Skip to main content

Advertisement

SpringerLink
Log in

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.

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

Similar content being viewed by others

Article Open access 01 July 2023

Enisa Shevroja, Jean-Yves Reginster, … Nicholas C. Harvey

References

  1. Gough A, Sambrook P, Devlin J, Huisson A, Njeh C, Robbins S, Nguyen T, Emery P (1998) Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 25:1282–1289

    PubMed  CAS  Google Scholar 

  2. Romas E, Gillespie MT, Martin TJ (2002) Involvement of receptor activator of NfkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 30:340–346

    Article  PubMed  CAS  Google Scholar 

  3. Shimizu S, Shiozawa S, Shiozawa K, Imura S, Fujita T (1985) Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis. Arthritis Rheum 28:25–31

    Article  PubMed  CAS  Google Scholar 

  4. Kröger H, Arnala I, Rehnberg V, Hamalainen M, Alhava E (1994) Histomorphometry of periarticular bone in rheumatoid arthritis. Ann Chir Gynaecol 83:56–62

    PubMed  Google Scholar 

  5. Tanabe M, Ochi T, Tomita T, Suzuki R, Sakata T, Shimaoka Y, Nakagawa S, Ono K (1994) Remarkable elevation of interleukin 6 and interleukin 8 levels in the bone marrow serum of patients with rheumatoid arthritis. J Rheumatol 21:830–835

    PubMed  CAS  Google Scholar 

  6. Toritsuka Y, Nakamura N, Lee SB, Hashimoto J, Yasui N, Shino K, Ochi T (1997) Osteoclastogenesis in iliac bone marrow of patients with rheumatoid arthritis. J Rheumatol 24:1690–1696

    PubMed  CAS  Google Scholar 

  7. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM (2005) Molecular mechanisms of breast cancer metastases to bone. Clin Breast Cancer 5(Suppl 2):46–53

    Article  Google Scholar 

  8. Roux S, Mariette X (2004) The high rate of bone resorption in multiple myeloma is due to RANK (receptor activator of nuclear factor-kappaB) and RANK ligand expression. Leukoc Lymphoma 45:1111–1118

    Article  CAS  Google Scholar 

  9. Lai FP, Cole-Sinclair M, Cheng WJ, Quinn JM, Gillespie MT, Sentry JW, Schneider HG (2004) Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation. Br J Haematol 126:192–201

    Article  PubMed  CAS  Google Scholar 

  10. Giuliani N, Colla S, Morandi F, Rizzoli V (2004) The RANK/RANK ligand system is involved in interleukin-6 and interleukin-11 upregulation by human myeloma cells in the bone marrow microenvironment. Haematologica 89:1118–1123

    PubMed  CAS  Google Scholar 

  11. Bendre M, Gaddy D, Nicholas RW, Suva LJ (2003) Breast cancer metastasis to bone: it is not all about PTHrP. Clin Orthop Relat Res 415(Suppl):39–45

    Article  Google Scholar 

  12. Barton BE (2005) Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes. Expert Opin Ther Targets 9:737–752

    Article  PubMed  CAS  Google Scholar 

  13. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, Kido S, Oshima T, Shibata H, Ozaki S, Inoue D, Matsumoto T (2004) Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 104:2484–2491

    Article  PubMed  CAS  Google Scholar 

  14. Miyazawa K, Mori A, Yamamoto K, Okudaira H (1998) Constitutive transcription of the human interleukin-6 gene by rheumatoid synoviocytes: spontaneous activation of NF-kappaB and CBF1. Am J Pathol 152:793–803

    PubMed  CAS  Google Scholar 

  15. Sung JY, Hong JH, Kang HS, Choi I, Lim SD, Lee JK, Seok JH, Lee JH, Hur GM (2000) Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis. Immunopharmacology 47:35–44

    Article  PubMed  CAS  Google Scholar 

  16. Kohno H, Shigeno C, Kasai R, Akiyama H, Iida H, Tsuboyama T, Sato K, Konishi J, Nakamura T (1997) Synovial fluids from patients with osteoarthritis and rheumatoid arthritis contain high levels of parathyroid hormone-related peptide. J Bone Miner Res 12:847–854

    Article  PubMed  CAS  Google Scholar 

  17. Funk JL, Cordaro LA, Wie H, Benjamin JB, Yocum DE (1998) Synovium as a source of increased amino-terminal parathyroid hormone-related protein expression in rheumatoid arthritis. A possible role for locally produced parathyroid hormone-related protein in the pathogenesis of rheumatoid arthritis. J Clin Invest 101:1362–1371

