Seminar 09-04-2008 - glucocorticoid induced osteoporosis

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

http://www.sciencedirect.com/science?_ob=MiamiCaptionURL&_method=retrieve&_udi=B6T1B-4RM7V06-X&_image=B6T1B-4RM7V06-X-F&_ba=&_user=4330146&_rdoc=1&_fmt=full&_orig=search&view=c&_isHiQual=Y&_acct=C000024498&_version=1&_urlVersion=0&_userid=4330146&md5=47c01d92e43f52eb9b31e24fbd52b2a9

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


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

Harada and Rodan, Nature 2003


Hofbauer, L. C. et al. Endocrinology 1999;140:4382-4389

No Caption Found

Hofbauer et al, Endocrinology 1999


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!


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

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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

Seminar 09-04-2008 - glucocorticoid induced osteoporosis

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