Download PDF
Z Orthop Unfall 2014; 152(2): 170-176
DOI: 10.1055/s-0034-1368247
Varia
Georg Thieme Verlag KG Stuttgart · New York

Osteoporose – inflammatorische Effekte auf den Knochenstoffwechsel und das Frakturrisiko

Osteoporosis – Inflammatory Effects on Bone Metabolism and Fracture Risk
G. Dischereit
Abteilung für Internistische Rheumatologie, Osteologie, Physikalische Medizin, Justus-Liebig-Universität Gießen
,
U. Lange
Abteilung für Internistische Rheumatologie, Osteologie, Physikalische Medizin, Justus-Liebig-Universität Gießen
› Author Affiliations
Further Information

Publication History

Publication Date:
23 April 2014 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Sowohl experimentelle als auch epidemiologische Studien haben gezeigt, dass proinflammatorische Zytokine, insbesondere Interleukin-1, Interleukin-6 und Tumornekrosefaktor-α, wichtige Regulatoren im Knochenmetabolismus darstellen. Zudem wird vermutet, dass proinflammatorischen Zytokinen auch in der Pathogenese des altersassoziierten und östrogenmangelinduzierten Knochenmasseverlusts eine bedeutende Rolle zugeschrieben werden kann. Obwohl eine Beschleunigung des Knochenabbaus bei Patienten mit chronisch-entzündlichen Systemerkrankungen bereits belegt werden konnte, ist die endgültige Bedeutung proinflammatorischer Zytokine in der Ätiologie der Osteoporose noch unklar. Einige Studien lassen zwar einen Zusammenhang zwischen erhöhten Konzentrationen proinflammatorischer Zytokine und einer Verminderung der Knochendichte sowie einem gesteigerten Frakturrisiko vermuten, in Summe ist die Evidenzlage jedoch eher rar und erlaubt keine eindeutigen Rückschlüsse auf die Effekte einzelner Zytokine im Knochenstoffwechsel. Um exakter definieren zu können, welche Parameter einer systemischen Inflammation in welchem Stadium der Pathogenese einer Osteoporose zum Tragen kommen, werden weitere Studien vonnöten sein. Besonders auch vor dem Hintergrund der Entwicklung eines geeigneten diagnostischen Markers für den Kliniker, mit dem sich das Osteoporoserisiko und damit auch das Frakturrisiko besser vorhersagen lässt. Dies würde im Krankheitsverlauf frühzeitige Interventionen zum Erhalt eines mikroarchitektonisch gesunden und stabilen Knochens, bspw. durch den Einsatz einer Anti-Zytokin-Therapie, erleichtern.

Abstract

There is a large body of evidence that proinflammatory cytokines, particularly interleukin-1, interleukin-6, and tumour necrosis factor-α, play an important role in bone metabolism. Moreover, it is suspected that proinflammatory cytokines are also important in the pathogenesis of age- and estrogen deficiency-related bone loss. Although an accelerated decrease in bone mass is observed in patients with chronic inflammatory disorders, the definite meaning of proinflammatory cytokines in the aetiology of osteoporosis is still unclear. Some studies suggest a relationship between increased concentrations of proinflammatory cytokines and a decrease in bone mineral density, as well as an increased risk of fracture. In sum, the evidence is rather scarce and does not permit any clear conclusions about the effects of single cytokines in bone metabolism. To be able to define more exactly at which stage of the pathogenesis of osteoporosis parameters of a systemic inflammation take effect, further studies will be necessary, particularly for developing suitable diagnostic markers for clinicians. These diagnostic markers may be able to identify patients at risk for osteoporosis and therefore predict fracture risks. Thus, early interventions to preserve bone health, for example, by anti-cytokine therapy, could be more effective and efficient.

