Osteoporosis International

, Volume 25, Issue 3, pp 943–952 | Cite as

Reference intervals of bone turnover markers determined by using their curve-fitting valley for adult females in China

  • X.-Y. Wu
  • H. Zhang
  • H. Xie
  • X.-H. Luo
  • Y.-Q. Peng
  • L.-Q. Yuan
  • R.-C. Dai
  • Z.-F. Sheng
  • X.-P. Wu
  • E.-Y. Liao
Original Article



The reference values for bone turnover markers (BTMs) have a significant role in the diagnosis, monitoring, and treatment of metabolic bone disease. This study proposes that the peak value of bone mineral density and the trough value for the BTM curve can be used to determine the reference range of BTM.


The aim of this study is to determine the reference intervals of BTMs for adult females in China with an attempt to reference the peak bone mineral density (BMD) with the corresponding BTM valley.


This study included 546 premenopausal and 394 postmenopausal women. The levels of several BTMs were determined, and the BMD was measured using a dual-energy X-ray absorptiometry.


The BTMs of postmenopausal women were 17–96 % higher than premenopausal women. The change of BTM with age presented an optimal goodness-of-fit according to the cubic regression model (R2 = 0.074–0.346, all P = 0.000). All kinds of BTM levels were positively correlated with age in premenopausal women aged 27–56 years old (r = 0.167–0.502, P = 0.023–0.000). Except for uCTX, the BTM reference value determined using a curve-fitting valley was significantly lower than the reference values for premenopausal women. The BTM reference values determined in this study were also significantly different from the reference values given by the manufacturers of the reagents used.


This study found that the changes of level with age of BTMs in Chinese women present an optimal goodness-of-fit according to the cubic regression model. The fitting valley corresponds to the BMD fitting peak and may possibly be an effective means of determining the BTM reference intervals.


Bone turnover markers Chinese women Curve fitting Reference intervals Valley bone turnover markers 


