Skip to main content
SpringerLink
Log in

Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis

  • Original Articles
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)-receptor activator of NFκB ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemica markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63±7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.

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

Similar content being viewed by others

References

  1. Hofbauer LC, Khosla S, Dunstan CR, Lacey D, Boyle WJ, Riggs BL. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000, 15: 2–12.

    Article  PubMed  CAS  Google Scholar 

  2. Khosla S. The OPG/RANKL/RANK system. Endocrinology 2001, 142: 5050–5.

    Article  PubMed  CAS  Google Scholar 

  3. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000, 289: 1504–8.

    Article  PubMed  CAS  Google Scholar 

  4. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002, 23: 279–302.

    Article  PubMed  CAS  Google Scholar 

  5. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999, 140: 4367–70.

    PubMed  CAS  Google Scholar 

  6. Shevde NK, Bendixen A, Dienger KM, Pike JW. Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 2000, 97: 7829–34.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004, 19: 1059–66.

    Article  PubMed  CAS  Google Scholar 

  8. Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003, 111: 1221–30.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Ettinger B, Black D, Cummings S, Genant H, Gluer C, Lips P and the MORE study group. Raloxifene reduces the risk of incident vertebral fractures: 24 month interim analyses. Ost Int 1998, 8(Suppl 3): 11 (abstract).

    Google Scholar 

  10. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999, 282: 637–45.

    Article  PubMed  CAS  Google Scholar 

  11. Riggs BL, Hartmann LC. Selective estrogen-receptor modulators-mechanisms of action and application to clinical practice. N Eng J Med 2003, 348: 618–29.

    Article  CAS  Google Scholar 

  12. McDonnell DP. Selective estrogen receptor modulators (SERMs): A first step in the development of perfect hormone replaxement therapy regimen. J Soc Gynecol Invest 2000, 7(1 Suppl): S10–5.

    Article  CAS  Google Scholar 

  13. Cheung J, Mak YT, Papaioannou S, Evans BA, Fogelman I, Hampson G. Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene. J Endocrinol 2003, 177: 423–33.

    Article  PubMed  CAS  Google Scholar 

  14. Viereck V, Gründker C, Blashke S, et al. Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J Clin Endocrinol Metab 2003, 88: 4206–13.

    Article  PubMed  CAS  Google Scholar 

  15. Bashir A, Mak YT, Sankaralingam S, et al. Changes in RAN-KL/OPG/RANK gene expression in peripheral mononuclear cells following treatment with estrogen or raloxifene. Steroids 2005, 70: 847–55.

    Article  PubMed  CAS  Google Scholar 

  16. Messalli EM, Mainini G, Scaffa C, et al. Raloxifene theraphy interacts with serum osteoprotegerin in postmenopausal ostoporosis. Maturitas 2007, 56: 38–44.

    Article  PubMed  CAS  Google Scholar 

  17. Mezquita-Raya P, de la Higuera M, Fernández-García D, et al. The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos Int 2005, 6: 1368–74.

    Article  Google Scholar 

  18. Compston JE. Sex esteroides and bone. Physiol Rev 2001, 81: 419–47.

    PubMed  CAS  Google Scholar 

  19. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin /RANKL/RANK system for bone and vascular diseases. JAMA 2004, 292: 490–5.

    Article  PubMed  CAS  Google Scholar 

  20. Naylor KE, Rogers A, Fraser RB, Hall V, Eastell R, Blumsohn A. Serum osteoprotegerin as a determinant of bone metabolism in a longitudinal study of human pregnancy and lactation. J Clin Endocrinol Metab 2003, 88: 5361–5.

    Article  PubMed  CAS  Google Scholar 

  21. Hegedus D, Ferencz V, Lakatos PL, et al. Decreased bone density, elevated serum osteoprotegerin, and b-cross-laps in Wilson disease. J Bone Miner Res 2002, 17: 1961–7.

    Article  PubMed  CAS  Google Scholar 

  22. Hofbauer LC, Schoppet M, Schüller P, Viereck V, Christ M. Effects of oral contraceptives on circulating osteoprotegerin and soluble RANK ligand serum levels in healthy young women. Clin Endocrinol (Oxf) 2004, 60: 214–9.

    Article  CAS  Google Scholar 

  23. Hofbauer LC, Dunstan CR, Spelberg TC, Riggs BL, Khosla S. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein 2, and cytokines. Byochem Biophys Res Commun 2001, 280: 334–9.

    Article  CAS  Google Scholar 

  24. Kitazawa S, Kajimoto K, Kondo T, Takeshi Kondo, Kitazawa R. Vitamin D3 supports osteoclastogenesis via functional vitamin D response element of human RANKL gene promoter. J Cell Biochem 2003, 89: 771–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bone Metabolic Unit, Endocrinology Division, University Hospital San Cecilio Granada, RETICEF, Spain

    D. Fernández-García, M. Muñoz-Torres, M. de la Higuera, G. Alonso, R. Reyes-García, A. Sebastian Ochoa & F. Escobar-Jiménez

  2. Endocrinology Division, Hospital Torrecárdenas, Spain

    P. Mezquita-Raya

  3. Biochemistry Division, University Hospital San Cecilio, Granada

    M. E. Ruiz-Requena

  4. Biostatistics Department, School of Medicine, Granada, Spain

    J. Dios Luna

Authors
  1. D. Fernández-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Muñoz-Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Mezquita-Raya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. de la Higuera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G. Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Reyes-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Sebastian Ochoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. E. Ruiz-Requena
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Dios Luna
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F. Escobar-Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Muñoz-Torres.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernández-García, D., Muñoz-Torres, M., Mezquita-Raya, P. et al. Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis. J Endocrinol Invest 31, 416–421 (2008). https://doi.org/10.1007/BF03346385

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03346385

Key-words

Search

Navigation