Schlüsselwörter

Knochenstoffwechsel - Osteoporose - proinflammatorische Zytokine - Frakturrisiko

Key words

bone metabolism - osteoporosis - proinflammatory cytokines - fracture risk
 

  • Literatur

  • 1 Goldring SR. Inflammatory mediators as essential elements in bone remodeling. Calcif Tissue Int 2003; 73: 97-100
    CrossrefPubMedGoogle Scholar
  • 2 Sinigaglia L, Varenna M, Girasole G et al. Epidemiology of osteoporosis in rheumatic diseases. Rheum Dis Clin North Am 2006; 32: 631-658
    CrossrefPubMedGoogle Scholar
  • 3 Clowes JA, Riggs BL, Khosla S. The role of the immune system in the pathophysiology of osteoporosis. Immunol Rev 2005; 208: 207-227
    CrossrefPubMedGoogle Scholar
  • 4 Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002; 23: 279-302
    CrossrefPubMedGoogle Scholar
  • 5 Jilka RL. Cytokines, bone remodeling, and estrogen deficiency: a 1998 update. Bone 1998; 23: 75-81
    CrossrefPubMedGoogle Scholar
  • 6 Hofbauer LC, Khosla S, Dunstan CR et al. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000; 15: 2-12
    CrossrefPubMedGoogle Scholar
  • 7 Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490-495
    CrossrefPubMedGoogle Scholar
  • 8 Hofbauer LC. Pathophysiology of RANK ligand (RANKL) and osteoprotegerin (OPG). Ann Endocrinol (Paris) 2006; 67: 139-141
    CrossrefPubMedGoogle Scholar
  • 9 Braun T, Zwerina J. Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis Res Ther 2011; 13: 235
    CrossrefPubMedGoogle Scholar
  • 10 Hwang S, Putney JW. Orai1-mediated calcium entry plays a critical role in osteoclast differentiation and function by regulating activation of the transcription factor NFATc1. FASEB J 2012; 26: 1484-1492
    CrossrefPubMedGoogle Scholar
  • 11 Neumann E, Schett G. Knochenstoffwechsel. Molekulare Mechanismen. Z Rheumatol 2007; 66: 286-289
    CrossrefPubMedGoogle Scholar
  • 12 Moon S, Ahn IE, Jung H et al. Temporal differential effects of proinflammatory cytokines on osteoclastogenesis. Int J Mol Med 2013; 31: 769-777
    PubMedGoogle Scholar
  • 13 Nakamura I, Takahashi N, Jimi E et al. Regulation of osteoclast function. Mod Rheumatol 2012; 22: 167-177
    CrossrefPubMedGoogle Scholar
  • 14 Visvanathan S, van der Heijde D, Deodhar A et al. Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis 2009; 68: 175-182
    CrossrefPubMedGoogle Scholar
  • 15 Jagger CJ, Lean JM, Davies JT et al. Tumor necrosis factor-alpha mediates osteopenia caused by depletion of antioxidants. Endocrinology 2005; 146: 113-118
    CrossrefPubMedGoogle Scholar
  • 16 Lean JM, Davies JT, Fuller K et al. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J Clin Invest 2003; 112: 915-923
    CrossrefPubMedGoogle Scholar
  • 17 Lean JM, Jagger CJ, Kirstein B et al. Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation. Endocrinology 2005; 146: 728-735
    CrossrefPubMedGoogle Scholar
  • 18 Abrahamsen B, Bonnevie-Nielsen V, Ebbesen EN et al. Cytokines and bone loss in a 5-year longitudinal study–hormone replacement therapy suppresses serum soluble interleukin-6 receptor and increases interleukin-1-receptor antagonist: the Danish Osteoporosis Prevention Study. J Bone Miner Res 2000; 15: 1545-1554
    CrossrefPubMedGoogle Scholar
  • 19 Hustmyer FG, Walker E, Yu XP et al. Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis. J Bone Miner Res 1993; 8: 51-59
    PubMedGoogle Scholar
  • 20 Pacifici R, Vannice JL, Rifas L et al. Monocytic secretion of interleukin-1 receptor antagonist in normal and osteoporotic women: effects of menopause and estrogen/progesterone therapy. J Clin Endocrinol Metab 1993; 77: 1135-1141
    CrossrefPubMedGoogle Scholar
  • 21 Bismar H, Diel I, Ziegler R et al. Increased cytokine secretion by human bone marrow cells after menopause or discontinuation of estrogen replacement. J Clin Endocrinol Metab 1995; 80: 3351-3355
    CrossrefPubMedGoogle Scholar
  • 22 Scheidt-Nave C, Bismar H, Leidig-Bruckner G et al. Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Clin Endocrinol Metab 2001; 86: 2032-2042
    PubMedGoogle Scholar
  • 23 Romas E, Martin TJ. Cytokines in the pathogenesis of osteoporosis. Osteoporos Int 1997; 7 (Suppl. 03) S47-S53
    CrossrefPubMedGoogle Scholar
  • 24 Chao T, Yu H, Huang C et al. Association of interleukin-1 beta (− 511C/T) polymorphisms with osteoporosis in postmenopausal women. Ann Saudi Med 2010; 30: 437-441
    PubMedGoogle Scholar
