Seminar 09-04-2008 - glucocorticoid induced osteoporosis

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  • It is well-known that GC have severable desirable effects, as described in this paper with the very attractive title: optimizing GC: the sharpening of an old spear. Osteoporosis and osteonecrosis are one of the adverse effects.
  • Figure 2. Three General Mechanisms of Action of Glucocorticoids and the Glucocorticoid Receptor in the Inhibition of Inflammation. First the cortisol-glucocorticoidreceptor complex, secondly interaction of the cortisol-glucocorticoid receptor compelx and other transcription factors, such as NF-{kappa}B, and thirdly the non- genomic pathway.
  • FIG. 2. Wnt signaling pathway in osteoblasts. In the liganded state on the right side of the figure, the ligand Wnt is shown binding to the receptor frizzled and its coreceptor LRP-5. With a host of cofactors (Axin, Frat-1, Dsh), the signal is transduced, leading to inhibition of the activity of the enzyme glycogen synthetase kinase 3 (GSK3). This inhibitory effect leads to a stabilization of the levels of the protein ß-catenin that then translocates to the nucleus and activates genes that promote osteoblastic differentiation. A coactivator for ß-catenin (p300/cAMP response element-binding protein-binding protein) and a corepressor [silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NcoR)] are shown. In the unliganded state on the left side of the figure, the frizzled protein is not associated with the ligand Wnt and no signaling can occur. Two known inhibitors Dkk and SOST (sclerostin or the product of the SOST gene) can engage LRP-5 and block Wnt signaling. Under unliganded conditions, inhibition of GSK3 and the stabilization of ß-catenin do not occur, and transcription does not become active. ß-Catenin, by a series of steps involving phosphorylation, is transported to the proteosome for degradation. APC, adenomatous polyposiscoli tumor suppressor protein; TCF/LEF, T cell factor/lymphocyte enhancer factor. [Modified with permission from V. Krishnan, H. U. Bryant, and O. A. Macdougald: J Clin Invest 116:1202–1209, 2006 (19 ).] FIG. 2. Wnt signaling pathway in osteoblasts. In the liganded state on the right side of the figure, the ligand Wnt is shown binding to the receptor frizzled and its coreceptor LRP-5. With a host of cofactors (Axin, Frat-1, Dsh), the signal is transduced, leading to inhibition of the activity of the enzyme glycogen synthetase kinase 3 (GSK3). This inhibitory effect leads to a stabilization of the levels of the protein ß-catenin that then translocates to the nucleus and activates genes that promote osteoblastic differentiation. A coactivator for ß-catenin (p300/cAMP response element-binding protein-binding protein) and a corepressor [silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NcoR)] are shown. In the unliganded state on the left side of the figure, the frizzled protein is not associated with the ligand Wnt and no signaling can occur. Two known inhibitors Dkk and SOST (sclerostin or the product of the SOST gene) can engage LRP-5 and block Wnt signaling. Under unliganded conditions, inhibition of GSK3 and the stabilization of ß-catenin do not occur, and transcription does not become active. ß-Catenin, by a series of steps involving phosphorylation, is transported to the proteosome for degradation. APC, adenomatous polyposiscoli tumor suppressor protein; TCF/LEF, T cell factor/lymphocyte enhancer factor. [Modified with permission from V. Krishnan, H. U. Bryant, and O. A. Macdougald: J Clin Invest 116:1202–1209, 2006 (19 ).] FIG. 2. Wnt signaling pathway in osteoblasts. In the liganded state on the right side of the figure, the ligand Wnt is shown binding to the receptor frizzled and its coreceptor LRP-5. With a host of cofactors (Axin, Frat-1, Dsh), the signal is transduced, leading to inhibition of the activity of the enzyme glycogen synthetase kinase 3 (GSK3). This inhibitory effect leads to a stabilization of the levels of the protein ß-catenin that then translocates to the nucleus and activates genes that promote osteoblastic differentiation. A coactivator for ß-catenin (p300/cAMP response element-binding protein-binding protein) and a corepressor [silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NcoR)] are shown. In the unliganded state on the left side of the figure, the frizzled protein is not associated with the ligand Wnt and no signaling can occur. Two known inhibitors Dkk and SOST (sclerostin or the product of the SOST gene) can engage LRP-5 and block Wnt signaling. Under unliganded conditions, inhibition of GSK3 and the stabilization of ß-catenin do not occur, and transcription does not become active. ß-Catenin, by a series of steps involving phosphorylation, is transported to the proteosome for degradation. APC, adenomatous polyposiscoli tumor suppressor protein; TCF/LEF, T cell factor/lymphocyte enhancer factor. [Modified with permission from V. Krishnan, H. U. Bryant, and O. A. Macdougald: J Clin Invest 116:1202–1209, 2006 (19 ).] F IG . 