugs in development and identifying the correct dose; they are also potentially useful as surrogate biomarkers for fracture.

Key Points

  • In bone remodelling, resorption and formation are tightly coupled; however, pathological and age-related imbalances can cause net bone loss

  • Bone turnover markers (BTMs) comprise markers of formation and of resorption, and can provide a non-invasive assessment of skeletal health

  • Automated analysis has enabled the measurement of BTMs to become widely accessible

  • BTMs are useful for detecting secondary causes of osteoporosis and for monitoring the effects of treatment and/or treatment withdrawal

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Figure 1: Change in BTM levels in response to denosumab therapy for osteoporosis.

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References

  1. Eriksen, E. F., Axelrod, D. W. & Melsen, F. Skeletal growth, modeling and remodeling in Bone Histomorphometry 1–2 (Raven Press, New York, 1994).

    Google Scholar 

  2. Delmas, P. D., Eastell, R., Garnero, P., Seibel, M. J. & Stepan, J. The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos. Int. 11 (Suppl. 6), S2–S17 (2000).

    Article  PubMed  Google Scholar 

  3. Singer, F. R. & Eyre, D. R. Using biochemical markers of bone turnover in clinical practice. Cleve. Clin. J. Med. 75, 739–750 (2008).

    Article  PubMed  Google Scholar 

  4. Brown, J. P. et al. Bone turnover markers in the management of postmenopausal osteoporosis. Clin. Biochem. 42, 929–942 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Kucharz, E. J. The Collagens: Biochemistry and Pathophysiology (Springer-Verlag, Heidelberg, 1992).

    Book  Google Scholar 

  6. Black, D., Duncan, A. & Robins, S. P. Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reversed-phase high performance chromatography. Anal. Biochem. 169, 197–203 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Colwell, A., Russell, R. G. G. & Eastell, R. Factors affecting the assay of urinary 3-hydroxy pyridinium cross-links of collagen as markers of bone resorption. Eur. J. Clin. Invest. 23, 341–349 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Fujimoto, D., Suzuki, M., Uchiyama, A., Miayamoto, S. & Inoue, T. Analysis of pyridinoline, a crosslinking compound of collagen fibres, in human urine. J. Biochem. 94, 1133–1136 (1983).

    Article  CAS  PubMed  Google Scholar 

  9. Eyre, D. R., Koob, T. J. & Van Ness, K. P. Quantitation of hydroxypyridinium crosslinks in collagen by high-performance liquid chromatography. Anal. Biochem. 137, 380–388 (1984).

    Article  CAS  PubMed  Google Scholar 

  10. Robins, S. P. et al. Direct enzyme linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption. J. Bone Miner. Res. 9, 1643–1649 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Fledelius, C., Johansen, J. S., Cloos, P. A. C., Bonde, M. & Qvist, P. Characterization of urinary degradation products derived from type I collagen: identification of a β isomerized ASP-GLY sequence within the C-terminal telopeptide(α-I) region. J. Biol. Chem. 272, 9755–9763 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Hanson, D. A. et al. A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen crosslinked N-telopeptides in urine. J. Bone Miner. Res. 7, 1251–1258 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Clemens, J. D., Herrick, M. V., Singer, F. R. & Eyre, D. R. Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption. Clin. Chem. 43, 2058–2063 (1997).

    CAS  PubMed  Google Scholar 

  14. Bonde, M., Qvist, P., Fledelius, C., Riis, B. J. & Christiansen, C. Immunoassay for quantifying type I collagen degradation products in urine evaluated. Clin. Chem. 40, 2022–2025 (1994).

    CAS  PubMed  Google Scholar 

  15. Risteli, J., Elomaa, I., Niemi, S., Novamo, A. & Risteli, L. Radioimmunoassay for the pyridinoline cross-linked carboxy- terminal telopeptide of Type I collagen degradation. Clin. Chem. 39, 635–640 (1993).

