Skip to main content

Advertisement

SpringerLink
Log in

Acute Effects of Glucocorticoids on Serum Markers of Osteoclasts, Osteoblasts, and Osteocytes

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

The aim of this study was to investigate the acute effects of oral glucocorticoids in doses used in clinical practice on biochemical indices of the function of osteoclasts, osteoblasts, and osteocytes. In 17 adult patients suffering from various medical pathologies requiring systemic steroid therapy that were never before treated with glucocorticoids, glucocorticoid treatment was initiated (mean prednisolone equivalent dose of 23.1 ± 12.7 mg/day, range 10–50). Fasting morning serum concentrations of osteocalcin (OC), amino-terminal propeptide of type I procollagen (PINP), type 1 collagen cross-linked C-telopeptide (βCTX), soluble receptor activator of nuclear factor kappaB ligand (sRANKL), osteoprotegerin (OPG), sclerostin, Dickkopf-1 (Dkk-1), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline and on three consecutive days. Significant reductions in serum OC, PINP, OPG, sclerostin, and hsCRP were observed during 96 h of glucocorticoid administration, while serum βCTX showed a significant percentual increase. A significant positive correlation was found between serum concentrations of Dkk-1 and βCTX after 96 h of treatment with glucocorticoids. A significant drop in serum sclerostin, OPG, and OC observed in this study may reflect the rapid glucocorticoid-induced apoptosis of osteocytes.

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. Diez-Perez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Boonen S, Chapurlat R, Compston JE, Cooper C, Delmas P, Greenspan SL, Lacroix AZ, Lindsay R, Netelenbos JC, Pfeilschifter J, Roux C, Saag KG, Sambrook P, Silverman S, Siris ES, Watts NB, Nika G, Gehlbach SH (2011) Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone 49:493–498

    Article  PubMed  Google Scholar 

  2. Henneicke H, Herrmann M, Kalak R, Brennan-Speranza TC, Heinevetter U, Bertollo N, Day RE, Huscher D, Buttgereit F, Dunstan CR, Seibel MJ, Zhou H (2011) Corticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism. Bone 49:733–742

    Article  PubMed  CAS  Google Scholar 

  3. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15:993–1000

    Article  PubMed  Google Scholar 

  4. Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328

    Article  PubMed  CAS  Google Scholar 

  5. Yao W, Cheng Z, Busse C, Pham A, Nakamura MC, Lane NE (2008) Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 58:1674–1686

    Article  PubMed  CAS  Google Scholar 

  6. Weinstein RS (2010) Glucocorticoids, osteocytes, and skeletal fragility: the role of bone vascularity. Bone 46:564–570

    Article  PubMed  CAS  Google Scholar 

  7. Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, Ross FP, Teitelbaum SL (2006) Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 116:2152–2160

    Article  PubMed  CAS  Google Scholar 

  8. Smith E, Frenkel B (2005) Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3beta-dependent and -independent manner. J Biol Chem 280:2388–2394

    Article  PubMed  CAS  Google Scholar 

  9. Ohnaka K, Tanabe M, Kawate H, Nawata H, Takayanagi R (2005) Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts. Biochem Biophys Res Commun 329:177–181

    Article  PubMed  CAS  Google Scholar 

  10. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841

    Article  PubMed  Google Scholar 

  11. Xia X, Kar R, Gluhak-Heinrich J, Yao W, Lane NE, Bonewald LF, Biswas SK, Lo WK, Jiang JX (2010) Glucocorticoid-induced autophagy in osteocytes. J Bone Miner Res 25:2479–2488

    Article  PubMed  CAS  Google Scholar 

  12. Guo J, Liu M, Yang D, Bouxsein ML, Saito H, Galvin RJ, Kuhstoss SA, Thomas CC, Schipani E, Baron R, Bringhurst FR, Kronenberg HM (2010) Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab 11:161–171

    Article  PubMed  CAS  Google Scholar 

  13. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17:1231–1234

    Article  PubMed  CAS  Google Scholar 

  14. Dempster DW (1989) Bone histomorphometry in glucocorticoid-induced osteoporosis. J Bone Miner Res 4:137–141

    Article  PubMed  CAS  Google Scholar 

  15. Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, Kinney JH, Bonewald LF (2006) Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res 21:466–476

    Article  PubMed  CAS  Google Scholar 

  16. Dovio A, Perazzolo L, Osella G, Ventura M, Termine A, Milano E, Bertolotto A, Angeli A (2004) Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab 89:4923–4928