  • 25 Jabbar S, Drury J, Fordham JN et al. Osteoprotegerin, RANKL and bone turnover in postmenopausal osteoporosi. J Clin Pathol 2011; 64: 354-357
    CrossrefPubMedGoogle Scholar
  • 26 Pacifici R, Rifas L, Teitelbaum S et al. Spontaneous release of interleukin 1 from human blood monocytes reflects bone formation in idiopathic osteoporosis. Proc Natl Acad Sci U S A 1987; 84: 4616-4620
    CrossrefPubMedGoogle Scholar
  • 27 Zheng SX, Vrindts Y, Lopez M et al. Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis. Maturitas 1997; 26: 63-71
    CrossrefPubMedGoogle Scholar
  • 28 Khosla S, Peterson JM, Egan K et al. Circulating cytokine levels in osteoporotic and normal women. J Clin Endocrinol Metab 1994; 79: 707-711
    PubMedGoogle Scholar
  • 29 Zarrabeitia MT, Riancho JA, Amado JA et al. Cytokine production by peripheral blood cells in postmenopausal osteoporosis. Bone Miner 1991; 14: 161-167
    CrossrefPubMedGoogle Scholar
  • 30 Papadopoulos NG, Georganas K, Skoutellas V et al. Correlation of interleukin-6 serum levels with bone density in postmenopausal women. Clin Rheumatol 1997; 16: 162-165
    CrossrefPubMedGoogle Scholar
  • 31 Giuliani N, Sansoni P, Girasole G et al. Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 2001; 36: 547-557
    CrossrefPubMedGoogle Scholar
  • 32 Tamura T, Udagawa N, Takahashi N et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A 1993; 90: 11924-11928
    CrossrefPubMedGoogle Scholar
  • 33 Kania DM, Binkley N, Checovich M et al. Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J Am Geriatr Soc 1995; 43: 236-239
    PubMedGoogle Scholar
  • 34 McKane WR, Khosla S, Peterson JM et al. Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. J Bone Mine Res 1994; 9: 1313-1318
    PubMedGoogle Scholar
  • 35 Ding C, Parameswaran V, Udayan R et al. Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab 2008; 93: 1952-1958
    CrossrefPubMedGoogle Scholar
  • 36 Salamone LM, Whiteside T, Friberg D et al. Cytokine production and bone mineral density at the lumbar spine and femoral neck in premenopausal women. Calcif Tissue Int 1998; 63: 466-470
    CrossrefPubMedGoogle Scholar
  • 37 Bouxsein ML, Karasik D. Bone geometry and skeletal fragility. Curr Osteoporos Rep 2006; 4: 49-56
    CrossrefPubMedGoogle Scholar
  • 38 Lauretani F, Bandinelli S, Russo CR et al. Correlates of bone quality in older persons. Bone 2006; 39: 915-921
    CrossrefPubMedGoogle Scholar
  • 39 Russo CR, Lauretani F, Seeman E et al. Structural adaptations to bone loss in aging men and women. Bone 2006; 38: 112-118
    CrossrefPubMedGoogle Scholar
  • 40 Barbour KE, Boudreau R, Danielson ME et al. Inflammatory markers and the risk of hip fracture: The womenʼs health initiative. J Bone Miner Res 2012; 27: 1167-1176
    CrossrefPubMedGoogle Scholar
  • 41 McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep 2009; 7: 134-139
    CrossrefPubMedGoogle Scholar
  • 42 Cauley JA, Danielson ME, Boudreau RM et al. Inflammatory markers and incident fracture risk in older men and women: the Health Aging and Body Composition Study. J Bone Mine Res 2007; 22: 1088-1095
    CrossrefPubMedGoogle Scholar
  • 43 Aderka D, Engelmann H, Shemer-Avni Y et al. Variation in serum levels of the soluble TNF receptors among healthy individuals. Lymphokine Cytokine Res 1992; 11: 157-159
    PubMedGoogle Scholar
  • 44 Xing Z, Gauldie J, Cox G et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J clin Invest 1998; 101: 311-320
    CrossrefPubMedGoogle Scholar
  • 45 Ridker PM, Hennekens CH, Buring JE et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836-843
    CrossrefPubMedGoogle Scholar
  • 46 Weinhold B, Rüther U. Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 1997; 327 (Pt 2) 425-429
    PubMedGoogle Scholar
  • 47 Koh J, Khang Y, Jung C et al. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int 2005; 16: 1263-1271
    CrossrefPubMedGoogle Scholar
  • 48 Kim B, Yu YM, Kim EN et al. Relationship between serum hsCRP concentration and biochemical bone turnover markers in healthy pre- and postmenopausal women. Clin Endocrinol (Oxf) 2007; 67: 152-158
    CrossrefPubMedGoogle Scholar
  • 49 Pasco JA, Kotowicz MA, Henry MJ et al. High-sensitivity C-reactive protein and fracture risk in elderly women. JAMA 2006; 296: 1353-1355
    PubMedGoogle Scholar
  • 50 Schett G, Kiechl S, Weger S et al. High-sensitivity C-reactive protein and risk of nontraumatic fractures in the Bruneck study. Arch Intern Med 2006; 166: 2495-2501
    CrossrefPubMedGoogle Scholar