2. Wnt signaling pathway in osteoblasts. In the liganded state on the right side of the figure, the ligand Wnt is shown binding to the receptor frizzled and its coreceptor LRP-5. With a host of cofactors (Axin, Frat-1, Dsh), the signal is transduced, leading to inhibition of the activity of the enzyme glycogen synthetase kinase 3 (GSK3). This inhibitory effect leads to a stabilization of the levels of the protein ß-catenin that then translocates to the nucleus and activates genes that promote osteoblastic differentiation. A coactivator for ß-catenin (p300/cAMP response element-binding protein-binding protein) and a corepressor [silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NcoR)] are shown. In the unliganded state on the left side of the figure, the frizzled protein is not associated with the ligand Wnt and no signaling can occur. Two known inhibitors Dkk and SOST (sclerostin or the product of the SOST gene) can engage LRP-5 and block Wnt signaling. Under unliganded conditions, inhibition of GSK3 and the stabilization of ß-catenin do not occur, and transcription does not become active. ß-Catenin, by a series of steps involving phosphorylation, is transported to the proteosome for degradation. APC, adenomatous polyposiscoli tumor suppressor protein; TCF/LEF, T cell factor/lymphocyte enhancer factor. [Modified with permission from V. Krishnan, H. U. Bryant, and O. A. Macdougald: J Clin Invest 116:1202–1209, 2006 (19 ).]
  • Ohnaka et al investigated the effects of dexamethason, vitamin D and estogens on bone formation in primary cultured human osteoblasts. Bone formation was estimated by the TcF/Lef transcriptional activity (TcelFactor, lymphoid enhancing factor). The addition of a WnT conditioned medium enhanced the TcF/Lef transcriptional activity, while is was suppressed by dexamethasone in a dose dependent manner.
  • In mice, the changes in apoptosis of osteoblasts were observed after 27 days of exposure to prednisone and to placebo:there was a large decrease in osteobalsts, probably due to apoptosis.
  • In this experiment, the GC action oo osteoblasts and osteocytes was blocked via/by transgenic expession of 11B hydroxysteroid dehydrogenase 2 in these cells. This enzyme converts the biologivcally active glucocorticoids into inactive compounds. Wildtype mice and transgenic exhibited a similar decrease in spinal bmd, suggesting that endogeneous GC action is not necessary for normal skeletal development. A striking difference was the increased apoptosis of osteoblasts in wild type mice, but not in transgenic mice. The same was found for osteocytes. In histomorphometry, it was shown that the bone formation was lower in wild type: perimeter of osteoblasts was lower, mineral appostion rate, bone fromation rate, etc, while the perimeter of osteoclasts was not different between wild type and transgenic mice. Interestingly, vertebral compression strength was much lower in the wild type mice, suggesting that the increased number of apoptotic osteoblasts and osteocytes is associated with loss of bone strength.
  • Bone marrow stroma contain pluripotent cells with the potential to differentiate into various mesenchymal cell lineages including myocytes, adipocytes, chondrocytes and osteoblasts. The ultimate cellular phenotype depends on systematic signals and influences present in the cellular microenvironment. In some studies it is suggested that GC have the potential to induce differentiation of bone marrow stromal cells towards the adipocyte pathway, and this may occur at the expense of osteoblastic cell differentiation.
  • This is one example of the changes in the differentiation of mesenchymal stem cells, induced by GC. On the left panel alizaline red staining, showing mineralized nodule formation in red. It is obvious that BMP induces accelerated and enhanced nodule formation versus control, while cortisol prevented the formation of mineralized nodules. On the right panel, cell exposed to cortisol were filled with lipid-containing vacuoles after 21 days, indicating mmature adipocytes. Aftre 27 mature adipocytes were detected; these changes were not seen in those cells stimulated by BMP.
  • Osteoclasts are multinucleated cells derived from he monocyte/macrophage family. Osteoclast development requires the presence of marrow stromal cells and osteoblasts, which express the essential stimuli to promote osteoclastogenesis: M-CSF and RANKL. It is well-known that RANKl can be counteracted by OPG.
