Skip to main content

Advertisement

SpringerLink
Log in

Osteoporose bei rheumatoider Arthritis – Bedeutung von Alfacalcidol in Prävention und Therapie

Osteoporosis in rheumatoid arthritis – rationale for alfacalcidol in prevention and therapy

  • ORIGINALARBEIT
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Neben einer lokalisierten Osteopenie, entwickeln Patienten mit rheumatoider Arthritis (RA) in 30–50% mit und ohne Kortikosteroide eine generalisierte, multifaktorielle Osteoporose und besitzen ein erhöhtes Frakturrisiko. Der Knochenverlust tritt früh auf und korreliert direkt mit der Krankheitsaktivität und später auch mit den negativen Effekten einer eingeschränkten Mobilität. Kortikosteroide reduzieren als pathogenetischer Kofaktor die Kalziumabsorption im Darm und steigern den Kalziumverlust in der Niere mit der Folge einer kompensatorisch erhöhten PTH-Freisetzung bzw. erhöhen die Sensitivität des Knochens betreffend PTH-induzierten Abbaus. Daneben hemmen diese Medikamente die Funktion der knochenaufbauenden Osteoblasten und die günstigen Effekte von Wachstumsfaktoren und Sexualhormonen am Knochen. Neu erkannt wurde die Unterdrückung der Expression von D-Hormon-Rezeptoren (VDR) und die Induktion von VDR-Störungen. Unterbewertet bleibt meist der negative Einfluß der Kortikosteroide auf die Muskelkraft indirekt über erhöhte PTH-Spiegel, erniedrigte IGF-1-Spiegel oder reduzierte D-Hormon-Aktivität. Der Abfall der 1,25 (OH)2D3 (D-Hormon)-Spiegel bei Patienten mit RA in Korrelation zum C-reaktiven Protein (CRP) ist von Bedeutung bei der Pathogenese von RA-induzierten Osteoporosen und könnte außerdem den Entzündungsprozeß fördern. Es herrscht im allgemeinen Konsens, daß Zytokine (z.B. IL-1, IL-6, IL-12, TNF-α) bei entzündlichen rheumatischen Erkrankungen den Knochenabbau induzieren. Neu dagegen sind Befunde, die zeigen, daß Zytokine wie z.B. TNF-α, auch den Knochenaufbau stören, indem sie die Osteoblastenapoptosis fördern und zusätzlich die Muskelkraft reduzieren.¶ D-Hormon-Präparate (Alfacalcidol, Calcitriol) besitzen immunregulierende Wirkungen in vitro und in vivo, durch die Hemmung der Zytokine IL-1, IL-6, TNF-α und insbesondere IL-12. Auf zelluläre Ebene vermindert D-Hormon die Expression von Th1-Helferzellen direkt und indirekt via Hemmung von IL-12 aus Monozyten. Die infolge der Therapie mit D-Hormon-Präparaten vermehrt gebildeten Th2-Helferzellen produzieren knochenprotektive Zytokine, wie z.B. IL-4 und IL-10. Äußerst bemerkenswert ist der Schutz der Osteoblasten durch D-Hormon vor dem TNF-α-induzierten Zelltod. Alfacalcidol antagonisiert nach Umwandlung in Leber und Knochen zu Calcitriol (D-Hormon) die beschriebenen pathogenetischen Faktoren der Kortikosteroide. ¶D-Hormon kann als körpereigener Immunregulator bezeichnet werden, welcher bei Bedarf in den Makrophagen produziert wird und immunologische Überreaktionen in einem „feed back loop“ abwehrt.¶ Das erweitere Verständnis der Pathogenese der Kortikosteroid-induzierten Osteoporose und die pharmakologischen Wirkungen von Alfacalcidol, die diesem iatrogenen Knochenverlust entgegensteuern sowie die Erkenntnisse aus speziellen tierexperimentellen Untersuchungen, in denen der Knochenverlust bei entzündlichen Erkrankungen simuliert wurde, erklären die besonders gute Wirkung von Alfacalcidol in dieser Indikation. Sehr deutlich ist in mehreren klinischen Studien der Beweis erbracht worden, daß Alfacalcidol den Kortikosteroid-induzierten Knochenverlust aufhalten kann im Gegensatz zu genuinem Vitamin D. Aufgrund seiner immunmodulierenden Eigenschaften ist Alfacalcidol besonders geeignet zur Hemmung des Knochenverlustes induziert durch entzündliche rheumatische Erkrankungen und auch zur Prävention der Transplantationsosteoporose und ein adjuvanter Beitrag zur Basistherapie bei RA bzw. zur Immunsuppression nach Transplantationen kann nicht ausgeschlossen werden.