    Article  PubMed  CAS  Google Scholar 

  17. Ekenstam E, Stalenheim G, Hallgren R (1988) The acute effect of high dose corticosteroid treatment on serum osteocalcin. Metabolism 37:141–144

    Article  PubMed  CAS  Google Scholar 

  18. Ton FN, Gunawardene SC, Lee H, Neer RM (2005) Effects of low-dose prednisone on bone metabolism. J Bone Miner Res 20:464–470

    Article  PubMed  CAS  Google Scholar 

  19. Szappanos A, Toke J, Lippai D, Patocs A, Igaz P, Szucs N, Futo L, Glaz E, Racz K, Toth M (2010) Bone turnover in patients with endogenous Cushing’s syndrome before and after successful treatment. Osteoporos Int 21:637–645

    Article  PubMed  CAS  Google Scholar 

  20. Kearns AE, Khosla S, Kostenuik PJ (2008) Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 29:155–192

    Article  PubMed  CAS  Google Scholar 

  21. Schett G, Kiechl S, Weger S, Pederiva A, Mayr A, Petrangeli M, Oberhollenzer F, Lorenzini R, Redlich K, Axmann R, Zwerina J, Willeit J (2006) High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med 166:2495–2501

    Article  PubMed  CAS  Google Scholar 

  22. Pasco JA, Kotowicz MA, Henry MJ, Nicholson GC, Spilsbury HJ, Box JD, Schneider HG (2006) High-sensitivity C-reactive protein and fracture risk in elderly women. JAMA 296:1353–1355

    Article  PubMed  CAS  Google Scholar 

  23. Ding C, Parameswaran V, Udayan R, Burgess J, Jones G (2008) Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab 93:1952–1958

    Article  PubMed  CAS  Google Scholar 

  24. Kim BJ, Yu YM, Kim EN, Chung YE, Koh JM, Kim GS (2007) Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women. Clin Endocrinol (Oxf) 67:152–158

    Article  CAS  Google Scholar 

  25. Nabipour I, Larijani B, Vahdat K, Assadi M, Jafari SM, Ahmadi E, Movahed A, Moradhaseli F, Sanjdideh Z, Obeidi N, Amiri Z (2009) Relationships among serum receptor of nuclear factor-kappaB ligand, osteoprotegerin, high-sensitivity C-reactive protein, and bone mineral density in postmenopausal women: osteoimmunity versus osteoinflammatory. Menopause 16:950–955

    Article  PubMed  Google Scholar 

  26. Compston JE, Vedi S, Mellish RW, Croucher P, O’Sullivan MM (1989) Reduced bone formation in non-steroid treated patients with rheumatoid arthritis. Ann Rheum Dis 48:483–487

    Article  PubMed  CAS  Google Scholar 

  27. Pereira RM, Falco V, Corrente JE, Chahade WH, Yoshinari NH (1999) Abnormalities in the biochemical markers of bone turnover in children with juvenile chronic arthritis. Clin Exp Rheumatol 17:251–255

    PubMed  CAS  Google Scholar 

  28. Paglia F, Dionisi S, De Geronimo S, Rosso R, Romagnoli E, Raejentroph N, Ragno A, Celi M, Pepe J, D’Erasmo E, Minisola S (2001) Biomarkers of bone turnover after a short period of steroid therapy in elderly men. Clin Chem 47:1314–1316

    PubMed  CAS  Google Scholar 

  29. Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y (2001) Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant 16:479–482

    Article  PubMed  CAS  Google Scholar 

  30. Webster JC, Cidlowski JA (1999) Mechanisms of glucocorticoid-receptor-mediated repression of gene expression. Trends Endocrinol Metab 10:396–402

    Article  PubMed  CAS  Google Scholar 

  31. Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140:4382–4389

    Article  PubMed  CAS  Google Scholar 

  32. Weinstein RS, O’Brien CA, Almeida M, Zhao H, Roberson PK, Jilka RL, Manolagas SC (2011) Osteoprotegerin prevents glucocorticoid-induced osteocyte apoptosis in mice. Endocrinology 152:3323–3331

    Article  PubMed  CAS  Google Scholar 

  33. van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Lowik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

    Article  PubMed  Google Scholar 

  34. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887

    Article  PubMed  CAS  Google Scholar 

  35. Balemans W, Ebeling M, Patel N, Van Hul E, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van Hul W (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543