    CAS  PubMed  Google Scholar 

  16. Garnero, P. et al. Decreased β-isomerization of the C-terminal telopeptide of type I collagen αI chain in Paget's disease of bone. J. Bone Miner. Res. 12, 1407–1415 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Garnero, P. et al. Effects of PTH and alendronate on type I collagen isomerization in postmenopausal women with osteoporosis: the PaTH study. J. Bone Miner. Res. 23, 1442–1448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vasikaran, S. et al. International Osteoporosis Foundation and International Federation of Clinical Chemistry and Laboratory Medicine Position on bone marker standards in osteoporosis. Clin. Chem. Lab Med. 49, 1271–1274 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Vasikaran, S. et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos. Int. 22, 391–420 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Garnero, P. et al. The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. J. Bone Miner. Res. 18, 859–867 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Halleen, J. M., Tiitinen, S. L., Ylipahkala, H., Fagerlund, K. M. & Vaananen, H. K. Tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of bone resorption. Clin. Lab 52, 499–509 (2006).

    CAS  PubMed  Google Scholar 

  22. Hannon, R. A. et al. Clinical performance of immunoreactive tartrate-resistant acid phosphatase isoform 5b as a marker of bone resorption. Bone 34, 187–194 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Meier, C. et al. Serum cathepsin K concentrations reflect osteoclastic activity in women with postmenopausal osteoporosis and patients with Paget's disease. Clin. Lab 52, 1–10 (2006).

    CAS  PubMed  Google Scholar 

  24. Melkko, J., Niemi, S., Risteli, L. & Risteli, J. Radioimmunoassay for the carboxyterminal propeptide of human type I procollagen (PICP). Clin. Chem. 36, 1328–1332 (1990).

    CAS  PubMed  Google Scholar 

  25. Melkko, J. et al. Immunoassay for intact amino-terminal propeptide of human type I procollagen. Clin. Chem. 42, 947–954 (1996).

    CAS  PubMed  Google Scholar 

  26. Calvo, M. S., Eyre, D. R. & Gundberg, C. M. Molecular basis and clinical application of biological markers of bone turnover. Endocrine Rev. 17, 333–368 (1996).

    CAS  Google Scholar 

  27. Seibel, M. J. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin. Biochem. Rev. 26, 97–122 (2005).

    PubMed  PubMed Central  Google Scholar 

  28. Price, P. A. & Nishimoto, S. K. Radioimmunoassay for the vitamin K-dependent protein of bone and its discovery in plasma. Proc. Natl Acad. Sci. USA 77, 2234–2238 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cloos, P. A. & Christgau, S. Characterization of aged osteocalcin fragments derived from bone resorption. Clin. Lab. 50, 585–598 (2004).

    CAS  PubMed  Google Scholar 

  30. Mokuda, S. et al. Postmenopausal women with rheumatoid arthritis who are treated with raloxifene or alendronate or glucocorticoids have lower serum undercarboxylated osteocalcin (ucOC) levels. J. Endocrinol. Invest. (2011).

  31. Vergnaud, P. et al. Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS study. J. Clin. Endocrinol. Metab. 82, 719–724 (1997).

    CAS  PubMed  Google Scholar 

  32. Clemens, T. L. & Karsenty, G. The osteoblast: an insulin target cell controlling glucose homeostasis. J. Bone Miner. Res. 26, 677–680 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Vesper, H. W. et al. Assessment and recommendations on factors contributing to preanalytical variability of urinary pyridinoline and deoxypyridinoline. Clin. Chem. 48, 220–235 (2002).

    CAS  PubMed  Google Scholar 

  34. Hannon, R. & Eastell, R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos. Int. 11 (Suppl. 6), S30–S44 (2000).

    Article  PubMed  Google Scholar 

  35. Jensen, J.-E. B., Kollerup, G., Sorensen, H. A. & Sorensen, O. H. Intraindividual variability in bone markers in urine. Scand. J. Clin. Lab. Invest. 57, 29–34 (1997).

    Article  Google Scholar 

  36. Garnero, P., Borel, O. & Delmas, P. D. Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis. Clin. Chem. 47, 694–702 (2001).

