Skip to main content

Markers of Bone Turnover in Bone Metastasis from Prostate Cancer

Abstract

Bone homeostasis is achieved through a continuous remodelling process on the bone surface of the balanced resorption of old bone by osteoclasts and the formation of new bone by osteoblasts. Local and systemic growth factors regulate the differentiation and activity of the osteoclasts and osteoblasts (and osteocytes). Maintenance and repair of normal bone result in the release of enzymes, peptides and mineral components that have been characterised as serum and urinary biochemical markers of bone remodelling [1]. High bone turnover in cancer patients is crucial for all the steps of bone metastatic disease, from the homing of circulating cancer cells into the bone (premetastatic niche) to the complication of bone metastasis (BMT) (skeletally related events [SREs]). Therefore, elevated bone turnover marker could predict bone metastasis, risk of bone progression and risk of SREs, potentially becoming a potent prognostic predictor (Fig. 2.1). For this reason, biochemical markers of bone remodelling are potentially an ideal tool for evaluating changes in bone turnover, such as those associated with malignant bone lesions and response to treatment. Osteoclast and osteoblast activity (and probably that of cancer cells) is associated with the release of distinct biochemical markers that are amenable to non-invasive measurements of the blood or urine.

Keywords

  • Zoledronic Acid
  • Prostate Cancer Patient
  • Bone Turnover Marker
  • Bone Marker
  • Bone Metastatic Disease

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.

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-42327-2_2
  • Chapter length: 11 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   109.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-42327-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   149.99
Price excludes VAT (USA)
Hardcover Book
USD   149.99
Price excludes VAT (USA)
Fig. 2.1
Fig. 2.2
Fig. 2.3

References

  1. Fohr B, Dunstan CR, Seibel MJ (2003) Clinical review 165: markers of bone remodeling in metastatic bone disease. J Clin Endocrinol Metab 88(11):5059–5075

    CAS  CrossRef  PubMed  Google Scholar 

  2. 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(2):391–420

    CAS  CrossRef  PubMed  Google Scholar 

  3. Schafer AL, Vittinghoff E, Ramachandran R, Mahmoudi N, Bauer DC (2010) Laboratory reproducibility of biochemical markers of bone turnover in clinical practice. Osteoporos Int 21(3):439–445

    CAS  CrossRef  PubMed  Google Scholar 

  4. Coleman R, Brown J, Terpos E, Lipton A, Smith MR, Cook R, Major P (2008) Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions. Cancer Treat Rev 34(7):629–639

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  5. Jung K, Lein M (2014) Bone turnover markers in serum and urine as diagnostic, prognostic and monitoring biomarkers of bone metastasis. Biochim Biophys Acta 1846(2):425–438

    CAS  PubMed  Google Scholar 

  6. Michaelson MD, Marujo RM, Smith MR (2004) Contribution of androgen deprivation therapy to elevated osteoclast activity in men with metastatic prostate cancer. Clin Cancer Res 10(8):2705–2708

    CAS  CrossRef  PubMed  Google Scholar 

  7. Garnero P, Buchs N, Zekri J, Rizzoli R, Coleman RE, Delmas PD (2000) Markers of bone turnover for the management of patients with bone metastases from prostate cancer. Br J Cancer 82(4):858–864

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  8. Garnero P, Ferreras M, Karsdal MA, Nicamhlaoibh R, Risteli J, Borel O, Qvist P, Delmas PD, Foged NT, Delaissé JM (2003) The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. J Bone Miner Res 18(5):859–867

    CAS  CrossRef  PubMed  Google Scholar 

  9. Costa L, Demers LM, Gouveia-Oliveira A, Schaller J, Costa EB, de Moura MC, Lipton A (2002) Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20(3):850–856

    CAS  CrossRef  PubMed  Google Scholar 

  10. Koizumi M, Yonese J, Fukui I, Ogata E (2001) The serum level of the amino-terminal propeptide of type I procollagen is a sensitive marker for prostate cancer metastasis to bone. BJU Int 87(4):348–351

    CAS  CrossRef  PubMed  Google Scholar 

  11. Zafeirakis AG, Papatheodorou GA, Limouris GS (2010) Clinical and imaging correlations of bone turnover markers in prostate cancer patients with bone only metastases. Nucl Med Commun 31(3):249–253

    CrossRef  PubMed  Google Scholar 

  12. Koopmans N, de Jong IJ, Breeuwsma AJ, van der Veer E (2007) Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach. J Urol 178(3 Pt 1):849–853

    CAS  CrossRef  PubMed  Google Scholar 

  13. Fedarko NS, Jain A, Karadag A, Van Eman MR, Fisher LW (2001) Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer. Clin Cancer Res 7(12):4060–4066