Conflicts of interest



  1. 1.
    Stepan JJ (2000) Prediction of bone loss in postmenopausal women. Osteoporos Int 11(Suppl 6):S45–S54PubMedCrossRefGoogle Scholar
  2. 2.
    Chaki O, Yoshikata I, Kikuchi R, Nakayama M, Uchiyama Y, Hirahara F, Gorai I (2000) The predictive value of biochemical markers of bone turnover for bone mineral density in postmenopausal Japanese women. J Bone Miner Res 15:1537–1544PubMedCrossRefGoogle Scholar
  3. 3.
    Löfman O, Magnusson P, Toss G, Larsson L (2005) Common biochemical markers of bone turnover predict future bone loss: a 5-year follow-up study. Clin Chim Acta 356:67–75PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshimura N, Hashimoto T, Sakata K, Morioka S, Kasamatsu T, Cooper C (1999) Biochemical markers of bone turnover and bone loss at the lumbar spine and femoral neck: the Taiji study. Calcif Tissue Int 65:198–202PubMedCrossRefGoogle Scholar
  5. 5.
    Dresner-Pollak R, Parker RA, Poku M, Thompson J, Seibel MJ, Greenspan SL (1996) Biochemical markers of bone turnover reflect femoral bone loss in elderly women. Calcif Tissue Int 59:328–333PubMedCrossRefGoogle Scholar
  6. 6.
    Bauer DC, Sklarin PM, Stone KL, Black DM, Nevitt MC, Ensrud KE, Arnaud CD, Genant HK, Garnero P, Delmas PD, Lawaetz H, Cummings SR (1999) Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 14:1404–1410PubMedCrossRefGoogle Scholar
  7. 7.
    Iki M, Morita A, Ikeda Y, Sato Y, Akiba T, Matsumoto T, Nishino H, Kagamimori S, Kagawa Y, Yoneshima H, JPOS Study Group (2006) Biochemical markers of bone turnover predict bone loss in perimenopausal women but not in postmenopausal women—the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 17:1086–1095PubMedCrossRefGoogle Scholar
  8. 8.
    Lenora J, Ivaska KK, Obrant KJ, Gerdhem P (2007) Prediction of bone loss using biochemical markers of bone turnover. Osteoporos Int 18:1297–1305PubMedCrossRefGoogle Scholar
  9. 9.
    Ebeling PR, Atley LM, Guthrie JR, Burger HG, Dennerstein L, Hopper JL, Wark JD (1996) Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab 81:3366–3371PubMedGoogle Scholar
  10. 10.
    Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J (2000) 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–S17PubMedCrossRefGoogle Scholar
  11. 11.
    Garnero P (2000) Markers of bone turnover for the prediction of fracture risk. Osteoporos Int 11(Suppl 6):S55–S65PubMedCrossRefGoogle Scholar
  12. 12.
    Gerdhem P, Ivaska KK, Alatalo SL, Halleen JM, Hellman J, Isaksson A, Pettersson K, Väänänen HK, Akesson K, Obrant KJ (2004) Biochemical markers of bone metabolism and prediction of fracture in elderly women. J Bone Miner Res 19:386–393PubMedCrossRefGoogle Scholar
  13. 13.
    Civitelli R, Armamento-Villareal R, Napoli N (2009) Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int 20:843–851PubMedCrossRefGoogle Scholar
  14. 14.
    Ivaska KK, Gerdhem P, Väänänen HK, Akesson K, Obrant KJ (2010) Bone turnover markers and prediction of fracture: a prospective follow-up study of 1,040 elderly women for a mean of 9 years. J Bone Miner Res 25:393–403PubMedCrossRefGoogle Scholar
  15. 15.
    Vasikaran S, Eastell R, Bruyère 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 (2011) Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 22:391–420PubMedCrossRefGoogle Scholar
  16. 16.
    Reginster JY, Collette J, Neuprez A, Zegels B, Deroisy R, Bruyere O (2008) Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy. Bone 42:832–836PubMedCrossRefGoogle Scholar
  17. 17.
    Tsujimoto M, Chen P, Miyauchi A, Sowa H, Krege JH (2011) PINP as an aid for monitoring patients treated with teriparatide. Bone 48:798–803PubMedCrossRefGoogle Scholar
  18. 18.
    Ravn P, Hosking D, Thompson D, Cizza G, Wasnich RD, McClung M, Yates AJ, Bjarnason NH, Christiansen C (1999) Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 84:2363–2368PubMedGoogle Scholar
  19. 19.
    Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung MR, Reid IR, Resch H, Siris E, Uebelhart D, Wang A, Weryha G, Cummings SR (2011) Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 26:530–537PubMedCrossRefGoogle Scholar
  20. 20.
    Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, Wang A, Siddhanti S, Fitzpatrick LA (2007) Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 22:1832–1841PubMedCrossRefGoogle Scholar
  21. 21.
    McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831PubMedCrossRefGoogle Scholar
  22. 22.
    Cremers S, Garnero P (2006) Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs 66:2031–2058PubMedCrossRefGoogle Scholar
  23. 23.
    Eastell R, Garnero P, Audebert C, Cahall DL (2012) Reference intervals of bone turnover markers in healthy premenopausal women: results from a cross-sectional European study. Bone 50:1141–1147PubMedCrossRefGoogle Scholar