  • This is a slide on the effects of glucocorticoids on osteoblasts. On the left panel, the dose response curve of OPG-Ligand, or RANK Ligand, following dexamethasone treatment of fetal osteoblasts: RANKL is upregulated when higher dosages of dexamethasone are used. On the right panel, it can be seen that when higher dosages of dexamethsone are used, the OPG production goes down.
  • In this study, the mechanism of GC-induced apoptosis of osteoclasts was studied. Apoptosis was estimated by caspase 3 activity. In wild type mice treatment with dexamethasone induced osteoclast apoptosis, as indicated by a 25% decrease in caspase 3 activity: in transgenic mice, the changes in caspase 3 activity were smaller. In the lower part of the slide it is demonstrated that bisphosphonates (in this case alendronate) has osteoclast apoptotic effects, which can be antagonized by the use of GC.
  • 16 As with any structure the strength of bone depends on its structure and material properties. As mentioned previously, bone undergoes continuous renewal by the process of bone turnover or remodelling. This process may then influence both the structural and material properties and thereby impact bone strength. Let us look in some more detail .
  • In mice, the changes in apoptosis of osteoblasts were observed after 27 days of exposure to prednisone and to placebo:there was a large decrease in osteobalsts, probably due to apoptosis.
  • In wild type mice, prednisone administration resulted in a 102% increase in the mRNA level of the calcitoninreceptor, an osteoclast specific gene. However, this effect was not observed in transgenic mice. In contrast, prednisone induced similar decreases in the mRNAlevels of osteocalcin, a marker of osteoblast activity (in osteoclasts the effect of cortisol was not blocked).
  • 2 risedronate RCTs of 306 total patients, 30 incident fractures Rate of fractures about 6x in GC users after adjustment Placebo and/or risedronate Non-users from 3 other residronate trials
  • Seminar 09-04-2008 - glucocorticoid induced osteoporosis

    1. 1. Glucocorticoid Induced Osteoporosis: pathogenesis • IWO, Utrecht, 9 april 2008 • Willem F Lems • Afdeling Reumatologie • Vrije Universiteit en • Jan van Breemen Instituut • Amsterdam
    2. 2. Trabecular micro-architecture in GIOP and postmenopausal osteoporosis (PMOP) 0 3 6 9 12 15 MS/BS BFR/BS ES/BS N.oc/BS PMOP GIOP Carbonare et al, JBMR 2001 MS/BS: mineralizing surface/bone surface; Bone Formation Rate/BS; Eroded Surface/BS; Number of Osteoclasts/BS.
    3. 3. Rhen T and Cidlowski J. N Engl J Med 2005;353:1711-1723 Three Mechanisms of Action of Glucocorticoids and the Glucocorticoid Receptor in the Inhibition of Inflammation
    4. 4. Pathogenesis GIOP: what’s new? • Wnt Signaling pathway; • Apoptosis Osteoblasts and Osteocytes; • Fat instead of Bone • Osteoclasts: Prolonged Life Span.
    5. 5. Copyright ©2007 The Endocrine Society Shoback, D. J Clin Endocrinol Metab 2007;92:747-753 FIG. 2. Wnt signaling pathway in osteoblasts
    6. 6. Pathogenesis GIOP: what’s new? • Wnt Signaling pathway; • Apoptosis Osteoblasts and Osteocytes; • Fat instead of Bone • Osteoclasts: Prolonged Life Span.
    7. 7. Copyright ©2004 The Endocrine Society O'Brien, C. A. et al. Endocrinology 2004;145:1835-1841 FIG. 4. Osteoblast-specific expression of 11{beta}-HSD2 prevents glucocorticoid-induced osteoblast and osteocyte apoptosis as well as loss of bone strength O’Brien, et al. Endocrinology 2004
    8. 8. Pathogenesis GIOP: what’s new? • Wnt Signaling pathway; • Apoptosis Osteoblasts and Osteocytes; • Fat instead of Bone • Osteoclasts: Prolonged Life Span.
    9. 9. Harada and Rodan, Nature 2003
    10. 10. Pathogenesis GIOP: what’s new? • Wnt Signaling pathway; • Apoptosis Osteoblasts and Osteocytes; • Fat instead of Bone • Osteoclasts: Prolonged Life Span.