Summary

Besides localised osteopenia, patients with rheumatoid arthritis (RA) with or without corticosteroids develop in 30–50% osteoporosis induced by several factors and thus a higher risk of fractures. Bone loss appears very early and correlates directly with disease activity and also later with the negative effects of restrictive mobility. Corticosteroids reduce as a pathogenetic co-factor intestinal calcium absorption and increase renal calcium excretion resulting in compensatory increased PTH-release and increased sensitivity of bone to PTH. In addition, corticosteroids inhibit osteoblast function as well as the favourable effects of growth factors and sex hormones on bone. It has recently been recognised that the expression of D-hormone receptors (VDRs) is suppressed by these medications and that corticosteroids probably induce VDR disorders. The negative influence of corticosteroids on muscle strength (indirectly – via increased PTH-levels, lowered IGF-1-levels or reduced D-hormone activity) is a feature which has been underestimated. The demonstrated drop in 1,25(OH)2D3 (D-hormone) levels in patients with RA in correlation with C-reactive protein (CRP) is of significance in the pathogenesis of RA-induced osteoporosis and could further promote the process of inflammation. There is a general consensus that cytokines (e.g. IL-1, IL-6, IL-12, TNF-α) induce bone resorption in inflammatory rheumatic diseases. There are, however, new findings which show that cytokines like TNF-α also interfere with bone formation by promoting apoptosis of osteoblasts and reduce the muscle strength, too.¶ D-hormone preparations (alfacalcidol, calcitriol) possess immunoregulatory effects in vitro and in vivo by inhibiting the cytokines IL-1, IL-6, TNF-α and particularly IL-12. At the cellular level, D-hormone reduces the expression of Th1 helper cells directly or indirectly by inhibition of IL-12 from monocytes. Therapy with alfacalcidol or calcitriol results in increased production of Th2 helper cells which produce bone protective cytokines like IL-4 and IL-10. It is important to know that D-hormone protects osteoblasts against TNF-α-induced cell death. After conversion to D-hormone in the liver and bone, alfacalcidol antagonises the above described pathogenetic factors of the corticosteroids. D-hormone is one of the body‘s own immunoregulators, which is produced in macrophages in cases of need to reduce immunological overreactions in a feed-back loop.¶ Improved understanding of the pathogenesis of corticosteroid-induced osteoporosis and of the pharmacological effects of alfacalcidol in this type of iatrogenic bone loss as well as the results of specific animal models simulating bone loss in inflammatory diseases explain the favourable effects of alfacalcidol in this indication. Various clinical studies have demonstrated clearly that alfacalcidol retards corticosteroid-induced bone loss in contrast to plain vitamin D. Due to its immunomodulating properties, alfacalcidol is particularly suitable for RA-induced bone loss and for the prevention of transplantation osteoporosis, and an adjuvant contribution to the disease-modifying therapy of RA and to the immunosuppressive therapy after transplantation can not be excluded

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

Literatur

  1. Peel NFA, Spittlehouse AJ, Bax DE, Eastell R (1994) Bone mineral density of hand in rheumatoid arthritis. Arthritis Rheum 37(5):983–991

    Article  CAS  PubMed  Google Scholar 

  2. Ringe JD (1996) Generalisierte Osteoporose bei chronischer Polyarthritis — Pathomechanismen und Behandlungsansätze. Z Rheumatol 55:149–