    CAS  PubMed  Google Scholar 

  14. Brown JM, Vessella RL, Kostenuik PJ, Dunstan CR, Lange PH, Corey E (2001) Serum osteoprotegerin levels are increased in patients with advanced prostate cancer. Clin Cancer Res 7(10):2977–2983

    CAS  PubMed  Google Scholar 

  15. Mountzios G, Terpos E, Syrigos K, Papadimitriou C, Papadopoulos G, Bamias A, Mavrikakis M, Dimopoulos MA (2010) Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid. Transl Res 155(5):247–255

    CAS  CrossRef  PubMed  Google Scholar 

  16. Todenhöfer T, Hennenlotter J, Leidenberger P, Wald A, Hohneder A, Kühs U, Mischinger J, Aufderklamm S, Gakis G, Blumenstock G, Stenzl A, Schwentner C (2014) Serum receptor activator of nuclear factor kB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy. BJU Int 113(1):152–159

    CrossRef  PubMed  Google Scholar 

  17. Metwalli AR, Rosner IL, Cullen J, Chen Y, Brand T, Brassell SA, Lesperance J, Porter C, Sterbis J, McLeod DG (2014) Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer. Urol Oncol 32(6):761–768

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  18. Coleman R, Costa L, Saad F, Cook R, Hadji P, Terpos E, Garnero P, Brown J, Body JJ, Smith M, Lee KA, Major P, Dimopoulos M, Lipton A (2011) Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol 80(3):411–432

    CrossRef  PubMed  Google Scholar 

  19. Kamiya N, Suzuki H, Yano M, Endo T, Takano M, Komaru A, Kawamura K, Sekita N, Imamoto T, Ichikawa T (2010) Implications of serum bone turnover markers in prostate cancer patients with bone metastasis. Urology 75(6):1446–1451

    CrossRef  PubMed  Google Scholar 

  20. Saad F, Eastham JA, Smith MR (2012) Biochemical markers of bone turnover and clinical outcomes in men with prostate cancer. Urol Oncol 30(4):369–378

    CAS  CrossRef  PubMed  Google Scholar 

  21. Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, Saad F, Zheng M, Hei YJ, Seaman J, Cook RJ (2005) Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. Clin Oncol 23(22):4925–4935

    CAS  CrossRef  Google Scholar 

  22. Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, Saad F, Smith MR (2006) Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 12(11 Pt 1):3361–3367.99–100

    CAS  CrossRef  PubMed  Google Scholar 

  23. Smith MR, Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, Saad F (2007) Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology 70(2):315–319

    CrossRef  PubMed  PubMed Central  Google Scholar 

  24. Som A, Tu SM, Liu J, Wang X, Qiao W, Logothetis C, Corn PG (2012) Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. Br J Cancer 107(9):1547–1553

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  25. Jung K, Miller K, Wirth M, Albrecht M, Lein M (2011) Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid. Eur Urol 59(4):604–129

    CAS  CrossRef  PubMed  Google Scholar 

  26. Alcaraz A, González-López R, Morote J, de la Piedra C, Meseguer C, Esteban E, Climent M, González-Gragera B, Alvarez-Ossorio JL, Chirivella I, Mellado B, Lara PC, Vázquez F, Contreras JA, Carles J, Murias A, Calderero V, Comet-Batlle J, González-Del Alba A, León-Mateos L, Mañas A, Segarra J, Lassa A, González-Enguita C, Méndez MJ, Samper P, Unda M, Mahillo-Fernández I, Bellmunt J; TUGAMO GROUP (2013) Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: the TUGAMO study. Br J Cancer 109(1):121–30

    Google Scholar 

  27. Brasso K, Christensen IJ, Johansen JS, Teisner B, Garnero P, Price PA, Iversen P (2006) Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate 66(5):503–513

    CAS  CrossRef  PubMed  Google Scholar 

  28. Coleman R, Body JJ, Aapro M et al (2014) Bone health in cancer patients: ESMO Clinical Practice guidelines. Ann Oncol 25:1–14. doi:10.1093/annonc/mdu103

    CrossRef  Google Scholar 

  29. 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(10):2425–2433

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  30. Cavalier E, Bergmann P, Bruyère O, Delanaye P, Durnez A, Devogelaer JP, Ferrari SL, Gielen E, Goemaere S, Kaufman JM, Toukap AN, Reginster JY, Rousseau AF, Rozenberg S, Scheen AJ, Body JJ (2016) The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club. Osteoporos Int 27(7):2181–2195