    11. 11. Copyright ©1999 The Endocrine Society Hofbauer, L. C. et al. Endocrinology 1999;140:4382-4389 No Caption Found Hofbauer et al, Endocrinology 1999
    12. 12. Copyright ©2006 The Endocrine Society Jia, D. et al. Endocrinology 2006;147:5592-5599 FIG. 2. The TRAP-11{beta}-HSD2 transgene blocked dexamethasone (Dex) reduction of basal and alendronate-induced caspase-3 activity in osteoclasts in vitro Jia, et al. Endocrinology 2006
    13. 13. Harada and Rodan, Nature 2003
    14. 14. “Some data suggest that GCs may even benefit the bones of patients with RA” • disease activity ↓ • weightbearing activity ↑ • pro-inflammatory cytokines deleterious to bone ↓ Bijlsma: Annals Rheum Dis 2003 1033-37
    15. 15. Effect of low dose prednisone (10 mg/day during 1 week) on markers of bone metabolism in healthy volunteers 0 5 10 15 20 25 30 35 osteocalcin Pyr Dpyr before during after WF Lems et al, Br J Rheum 1998; 37: 23-33. ** **: p <0,05
    16. 16. Trabecular micro-architecture in GIOP and postmenopausal osteoporosis (PMOP) Carbonare et al, JBMR 2001 N.Nd/TV: number of nods/trabecular volume PMOP: postmenopausal; LGC: < 10 g (cumulative) GC; HGC: > 10 g (cumulative) GC,
    17. 17. Bone Turnover (Remodelling) Bone Strength Structural Properties Material Properties Lems WF, Arthritis Rheum Editorial, october 2007.
    18. 18. • Dank voor uw aandacht!
    19. 19. Copyright ©2006 The Endocrine Society Jia, D. et al. Endocrinology 2006;147:5592-5599 FIG. 3. The TRAP-11{beta}-HSD2 transgene blocked prednisolone stimulation of calcitonin receptor mRNA expression but not inhibition of osteocalcin
    20. 20. Glucocorticoids alter the BMD Fracture Threshold van Staa. Arth Rheum 2003; 48: 3224-9 Steroid users Nonusers Femoral neck BMD Lumbar spine BMD 40 30 20 10 0 40 30 20 10 0 %Fractures -4.5 -3.5 -2.5 -1.5 -0.5 0.5 -4.5 -3.5 -2.5 -1.5 -0.5 0.5
    21. 21. Summary (1) • Inhibition of bone formation plays a crucial role in the pathogenesis of GIOP; • Bone loss is much larger in patients starting with GC than on those on chronic treatment; • Life style measures (calcium, vitamin D, exercises and prevention of falling) are important.
    22. 22. Conclusions (I) • GC have a devastating effect on bone strength, because of an inhibiting effect on bone formation and an (absolutely or relatively) increase in bone resorption; • Bone loss in GC-users is higher in starters, patients with high dose GC, and patients without vitamin D; • The risk of fractures is elevated in GC-users, also in patients with moderate dosages of GC (2,5-7,5 mg/day).
    23. 23. Conclusions (II) • Bisphosphonates (risedronate and alendronate) are effective drugs for prevention of fractures in GIOP; • Teriparatide is the first anabolic agent with a positive effect on lumbar spine BMD and vertebral fracture rate, compared to a bisphosphonate; • Several guidelines for prevention of GIOP are available; • Adherence to guidelines is only moderate.
    24. 24. RANKL/OPG
    25. 25. Pathogenesis CIOP • Early phase: RANKl ↑ and OPG ↓, resulting in increased Osteoclastogenesis. • Late Phase: Apoptosis Osteoblasts, leading to RANKl ↓, resulting in decreased osteoclastogenesis and decreased bone remodeling.
    26. 26. Manolagas JBMR 2000
    27. 27. “Some data suggest that GCs may even benefit the bones of patients with RA” • disease activity ↓ • weightbearing activity ↑ • pro-inflammatory cytokines deleterious to bone ↓ Annals Rheum Dis 2003 1033-37
    28. 28. Prevention of Fractures in GIOP(5): anti-osteoporotic drugs. • For both alendronate and risedronate, and increase in BMD and reduction in patients with new vertebral fractures was shown during GC-treatment. • Bisphosphonates (alendronate) are superior to active Vitamin D; • Bisphosphonates (alendronate) are also effective in patients chonically treated with low dose prednisone.
    29. 29. • ACR Recommendations CIOP 2001
    30. 30. Treatment thresholds in GIOP • Uk Guidelines (1998):T-score >1,5; • ACR recommendations (2001) : T> -1; • Dutch CBgui

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