  24. 24.
    Ardawi MS, Maimani AA, Bahksh TA, Rouzi AA, Qari MH, Raddadi RM (2010) Reference intervals of biochemical bone turnover markers for Saudi Arabian women: a cross-sectional study. Bone 47:804–814PubMedCrossRefGoogle Scholar
  25. 25.
    Nishizawa Y, Inaba M, Ishii M, Yamashita H, Miki T, Goto H, Yamada S, Chaki O, Kurasawa K, Mochizuki Y (2008) Reference intervals of serum tartrate-resistant acid phosphatase type 5b activity measured with a novel assay in Japanese subjects. J Bone Miner Metab 26:265–270PubMedCrossRefGoogle Scholar
  26. 26.
    Glover SJ, Gall M, Schoenborn-Kellenberger O, Wagener M, Garnero P, Boonen S, Cauley JA, Black DM, Delmas PD, Eastell R (2009) Establishing a reference interval for bone turnover markers in 637 healthy, young, and premenopausal women from the United Kingdom, France, Belgium, and the United States. J Bone Miner Res 24:389–397PubMedCrossRefGoogle Scholar
  27. 27.
    Glover SJ, Garnero P, Naylor K, Rogers A, Eastell R (2008) Establishing a reference range for bone turnover markers in young, healthy women. Bone 42:623–630PubMedCrossRefGoogle Scholar
  28. 28.
    de Papp AE, Bone HG, Caulfield MP, Kagan R, Buinewicz A, Chen E, Rosenberg E, Reitz RE (2007) A cross-sectional study of bone turnover markers in healthy premenopausal women. Bone 40:1222–1230PubMedCrossRefGoogle Scholar
  29. 29.
    Adami S, Bianchi G, Brandi ML, Giannini S, Ortolani S, DiMunno O, Frediani B, Rossini M (2008) Determinants of bone turnover markers in healthy premenopausal women. Calcif Tissue Int 82:341–347PubMedCrossRefGoogle Scholar
  30. 30.
    Nishizawa Y, Nakamura T, Ohta H, Kushida K, Gorai I, Shiraki M, Fukunaga M, Hosoi T, Miki T, Chaki O, Ichimura S, Nakatsuka K, Miura M (2005) Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004). J Bone Miner Metab 23:97–104PubMedCrossRefGoogle Scholar
  31. 31.
    Iki M, Akiba T, Matsumoto T, Nishino H, Kagamimori S, Kagawa Y, Yoneshima H (2004) Reference database of biochemical markers of bone turnover for the Japanese female population. Japanese Population-based Osteoporosis (JPOS) Study. Osteoporos Int 15:981–991PubMedCrossRefGoogle Scholar
  32. 32.
    Kraenzlin ME, Kraenzlin CA, Meier C, Giunta C, Steinmann B (2008) Automated HPLC assay for urinary collagen cross-links: effect of age, menopause, and metabolic bone diseases. Clin Chem 54:1546–1553PubMedCrossRefGoogle Scholar
  33. 33.
    Pidetcha P, Intramanee S, Patrakarn K, Leelahakul P, Fongsupa S (1999) Reference value for urinary deoxypyridinoline as a specific marker for measuring bone resorption in Thais. J Med Assoc Thail 82:1136–1141Google Scholar
  34. 34.
    Wu XP, Liao EY, Zhang H, Shan PF, Cao XZ, Liu SP (2004) Establishment of BMD reference plots and determination of peak BMD at multiple skeletal regions in mainland Chinese women and the diagnosis of osteoporosis. Osteoporos Int 15:71–79PubMedCrossRefGoogle Scholar
  35. 35.
    Brown JP, Albert C, Nassar BA, Adachi JD, Cole D, Davison KS, Dooley KC, Don-Wauchope A, Douville P, Hanley DA, Jamal SA, Josse R, Kaiser S, Krahn J, Krause R, Kremer R, Lepage R, Letendre E, Morin S, Ooi DS, Papaioaonnou A, Ste-Marie LG (2009) Bone turnover markers in the management of postmenopausal osteoporosis. Clin Biochem 42:929–942PubMedCrossRefGoogle Scholar
  36. 36.
    Szulc P (2012) The role of bone turnover markers in monitoring treatment in postmenopausal osteoporosis. Clin Biochem 45:907–919PubMedCrossRefGoogle Scholar
  37. 37.
    Naylor K, Eastell R (2012) Bone turnover markers: use in osteoporosis. Nat Rev Rheumatol 8:379–389PubMedCrossRefGoogle Scholar
  38. 38.
    Cohen FJ, Eckert S, Mitlak BH (1998) Geographic differences in bone turnover: data from a multinational study in healthy postmenopausal women. Calcif Tissue Int 63:277–282PubMedCrossRefGoogle Scholar
  39. 39.
    Horowitz GL (2010) Estimating reference intervals. Am J Clin Pathol 133:175–177PubMedCrossRefGoogle Scholar
  40. 40.
    Bauer D, Krege J, Lane N, Leary E, Libanati C, Miller P, Myers G, Silverman S, Vesper HW, Lee D, Payette M, Randall S (2012) National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges. Osteoporos Int 23:2425–2433PubMedCrossRefGoogle Scholar
  41. 41.
    Vasikaran SD, Morris HA, Cooper C, Kanis JA (2011) Standardizing biochemical assessment of bone turnover in osteoporosis. Clin Biochem 44:1033–1034PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • X.-Y. Wu
    • 1
  • H. Zhang
    • 1
  • H. Xie
    • 1
  • X.-H. Luo
    • 1
  • Y.-Q. Peng
    • 1
  • L.-Q. Yuan
    • 1
  • R.-C. Dai
    • 1
  • Z.-F. Sheng
    • 1
  • X.-P. Wu
    • 1
  • E.-Y. Liao
    • 1
  1. 1.Institute of Metabolism and Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China

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