Skip to main content

Advertisement

SpringerLink
Log in

Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study

  • CANCER
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

The purpose was to investigate the association between serum osteoprotegerin (OPG) and risk of incident cancer and cancer mortality in a general population. OPG was measured in serum collected from 6,279 subjects without prior cancer recruited from a general population. Incident cancer and cancer-related mortality were registered from inclusion in 1994–95 until end of follow-up December 31, 2008. Cox regression models were used to estimate crude and adjusted (for age, sex and other confounders) hazard ratios and 95 % confidence intervals (HR 95 % CI). There were 948 incident cancers and 387 deaths in the cohort during 71,902 person-years of follow up (median 13.5 years). Subjects with serum OPG in the upper tertile had 79 % higher risk of incident gastrointestinal cancer than those in the lowest tertile (HR 1.79, 95 % CI 1.19–2.67). In women <60 years, serum OPG (per SD 0.81 ng/ml) was associated with reduced risk of incident cancer (all cancers merged; 0.73; 0.57–0.94) and breast cancer (0.51; 0.31–0.83) after adjustment. Subjects in the upper tertile of OPG had higher risk of cancer-related mortality (1.63; 1.16–2.28), particularly mortality from cancer in the gastrointestinal system (2.28; 1.21–4.28) compared to those in the lowest OPG tertile. No significant association was detected between OPG and risk of death from cancer in the respiratory system or death from prostatic cancer. Our findings from a large population based cohort study suggest that serum OPG was associated with increased risk of incident gastrointestinal cancer, inversely associated with breast cancer, and predicts cancer-related mortality.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. PNAS. 1998;95(7):3597–602.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273(23):14363–7.

    Article  CAS  PubMed  Google Scholar 

  3. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89(2):309–19.

    Article  CAS  PubMed  Google Scholar 

  4. Reid P, Holen I. Pathophysiological roles of osteoprotegerin (OPG). Eur J Cell Biol. 2009;88(1):1–17.

    Article  CAS  PubMed  Google Scholar 

  5. Holen I, Croucher PI, Hamdy FC, Eaton CL. Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer Res. 2002;62(6):1619–23.

    CAS  PubMed  Google Scholar 

  6. Neville-Webbe HL, Cross NA, Eaton CL, et al. Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. Breast Cancer Res Treat. 2004;86(3):269–79.

    Article  CAS  PubMed  Google Scholar 

  7. Shipman CM, Croucher PI. Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res. 2003;63(5):912–6.

    CAS  PubMed  Google Scholar 

  8. Holen I, Cross SS, Neville-Webbe HL, et al. Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo–a role in tumour cell survival? Breast Cancer Res Treat. 2005;92(3):207–15.

    Article  CAS  PubMed  Google Scholar 

  9. Cross SS, Yang Z, Brown NJ, et al. Osteoprotegerin (OPG)–a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis? Int J Cancer. 2006;118(8):1901–8.

    Article  CAS  PubMed  Google Scholar 

  10. Benslimane-Ahmim Z, Heymann D, Dizier B, et al. Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties. J Thromb Haemost. 2011;9(4):834–43.

    Article  CAS  PubMed  Google Scholar 

  11. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immun. 1995;3(6):673–82.

    Article  CAS  Google Scholar 

  12. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271(22):12687–90.

    Article  CAS  PubMed  Google Scholar 

  13. Schramek D, Leibbrandt A, Sigl V, et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature. 2010;468(7320):98–102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Gonzalez-Suarez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature. 2010;468(7320):103–7.

    Article  CAS  PubMed  Google Scholar 

  15. Tan W, Zhang W, Strasner A, et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011;470(7335):548–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Vik A, Mathiesen EB, Brox J, et al. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromso Study. J Thromb Haemost. 2011;9(4):638–44.

    Article  CAS  PubMed  Google Scholar 

  17. Vik A, Mathiesen EB, Johnsen SH, et al. Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population—the Tromso study. J Thromb Haemost. 2010;8(5):898–905.

    CAS  PubMed  Google Scholar 

  18. Larsen IK, Småstuen M, Johannesen TB, et al. Data quality at the cancer registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45(7):1218–31.

    Article  PubMed  Google Scholar 

  19. Kiechl S, Schett G, Wenning G, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109(18):2175–80.

    Article  CAS  PubMed  Google Scholar 

  20. Kiechl S, Willeit J, Schett G, et al. Denosumab, Osteoporosis, and prevention of fractures. N Engl J Med. 2009;361(22):2188–91.

    Article  CAS  PubMed  Google Scholar 

  21. Ito R, Nakayama H, Yoshida K, et al. Expression of osteoprotegerin correlates with aggressiveness and poor prognosis of gastric carcinoma. Virchows Arch. 2003;443(2):146–51.

    Article  CAS  PubMed  Google Scholar 

  22. Pettersen I, Bakkelund W, Smedsrød B, Sveinbjørnsson B. Osteoprotegerin is expressed in colon carcinoma cells. Anticancer Res. 2005;25(6B):3809–16.