    CAS  PubMed  Google Scholar 

  3. Gulko PS, Mulloy AL (1996) Glucocorticoid-induced osteoporosis: pathogenesis, prevention and treatment.Clin Exp Rheumatol 14:199–206

    CAS  PubMed  Google Scholar 

  4. Mellish RW, O'Sullivan MM, Garrahan NJ, Compston JE (1987) Iliac crest trabecular bone mass and structure in patients with non-steroid-treated rheumatoid arthritis.Ann Rheum Dis 46:830–836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Kröger H, Honkanen R, Sarrikoski S, Alhava E (1994) Decreased axial bone mineral density in perimenopausal women with rheumatoid arthritis — a population based study.Ann Rheum Dis 53:18–23

    Article  PubMed Central  PubMed  Google Scholar 

  6. Peel NFA, Moore DJ, Barrington NA, Bax DE, Eastell R (1995) Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis.Ann Rheum Dis 54:801–806

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Cooper C, Coupland C, Mitchell M (1995) Rheumatoid arthritis, corticosteroid therapy and hip fracture.Ann Rheum Dis 54:49–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Gough AKS, Lilley J, Eyre S, Holder RL, Emery P (1994) Generalised bone loss in patients with early rheumatoid arthritis.Lancet 344:23–27

    Article  CAS  PubMed  Google Scholar 

  9. Welsh JE, Jones WA (1997) 1,25(OH)2D3 protects MG-63 osteoblasts from TNF-α and ceramide induced apoptosis.10th Workshop on Vitamin D, Strasbourg, Proceedings: 405–406

    Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Dequeker J, Maenaut K, Verwilghen J, Westhovens R (1995) Osteoporosis in rheumatoid arthritis.Clin Exp Rheumatol 13 (Suppl 12):21–26

    Google Scholar 

  12. Olbricht T, Benker G (1993) Glucocorticoid-induced osteoporosis: pathogenesis, prevention and treatment, with special regard to the rheumatic diseases.J Intern Med 234:237–244

    Article  CAS  PubMed  Google Scholar 

  13. Chavassieux P, Pastoureau P, Chapuy MC, Delmas PD, Meunier PJ (1993) Glucocorticoid-induced inhibition of osteoblastic bone formation in ewes: a biochemical and histomorphometric study.Osteoporosis Int 3:97–102

    Article  CAS  Google Scholar 

  14. Gronowicz GA, McCarthy MB (1995) Glucocorticoids inhibit the attachment of osteoblasts to bone extracellular matrix proteins and decrease beta-1 integrin levels.Endocrinology 136:598–608

    CAS  PubMed  Google Scholar 

  15. Godschlak M, Levy JR, Downs RW (1992) Glucocorticoids decrease vitamin D receptor numbers and gene expression in human osteosarcoma cells.J Bone Miner Res 7:21–27

    Article  Google Scholar 

  16. Selby PL, Kelsall J, Adams JE, Mee AP, Mawer EB (1997) Are polymorphisms of the vitamin D receptor gene risk factors for corticosteroid induced osteoporosis? Bone 20(4S):31S

    Google Scholar 

  17. Khaleeli AA, Edwards CHT, Gohil K et al. (1983) Corticosteroid myopathy: a clinical and pathological study.Clin Endocrinol 18:155–166

    Article  CAS  Google Scholar 

  18. Tanaka K, Natsui K, Suda M, Yasoda A, Sakuma Y, Akamizu T, Ozaki S, Shigeno C, Konishi J, Nakao K (1997) Intensive glucocorticoid treatment induces rapid loss of trabecular bone volume and lean body mass.Osteoporosis 7(Suppl 2):20

    Google Scholar 

  19. Laan RFJM, Buijs WCAM, Verbeek ALM et al. (1993) Bone mineral density in patients with recent onset rheumatoid arthritis: influence of disease activity and functional capacity.Ann Rheum Dis 52:21–26

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Roubenoff R, Roubenoff RA; Cannon JG et al. (1994) Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.J Clin Invest 93:2379–2386