    CAS  CrossRef  PubMed  Google Scholar 

  31. Wada N, Fujisaki M, Ishii S, Ikeda T, Kitajima M (2001) Evaluation of bone metabolic markers in breast cancer with bone metastasis. Breast Cancer 8:131–137

    CAS  CrossRef  PubMed  Google Scholar 

  32. Ulrich U, Rhiem K, Schmolling J, Flaskamp C, Paffenholz I, Salzer H et al (2001) Cross-linked type Icollagen C- and N-telopeptides in women with bone metastases from breast cancer. Arch Gynecol Obstet 264:186–190

    CAS  CrossRef  PubMed  Google Scholar 

  33. Morra L, Moch H (2011) Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update. Virchows Arch 459(5):465–475

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  34. Sasaki H, Yu CY, Dai M, Tam C, Loda M, Auclair D, Chen LB, Elias A (2003) Elevated serum periostin levels in patients with bone metastases from breast but not lung cancer. Breast Cancer Res Treat 77(3):245–252

    CAS  CrossRef  PubMed  Google Scholar 

  35. Kyutoku M, Taniyama Y, Katsuragi N, Shimizu H, Kunugiza Y, Iekushi K, Koibuchi N, Sanada F, Oshita Y, Morishita R (2011) Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int J Mol Med 28(2):181–186

    CAS  PubMed  Google Scholar 

  36. Contié S, Voorzanger-Rousselot N, Litvin J, Clézardin P, Garnero P (2011) Increased expression and serum levels of the stromal cell-secreted protein periostin in breast cancer bone metastases. Int J Cancer 128(2):352–360

    CrossRef  PubMed  Google Scholar 

  37. Bonnet N, Garnero P, Ferrari S (2015) Periostin action in bone. Mol Cell Endocrinol. pii: S0303-7207(15)30170-2. doi:10.1016/j.mce.2015.12.014

  38. Kruger TE, Miller AH, Godwin AK, Wang J (2014) Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers. Crit Rev Oncol Hematol 89(2):330–341

    CrossRef  PubMed  Google Scholar 

  39. Carlinfante G, Vassiliou D, Svensson O et al (2003) Differential expression of osteopontin and bone sialoprotein in bone metastasis of breast and prostate carcinoma. Clin Exp Metastasis 20:437–444

    CAS  CrossRef  PubMed  Google Scholar 

  40. Khodavirdi AC, Song Z, Yang S et al (2006) Increased expression of osteopontin contributes to the progression of prostate cancer. Cancer Res 66:883–888

    CAS  CrossRef  PubMed  Google Scholar 

  41. Waltregny D, Bellahcene A, Van Riet I, Fisher LW, Young M, Fernandez P et al (1998) Prognostic value of bone sialoprotein expression in clinically localized human prostate cancer. J Natl Cancer Inst 90:1000–1008

    CAS  CrossRef  PubMed  Google Scholar 

  42. Bellahcene A, Kroll M, Liebens F, Castronovo V (1996) Bone sialoprotein expression in primary human breast is associated with bone metastases development. J Bone Miner Res 11:665–670

    CAS  CrossRef  PubMed  Google Scholar 

  43. Uccello M, Malaguarnera G, Vacante M, Motta M (2011) Serum bone sialoprotein levels and bone metastases. J Cancer Res Ther 7:115–119

    CAS  CrossRef  PubMed  Google Scholar 

  44. Jain A, McKnight DA, Fisher LW, Humphreys EB, Mangold LA, Partin AW et al (2009) Small integrin-binding proteins as serum markers for prostate cancer detection. Clin Cancer Res 15:5199–5207

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  45. Ferreira A, Alho I, Casimiro S, Costa L (2015) Bone remodeling markers and bone metastases: from cancer research to clinical implications. Bonekey Rep 4:668

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  46. Larson SR, Zhang X, Dumpit R, Coleman I, Lakely B, Roudier M, Higano CS, True LD, Lange PH, Montgomery B, Corey E, Nelson PS, Vessella RL, Morrissey C (2013) Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate 73(9):932–940

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  47. D’Amelio P, Roato I, Oderda M, Soria F, Zitella A, Ferracini R, Mengozzi G, Gontero P, Isaia GC (2014) DKK-1 in prostate cancer diagnosis and follow up. BMC Clin Pathol 14(1):11

    CrossRef  PubMed  PubMed Central  Google Scholar 

  48. Roato I, D’Amelio P, Gorassini E, Grimaldi A, Bonello L, Fiori C, Delsedime L, Tizzani A, De Libero A, Isaia G, Ferracini R (2008) Osteoclasts are active in bone forming metastases of prostate cancer patients. PLoS One 3(11):e3627