    CAS  PubMed  Google Scholar 

  23. De Toni EN, Thieme SE, Herbst A, et al. OPG is regulated by beta-catenin and mediates resistance to TRAIL-induced apoptosis in colon cancer. Clin Cancer Res. 2008;14(15):4713–8.

    Article  PubMed  Google Scholar 

  24. Lipton A, Ali SM, Leitzel K, et al. Serum osteoprotegerin levels in healthy controls and cancer patients. Clin Cancer Res. 2002;8(7):2306–10.

    CAS  PubMed  Google Scholar 

  25. Tsukamoto S, Ishikawa T, Iida S, et al. Clinical significance of osteoprotegerin expression in human colorectal cancer. Clin Cancer Res. 2011;17(8):2444–50.

    Article  CAS  PubMed  Google Scholar 

  26. Canon J, Bryant R, Roudier M, Branstetter DG, Dougall WC. RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. Breast Cancer Res Treat. 2012;135(3):771–80.

    Article  CAS  PubMed  Google Scholar 

  27. Santini D, Schiavon G, Vincenzi B, et al. Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PLoS ONE. 2011;6(4):e19234.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kamiya N, Suzuki H, Endo T, et al. Significance of serum osteoprotegerin and receptor activator of nuclear factor κB ligand in Japanese prostate cancer patients with bone metastasis. Int J Clin Oncol. 2011;16(4):366–72.

    Article  Google Scholar 

  29. Peng X, Guo W, Ren T, et al. Differential expression of the RANKL/RANK/OPG system is associated with bone metastasis in human non-small cell lung cancer. PLoS ONE. 2013;8(3):e58361.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Van Geelen CM, de Vries EG, de Jong S. Lessons from TRAIL-resistance mechanisms in colorectal cancer cells: paving the road to patient-tailored therapy. Drug Resist Updates. 2004;7(6):345–58.

    Article  Google Scholar 

  31. Ryser MD, Qu Y, Komarova SV. Osteoprotegerin in bone metastases: mathematical solution to the puzzle. PLoS Comput Biol. 2012;8(10):e1002703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Vik A, Brodin E, Sveinbjornsson B, Hansen JB. Heparin induces mobilization of osteoprotegerin into the circulation. Thromb Haemost. 2007;98(1):148–54.

    CAS  PubMed  Google Scholar 

  33. Kiechl S, Schett G, Schwaiger J, et al. Soluble receptor activator of nuclear factor-kappa B ligand and risk for cardiovascular disease. Circulation. 2007;116(4):385–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors disclose no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Hematological Research Group (HERG), Department of Clinical Medicine, University of Tromsø, N-9037, Tromsø, Norway

    Anders Vik, Ellen E. Brodin, Jan Brox, Sigrid K. Brækkan & John-Bjarne Hansen

  2. Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway

    Anders Vik, Ellen E. Brodin, Sigrid K. Brækkan & John-Bjarne Hansen

  3. Brain and Circulation Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway

    Ellisiv B. Mathiesen

  4. Department of Neurology and Clinical Neurophysiology, University Hospital of North Norway, Tromsø, Norway

    Ellisiv B. Mathiesen

  5. Division of Laboraory Medicine, University Hospital of North Norway, Tromsø, Norway

    Jan Brox

  6. Department of Health and Care Sciences, University of Tromsø, Tromsø, Norway

    Lone Jørgensen

  7. Department of Clinical Therapeutic Services, University Hospital of North Norway, Tromsø, Norway

    Lone Jørgensen

  8. Department of Community Medicine, University of Tromsø, Tromsø, Norway

    Inger Njølstad

Authors
  1. Anders Vik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ellen E. Brodin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ellisiv B. Mathiesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Brox
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lone Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Inger Njølstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sigrid K. Brækkan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John-Bjarne Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anders Vik.

Additional information

The study is supported by independent grants from the University of Tromsø and the Northern Norway Regional Health Authority.

Appendix

Appendix

See Tables 6, 7 and 8.

Table 6 Age- and sex-stratified hazard ratios (HR) with 95 % confidence intervals (CI) for incident cancer across OPG tertile groups and per SD increase in OPG levels
Full size table
Table 7 Age stratified hazard ratios (HR) with 95 % confidence intervals (CI) for incident breast cancer and gastrointestinal cancer across tertiles of osteoprotegerin (OPG) and per 1 standard deviation (SD)* increase in OPG levels
Full size table
Table 8 Hazard ratios with 95 % confidence intervals (HR 95 % CI) of death of cancer calculated for OPG tertile groups and per SD (women; 1.06 ng/ml, men; 1.17 ng/ml) increase in OPG levels in women (n = 3,174) and men (n = 3,105)
Full size table

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vik, A., Brodin, E.E., Mathiesen, E.B. et al. Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study. Eur J Epidemiol 30, 219–230 (2015). https://doi.org/10.1007/s10654-014-9975-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-014-9975-3

Keywords

Search

Navigation