Unusual Association between Increased Bone Resorption and Presence of Paroxysmal Nocturnal Hemoglobinuria Phenotype in Multiple Myeloma

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) clones deficient in glycosylphosphatidylinositol-anchored molecules, including CD55 and CD59, have been previously described in patients with multiple myeloma (MM). The aim of this study was to investigate the possible association between existence of the PNH phenotype and myeloma bone disease. Forty-three patients with newly diagnosed MM were the subjects of the study. Radiographic evaluation of the skeleton was performed in all patients at diagnosis. The following biochemical markers were measured: bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b]and N-terminal cross-linking telopeptide of type-I collagen [NTX]), bone formation markers (bone alkaline phosphatase [bALP] and osteocalcin [OC]), osteoprotegerin (OPG), soluble receptor activator of nuclear factor κB ligand (sRANKL), and interleukin 6 (IL-6). Detection of CD55- and/or CD59-deficient red cell populations was performed after diagnosis. Patients with MM had elevated mean baseline NTX, TRACP-5b, sRANKL, and IL-6 levels compared with controls, whereas the mean values of bALP, OC, and OPG were significantly decreased. Four patients had no osteolytic lesions, whereas 8 patients had 1 to 3 lytic lesions, and 31 patients had more than 3 lytic lesions and/or pathologic fractures in the skeletal survey. CD55- and/or CD59-deficient red cell populations were observed in 56% of patients with MM. There was a strong correlation between the presence of PNH-like erythrocytes and increased bone resorption, as measured by NTX,TRACP-5b, and sRANKL/OPG ratio (P < .03,P < .02, andP < .02, respectively). There was also a significant correlation between PNH phenotype and severe bone disease (P < .02). These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment on a preexisting PNH clone. Further studies are required for clarifying this phenomenon and investigating possible mechanisms of this unusual association.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Berenson JR. New advances in the biology and treatment of myeloma bone disease.Semin Hematol. 2001;38:15–20.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Suda T, Nakamura I, Jimi E, Takahashi N. Regulation of osteoclast function.J Bone Miner Res. 1997;12:869–879.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Seidel C, Hjertner O, Abildgaard N, et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease.Blood. 2001;98:2269–2271.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Terpos E, Szydlo R, Apperley J, et al. Soluble receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio predicts survival in multiple myeloma: proposal for a novel prognostic index.Blood. 2003;102:1064–1069.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment.Blood. 2001;98:3527–3533.

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Szulc P, Delmas PD. Biochemical markers of bone turnover in men.Calcif Tissue Int. 2001;69:229–234.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Halleen JM, Ylipahkala H, Alatalo SL, et al. Serum tartrate-resistant acid phosphatase 5b, but not 5a, correlates with other markers of bone turnover and bone mineral density.Calcif Tissue Int. 2002;71:20–25.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Halleen JM, Alatalo SL, Suominen H, Cheng S, Janckila AJ, Vaananen HK. Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption.J Bone Miner Res. 2000;15:1337–1345.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Terpos E, Viniou N, de la Fuente J, et al. Pamidronate is superior to ibandronate in decreasing bone resorption, interleukin-6 and beta2-microglobulin in multiple myeloma.Eur J Haematol. 2003;70:34–42.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Halleen JM, Alatalo SL, Janckila AJ, Woitge HW, Seibel MJ, Vaananen HK. Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption.Clin Chem. 2001;47:597–600.

    PubMed  CAS  Google Scholar 

  11. 11.

    Terpos E, de la Fuente J, Szydlo R, et al. Tartrate-resistant acid phosphatase isoform 5b: a novel serum marker for monitoring bone disease in multiple myeloma.Int J Cancer. 2003;106:455–457.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Meletis J, Terpos E. Paroxysmal nocturnal haemoglobinuria: clinical presentation and association with other haematological disorders.Haema. 2001;4:79–88.

    Google Scholar 

  13. 13.

    Tremml G, Karadimitris A, Luzzatto L. Paroxysmal nocturnal hemoglobinuria: learning about PNH cells from patients and mice.Haema. 1998;1:12–20.

    Google Scholar 

  14. 14.

    Luzzatto L, Bessler M. The dual pathogenesis of PNH.Curr Opin Hematol. 1996;3:101–110.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Nakakuma H, Kawaguchi T. Pathogenesis of selective expansion of PNH clones.Int J Hematol. 2003;77:121–124.

    Article  PubMed  Google Scholar 

  16. 16.