    CAS  PubMed  Google Scholar 

  37. Garnero, P., Vergnaud, P. & Hoyle, N. Evaluation of a fully automated serum assay for total N-terminal propeptide of type I collagen in postmenopausal osteoporosis. Clin. Chem. 54, 188–196 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Bergmann, P. et al. Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int. J. Clin. Pract. 63, 19–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, A. J., Hodges, S. & Eastell, R. Measurement of osteocalcin. Ann. Clin. Biochem. 37, 432–446 (2000).

    Article  PubMed  Google Scholar 

  40. Wichers, M., Schmidt, E., Bidlingmaier, F. & Klingmuller, D. Diurnal rhythm of CrossLaps in human serum. Clin. Chem. 45, 1858–1860 (1999).

    CAS  PubMed  Google Scholar 

  41. Qvist, P., Christgau, S., Pedersen, B. J., Schlemmer, A. & Christiansen, C. Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone 31, 57–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Clowes, J. A. et al. Effect of feeding on bone turnover markers and its impact on biological variability of measurements. Bone 30, 886–890 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Henriksen, D. B. et al. Role of gastrointestinal hormones in postprandial reduction of bone resorption. J. Bone Miner. Res. 18, 2180–2189 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Sato, J., Hasegawa, K., Tanaka, H. & Morishima, T. Urinary N-telopeptides of type I collagen in healthy children. Pediatr. Int. 52, 398–401 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Lapillonne, A., Travers, R., Dimaio, M., Salle, B. L. & Glorieux, F. H. Urinary excretion of cross-linked N-telopeptides of type 1 collagen to assess bone resorption in infants from birth to 1 year of age. Pediatrics 110, 105–109 (2002).

    Article  PubMed  Google Scholar 

  46. Naylor, K. E., Iqbal, P., Fledelius, C., Fraser, R. B. & Eastell, R. The effect of pregnancy on bone density and bone turnover. J. Bone Miner. Res. 15, 129–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Veitch, S. W. et al. Changes in bone mass and bone turnover following tibial shaft fracture. Osteoporos. Int. 17, 364–372 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Ivaska, K. K., Gerdhem, P., Akesson, K., Garnero, P. & Obrant, K. J. Effect of fracture on bone turnover markers: a longitudinal study comparing marker levels before and after injury in 113 elderly women. J. Bone Miner. Res. 22, 1155–1164 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Bahar, S. et al. Comparison of the acute alterations in serum bone turnover markers and bone mineral density among women with surgical menopause. Eur. J. Obstet. Gynecol. Reprod. Biol. 159, 194–197. (2011).

    Article  PubMed  Google Scholar 

  50. Prior, J. C. et al. Premenopausal ovariectomy-related bone loss: a randomized, double-blind, one-year trial of conjugated estrogen or medroxyprogesterone acetate. J. Bone Miner. Res. 12, 1851–1863 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Glover, S. J., Garnero, P., Naylor, K., Rogers, A. & Eastell, R. Establishing a reference range for bone turnover markers in young, healthy women. Bone 42, 623–630 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Adami, S. et al. Determinants of bone turnover markers in healthy premenopausal women. Calcif. Tissue Int. 82, 341–347 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Horowitz, G. L. Estimating reference intervals. Am. J. Clin. Pathol. 133, 175–177 (2010).

    Article  PubMed  Google Scholar 

  54. Glover, S. J. et al. Establishing a reference interval for bone turnover markers in 637 healthy, young, premenopausal women from the United Kingdom, France, Belgium, and the United States. J. Bone Miner. Res. 24, 389–397 (2009).

    Article  PubMed  Google Scholar 

  55. Seibel, M. J., Lang, M. & Geilenkeuser, W. J. Interlaboratory variation of biochemical markers of bone turnover. Clin. Chem. 47, 1443–1450 (2001).

    CAS  PubMed  Google Scholar 

  56. United Kingdom National External Quality Assessment Service (online) (2010).

  57. Walsh, L. J., Wong, C. A., Pringle, M. & Tattersfield, A. E. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. BMJ 313, 344–346 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Osteoporosis prevention, diagnosis, and therapy. JAMA 285, 785–795 (2001).