    PubMed  CAS  Google Scholar 

  18. Horiuchi T, Yoshida T, Koshihara Y, Sakamoto H, Kanai H, Yamamoto S, Ito H (1999) The increase of parathyroid hormone-related peptide and cytokine levels in synovial fluid of elderly rheumatoid arthritis and osteoarthritis. Endocr J 46:643–649

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  20. Gravallese EM, Manning C, Tsay A, Naito A, Pan C, Amento E, Goldring SR (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43:250–258

    Article  PubMed  CAS  Google Scholar 

  21. Meinecke I, Rutkauskaite E, Gay S, Pap T (2005) The role of synovial fibroblasts in mediating joint destruction in rheumatoid arthritis. Curr Pharm Des 11:563–568

    Article  PubMed  CAS  Google Scholar 

  22. Niwa Y, Iio A, Niwa G, Sakane T, Tsunematsu T, Kanoh T (1990) Serum albumin metabolism in rheumatic diseases: relationship to corticosteroids and peptic ulcer. J Clin Lab Immunol 31:11–16

    PubMed  CAS  Google Scholar 

  23. Huang Y, Shinzawa H, Togashi H, Takahashi T, Kuzumaki T, Otsu K, Ishikawa K (1995) Interleukin-6 down-regulates expressions of the aldolase B and albumin genes through a pathway involving the activation of tyrosine kinase. Arch Biochem Biophys 320:203–209

    Article  PubMed  CAS  Google Scholar 

  24. Arnett FC, Edworthy SM, Bloch DA (1988) The American Rheumatism Association 1987 revised criteria for classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  PubMed  CAS  Google Scholar 

  25. Müller A, Hein G, Franke S, Herrmann D, Henzgen S, Roth A, Stein G (1996) Quantitative analysis of pyridinium crosslinks of collagen in the synovial fluid of patients with rheumatoid arthritis using high-performance liquid chromatography. Rheumatol Int 16:23–28

    Article  PubMed  Google Scholar 

  26. Reed A, Haugen M, Pachmann LM, Langman CB (1990) Abnormilities in serum osteocalcin values in children with chronic rheumatic diseases. J Pediatr 116:574–580

    Article  PubMed  CAS  Google Scholar 

  27. Broadus AE, Silverberg SJ, Lemann J Jr (1993) Calcium, magnesium and phosphorus homeostasis. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. Raven Press, New York, NY, pp 29–39

    Google Scholar 

  28. Need AG, Morris HA, Horowitz M, Scopacasa E, Nordin BE (1998) Intestinal calcium absorption in men with spinal osteoporosis. Clin Endocrinol 48:163–168

    Article  CAS  Google Scholar 

  29. Oelzner P, Müller A, Deschner F, Hüller M, Abendroth K, Hein G, Stein G (1998) Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int 62:193–198

    Article  PubMed  CAS  Google Scholar 

  30. Morris HA, Need AG, O’Loughlin PD, Horowitz M, Bridges A, Nordin BE (1990) Malabsorption of calcium in corticosteroid-induced osteoporosis. Calcif Tissue Int 46:305–308

    Article  PubMed  CAS  Google Scholar 

  31. Bauer J, Lengyel G, Thung SN, Jonas U, Gerok W, Acs G (1991) Human fetal hepatocytes respond to inflammatory mediators and excrete bile. Hepatology 13:1131–1141

    Article  PubMed  CAS  Google Scholar 

  32. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88–95

    Article  PubMed  CAS  Google Scholar 

  33. Hayashida K, Ochi T, Fujimoto M, Owaki H, Shimaoka Y, Ono K, Matsumoto K (1992) Bone marrow changes in adjuvant-induced and collagen-induced arthritis. Interleukin-1 and interleukin-6 activity and abnormal myelopoiesis. Arthritis Rheum 35:241–245

    Article  PubMed  CAS  Google Scholar 

  34. Suzuki Y, Tanihara M, Ichikawa Y, Osanai A, Nakagawa M, Ide M, Mizushima Y (1995) Periarticular osteopenia in adjuvant induced arthritis: role of interleukin-1 in decreased osteogenic and increased resorptive potential of bone marrow cells. Ann Rheum Dis 54:484–490

    PubMed  CAS  Google Scholar 

  35. Sugiyama T (2001) Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmenopausal women with rheumatoid arthritis. J Bone Miner Metab 19:89–96

    Article  PubMed  CAS  Google Scholar 

  36. Toffaletti J, Abrams B (1989) Effects of in vivo and in vitro production of lactic acid on ionized, protein-bound, and complex-bound calcium in blood. Clin Chem 35:935–938

    PubMed  CAS  Google Scholar 

  37. Farr M, Garvey K, Bold AM, Kendall MJ, Bacon PA (1985) Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clin Exp Rheumatol 3:99–104