    Walport MJ. Complement. First of two parts.N Engl J Med. 2001;344:1058–1066.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Meletis J, Terpos E, Samarkos M, et al. Detection of CD55 and/or CD59 deficient red cell populations in patients with aplastic anemia, myelodysplastic syndromes and myeloproliferative disorders.Haematologia (Budap). 2001;31:7–16.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Wang H, Chuhjo T, Yasue S, Omine M, Nakao S. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome.Blood. 2002;100:3897–3902.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Meletis J, Terpos E, Samarkos M, et al. Detection of CD55 and/or CD59 deficient red cell populations in patients with lymphoproliferative syndromes.Hematol J. 2001;2:33–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. 20.

    Meletis J, Terpos E, Samarkos M, et al. Red cells with paroxysmal nocturnal hemoglobinuria-phenotype in patients with acute leukemia.Hematology. 2002;7:69–74.

    Article  PubMed  Google Scholar 

  21. 21.

    Meletis J, Terpos E, Samarkos M, et al. Detection of CD55 and/or CD59 deficient red cell populations in patients with plasma cell dyscrasias.Int J Hematol. 2002:75:40–44.

    Article  PubMed  Google Scholar 

  22. 22.

    Meletis J, Michali E, Samarkos M, et al. Detection of “PNH red cell” populations in hematological disorders using the Sephacryl Gel Test micro typing system.Leuk Lymphoma. 1997;28:177–182.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Noguera ME, Leymarie V, Bittencourt E, Gluckman E, Sigaux F, Socie G. Aplastic anemia and paroxysmal nocturnal hemoglobinuria: a follow-up study of the glycosylphosphatidylinositol-anchored proteins defect.Hematol J. 2000;1:250–253.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Ware RE, Pickens CV, DeCastro CM, Howard TA. Circulating PIG-A mutant T lymphocytes in healthy adults and patients with bone marrow failure syndromes.Exp Hematol. 2001;29:1403–1409.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression.Proc Natl Acad Sci U S A. 2001;98:11581–11586.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Sezer O, Heider U, Zavrski I, Kuehne CA, Hofbauer LC. RANK ligand and osteoprotegerin in myeloma bone disease.Blood. 2003;101:2094–2098.

    Article  PubMed  CAS  Google Scholar 

  27. 27.

    Standal T, Seidel C, Hjertner O, et al. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells.Blood. 2002;100:3002–3007.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Terpos E, Hatziharissi E, Szydlo R, et al. Autologous stem cell transplantation improves abnormal bone turnover in multiple myeloma [abstract].Blood. 2002;100:434a.

    Google Scholar 

  29. 29.

    Chaidos AI, Bai MC, Kamina SA, Kanavaros PE, Agnantis NJ, Bourantas KL. Incidence of apoptosis and cell proliferation in multiple myeloma: correlation with bcl-2 protein expression and serum levels of interleukin-6 (IL-6) and soluble IL-6 receptor.Eur J Haematol. 2002;69:90–94.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Terpos E, Palermos J, Tsionos K, et al. Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma.Eur J Haematol. 2000;65:331–336.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Hatanaka M, Seya T, Matsumoto M, et al. Mechanisms by which the surface expression of the glycosyl-phosphatidylinositol-anchored complement regulatory proteins decay-accelerating factor (CD55) and CD59 is lost in human leukaemia cell lines.Biochem J. 1996;314:969–976.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Araten D, Nafa K, Pakdeesuwan K, Luzzatto L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals.Proc Natl Acad Sci U S A. 1999;96:5209–5214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Yamaguchi M, Machii T, Azenishi Y, et al. Detection of small population of CD59-deficient erythrocytes in patients with aplastic anemia or myelodysplastic syndromes and normal individuals.Blood Cells Mol Dis. 2000;26:247–254.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Rawstron AC, Rollinson SJ, Richards S, et al. The PNH phenotype cells that emerge in most patients after CAMPATH-1H therapy are present prior to treatment.Br J Haematol. 1999;107:148–153.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Evangelos Terpos or Michalis Samarkos or Christos Meletis or Effie Apostolidou or Maria Tsironi or Konstantinos Korovesis or Despina Mavrogianni or Nora Viniou or John Meletis.

About this article

Cite this article

Terpos, E., Samarkos, M., Meletis, C. et al. Unusual Association between Increased Bone Resorption and Presence of Paroxysmal Nocturnal Hemoglobinuria Phenotype in Multiple Myeloma. Int J Hematol 78, 344–348 (2003). https://doi.org/10.1007/BF02983560

Download citation

Key words

  • Multiple myeloma
  • Paroxysmal nocturnal hemoglobinuria
  • Tartrate-resistant acid phosphatase isoform 5b (TRACP-5b)
  • N-terminal cross-linking telopeptide of type I collagen (NTX)
  • Soluble receptor activator of nuclear factor κB ligand (sRANKL)