Kortisolwirkungen im Knochen

Zusammenfassung

Eine Glukokortikoid-induzierte Osteoporose ist eine schwere Komplikation einer Langzeit- Glukokortikoidtherapie und die häufigste Form der sekundären Osteoporosen. Die zugrundeliegenden Mechanismen der Pathogenese sind komplex. Glukokortikoide haben vielfältige physiologische Funktionen, wie die Regulation des Glukosestoffwechsels. Obwohl Glukokortikoide in physiologischen Konzentrationen für die Knochenentwicklung notwendig sind, wirken sie in therapeutischen Konzentrationen katabol auf den Knochen. Sie begünstigen die Aktivität der knochen resorbierenden Osteoklasten und hemmen gleichzeitig langfristig die knochenbildenden Osteoblasten und Osteozyten. Die frühzeitige Anwendung von Bisphosphonaten reduziert effektiv das Auftreten von Frakturen und die Therapie mit Teriparatid verhindert die Hemmung der Knochenformation, verbessert die Knochenqualität und führt zur einer signifikanten Frakturreduktion bei Patienten mit Glukokortikoid-induzierter Osteoporose. Weitere osteoanabol wirkende Substanzen, wie Romosozumab, ein monoklonaler Antikörper gegen Sklerostin, befinden sich in der klinischen Erprobung und könnten attractive Therapiealternativen für die Behandlung der Glukokortikoid-induzierten Osteoporose darstellen.

Summary

Glucocorticoid-induced osteoporosis is a severe side effect of long-term glucocorticoid therapy and the most common form of secondary osteoporosis. The molecular mechanisms underlying the deleterious effects of glucocorticoids in bone are complex. Glucocorticoids exert several physiological metabolic actions including the regulation of glucose homeostasis and lipid metabolism and play a pivotal role in the regulation of inflammatory processes as well as in the maintenance of circadian rhythms and regulation of acute and chronic stress. They have multiple effects on fetal development and in physiological concentrations, they are necessary for bone accrual and growth. Nevertheless, supraphysiological concentrations of glucocorticoids, either as part of the treatment of chronic inflammatory medical conditions or as a result of Cushing’s syndrome negatively affect the bone. They enhance the activity of the boneresorbing osteoclasts through the up-regulation of M-CSF und RANKL and concomitant down-regulation of OPG and activate inhibitors of the Wnt-signaling pathway such as sclerostin, thereby thwarting bone formation. Their direct inhibitory actions on bone-forming osteoblasts and osteocytes are considered pivotal for the pathogenesis of glucocorticoid-induced osteoporosis. Supraphysiological glucocorticoid concentrations block osteoblast differentiation and proliferation, activate pro-apoptotic signaling pathways in osteoblasts and osteocytes and hamper the mineralization process. Currently, therapeutic options to treat patients with glucocorticoid-induced osteoporosis are anti-resorptive and osteoanabolic drugs. The rationale of an early-on treatment with antiresorptive drugs is based on the fact that glucocorticoids lead to an initial phase of accentuated bone resorption. Thus, clinical studies have proven that bisphosphonates are effective at reducing the occurrence of fractures in patients with glucocorticoid-induced osteoporosis. On the other hand, the inhibitory actions of glucocorticoids on bone formation render osteoanabolic drugs very attractive therapeutic options. The intermittent therapy with teriparatide leads to a significant improvement of bone architecture and strength parameters as well as to a reduction of vertebral fractures and should thus be implemented especially by patients with severe forms of glucocorticoid-induced osteoporosis. Novel osteoanabolic agents such as romosozumab, a monoclonal antibody against sclerostin are currently being evaluated in clinical studies.

