Zelluläre Mechanismen der Gluko-kortikoid-induzierten Osteoporose und therapeutische Ansatzpunkte

Zusammenfassung

Der therapeutische Einsatz von Glukokortikoi-den ist aufgrund ihrer potenten immunmodu-latorischen Wirkung häufig unverzichtbar. Je-doch ist der klinische Nutzen aufgrund ihres Nebenwirkungsprofils oft begrenzt. Im Skelett-system führt eine länger dauernde systemische Therapie mit Glukokortikoiden zu einem rapi-den Verlust von Knochenmasse sowie einer deutlichen Steigerung des Frakturrisikosins-besondere an der Wirbelsäule. Im Verlauf der vergangenen Jahre hat sich das Verständnis der skelettalen Effekte von Glukokortikoiden durch den Einsatz genetisch modifizierter Mäu-se deutlich verbessert: Glukokortikoide intera-gieren mit allen Zellen im Knochen, jedoch werden die skelettalen Nebenwirkungen einer Glukokortikoidtherapie primär durch eine verminderte Osteoblasten- und Osteozytenfunkti-on verursacht. Aufgrund dieses Wirkmechanismus legen präklinische Studien in Modellorga-nismen als auch Studien bei Patienten mit Glu-kokortikoid-induzierter Osteoporose den Schluss nahe, dass eine osteoanabole Therapie einer Therapie mit Antiresorptiva langfristig überlegen sein kann. In diesem Artikel fassen wir neue Er-kenntnisse über die Glukokortikoidwirkung im Knochen systematisch zusammen und diskutie-ren deren Konsequenzen für die Therapie der Glukokortikoid-induzierten Osteoporose.

Summary

Although glucocorticoids are highly effective in the treatment of autoimmune inflammatory diseases, their use is limited by significant adverse outcomes including diabetes, sarcopenia and osteoporosis. Recent insights into the skeletal mechanisms of glucocorticoid action have identified osteoblasts and osteocytes as their main target cells in bone. At supraphysiological levels, glucocorticoids suppress osteoblastogenesis and osteoblast function, induce osteoblast cell cycle arrest and apoptosis and redirect mesenchymal stem cell differentiation towards the adipocyte lineage. More recently, disturbances in the lacunar-canalicular system and reduced osteocyte viability have been identified to also negatively affect skeletal health during glucocorticoid therapy. As the predominant active mechanism in glucocorticoid-induced osteoporosis is the suppression of bone formation, concerns have been raised about the long-term use of anti-resorptive agents in these patients. Thus, osteo-anabolic treatments such as Teriparatide, which stimulate osteoblast activity and bone modelling, may be better suited to address the pathomechanism underlying glucocorticoid-induced osteoporosis. In regards to the metabolic adverse effects of glucocorti-coids (i. e. insulin resistance, diabetes), recent studies in rodents have indicated that the bone-derived peptide, osteocalcin, may play a role in mediating some of these outcomes. These findings link the detrimental effects of glucocorticoids on energy metabolism directly to their suppressive actions on bone cells. In this article, we review the pathophysiology of glucocorticoid action on bone cells, and discuss current and novel concepts regarding the cellular mechanisms underlying adverse effects of glucocorticoids such as osteoporosis and diabetes.

Schlüsselwörter

Glukokortikoide - Osteoporose - Osteoblast - Osteoklast - Osteokalzin - 11 β-Hydroxysteroid-dehydrogenase Typ 2 (11β-HSD2)

Keywords

Glucocorticoids - osteoporosis - osteoblast - osteoclast - osteocalcin - 11 β-hydroxysteroid-dehydrogenase type 2 (11β-HSD2)

