Skip to main content

Advertisement

SpringerLink
Log in

Cyclic variations of bone resorption mediators and markers in the different phases of the menstrual cycle

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Female hormones are very important in regulating bone homeostasis; the drop of estrogen levels occurring at menopause is linked to a dramatic prevalence of bone resorption on formation. Only a small number of studies investigated the relationship between changes in circulating female sex hormones and the markers and mediators of bone homeostasis and they showed conflicting results. To explore such relationships we studied 20 young fertile healthy women, aged between 19 and 32 years. None had received hormone treatment for at least 6 months. We assayed luteinizing hormone, follicle-stimulating hormone, progesterone and 17β-estradiol, as well as the levels of osteoprotegerin (OPG), C-terminal telopeptide of collagen type I (CTx) and RANKL (receptor activator of nuclear factor-B ligand) in samples drawn from every subject at four different times during the menstrual cycle when estrogens are lowest, at the start of the cycle: T 0 (2–4th day); when estrogens are highest, in the pre-ovulatory period: T 14 (12–14th day); when progesterone activity is highest, in the advanced luteal phase: T 26 (24–26th day); and again at the start of the next cycle: T 01 (2–4th day). We observed that CTx levels are highest at the start of the cycle, decreased significantly from T 0 to T 26 (pfwe = 0.0455) and then increased from T 26 to T 01 (pfwe = 0.0415); OPG, on the other hand, which was also highest at the start of the cycle, decreased significantly from T 0 to T 14 (pfwe = 0.02) and then increased, though not significantly, from T 14 to T 01; no variation was observed in RANKL values at any time. We observed inverse correlations between estradiol and OPG levels, which became highly significant at T 01 between estradiol nadir and OPG peak levels (pfw = 0.0095). Furthermore, the increase of estradiol from T 0 to T 14 was negatively correlated with the concomitant decrease of OPG (pfwe = 0.0277), as was the fall of estradiol from T 26 to T 01 with the OPG peak levels, both at T 01 (pfw = 0.0045) and at T 0 (pfwe = 0.0381). We also observed direct correlations between the OPG levels and the variations of progesterone in the preceding intervals, but they never attained statistical significance. We conclude that OPG and CTx fluctuation during the menstrual cycle are likely due to the physiological variations of sex steroids levels.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gorai I, Taguchi Y, Chaki O, Kikuchi R, Nakayama M, Yang BC, Yokota S, Minaguchi H (1998) Serum soluble interleukin-6 receptor and biochemical markers of bone metabolism show significant variations during the menstrual cycle. J Clin Endocrinol Metab 83:326–332

    Article  PubMed  CAS  Google Scholar 

  2. Chiu KM, Ju J, Mayes D, Bacchetti P, Weitz S, Arnaud CD (1999) Changes in bone resorption during the menstrual cycle. J Bone Miner Res 14:609–615

    Article  PubMed  CAS  Google Scholar 

  3. Zittermann A, Schwarz I, Scheld K, Sudhop T, Berthold HK, von Bergmann K, van der Ven H, Stehle P (2000) Physiologic fluctuations of serum estradiol levels influence biochemical markers of bone resorption in young women. J Clin Endocrinol Metab 85:95–101

    Article  PubMed  CAS  Google Scholar 

  4. Abrahamsen B, Stilgren LS, Rettmer E, Bonnevie-Nielsen V, Beck-Nielsen H (2003) Effects of the natural and artificial menstrual cycle on the production of osteoprotegerin and the bone resorptive cytokines IL-1beta and IL-6. Calcif Tissue Int 72:18–23

    Article  PubMed  CAS  Google Scholar 

  5. Kato S (2009) Hormones and osteoporosis update. Estrogen and bone remodeling. Clin Calcium 19:951–956

    PubMed  CAS  Google Scholar 

  6. Kamel HK (2006) Postmenopausal osteoporosis: etiology, current diagnostic strategies, and nonprescription interventions. J Manag Care Pharm 12:S4–S9

    PubMed  Google Scholar 

  7. Zallone A (2006) Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci 1068:173–179

    Article  PubMed  CAS  Google Scholar 

  8. Nielsen HK, Brixen K, Bouillon R, Mosekilde L (1990) Changes in biochemical markers of osteoblastic activity during the menstrual cycle. J Clin Endocrinol Metab 70:1431–1437

    Article  PubMed  CAS  Google Scholar 

  9. Mochizuki S, Kiyokawa A, Nagayama Y (2005) Osteoclastogenesis Inhibitory Factor (OCIF)/Osteoprotegerin (OPG) as a new therapeutic agent for osteoporosis. Clin Calcium 15:35–42

    PubMed  CAS  Google Scholar 

  10. Murakami T, Yamamoto M, Ono K, Nishikawa M, Nagata N, Motoyoshi K, Akatsu T (1998) Transforming growth factor-beta1 increases mRNA levels of osteoclastogenesis inhibitory factor in osteoblastic/stromal cells and inhibits the survival of murine osteoclast-like cells. Biochem Biophys Res Commun 252:747–752