Schlüsselwörter

Glukokortikoid-induzierte Osteoporose - Frakturrisiko - Knochenstoffwechsel

Keywords

Glucocorticoid-induced osteoporosis - fracture risk - bone homeostasis

• Literatur

• 1 van Staa TP, Leufkens HG, Abenhaim L. et al. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 2000; 39 (12) 1383-1389.
• 2 Canalis E, Bilezikian JP, Angeli A, Giustina A. Perspectives on glucocorticoid-induced osteoporosis. Bone 2004; 34 (04) 593-598.
• 3 Hench P. Effects of cortisone in the rheumatic diseases. Lancet 1950; 02 (6634): 483-484.
• 4 Papadimitriou A, Priftis KN. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation 2009; 16 (05) 265-271.
• 5 Hartmann K, Koenen M, Schauer S. et al. Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy. Physiol Rev 2016; 96 (02) 409-447.
• 6 Amann J, Lang A, Hoff P, Buttgereit F. Effekte der Glukokortikoide auf den Knochen. Osteologie 2014; 23: 179-186.
• 7 Durbridge TC, Morris HA, Parsons AM. et al. Progressive cancellous bone loss in rats after adrenalectomy and oophorectomy. Calcif Tissue Int 1990; 47 (06) 383-387.
• 8 Bjornsdottir S, Saaf M, Bensing S. et al. Risk of hip fracture in Addison’s disease: a population-based cohort study. J Intern Med 2011; 270 (02) 187-195.
• 9 Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab 2012; 97 (01) 85-92.
• 10 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 (01) 61-67.
• 11 Sher LB, Harrison JR, Adams DJ, Kream BE. Impaired cortical bone acquisition and osteoblast differentiation in mice with osteoblast-targeted disruption of glucocorticoid signaling. Calcif Tissue Int 2006; 79 (02) 118-125.
• 12 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 (03) 427-436.
• 13 Doerr P, Pirke KM. Cortisol-induced suppression of plasma testosterone in normal adult males. J Clin Endocrinol Metab 1976; 43 (03) 622-629.
• 14 Hsueh AJ, Erickson GF. Glucocorticoid inhibition of FSH-induced estrogen production in cultured rat granulosa cells. Steroids 1978; 32 (05) 639-648.
• 15 Sakakura M, Takebe K, Nakagawa S. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment with glucocorticoids in human subjects. J Clin Endocrinol Metab 1975; 40 (05) 774-779.
• 16 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 paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999; 140 (10) 4382-4389.
• 17 Rauner M, Goettsch C, Stein N. et al. Dissociation of osteogenic and immunological effects by the selective glucocorticoid receptor agonist, compound A, in human bone marrow stromal cells. Endocrinology 2011; 152 (01) 103-112.
• 18 Sato AY, Cregor M, Delgado-Calle J. et al. Protection from Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin. J Bone Miner Res. 2016 May 10.
• 19 Hofbauer LC, Zeitz U, Schoppet M. et al. Prevention of glucocorticoid-induced bone loss in mice by inhibition of RANKL. Arthritis Rheum 2009; 60 (05) 1427-1437.
• 20 Yao W, Cheng Z, Busse C. et al. 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 2008; 58 (06) 1674-1686.
• 21 Dore RK, Cohen SB, Lane NE. et al. Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates. Ann Rheum Dis 2010; 69 (05) 872-875.
• 22 Dempster DW. Bone histomorphometry in glucocorticoid-induced osteoporosis. J Bone Miner Res 1989; 04 (02) 137-141.
• 23 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 (04) 1835-1841.
• 24 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 (06) 517-531.
• 25 Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone?. Nature clinical practice Rheumatology 2006; 02 (01) 35-43.
• 26 Vande Berg BC, Malghem J, Lecouvet FE. et al. Fat conversion of femoral marrow in glucocorticoidtreated patients: a cross-sectional and longitudinal study with magnetic resonance imaging. Arthritis Rheum 1999; 42 (07) 1405-1411.
• 27 Thiele S, Ziegler N, Tsourdi E. et al. Selective glucocorticoid receptor modulation maintains bone mineral density in mice. J Bone Miner Res 2012; 27 (11) 2242-2250.
• 28 Wang FS, Ko JY, Yeh DW. et al. Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. Endocrinology 2008; 149 (04) 1793-1801.
• 29 Luppen CA, Smith E, Spevak L. et al. Bone morphogenetic protein-2 restores mineralization in glucocorticoid-inhibited MC3T3-E1 osteoblast cultures. J Bone Miner Res 2003; 18 (07) 1186-1197.
• 30 Pereira RM, Delany AM, Durant D, Canalis E. Cortisol regulates the expression of Notch in osteoblasts. J Cell Biochem 2002; 85 (02) 252-258.
• 31 Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. The Journal of clinical investigation 1998; 102 (02) 274-282.
• 32 Espina B, Liang M, Russell RG, Hulley PA. Regulation of bim in glucocorticoid-mediated osteoblast apoptosis. Journal of cellular physiology 2008; 215 (02) 488-496.
• 33 Plotkin LI, Weinstein RS, Parfitt AM. et al. Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. The Journal of clinical investigation 1999; 104 (10) 1363-1374.
• 34 Lane NE, Yao W, Balooch M. et al. Glucocorticoidtreated 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 2006; 21 (03) 466-476.
• 35 Yao W, Dai W, Jiang JX, Lane NE. Glucocorticoids and osteocyte autophagy. Bone 2013; 54 (02) 279-284.
• 36 Jia JJ, Yao W, Guan M. et al. Glucocorticoid dose determines osteocyte cell fate. Faseb Journal 2011; 25 (10) 3366-3376.
• 37 Teitelbaum SL, Seton MP, Saag KG. Should bisphosphonates be used for long-term treatment of glucocorticoid-induced osteoporosis?. Arthritis Rheum 2011; 63 (02) 325-328.
• 38 Saag KG, Zanchetta JR, Devogelaer JP. et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-sixmonth results of a randomized, double-blind, controlled trial. Arthritis Rheum 2009; 60 (11) 3346-3355.
• 39 Gluer CC, Marin F, Ringe JD. et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J Bone Miner Res 2013; 28 (06) 1355-1368.
• 40 McClung MR, Grauer A, Boonen S. et al. Romosozumab in postmenopausal women with low bone mineral density. The New England journal of medicine 2014; 370 (05) 412-420.