• Literatur

• 1 Hench PS, Kendall EC. et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin 1949; 24: 181-197.
• 2 Buttgereit F, Burmester GR, Lipworth BJ. Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet 2005; 365: 801-803.
• 3 Kanis JA, Johansson H, Oden A. et al. A meta-analysis of prior corticosteroid use and fracture risk. Journal of bone and mineral research 2004; 19: 893-899.
• 4 Curtiss PH, Clark WS, Herndon CH. Vertebral Fractures Resulting from Prolonged Cortisone and Corticotropin Therapy. J Am Med Assoc 1954; 156: 467-469.
• 5 Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005; 353: 1711-1723.
• 6 Van Staa TP, Leufkens HG, Abenhaim L. et al. Use of oral corticosteroids and risk of fractures. Journal of bone and mineral research 2000; 15: 993-1000.
• 7 Van Staa TP, Laan RF, Barton IP. et al. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 2003; 48: 3224-3229.
• 8 van Staa TP, Leufkens HG, Abenhaim L. et al. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39: 1383-1389.
• 9 Henneicke H, Gasparini SJ, Brennan-Speranza TC. et al. Glucocorticoids and bone: local effects and systemic implications. Trends in endocrinology and metabolism: TEM 2014; 25: 197-211.
• 10 O’Brien CA, Jia D, Plotkin LI. et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145: 1835-1841.
• 11 Sher LB, Woitge HW, Adams DJ. et al. Transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2 in osteoblasts reveals an anabolic role for endogenous glucocorticoids in bone. Endocrinology 2004; 145: 922-929.
• 12 Kalak R, Zhou H, Street J. et al. Endogenous glucocorticoid signalling in osteoblasts is necessary to maintain normal bone structure in mice. Bone 2009; 45: 61-67.
• 13 Sher LB, Harrison JR, Adams DJ, Kream BE. Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-argeted disruption of glucocorticoid signaling. Calcif Tissue Int 2006; 79: 118-125.
• 14 Zebaze RM, Ghasem-Zadeh A, Bohte A. et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 2010; 375: 1729-1736.
• 15 Wetzsteon RJ, Shults J, Zemel BS. et al. Divergent effects of glucocorticoids on cortical and trabecular compartment BMD in childhood nephrotic syndrome. Journal of bone and mineral research 2009; 24: 503-513.
• 16 Zhou H, Mak W, Kalak R. et al. Glucocorticoid-dependent Wnt signaling by mature osteoblasts is a key regulator of cranial skeletal development in mice. Development 2009; 136: 427-436.
• 17 Zhou H, Mak W, Zheng Y. et al. Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem 2008; 283: 1936-1945.
• 18 Henneicke H, Herrmann M, Kalak R. et al. Corticosterone selectively targets endo-cortical surfaces by an osteoblast-dependent mechanism. Bone 2011; 49: 733-742.
• 19 Weinstein RS, Wan C, Liu Q. et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010; 09: 147-161.
• 20 Zhou H, Cooper MS, Seibel MJ. Endogenous Glucocorticoids and Bone. Bone Res 2013; 01: 107-119.
• 21 Lee NK, Sowa H, Hinoi E. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007; 130: 456-469.
• 22 Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 2008; 105: 5266-5270.
• 23 Ekenstam EA, Ljunghall S, Hallgren R. Serum osteocalcin in rheumatoid arthritis and other inflammatory arthritides: relation between inflammatory activity and the effect of glucocorticoids and remission inducing drugs. Ann Rheum Dis 1986; 45: 484-490.
• 24 Lukert BP, Higgins JC, Stoskopf MM. Serum osteocalcin is increased in patients with hyperthyroidism and decreased in patients receiving glucocorticoids. J Clin Endocrinol Metab 1986; 62: 1056-1058.
• 25 Morrison N, Eisman J. Role of the negative glucocorticoid regulatory element in glucocorticoid repression of the human osteocalcin promoter. Journal of bone and mineral research 1993; 08: 969-975.
• 26 Herrmann M, Henneicke H, Street J. et al. The challenge of continuous exogenous glucocorticoid administration in mice. Steroids 2009; 74: 245-249.
• 27 Brennan-Speranza TC, Henneicke H, Gasparini SJ. et al. Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. J Clin Invest 2012; 122: 4172-4189.
• 28 Mazziotti G, Maffezzoni F, Doga M. et al. Outcome of glucose homeostasis in patients with glucocorticoid-induced osteoporosis undergoing treatment with bone active-drugs. Bone 2014; 67: 175-180.
• 29 Jia D, O’Brien CA, Stewart SA. et al. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006; 147: 5592-5599.
• 30 Dovio A, Perazzolo L, Osella G. et al. 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 2004; 89: 4923-4928.
• 31 Sivagurunathan S, Muir MM, Brennan TC. et al. Influence of glucocorticoids on human osteoclast generation and activity. Journal of bone and min- eral research 2005; 20: 390-398.
• 32 Hofbauer LC, Gori F, Riggs BL. et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential para- crine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999; 140: 4382-4389.
• 33 Kim HJ, Zhao H, Kitaura H. et al. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 2006; 116: 2152-2160.
• 34 Rauch A, Seitz S, Baschant U. et al. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab 2010; 11: 517-531.
• 35 Adachi JD, Bensen WG, Brown J. et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997; 337: 382-387.
• 36 Cohen S, Levy RM, Keller M. et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999; 42: 2309-2318.
• 37 Lems WF, Saag K. Bisphosphonates and glucocorticoid-induced osteoporosis: cons. Endocrine 2015; 49: 628-634.
• 38 Teitelbaum SL, Seton MP, Saag KG. Should bisphosphonates be used for long-term treatment of glucocorticoid-induced osteoporosis?. Arthritis Rheum 2011; 63: 325-328.
• 39 Saag KG, Zanchetta JR, Devogelaer JP. et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, con- trolled trial. Arthritis Rheum 2009; 60: 3346-3355.
• 40 Eastell R, Chen P, Saag KG. et al. Bone formation markers in patients with glucocorticoid-induced osteoporosis treated with teriparatide or alendronate. Bone 2010; 46: 929-934.
• 41 Saag KG, Agnusdei D, Hans D. et al. Trabecular Bone Score in Patients with Chronic Glucocorticoid-Induced Osteoporosis Treated with Alendronate or Teriparatide. Arthritis Rheumatol 2016; 68 (09) 2122-2128.
• 42 Lekamwasam S, Adachi JD, Agnusdei D. et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 2012; 23: 2257-2276.