Osteoporosis International

, Volume 16, Issue 11, pp 1368–1374 | Cite as

The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women

  • Pedro Mezquita-Raya
  • Magdalena de la Higuera
  • Diego Fernández García
  • Guillermo Alonso
  • María Estrella Ruiz-Requena
  • Juan de Dios Luna
  • Fernando Escobar-Jiménez
  • Manuel Muñoz-Torres
Original Article


Regulation of osteoclastic activity is critical for understanding bone loss associated with the postmenopausal period. In vitro and animal studies have revealed the role of OPG as a decoy receptor that neutralizes the effect of RANKL on the differentiation and activation of osteoclasts. However, the role of the OPG-RANKL system in postmenopausal osteoporosis is controversial. Thus, the aim of this study was to investigate the relationship among circulating levels of OPG, RANKL, bone turnover markers (BTM), bone mineral density (BMD) and vertebral fractures in postmenopausal women. We determined anthropometric parameters, circulating OPG and RANKL, BTM, estradiol, BMD by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN), and pre-existing vertebral fractures in 206 ambulatory postmenopausal women of a mean age of 62 years (SD 7). Circulating OPG was significantly related to age ( r =0.158; P =0.023), years since menopause ( r =0.167; P =0.016) and BMD (LS Z-score: r =0.240; P =0.001, FN Z-score: r =0.156; P =0.025). Over half of the women had undetectable RANKL ( n =113; 54.9%). There were no significant differences in clinical variables, BTM or BMD among women with detectable vs. undetectable RANKL. OPG was found to be independently associated with osteoporosis (OR: 2.9, 1.4–5.9) and prevalent vertebral fractures (OR: 2.5, 1.2–5.4). We conclude that serum OPG levels are independently associated with bone mass and prevalent vertebral fractures in postmenopausal women.


Bone mineral density Osteoprotegerin Postmenopausal osteoporosis RANK-L Vertebral fracture 