    Article  PubMed  CAS  Google Scholar 

  36. Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y, Alisch RS, Gillett L, Colbert T, Tacconi P, Galas D, Hamersma H, Beighton P, Mulligan J (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589

    Article  PubMed  CAS  Google Scholar 

  37. Marenzana M, Greenslade K, Eddleston A, Okoye R, Marshall D, Moore A, Robinson MK (2011) Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone. Arthritis Rheum 63:2385–2395

    Article  PubMed  CAS  Google Scholar 

  38. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, O’Brien CA, Manolagas SC, Jilka RL (2003) Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for why intermittent administration is needed for bone anabolism. J Biol Chem 278:50259–50272

    Article  PubMed  CAS  Google Scholar 

  39. Sutherland MK, Geoghegan JC, Yu C, Turcott E, Skonier JE, Winkler DG, Latham JA (2004) Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone 35:828–835

    Article  PubMed  CAS  Google Scholar 

  40. Bonewald LF (2011) The amazing osteocyte. J Bone Miner Res 26:229–238

    Article  PubMed  CAS  Google Scholar 

  41. van Lierop AH, van der Eerden AW, Hamdy NA, Hermus AR, den Heijer M, Papapoulos SE (2012) Circulating sclerostin levels are decreased in patients with endogenous hypercortisolism and increase after treatment. J Clin Endocrinol Metab 97:E1953–E1957

    Article  PubMed  Google Scholar 

  42. 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 

  43. 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 111:1221–1230

    PubMed  CAS  Google Scholar 

  44. Morvan F, Boulukos K, Clement-Lacroix P, Roman Roman S, Suc-Royer I, Vayssiere B, Ammann P, Martin P, Pinho S, Pognonec P, Mollat P, Niehrs C, Baron R, Rawadi G (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945

    Article  PubMed  CAS  Google Scholar 

  45. Glass DA 2nd, Karsenty G (2006) Canonical Wnt signaling in osteoblasts is required for osteoclast differentiation. Ann N Y Acad Sci 1068:117–130

    Article  PubMed  CAS  Google Scholar 

  46. Fujita K, Janz S (2007) Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer 6:71

    Article  PubMed  Google Scholar 

  47. Ohnaka K, Taniguchi H, Kawate H, Nawata H, Takayanagi R (2004) Glucocorticoid enhances the expression of Dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 318:259–264

    Article  PubMed  CAS  Google Scholar 

  48. Wang FS, Ko JY, Yeh DW, Ke HC, Wu HL (2008) Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. Endocrinology 149:1793–1801

    Article  PubMed  CAS  Google Scholar 

  49. Kaiser M, Mieth M, Liebisch P, Oberlander R, Rademacher J, Jakob C, Kleeberg L, Fleissner C, Braendle E, Peters M, Stover D, Sezer O, Heider U (2008) Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol 80:490–494

    Article  PubMed  CAS  Google Scholar 

  50. Voskaridou E, Christoulas D, Xirakia C, Varvagiannis K, Boutsikas G, Bilalis A, Kastritis E, Papatheodorou A, Terpos E (2009) Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration. Haematologica 94:725–728

    Article  PubMed  CAS  Google Scholar 

  51. Anastasilakis AD, Goulis DG, Polyzos SA, Gerou S, Pavlidou V, Koukoulis G, Avramidis A (2008) Acute changes in serum osteoprotegerin and receptor activator for nuclear factor-kappaB ligand levels in women with established osteoporosis treated with teriparatide. Eur J Endocrinol 158:411–415

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge the professional cooperation of Ms. Ludmila Hauptvoglova. The study was supported by the Grant Agency of Charles University in Prague (GAUK 84208/2008) and by the Ministry of Health (MZd CR 000 237280).

Author information

Authors and Affiliations

  1. Institute of Rheumatology, Prague, Czech Republic

    Kristyna Brabnikova Maresova, Karel Pavelka & Jan J. Stepan

  2. Department of Rheumatology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic

    Kristyna Brabnikova Maresova, Karel Pavelka & Jan J. Stepan

Authors
  1. Kristyna Brabnikova Maresova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karel Pavelka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan J. Stepan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jan J. Stepan.

Additional information

The authors have stated that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brabnikova Maresova, K., Pavelka, K. & Stepan, J.J. Acute Effects of Glucocorticoids on Serum Markers of Osteoclasts, Osteoblasts, and Osteocytes. Calcif Tissue Int 92, 354–361 (2013). https://doi.org/10.1007/s00223-012-9684-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-012-9684-4

Keywords

Search

Navigation