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Johansson AG, Baylink DJ, Ekenstam E, Lindth E, Mohan S, Ljungball S (1994) Circulating levels of insulin-like growth factor-I and -II, and IGF-binding protein-3 in inflammation and after parathyroid hormone infusion.Bone Miner 24:25–31

    Article  CAS  PubMed  Google Scholar 

  22. Oelzner P, Müller A, Deschner F, Hüller M, Abendroth K, Hein G, Stein G (1997) Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis.Calcif Tissue Int 62(3):193–198

    Article  Google Scholar 

  23. Ekenstam E (1991) Influence of inflammation and corticosteroid treatment on indices of bone turnover and parathyroid function.Scand J Rheumatol 20:220

    Google Scholar 

  24. Haug CJ, Aukrust P, Haug E, Morkrid L, Müller F, Froland SS (1998) Severe deficiency of 1,25-Dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis.J Clin Endocrinol Metab 83:3832–3838

    Article  CAS  PubMed  Google Scholar 

  25. Schacht E (1995) Neue Aspekte der Immunmodulation bei der rheumatoiden Arthritis: arthritis+rheuma 15/2:17–30

    Google Scholar 

  26. Bischoff HA, Stahelin HB, Urscheler N, Ehrsam R, Vonthein R, PerrigChiello P, Tyndall A, Theiler R (1999) Archives of physical medicine and rehabilitation 80:54–58

    Article  CAS  PubMed  Google Scholar 

  27. Scharla SH, Strong DD, Mohan S, Baylink DJ, Linkhart TA (1991) 1,25-dihydroxyvitamin D3 differentially regulates the production of IGF-I and IGFBP-4 in mouse osteoblasts.Endocrinology 129:3139–3146

    Article  CAS  PubMed  Google Scholar 

  28. Heaney RP, Barger-Lux MJ, Dowell MS, Chen TC, Holick MF (1997) Calcium absorptive effects of vitamin D and its major metabolites.J Clin Endocrinol Metab 83:4111–4116

    Google Scholar 

  29. Akesson K, Lau KHW, Baylink DJ (1997) Rational for active vitamin D analog therapy in senile osteoporosis.Calcif Tissue Int 60:100–105

    Article  CAS  PubMed  Google Scholar 

  30. Scharla SH, Strong DD, Mohan S, Linkhart TA (1993) Effect of 1,25-dihydroxyvitamin D3 on the secretion of insulin-like growth factor-II (IGF-II) and IGF-binding proteins (IGFBPs) in human osteoblast-like cells.Exp Clin Endocrinol 101 (Suppl 1):69

    Google Scholar 

  31. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF (1998) 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-b1 and IL-4.Journal of Immunology 160:5314–5319

    CAS  Google Scholar 

  32. Zofková I, Kancheva RL, Bendlová B (1997) Effect of 1,25(OH)2 vitamin D3 on circulating insulin-like growth factor- I and β2 microglobulin in patients with osteoporosis.CalcifTissue Int 60:236–239

    Google Scholar 

  33. Seino Y, Ishizuka S, Shima M, Tanaka H (1993) Vitamin D in bone formation.Osteoporosis Int 3:196–198

    Article  Google Scholar 

  34. Dambacher MA, Schacht E (1996) Osteoporose und aktive Vitamin D-Metabolite: Ein Blick in die Zukunft. EULAR Verlag Basel: Litera Rheumatologica 18

    Google Scholar 

  35. Zarrabeitia MT, Riancho JA, Amado JA, Olmos JM, Gonzalez-Macias J (1992) Effect of calcitriol on the secretion of prostagladin E2, interleukin 1 and tumor necrosis factor α by human monocystes.Bone 13:185–189

    Article  CAS  PubMed  Google Scholar 

  36. Müller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A, Bendtzen K (1992) 1,25-dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level.Cytokine 4(6):506–512