  1. 1.
    Hofbauer LC, Khosla S, Dunstan CR, Lacey D, Boyle WJ, Riggs BL (2000) The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 15:2–12PubMedGoogle Scholar
  2. 2.
    Yasuda H, Shima N, Nakagawa N et al (1998) Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 139:1329-1337CrossRefPubMedGoogle Scholar
  3. 3.
    Akatsu T, Murakami T, Ono K et al (1998) Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy. Bone 23:495-498CrossRefGoogle Scholar
  4. 4.
    Bekker PJ, Holloway D, Nakanishi A, Arrighi HM, Leese PT, Dunstan CR (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 16:348-360PubMedGoogle Scholar
  5. 5.
    Bekker PJ, Holoway DL, Rasmussen AS, et al (2004) A single-dose placebo-controlled study of AMG 162, fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059–1066PubMedGoogle Scholar
  6. 6.
    Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL (1999) Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 140:4367-4370CrossRefPubMedGoogle Scholar
  7. 7.
    Schevde NK, Bendixen A, Dienger KM, Pike JW (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 977:829–834Google Scholar
  8. 8.
    Simonet WS, Lacey DL, Dunstan CR et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309-319CrossRefPubMedGoogle Scholar
  9. 9.
    Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL (2003) Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 111:1221–1230CrossRefPubMedGoogle Scholar
  10. 10.
    Yano K, Tsuda E, Washida N et al (1999) Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 14:518–527PubMedGoogle Scholar
  11. 11.
    Khosla S, Arrighi HM, Melton III LJ et al (2002) Correlates of osteoprotegerin levels in women and men. Osteoporos Int 13:394–399CrossRefPubMedGoogle Scholar
  12. 12.
    Browner WS, Lui LY, Cummings SR (2001) Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 86:631–637CrossRefPubMedGoogle Scholar
  13. 13.
    Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R (2002) Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 87:4470–4475CrossRefPubMedGoogle Scholar
  14. 14.
    Kudlacek S, Schneider B, Woloszczuk W, Pietschmann P, Willvonseder R (2004) Serum levels of osteoprotegerin increase with age in a healthy adult population. Bone 32:681–686CrossRefGoogle Scholar
  15. 15.
    Schett G, Stefan K, Redlich K et al (2004) Soluble RANKL and risk of nontraumatic fracture. JAMA 291:1108–1113CrossRefPubMedGoogle Scholar
  16. 16.
    Pennisi P, Signorelli SS, Riccobene S et al (2004) Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels. Osteoporos Int 15:389–395CrossRefGoogle Scholar
  17. 17.
    Rinaldi S, Déchaud H, Biessy C et al (2001) Reliability and validity of commerciallyavailable, direct radioimmunoassays for measurements of blood androgens and estrogens in postmenopausal women. Cancer Epidemiol Biomark Prev 10:757–765Google Scholar
  18. 18.
    Diaz Curiel M, Carrasco de la Peña JL, Honorato Perez J, Perez Cano R, Rapado A, Ruiz Martinez I (1997) Study of bone mineral density in lumbar spine and femoral neck in a Spanish population. Multicentre Research Project on Osteoporosis. Osteoporos Int 7:59–64Google Scholar
  19. 19.
    Orwoll ES, Oviatt SK, Mann T (1990) The impact of osteophytic and vascular calcifications on vertebral mineral density measurements in men. J Clin Endocrinol Metab 70:1202–1207PubMedGoogle Scholar
  20. 20.
    Report of a WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. World Health Organ Tech Rep Ser 843:1–129Google Scholar
  21. 21.
    Cook GJ, Lodge MA, Blake GM, Marsden PK, Fogelman I (2000) Differences in skeletal kinetics between vertebral and humeral bone measured by 18Ffluoride positron emission tomography in postmenopausal women. J Bone Miner Res 15:763–769Google Scholar
  22. 22.
    Naylor KE, Rogers A, Fraser RB, Hall V, Eastell R, Blumsohn A (2003) Serum osteoprotegerin as a determinant of bone metabolism in a longitudinal study of human pregnancy and lactation. J Clin Endocrinol Metab 88:5361–5365CrossRefPubMedGoogle Scholar
  23. 23.
    Hegedus D, Ferencz V, Lakatos PL et al (2002) Decreased bone density, elevated serum osteoprotegerin, and b-cross-laps in Wilson disease. J Bone Miner Res 17:1961–1967Google Scholar
  24. 24.
    Szalay F, Hegedus D, Lakatos PL et al (2003) High serum osteoprotegerin and low RANKL in primary biliary cirrhosis. J Hepatol 38:395–400CrossRefGoogle Scholar
  25. 25.
    Hofbauer LC, Schoppet M, Schüller P, Viereck V, Michael Christ M (2004) Effects of oral contraceptives on circulating osteoprotegerin and soluble RANK ligand serum levels in healthy young women. Clin Endocrinol 60:14–219Google Scholar
  26. 26.
    Bord S, Ireland DC, Beavan SR, Compston JE (2003) The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32:136–141CrossRefGoogle Scholar
  27. 27.
    Seck T, Diel I, Bismar H, Ziegler R, Pfeilschifter J (2001) Serum parathyroid hormone, but no menopausal status, is associated with the expression of osteoprotegerin and RANKL mRNA in human bone samples. Eur J Endocrinol 145:199–205CrossRefGoogle Scholar
  28. 28.
    Riggs BL, Sundeep K, Melton LJ III (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302CrossRefPubMedGoogle Scholar
  29. 29.
    Looker AC, Bauer DC, Chesnut CH III, et al (2000) Clinical use of biochemical markers of bone remodelling: current status and future directions. Osteoporosis Int 11:467–480CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2005

Authors and Affiliations

  • Pedro Mezquita-Raya
    • 1
  • Magdalena de la Higuera
    • 1
  • Diego Fernández García
    • 1
  • Guillermo Alonso
    • 1
  • María Estrella Ruiz-Requena
    • 2
  • Juan de Dios Luna
    • 3
  • Fernando Escobar-Jiménez
    • 1
  • Manuel Muñoz-Torres
    • 1
  1. 1.Bone Metabolic Unit of the Endocrinology DivisionUniversity Hospital San CecilioGranadaSpain
  2. 2.Biochemistry DivisionUniversity Hospital San CecilioGranadaSpain
  3. 3.Biostatistics DepartmentUniversity School of MedicineGranadaSpain

Personalised recommendations