    PubMed  CAS  Google Scholar 

  38. Chen RA, Goodman WG (2004) Role of calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol 286:1005–1011

    Article  Google Scholar 

  39. Ebert R, Jovanovic M, Ulmer M, Schneider D, Meissner-Weigl J, Adamski J, Jakob F (2004) Down-regulation by nuclear factor kappaB of human 25-hydroxyvitamin D3 1 alpha-hydroxylase promoter. Mol Endocrinol 18:2440–2450

    Article  PubMed  CAS  Google Scholar 

  40. Nielsen PK, Rasmussen AK, Butters R, Feldt-Rasmussen U, Bendtzen K, Diaz R, Brown EM, Olgaard K (1997) Inhibition of PTH secretion by interleukin-1 beta in bovine parathyroid glands in vitro is associated with an up-regulation of the calcium-sensing receptor mRNA. Biochem Biophys Res Commun 238:880–885

    Article  PubMed  CAS  Google Scholar 

  41. Carlstedt E, Ridefelt P, Lind L, Rastad J (1999) Interleukin-6 induced suppression of bovine parathyroid hormone secretion. Biosci Rep 19:35–42

    Article  PubMed  CAS  Google Scholar 

  42. Kotake S, Higaki M, Sato K, Himeno S, Morita H, Kim KJ, Nara N, Miyasaka N, Nishioka K, Kashiwazaki S (1992) Detection of myeloid precursors (granulocyte/macrophage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints. J Rheumatol 19:1511–1516

    PubMed  CAS  Google Scholar 

  43. Fujikawa Y, Sabokbar A, Neale S, Athanasou NA (1996) Human osteoclast formation and bone resorption by monocytes and synovial macrophages in rheumatoid arthritis. Ann Rheum Dis 55:816–822

    Article  PubMed  CAS  Google Scholar 

  44. Hirohata S, Yanagida T, Itoh K, Nakamura H, Yoshino S, Tomita T, Ochi T (1996) Accelerated generation of CD14+ monocyte-lineage cells from the bone marrow of rheumatoid arthritis patients. Arthritis Rheum 39:836–843

    Article  PubMed  CAS  Google Scholar 

  45. Schulze-Koops H, Davis LS, Kavanaugh AF, Lipsky PE (1997) Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum 40:639–647

    Article  PubMed  CAS  Google Scholar 

  46. Suzuki Y, Nishikaku F, Nakatuka M, Koga Y (1998) Osteoclast-like cells in murine collagen induced arthritis. J Rheumatol 25:1154–1160

    PubMed  CAS  Google Scholar 

  47. Hirayama T, Danks L, Sabokbar A, Athanasou NA (2002) Osteoclast formation and activity in the pathogenesis of osteoporosis in rheumatoid arthritis. Rheumatology 41:1232–1239

    Article  PubMed  CAS  Google Scholar 

  48. Bornefalk E, Ljunghall S, Lindh E, Bengtson O, Johansson AG, Ljunggren O (1997) Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. J Bone Miner Res 12:228–233

    Article  PubMed  CAS  Google Scholar 

  49. Reeve J, Loftus J, Hesp R, Ansell BM, Wright DJ, Woo PM (1993) Biochemical prediction of changes in spinal bone mass in juvenile chronic (or rheumatoid) arthritis treated with glucocorticoids. J Rheumatol 20:1189–1195

    PubMed  CAS  Google Scholar 

  50. Cortet B, Flipo RM, Pigny P, Duquesnoy B, Boersma A, Marchandise X, Delcambre B (1998) Is bone turnover a determinant of bone mass in rheumatoid arthritis. J Rheumatol 25:2339–2344

    PubMed  CAS  Google Scholar 

  51. Cortet B, Guyot MH, Solau E, Pigny P, Dumoulin F, Flipo RM, Marchandise X, Delcambre B (2000) Factors influencing bone loss in rheumatoid arthritis: a longitudinal study. Clin Exp Rheumatol 18:683–690

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by the Thuringian Ministry of Science, Research and Art (FKZ B307-01025).

Author information

Authors and Affiliations

  1. Division of Rheumatology/Osteology, Department of Internal Medicine III, Friedrich-Schiller University, Erlanger Allee 101, 07740, Jena, Germany

    Peter Oelzner, Gabriele Lehmann, Thorsten Eidner, Sybille Franke, Andreas Müller, Gunter Wolf & Gert Hein

Authors
  1. Peter Oelzner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriele Lehmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorsten Eidner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sybille Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andreas Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gunter Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gert Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Oelzner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oelzner, P., Lehmann, G., Eidner, T. et al. Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism. Rheumatol Int 26, 908–915 (2006). https://doi.org/10.1007/s00296-005-0095-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-005-0095-y

Keywords

Search

Navigation