The role of bone metabolism parameters in the assessment of myeloma bone disease

Authors: V. Ščudla 1;  P. Petrová 2;  P. Lochman 2;  J. Minařík 1;  T. Pika 1;  J. Bačovský 1
Authors‘ workplace: III. interní klinika-nefrologická, revmatologická a endokrinologická FN a LF UP Olomouc 1;  Oddělení klinické biochemie FN a LF UP Olomouc 2
Published in: Klin. Biochem. Metab., 21 (42), 2013, No. 2, p. 71-78


The aim of this contribution is to present up to date information regarding bone metabolism in multiple myeloma (MM). Special attention is dedicated to the general role of bone remodellation markers in the assessment of myeloma bone disease (MBD), and the parameters of bone resorption and osteogenesis from the point of their significance in clinical practice. Individual chapters aim at the relationship of bone resorption and osteogenesis markers to the severity of MBD, and to the stage, grade, activity and prognosis of multiple myeloma, and differences between monoclonal gammopathy of undetermined significance (MGUS) and MM. Interest is dedicated to the contribution of monitoring of bone resorption markers, i.e. S-ICTP and U-NTX, and not very satisfactory significance of osteogenesis markers, i.e. S-bALP and S-osteocalcin in the course of MM treatment including anti-resorption treatment with bisphosphonates. We present information about new and perspective molecules involved in bone remodellation process in MM, i.e. RANKL/osteoprotegerin index, Dickkopf-1 (Dkk-1), activin-A and osteosclerostin. The outcome of the paper is the summary of convenient markers of bone metabolism, recommended for the use in standard clinical practice by International Myeloma Working Group.

multiple myeloma, myeloma bone disease, bone resorption markers (S-ICTP, U-NTX, S-TRACP-5b), osteogenesis markers (S-bALP, S-osteocalcin), RANKL/osteoprotegerin, DKK-1, therapy.


1. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Brit. J. Haematol., 2003, 12, p. 749-757.

2. Sezer, O. Myeloma bone disease: recent advances in biology, diagnosis, and treatment. Oncologist, 2009, 14, p. 276-283.

3. Dimopoulos, M., Terpos, E., Comenzo, R. L. et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia, 2009, 23, p. 1545-1556.

4. Ščudla, V. Postižení skeletu u mnohočetného myelomu. Postgr. Med., 2011, 13, p. 728-736.

5. Ščudla, V., Adam, Z. Současné možnosti diagnostiky a léčby myelomové kostní nemoci v klinické praxi. Vnitř. Lék., 2012, 58, CD164- CD174.

6. Adam, Z., Ševčík P., Vorlíček, J. et al. Kostní nádorová choroba. Praha: Grada Publishing, 2005, p. 296, ISBN 80-247-1357-8.

7. Roodman, G. D. Pathogenesis of myeloma bone di-sease. Leukemia, 2009, 23, p. 435-441.

8. Mundy, G. R., Raisz, L. G., Cooper, R. A. et al. Evidence for secretion of an osteoclast stimulating factor in myeloma. N. Engl. Med., 1974, 291, s.1041-1046.

9. Li, Z-W., Chen, H., Campbell, R. A. et al. NF-κB in the pathogenesis and treatment of multiple myeloma. Curr. Opinion Hematol., 2008, 15, p. 391-399.

10. Andrews, N. A. Multiple myeloma bone diseases: targeting osteoclasts and osteoblasts. IBMS BoneKEy 9, 50(2012)/ doi:10.1038/bonekey, 2012.50

11. Roodman, G. D. New potential targets for treating myeloma bone disease. Clin. Cancer Res., 2006, 12, Suppl. 20, p. 6270-6273.

12. Roodman, G. D. Pathogenesis of myeloma bone di-sease. Leukemia, 2009, 23, p. 435-441.

13. Roodman, G. D. Myeloma bone disease. New York: Human Press, 2010, 252 p. ISBN 978-1-60761-553-8.

14. Terpos, E., Dimopoulos, M. A., Sezer, O. et al. The use of biochemical markers of bone remodeling in multiple myeloma: a report of the International Myeloma Working Group. Leukemia, 2010, 24, p. 1700-1712.

15. Terpos, E., Dimopoulos, M. A. Myeloma bone di-sease: pathophysiology and management. Ann. Oncol., 2005, 16, p. 1223-1231.

16. Terpos, E., Sezer, O., Croucher, P. et al. Myeloma bone disease and proteosome inhibition therapy. doi:10.1182/blood-2007-03-067710.

17. Coleman, R. E., Major, P., Lipton, A. et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J. Clin. Oncol., 2005, 23, p. 4925-4935.

18. Janckila, A. J., Takahashi, K., Sun, S. Z. et al. Tartrate-resistant acid phosphatase isoform-5b as serum marker for osteoclastic activity. Clin. Chem., 2001, 47, p. 4-80.

19. Terpos, E. Biochemical markers of bone metabolism in multiple myeloma. Cancer Treat. Reviews, 2006, 32, Suppl.1, p. 15-19.

20. Heider, U., Kaiser, M., Muller, C. et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur. J. Haematol., 2006, 77, p. 233-238.

21. Delmas, P. D. Bone marker nomenclature. Bone, 2001, 28, p. 575-576.

22. Carlson, K., Larson, A., Simonsson, B. et al. Evaluation of bone disease in multiple myeloma: a comparison between the resorption marker urinary deoxypyrolidine/creatinine (DPD) and serum ICTP, and evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios. Eur. J. Haematol., 1999, 62, p. 300-306.