  59. Van Staa, T. P. et al. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum. 48, 3224–3229 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Dovio, A. et al. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J. Clin. Endocrinol. Metab. 89, 4923–4928 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Heuck, C. & Wolthers, O. D. A placebo-controlled study of three osteocalcin assays for assessment of prednisolone-induced suppression of bone turnover. J. Endocrinol. 159, 127–131 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. Suppl. S1–S130 (2009).

  63. Seiler, S., Heine, G. H. & Fliser, D. Clinical relevance of FGF-23 in chronic kidney disease. Kidney Int. Suppl. S34–S42 (2009).

  64. Fliser, D. et al. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J. Am. Soc. Nephrol. 18, 2600–2608 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Garnero, P., Sornay-Rendu, E., Chapuy, M. C. & Delmas, P. D. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J. Bone Miner. Res. 11, 337–349 (1996).

    Article  CAS  PubMed  Google Scholar 

  66. Lofman, O., Magnusson, P., Toss, G. & Larsson, L. Common biochemical markers of bone turnover predict future bone loss: a 5-year follow-up study. Clin. Chim. Acta 356, 67–75 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Rosen, C. J., Chesnut III, C. H. & Mallinak, N. J. S. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J. Clin. Endocrinol. Metab. 82, 1904–1910 (1997).

    CAS  PubMed  Google Scholar 

  68. Rogers, A., Hannon, R. A. & Eastell, R. Biochemical markers as predictors of rates of bone loss after menopause. J. Bone Miner. Res. 15, 1398–1404 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. Eastell, R. et al. Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence. J. Bone Miner. Res. 26, 1662–1669 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Bauer, D. C. et al. Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab 91, 1370–1375 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Garnero, P. et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study. J. Bone Miner. Res. 11, 1531–1538 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. van Daele, P. L. et al. Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study. BMJ 312, 482–483 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Garnero, P., Sornay-Rendu, E., Claustrat, B. & Delmas, P. D. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J. Bone Miner. Res. 15, 1526–1536 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Gerdhem, P. et al. Biochemical markers of bone metabolism and prediction of fracture in elderly women. J. Bone Miner. Res. 19, 386–393 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Ivaska, K. K., Gerdhem, P., Vaananen, H. K., Akesson, K. & Obrant, K. J. Bone turnover markers and prediction of fracture: a prospective follow-up study of 1040 elderly women for a mean of 9 years. J. Bone Miner. Res. 25, 393–403 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Garnero, P., Cloos, P., Sornay-Rendu, E., Qvist, P. & Delmas, P. D. Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study. J. Bone Miner. Res. 17, 826–833 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Johnell, O. et al. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 87, 985–992 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. Ross, P. D. et al. Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study. Osteoporos. Int. 11, 76–82 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Bjarnason, N. H. et al. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos. Int. 12, 922–930 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Bauer, D. C. et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J. Bone Miner. Res. 19, 1250–1258 (2004).

    Article  PubMed  Google Scholar 

  81. Delmas, P. D. et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J. Bone Miner. Res. 24, 1544–1551 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Reginster, J. Y. et al. Reduction in PINP, a marker of bone metabolism, with raloxifene treatment and its relationship with vertebral fracture risk. Bone 34, 344–351 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Sarkar, S. et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J. Bone Miner. Res. 19, 394–401 (2004).

    Article  PubMed  Google Scholar 

  84. Bauer, D. C. et al. Biochemical markers of bone turnover, hip bone loss, and fracture in older men: the MrOS study. J. Bone Miner. Res. 24, 2032–2038 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Riis, B. J., Hansen, M. A., Jensen, A. M., Overgaard, K. & Christiansen, C. 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, 9–12 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Johnell, O. et al. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos. Int. 13, 523–526 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Christiansen, C. et al. Dose dependent effects on bone resorption and formation of intermittently administered intravenous ibandronate. Osteoporos. Int. 14, 609–613 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Hodsman, A. B. et al. Efficacy and safety of human parathyroid hormone-(1–84) in increasing bone mineral density in postmenopausal osteoporosis. J. Clin. Endocrinol. Metab 88, 5212–5220 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Eastell, R. et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J. Bone Miner. Res. 26, 1303–1312 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Lewiecki, E. M. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat. Rev. Rheumatol. 7, 631–638 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Bouxsein, M. L. & Delmas, P. D. Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective. J. Bone Miner. Res. 23, 1155–1167 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Lewiecki, E. M. Benefits and limitations of bone mineral density and bone turnover markers to monitor patients treated for osteoporosis. Curr. Osteoporos. Rep. 8, 15–22 (2010).