    Article  PubMed  CAS  Google Scholar 

  11. Hofbauer LC, Kühne CA, Viereck V (2004) The OPG/RANKL/RANK system in metabolic bone diseases. J Musculoskelet Neuronal Interact 4:268–275

    PubMed  CAS  Google Scholar 

  12. Rachner TD, Schoppet M, Niebergall U, Hofbauer LC (2008) 17beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7. Biochem Biophys Res Commun 368:736–741

    Article  PubMed  CAS  Google Scholar 

  13. Rogers A, Eastell R (2005) Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 90:6323–6331

    Article  PubMed  CAS  Google Scholar 

  14. Khosla S (2001) Minireview: the OPG/RANKL/RANK system. Endocrinology 142:5050–5055

    Article  PubMed  CAS  Google Scholar 

  15. Hofbauer LC, Heufelder AE (2000) Clinical review 114: hot topic. The role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in the pathogenesis and treatment of metabolic bone diseases. J Clin Endocrinol Metab 85:2355–2363

    Article  PubMed  CAS  Google Scholar 

  16. Kostenuik PJ, Shalhoub V (2001) Osteoprotegerin: a physiological and pharmacological inhibitor of bone resorption. Curr Pharm Des 7:613–635

    Article  PubMed  CAS  Google Scholar 

  17. Stern A, Laughlin GA, Bergstrom J, Barrett-Connor E (2007) The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor kappaB legend with bone mineral density in older adults: the Rancho Bernardo study. Eur J Endocrinol 156:555–562

    Article  PubMed  CAS  Google Scholar 

  18. Wolman I, Gal TB, Jaffa AJ (2009) Cervical mucus status can be accurately estimated by transvaginal ultrasound during fertility evaluation. Fertil Steril 92:1165–1167

    Article  PubMed  Google Scholar 

  19. Lee J, Vasikaran S (2012) Current recommendations for laboratory testing and use of bone turnover markers in management of osteoporosis. Ann Lab Med 32:105–112

    Article  PubMed  CAS  Google Scholar 

  20. Di Carlo C, Tommaselli GA, Gargano V, Sammartino A, Bifulco G, Tauchmanova L, Colao A, Nappi C (2007) Effects of estrogen-progestin therapy on serum levels of RANKL, osteoprotegerin, osteocalcin, leptin, and ghrelin in postmenopausal women. Menopause 14:38–44

    Article  PubMed  Google Scholar 

  21. Salmaso L, Solari A (2005) Multiple aspect testing for case-control designs. Metrika 62:331–340

    Article  Google Scholar 

  22. Finos L, Salmaso L, Solari A (2007) Conditional inference under simultaneous stochastic ordering constraints. J Stat Plan Inference 137:2633–2641

    Article  Google Scholar 

  23. Corain L, Salmaso L (2004) Multivariate and multistrata nonparametric tests: the nonparametric combination method. J Modern Appl Stat Methods 3:443–461

    Google Scholar 

  24. Pesarin F (2002) Extending permutation conditional inference to unconditional ones. Stat Methods Appl 11:161–173

    Article  Google Scholar 

  25. Finos L, Salmaso L (2006) Weighted methods controlling the multiplicity when the number of variables is much higher than the number of observations. J Nonparametr Stat 18:245–261

    Article  Google Scholar 

  26. Pesarin F (2001) Multivariate permutation test with applications in biostatistics. Wiley, Chichester, pp 143–150

    Google Scholar 

  27. Rickard DJ, Waters KM, Ruesink TJ, Khosla S, Katzenellenbogen JA, Katzenellenbogen BS, Riggs BL, Spelsberg TC (2002) Estrogen receptor isoform-specific induction of progesterone receptors in human osteoblasts. J Bone Miner Res 17:580–592

    Article  PubMed  CAS  Google Scholar 

  28. Viereck V, Gründker C, Friess SC, Frosch KH, Raddatz D, Schoppet M, Nisslein T, Emons G, Hofbauer LC (2005) Isopropanolic extract of black cohosh stimulates osteoprotegerin production by human osteoblasts. J Bone Miner Res 20:2036–2043

    Article  PubMed  Google Scholar 

  29. West SL, Scheid JL, De Souza MJ (2009) The effect of exercise and estrogen on osteoprotegerin in premenopausal women. Bone 44:137–144

    Article  PubMed  CAS  Google Scholar 

  30. Bord S, Ireland DC, Beavan SR, Compston JE (2003) The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32:136–141

    Article  PubMed  CAS  Google Scholar 

  31. Rumpler M, Vagra F, Nemeth P, Klaushofer K (2003) Identification of an estrogen response element in the osteoprotegerin promoter. International Conference on Progress in Bone and Mineral Research 2003. Abstracts. Bone 33: S1–S29

