Glucocorticoid Induced Osteoporosis:pathogenesis
• IWO, Utrecht, 9 april 2008
• Willem F Lems• Afdeling Reumatologie • Vrije Universiteit en • Jan van Breemen Instituut • Amsterdam
Trabecular micro-architecture in GIOP and postmenopausal osteoporosis (PMOP)
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MS/BS BFR/BS ES/BS N.oc/BS
PMOPGIOP
Carbonare et al, JBMR 2001
MS/BS: mineralizing surface/bone surface; Bone Formation Rate/BS; Eroded Surface/BS; Number of Osteoclasts/BS.
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
Pathogenesis GIOP: what’s new?
• Wnt Signaling pathway;• Apoptosis Osteoblasts and Osteocytes;• Fat instead of Bone• Osteoclasts: Prolonged Life Span.
Copyright ©2007 The Endocrine Society
Shoback, D. J Clin Endocrinol Metab 2007;92:747-753
FIG. 2. Wnt signaling pathway in osteoblasts
Pathogenesis GIOP: what’s new?
• Wnt Signaling pathway;• Apoptosis Osteoblasts and Osteocytes;• Fat instead of Bone• Osteoclasts: Prolonged Life Span.
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
Pathogenesis GIOP: what’s new?
• Wnt Signaling pathway;• Apoptosis Osteoblasts and Osteocytes;• Fat instead of Bone• Osteoclasts: Prolonged Life Span.
Harada and Rodan, Nature 2003
Pathogenesis GIOP: what’s new?
• Wnt Signaling pathway;• Apoptosis Osteoblasts and Osteocytes;• Fat instead of Bone• Osteoclasts: Prolonged Life Span.
Copyright ©1999 The Endocrine Society
Hofbauer, L. C. et al. Endocrinology 1999;140:4382-4389
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Hofbauer et al, Endocrinology 1999
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
Harada and Rodan, Nature 2003
“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
Effect of low dose prednisone (10 mg/day during 1 week) on markers of bone metabolism
in healthy volunteers
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osteocalcin Pyr Dpyr
beforeduringafter
WF Lems et al, Br J Rheum 1998; 37: 23-33.
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**: p <0,05
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,
Bone Turnover (Remodelling)
Bone Strength
Structural Properties Material Properties
Lems WF, Arthritis Rheum Editorial, october 2007.
• Dank voor uw aandacht!
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 calcitoninreceptor mRNA expression but not inhibition of osteocalcin
Glucocorticoids alter the BMD
Fracture Threshold
van Staa. Arth Rheum 2003; 48: 3224-9
Steroid users
Nonusers
Femoral neck BMD
Lumbar spine BMD
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% F
ract
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-4.5 -3.5 -2.5 -1.5 -0.50.5
-4.5 -3.5 -2.5 -1.5 -0.50.5
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.
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).
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.
RANKL/OPG
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.
Manolagas JBMR 2000
“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
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.
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ACR Recommendations CIOP 2001
Treatment thresholds in GIOP
• Uk Guidelines (1998):T-score >1,5;
• ACR recommendations (2001) : T> -1;
• Dutch CBgui