23. Abildgaard, N., Bentzen, S. M., Nielsen, J. L. for the Nordic Myeloma Study Group (NMSG). Serum markers of bone metabolism in multiple myeloma: Prognostic va-lue of the carboxy-terminal telopeptide of type I collagen (ICTP). Brit. J. Haematol., 1997, 96, p. 103-110.

24. Abildgaard, N., Brixen, K., Kristensen, J. E. et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pre-treatment levels of S-ICTP and U-NTX are predictive for early progression of the bone disease during standard chemotherapy. Brit. J. Haematol., 2003, 120, p. 235-242.

25. Abildgaard N., Brixen, K., Eriksen, E. F. et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma. Haematologica, 2004, 89, p. 567-577.

26. Fonseca, R., Trendle, M. C., Leong, T. et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Brit. J. Haematol., 2000, 109, p. 24-29.

27. Jakob, C., Zavrski, I., Heider, U. et al. Serum levels of carboxy-terminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifesttations in magnetic resonance imaging but lacking lytic bone lesions in conventional radiography. Clin. Cancer. Res., 2003, 9, s.3047-3051.

28. Alexandrakis, M. G., Kyriakou, D. S., Passam, F. H. et al. Urinary N-telopeptide levels in multiple myeloma patients, correlation with Tc-99m-sestaMIBI scintigraphy and other biochemical markers of disease activity. Hematol. Oncol., 2003, 21, s.17-24.

29. Coleman, R. E., Major, P., Lipton, A. et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J. Clin. Oncol., 2005, 23, p. 4925-4935.

30. Jakob, C., Sterz, J., Liebisch, P. et al. Incorporation of the bone marker carboxy-terminal telopetide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma. Leukemia, 2008, 22, p. 1767-1772.

31. Ščudla, V., Budíková, M., Pika, T. et al. Srovnání sérových hladin vybraných biologických působků u mono-klonální gamapatie nejistého významu a mnohočetného myelomu. Čas. Lék. Čes., 2009, 148, p. 315-322.

32. Scudla, V., Pika, T., Budikova, M. et al. The importance of serum levels of selected biological parameters in the diagnosis, staging and prognosis of multiple myeloma. Neoplasma, 2010, 57, p. 102-110.

33. Terpos, E., Berenson, J., Lipton, A. et al. High baseline NTX predicts for inferior survival and shorter time to first SRE in multiple myeloma. Clin. Lymphoma Myeloma, 2009, 9,(Suppl 1), p. 50-51.

34. Raje, N., Roodman, D. Advances in the biology and treatment of bone disease in multiple myeloma. Clin. Cancer Res., 2011, 17, p. 1278-1286.

35. Berenson, J. R. The use of bisphosphonates in patients with multiple myeloma. UP To Date 2012.

36. Henry, D., Moss, R., Vadhan-Raj, S. et al. A double-blind, randomized study of denosumab versus zoledro-nic acid for the treatment of bone metastases in patients with advances cancer or multiple myeloma. Eur. J. Cancer, 2009, 12, Suppl.3, abstract 20LBA.

37. Lipton, A., Cook, R. J., Coleman, R. E. et al. Clinical utility of biochemical markers of bone metabolism for improving the management of patients with advanced multiple myeloma. Clin. Lymphoma Myeloma, 2007, 7, p. 346-353.

38. Tosi, P., Zamagni, E., Cellini, C. et al. First-line therapy with thalidomide, dexamethasone and zoledronic acid decreas bone resorption markers in patients with multiple myeloma. Eur. J. Haematol., 2006, 76, p. 399-404.

39. Terpos, E., Mihou, D., Szydlo, R. et al. The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia, 2005, 19, p. 1969-1976.

40. Breitkreutz, I., Raab, M. S., Vallet, S. et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia, 2008, 22, p. 1925-1932.

41. Terpos, E., Heath, D. J., Rahemtulla, A. et al. Borte-zomib reduces serum Dickkopf-1 and receptor activator of nuclear factor –κB ligand concentrations and normalises indices of bone remodeling in patients with relapsed multiple myeloma. Brit. J. Haematol., 2006, 135, p. 688-692.

42. Giuliani, N., Morandi, F., Tagliaferri, S. et al. The proteasome inhibitor bortezomib effects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood, 2007, 110, p. 334-338.

43. Terpos, E., Kastritis, E., Roussou, M. et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angioge-nesis. Leukemia, 2008, 22, p. 2247-2256.

44. Zangari, M., Esseltine, D., Cavallo, F. et al. Predictive value of alkaline phosphatase for response and time to progression in bortezomib-treated multiple myeloma patients. Am. J. Hematol., 2007, 82, p. 197-198.

45. Corso, A., Dovio, A., Rusconi, C. et al. Osteoprotegerin serum levels in multiple myeloma and MGUS patients compared with age and sex-matched healthy controls. Leukemia, 2004, 18, p. 1555- 1557.

46. Tian, E., Zhan, F., Walker, R. et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med., 2003, 349, p. 2483-2494.

47. Heider, U., Kaiser, M., Mieth, M. et al. Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment. Eur. J. Haematol., 2009, 82, p. 31-38

48. Zangari, M., Terpos, E., Zhan, F., Tricot, G. Impact of bortezomib on bone health in myeloma: a review of current evidence. doi:10.1016/j.ctrv.2011.12.007.

49. Yacoby, S., Ling, W., Zhan, F. et al. Antibody-based inhibition of DKK-1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. doi:10.1182/blood-2006-09-047712.

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