    Article  PubMed  Google Scholar 

  93. Hochberg, M. C. et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J. Clin. Endocrinol. Metab. 87, 1586–1592 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Bell, K. J. et al. The potential value of monitoring bone turnover markers among women on alendronate. J. Bone Miner. Res. http://dx.doi.org/10.1002/jbmr.525 (2011).

  95. de Papp, A. E. et al. A cross-sectional study of bone turnover markers in healthy premenopausal women. Bone 40, 1222–1230 (2007).

    Article  PubMed  Google Scholar 

  96. Delmas, P. D. et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J. Clin. Endocrinol. Metab 92, 1296–1304 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Clowes, J. A., Peel, N. F. & Eastell, R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J. Clin. Endocrinol. Metab. 89, 1117–1123 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Silverman, S. L., Nasser, K., Nattrass, S. & Drinkwater, B. Impact of bone turnover markers and/or educational information on persistence to oral bisphosphonate therapy: a community setting-based trial. Osteoporos. Int. 23, 1069–1074 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Braga de Castro, M. A., Hannon, R. & Eastell, R. Monitoring alendronate therapy for osteoporosis. J. Bone Miner. Res. 14, 602–608 (1999).

    Article  Google Scholar 

  100. Orwoll, E. et al. Alendronate for the treatment of osteoporosis in men. N. Engl. J. Med. 343, 604–610 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Orwoll, E. S. et al. Efficacy and safety of monthly ibandronate in men with low bone density. Bone 46, 970–976 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Orwoll, E. S. et al. Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J. Bone Miner. Res. 25, 2239–2250 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Boonen, S. et al. Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J. Bone Miner. Res. 24, 719–725 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Bolland, M. J. et al. Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial. J. Clin. Endocrinol. Metab 92, 1283–1288 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Black, D. M. et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 356, 1809–1822 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Delmas, P. D. et al. Effects of yearly zoledronic acid 5 mg on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J. Bone Miner. Res. 24, 1544–1551 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Eastell, R. et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 530–537 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Miller, P. D. et al. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J. Clin. Endocrinol. Metab 96, 394–402 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Grey, A. et al. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J. Bone Miner. Res. 25, 2251–2255 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Grey, A. et al. Five years of anti-resorptive activity after a single dose of zoledronate—results from a randomized double-blind placebo-controlled trial. Bone http://dx.doi.org/10.1016/j.bone.2012.03.016 (2012).

  111. Glover, S. J. et al. Rapid and robust response of biochemical markers of bone formation to teriparatide therapy. Bone 45, 1053–1058 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. McClung, M. R. et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch. Intern. Med. 165, 1762–1768 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Tsujimoto, M., Chen, P., Miyauchi, A., Sowa, H. & Krege, J. H. PINP as an aid for monitoring patients treated with teriparatide. Bone 48, 798–803 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Eastell, R. et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J. Bone Miner. Res. 18, 1051–1056 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Ensrud, K. E. et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J. Bone Miner. Res. 19, 1259–1269 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Naylor, K. E. et al. The effect of cessation of raloxifene treatment on bone turnover in postmenopausal women. Bone 46, 592–597 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Eastell, R., Hannon, R. A., Wenderoth, D., Rodriguez-Moreno, J. & Sawicki, A. Effect of stopping risedronate after long-term treatment on bone turnover. J. Clin. Endocrinol. Metab 96, 3367–3373 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Miller, P. D. et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43, 222–229 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Gallagher, J. C., Rapuri, P. B., Haynatzki, G. & Detter, J. R. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. J. Clin. Endocrinol. Metab. 87, 4914–4923 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Greenspan, S. L. et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 137, 875–883 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Wasnich, R. D. et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause 11, 622–630 (2004).