    CrossRef  PubMed  PubMed Central  Google Scholar 

  49. Windrichova J, Fuchsova R, Kucera R, Topolcan O, Fiala O, Finek J, Slipkova D, Karlikova M, Svobodova J (2016) Testing of a novel cancer metastatic multiplex panel for the detection of bone-metastatic disease – a pilot study. Anticancer Res 36(4):1973–1978

    PubMed  Google Scholar 

  50. Li C, Wang J, Kong J, Tang J, Wu Y, Xu E, Zhang H, Lai M (2016) GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget 7(1):860–872

    PubMed  Google Scholar 

  51. Vanhara P, Hampl A, Kozubik A, Soucek K (2012) Growth/differentiation factor-15: prostate-cancer suppressor or promoter? Prostate Cancer Prostatic Dis 15:320–328

    CAS  CrossRef  PubMed  Google Scholar 

  52. Westhrin M, Moen SH, Holien T, Mylin AK, Heickendorff L, Olsen OE, Sundan A, Turesson I, Gimsing P, Waage A, Standal T (2015) Growth differentiation factor 15 (GDF15) promotes osteoclast differentiation and inhibits osteoblast differentiation and high serum GDF15 levels are associated with multiple myeloma bone disease. Haematologica 100:e511–e514

    CrossRef  PubMed  PubMed Central  Google Scholar 

  53. Halleen JM, Tiitinen SL, Ylipahkala H, Fagerlund KM, Vaananen HK (2006) Tartrate-resistant acid phosphatase 5b (TRACP5b) as a marker of bone resorption. Clin Lab 52:499–509

    CAS  PubMed  Google Scholar 

  54. Sarvari BK, Sankara Mahadev D, Rupa S, Mastan SA (2015) Detection of bone metastases in breast cancer (BC) patients by serum tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker and serum alkaline phosphatase (ALP), a bone formation marker, in lieu of whole-body skeletal scintigraphy with technetium99m MDP. Indian J Clin Biochem 30:66–71

    CAS  CrossRef  PubMed  Google Scholar 

  55. Tang C, Liu Y, Qin H, Li X, Guo W, Li J, Wang W, Qu L, Hu H, Xu C, Zheng L, Huang Y, Liu B, Gao H, Halleen JM, Liu X (2013) Clinical significance of serum BAP, TRACP 5b and ICTP as bone metabolic markers for bone metastasis screening in lung cancer patients. Clin Chim Acta 426:102–107

    CAS  CrossRef  PubMed  Google Scholar 

  56. Nishimukai A, Higuchi T, Ozawa H, Yanai A, Miyagawa Y, Murase K, Imamura M, Takatsuka Y, Miyoshi Y (2016) Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases. Breast Cancer. doi:10.1007/s12282-016-0695-2

    Google Scholar 

  57. Mehta RS, Chong DQ, Song M, Meyerhardt JA, Ng K, Nishihara R, Qian Z, Morikawa T, Wu K, Giovannucci EL, Fuchs CS, Ogino S, Chan AT (2015) Association between plasma levels of macrophage inhibitory cytokine-1 before diagnosis of colorectal cancer and mortality. Gastroenterology 149:614–622

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  58. Volck B, Price PA, Johansen JS, Sorensen O, Benfield TL, Nielsen HJ, Calafat J, Borregaard N (1998) YKL40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proc Assoc Am Physicians 110:351–360

    CAS  PubMed  Google Scholar 

  59. Shidfar A, Fatokun T, Ivancic D, Chatterton RT, Khan SA, Wang J (2016) Protein biomarkers for breast cancer risk are specifically correlated with local steroid hormones in nipple aspirate fluid. Horm Cancer 7(4):252–259

    CAS  CrossRef  PubMed  Google Scholar 

  60. Thom I, Andritzky B, Schuch G, Burkholder I, Edler L, Johansen JS, Bokemeyer C, Schumacher U, Laack E (2010) Elevated pretreatment serum concentration of YKL40 — an independent prognostic biomarker for poor survival in patients with metastatic nonsmall cell lung cancer. Cancer 116:4114–4121

    CrossRef  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Francesco Bertoldo MD .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bertoldo, F. (2017). Markers of Bone Turnover in Bone Metastasis from Prostate Cancer. In: Bertoldo, F., Boccardo, F., Bombardieri, E., Evangelista, L., Valdagni, R. (eds) Bone Metastases from Prostate Cancer . Springer, Cham. https://doi.org/10.1007/978-3-319-42327-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-42327-2_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-42326-5

  • Online ISBN: 978-3-319-42327-2

  • eBook Packages: MedicineMedicine (R0)