    Article  PubMed  Google Scholar 

  37. Lempert UG, Minne HW, Albrecht B, Scharla SH, Matthes F, Ziegler R (1989) 1,25-dihydroxy-vitamin D3 prevents the decrease of bone mineral appositional rate in rats with inflammation-mediated osteopenia (IMO).Bone Miner 7:149–158

    Article  CAS  PubMed  Google Scholar 

  38. Boland R (1986) Role of vitamin D in skeletal muscle function.Endocr Rev 7:434–448

    Article  CAS  PubMed  Google Scholar 

  39. Glerup H, Andersen H, Clausen T, Eriksen EF (1997) Osteomalacia is characterised by low concentrations of Ca-ATPase in striated muscles. Normalisation after treatment with vitamin-D is associated with increased muscle power. 10th Workshop on Vitamin D, Strasbourg. Abstract: 106

    Google Scholar 

  40. Bach GL, Scharla S, Schacht E (1998) Osteoporose: neue Erkenntnisse einer physiologischen Therapie. arthritis+rheuma 18(3):157–163

    Google Scholar 

  41. Lemire JM (1995) Immunomodulatory actions of 1,25-dihydroxyvitamin D3.J Steroid Biochem Molec Biol Vol 53, 1–6:599–602

    Article  CAS  Google Scholar 

  42. Michel G, Gailis A, Jarzebska-Deussen B, Mueschen A, Mirmohammadsadegh A, Ruzicka T (1997) 1,25-(OH)2-vitamin D3 and calcipotriol induce IL-10 receptor gene expression in human epidermal cells.Inflammation Research 46(1):32–34

    Article  CAS  PubMed  Google Scholar 

  43. Zofková I, Kancheva RL (1997) The effect of 12,5(OH)2-vitamin D3 on CD3+/CD8+ subsets of T lymphocytes in postmenopausal women.Life Sci 61(2):147–152

    Article  PubMed  Google Scholar 

  44. Cantorna MT, Hayes CE, DeLuca HF (1998) 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis.J Nutr 128:68–72

    CAS  PubMed  Google Scholar 

  45. Andelkovic Z, Vojinovic J, Pejnovic N, Popovic M (1996) Immunomodulatory effects of high oral dose Alpha D3 in rheumatoid arthritis patients.Rheum Eur (Suppl 1) Vol 25:33

    Google Scholar 

  46. Dambacher MA, Schacht E (1998) Aktive Vitamin D-Metabolite (D-Hormone) in der Osteoporose-Therapie auf der Basis neuer Erkenntnisse zur Pathogenese.Osteologie 5–25

    Google Scholar 

  47. Reginster JY, Kuntz D, Verdickt W, Wouters M, Guillevin L, Menkès CJ, Nielsen K (1999) Prophylacic use of alfacalcidol in corticosteroid-induced osteoporosis.Osteoporos Int 9:75–81

    Article  CAS  PubMed  Google Scholar 

  48. Adachi JD, Bensen WG, Bianchi F, Cividino A, Pillersdorf S, Sebaldt JS, Tugwell P, Gordon M, Steele M, Webber C, Goldsmith CH (1996) Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: a 3 year followup.J Rheumatol 23(6):995–1000

    CAS  PubMed  Google Scholar 

  49. Van Cleemput J, Daenen W, Geusens P, Dequeker J, van de Werf F, Vanhaecke J (1996) Prevention of bone loss in cardiac transplant recipients.Transplantation 61(10):1495–1499

    Article  PubMed  Google Scholar 

  50. Casteels K, Bouillon R, Waer M, Mathieu C (1995) Immunomodulatory effects of 1,25-dihydroxyvitamin D3.Curr Opin Nephrol Hypertens 4:313–318

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Byk Gulden Byk-Gulden-Str. 2 D-78467 Konstanz, DE

    E. Schacht

Authors
  1. E. Schacht
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schacht, E. Osteoporose bei rheumatoider Arthritis – Bedeutung von Alfacalcidol in Prävention und Therapie. Z Rheumatol 59 (Suppl 1), I10–I20 (2000). https://doi.org/10.1007/s003930070032

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s003930070032

Search

Navigation