    Article  PubMed  Google Scholar 

  122. Sornay-Rendu, E., Garnero, P., Munoz, F., Duboeuf, F. & Delmas, P. D. Effect of withdrawal of hormone replacement therapy on bone mass and bone turnover: the OFELY study. Bone 33, 159–166 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Rogers, A., Saleh, G., Hannon, R. A., Greenfield, D. & Eastell, R. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J. Clin. Endocrinol. Metab 87, 4470–4475 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Naylor, K. E. et al. Serum osteoprotegerin as a determinant of bone metabolism in a longitudinal study of human pregnancy and lactation. J. Clin. Endocrinol. Metab 88, 5361–5365 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Jabbar, S. et al. Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosis. J. Clin. Pathol. 64, 354–357 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Ardawi, M. S., Al-Kadi, H. A., Rouzi, A. A. & Qari, M. H. Determinants of serum sclerostin in healthy pre- and postmenopausal women. J. Bone Miner. Res. 26, 2812–2822 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Mirza, F. S., Padhi, I. D., Raisz, L. G. & Lorenzo, J. A. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J. Clin. Endocrinol. Metab 95, 1991–1997 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Modder, U. I. et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J. Bone Miner. Res. 26, 373–379 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. Sridharan, M. et al. Circulating fibroblast growth factor-23 increases following intermittent parathyroid hormone (1–34) in postmenopausal osteoporosis: association with biomarker of bone formation. Calcif. Tissue Int. 87, 398–405 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Butler, J. S. et al. The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J. Orthop. Res. 29, 414–418 (2011).

    Article  PubMed  Google Scholar 

  131. Rosen, C. J. et al. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J. Bone Miner. Res. 20, 141–151 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Miller, P. D. et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J. Bone Miner. Res. 20, 1315–1322 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J Med. 361, 756–765 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Black, D. M. et al. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N. Engl. J Med. 353, 555–565 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Ettinger, B. et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282, 637–645 (1999).

    Article  CAS  PubMed  Google Scholar 

  136. Chesnut, C. H., III. et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am. J. Med. 109, 267–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. Meunier, P. J. et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J Med. 350, 459–468 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Kraenzlin, M. E. et al. The effect of intranasal salmon calcitonin on postmenopausal bone turnover as assessed by biochemical markers: evidence of maximal effect after 8 weeks of continuous treatment. Calcif. Tissue Int. 58, 216–220 (1996).

    Article  CAS  PubMed  Google Scholar 

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  1. Academic Unit of Bone Metabolism, University of Sheffield, Centre for Biomedical Research, Northern General Hospital, Herries Road, Sheffield, S5 7AU, South Yorkshire, UK

    Kim Naylor & Richard Eastell

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K. Naylor wrote the paper. Both authors contributed equally to researching data for the article, discussing the content and review and/or editing of the article.

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Correspondence to Richard Eastell.

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Competing interests

R. Eastell declares that he receives or has recently received grant support from the following companies: Amgen, Astrazeneca, Crescent Diagnostics, Eli Lilly, Osteologix, Nestle Foundation, Nittoboseki, Procter & Gamble, Sanofi Aventis and Unilever. He has recently received speaker's honoraria and/or travel expenses from the following companies: Amgen, Eli Lilly, Fonterra Brands, GlaxoSmithKline, Medtronics, Novartis, Ono Pharmaceuticals, Procter & Gamble, Roche, Takeda and Unilever. In 2010, he was a consultant for Amgen, Astrazeneca, Eli Lilly, Fonterra Brands, GlaxoSmithKline, Inverness Medical, Johnson & Johnson, Medtronics, Nastech, Nestle, Novartis, Ono Pharmaceuticals, Osteologix, Pfizer, Sanofi Aventis, Tethys, Unilever and Unipath. In 2010 he was on the Advisory Board of Procter & Gamble. K. Naylor declares no competing interests

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Naylor, K., Eastell, R. Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol 8, 379–389 (2012). https://doi.org/10.1038/nrrheum.2012.86

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