  32. Viereck V, Gründker C, Blaschke S, Niederkleine B, Siggelkow H, Frosch KH, Raddatz D, Emons G, Hofbauer LC (2003) Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J Clin Endocrinol Metab 88:4206–4213

    Article  PubMed  CAS  Google Scholar 

  33. Hofbauer LC, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1998) Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines. Biochem Biophys Res Commun 250:776–781

    Article  PubMed  CAS  Google Scholar 

  34. Brändström H, Jonsson KB, Vidal O, Ljunghall S, Ohlsson C, Ljunggren O (1998) Tumor necrosis factor-alpha and -beta upregulate the levels of osteoprotegerin mRNA in human osteosarcoma MG-63 cells. Biochem Biophys Res Commun 248:454–457

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  36. Inada M, Miyaura C (2010) Cytokines in bone diseases. Cytokine and postmenopausal Osteoporosis. Clin Calcium 20:1467–1472

    PubMed  CAS  Google Scholar 

  37. Jilka RL (2003) Biology of the basic multicellular unit and the pathophysiology of osteoporosis. Med Pediatr Oncol 41:182–185

    Article  PubMed  Google Scholar 

  38. Bashir A, Mak YT, Sankaralingam S, Cheung J, McGowan NW, Grigoriadis AE, Fogelman I, Hampson G (2005) Changes in RANKL/OPG/RANK gene expression in peripheral mononuclear cells following treatment with estrogen or raloxifene. Steroids 70:847–855

    Article  PubMed  CAS  Google Scholar 

  39. Rachner TD, Schoppet M, Niebergall U, Hofbauer LC (2008) 17beta-Estradiol inhibits osteoprotegerin production by the estrogen receptor-alpha-positive human breast cancer cell line MCF-7. Biochem Biophys Res Commun 368:736–741

    Article  PubMed  CAS  Google Scholar 

  40. Ohwada R, Hotta M, Sato K, Shibasaki T, Takano K (2007) The relationship between serum levels of estradiol and osteoprotegerin in patients with anorexia nervosa. Endocr J 54:953–959

    Article  PubMed  CAS  Google Scholar 

  41. Kim JG, Kim JH, Lee DO, Kim H, Kim JY, Suh CS, Kim SH, Choi YM (2008) Changes in the serum levels of osteoprotegerin and soluble receptor activator for nuclear factor kappaB ligand after estrogen-progestogen therapy and their relationships with changes in bone mass in postmenopausal women. Menopause 15:357–362

    Article  PubMed  Google Scholar 

  42. Indridason OS, Franzson L, Sigurdsson G (2005) Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover. Osteoporos Int 16:417–423

    Article  PubMed  CAS  Google Scholar 

  43. Liu JM, Zhao HY, Ning G, Zhao YJ, Chen Y, Zhang Zh, Sun LH, Xu MY, Chen JL (2005) Relationships between the changes of serum levels of OPG and RANKL with age, menopause, bone biochemical markers and bone mineral density in Chinese women aged 20–75. Calcif Tissue Int 76:1–6

    Article  PubMed  CAS  Google Scholar 

  44. Hofbauer LC, Schoppet M, Schüller P, Viereck V, Christ M (2004) Effects of oral contraceptives on circulating osteoprotegerin and soluble RANK ligand serum levels in healthy young women. Clin Endocrinol (Oxf) 60:214–219

    Article  CAS  Google Scholar 

  45. The Writing Group for the PEPI (1996) Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 276:1389–1396

    Article  Google Scholar 

Download references

Conflict of interest

Authors declare no conflict of interests.

Author information

Authors and Affiliations

  1. Dipartimento della Salute della Donna del Bambino, U.O.C. di Clinica Ginecologica e Ostetrica, Via Giustiniani 3, 35128, Padua, Italy

    Bruno Mozzanega, Salvatore Gizzo, Tito Silvio Patrelli & Giovanni Battista Nardelli

  2. Department of Laboratory Medicine, University of Padua, Padua, Italy

    Daniela Bernardi

  3. Department of Management and Engineering, University of Padua, Padua, Italy

    Luigi Salmaso & Livio Finos

  4. Department of Medical and Surgical Sciences, University of Padua, Padua, Italy

    Roberto Mioni

Authors
  1. Bruno Mozzanega
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Salvatore Gizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniela Bernardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luigi Salmaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tito Silvio Patrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roberto Mioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Livio Finos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanni Battista Nardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore Gizzo.

About this article

Cite this article

Mozzanega, B., Gizzo, S., Bernardi, D. et al. Cyclic variations of bone resorption mediators and markers in the different phases of the menstrual cycle. J Bone Miner Metab 31, 461–467 (2013). https://doi.org/10.1007/s00774-013-0430-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-013-0430-4

Keywords

Search

Navigation