Neue Vorlage fr Montage FR2

1
Biology of Fracture Healing in Osteoporotic Bone
and the influence of pharmaceutical treatment to
fracture healing
Wolf Mutschler
Franz Jakob
Universität Würzburg
Bezirk Unterfranken
2
Osteoporotic Fracture the Clinical Problem

• Retarded fracture healing in osteoporosis
• Mechanical instability
• Implant failure
• Prolonged patient immobilisation
• Enhanced bone loss

The vicious circle
3
Time course of bone healing and problems in
osteoporosis
Date about bone healing in a sheep fracture
model, adopted from Jasmin Lienau et al., J
Orthop Res 24254262, 2006
cartilage
stem cells?
trabecular bone
differentiation?
matrix?
callus area
serum?
angiogenesis?
callus formation
fibrous tissue
mechanics?
weeks
4
Evidence for the stem cell and differentiation
problem
5
The number of MSC / Bone marrow cells is
decreasing with age
Newborn
Teen
30
50
80
Age
A. Caplan, J. Cell. Physiol. 213 341347, 2007.
6
HutchinsonGilford progeria syndrome
Pollex RL, Hegele RA. Clin Genet 2004 66
375381.
7
Ageing Defects in stem cell differentiation
caused by Telomerase und Werner Protein KO
Robert J. Pignolo, et al. (2008) Defects in
telomere maintenance molecules impair osteoblast
differentiation and promote osteoporosis. Aging
Cell 7 (1) , 2331
8
Accelerated senescence and altered gene
expression in osteoporotic mesenchymal stem cells
Opo-hMSC
hMSC
Days in culture until senescence

• 22684 probesets unchanged
• 1439 probesets only in healthy MSC, lacking in
  osteoporosis
• 54 probesets specifically expressed in
  osteoporosis

Osteoporotic MSC show specific defects in gene
expression related to ageing, self renewal and
osteogenic differentiation
Data Peggy Benisch and Regina Ebert
9
Evidence for a serum problem
10
Sera of aged women inhibit osteogenic but not
adipogenic differentiation of MSC
FCS Young serum Aged serum
Basem M. Abdallah Bone 39 (2006) 181188
11
Low antioxidant glutathione peroxidase activity
in sera of patients with severe osteoporosis
Controls Osteopenia Osteoporosis



Selenium ng/ml
Seefried et al. submitted
12
Evidence for a matrix problem
13
MSC of osteoporotic patients produce collagen
type 1-deficient ECM favouring adipogenic
differentiation
80
Deposition of type 1 collagen (µg/106 cells)
60
40
20
0
4
3
CICP (µg/106 cells)
2
MSC from young donors MSC from osteoporotic donors
1
0
J.P. Rodriguez et al. J. Cell. Biochem.
79557565, 2000
14
MSC regeneration in osteoporosis
Reduced stem cell number
Adipogenic morphogens in aged serum
Altered osteogenic differentiation
Reduced collagen type I secretion
Mechanic instability
Reduced angiogenesis
Prolonged immobilisation
Arnold I. Caplan and Scott P. Bruder TRENDS in
Molecular Medicine Vol.7 No.6 June 2001
15
(No Transcript)
16
Targets in Osteoporosis-Therapy
Can we treat osteoporotic fracture healing?
17
1,25 Vitamin D-hormone enhances fracture healing
in a rat OVx model
Fu L, Tang T, Miao Y, Hao Y, Dai K. Effect of
1,25-dihydroxy vitamin D3 on fracture healing and
bone remodeling in ovariectomized rat femora.
Bone. 2009 May44(5)893-8. Epub 2009 Feb 5.
18
Zoledronic acid does not impair fracture healing
but in high doses prolongs remodeling in a rat
closed fracture model
Mc Donald et al., Bone 43 (2008) 653662
19
Stimulation of Fracture-Healing with Systemic
Intermittent Teriparatide
Closed femoral fractures were generated in
8-wk-old male C57Bl/6 mice followed by daily
systemic injections of either saline (control) or
30 microg/kg PTH(1-34) for 14 days after
fracture.
Barnes et al. J Bone Joint Surg Am.
200890120-127
20
Present and Future Options for stimulation of
osteoporotic fracture healing

• In perimenopausal enhanced bone resorption
• Estrogens and phytoestrogens
• Reduced number of stem cells
• Stimulators like PTH / Teriparatide
• Deficits in local growth factors
• IGF-1 locally or systemically?
• In high age and for enhanced expression of
  inhibitors of bone formation
• Antibodies / Antagonists to SFRP-1, sclerostin,
• For Deficits in Angiogenic factors
• VEGF, CYR61?
• Vitamin D-Hormone?
• Vitamin K?
• PDGF?
• More to come????

21
Osteoporotic Fracture the Clinical Problem

• Retarded fracture healing in osteoporosis
• Mechanical instability
• Implant failure
• Prolonged patient immobilisation
• Enhanced bone loss

• Stimulation of fracture healing is feasible in
  healthy bone
• Stimulation in osteoporotic fracture healing can
  probably be applied with teriparatide and local
  IGF-1
• Specific stimulation in osteoporotic fracture
  healing can be achieved with taylored
  supplementation of defective factors and pathways
  in future

The vicious circle
22
Cooperations

• J. Adamski, München
• M. Amling, Hamburg
• L. Claes, Ulm
• A. Ignatius, Ulm
• R. Brenner, Ulm
• G. Duda, Berlin
• C. Glueer, Kiel
• L. Hofbauer, Dresden
• C. Kitz, Würzburg
• J. Köhrle, Berlin
• H. Mertsching, Würzburg
• S. Mundlos, Berlin
• W. Mutschler, München
• M. Schieker, München
• J. Seufert, Freiburg
• H. Stopper, Würzburg
• E. Wolf, München

• C. Beck
• P. Benisch
• R. Ebert
• S. Goebel
• B. Klotz
• R. Laug
• B. Mentrup
• S. Müller-Deubert
• U. Nöth
• S. Reppenhagen
• K. Schlegelmilch
• N. Schütze
• T. Schwartz
• L. Seefried
• A. Steinert
• J. Eulert
• M. Rudert
• F. Jakob

• P. Bianco, Rome
• M. Kassem, Odense
• E. Schipani, Boston
• M. Rogers, Aberdeen
• R. Tuan, NIH
• P. Marie, Paris
• H. Bischoff, Zürich
• W. Drake, London
• C. Limbert, Lissabon

• V. Monz
• M. Kober
• M. Kunz
• J. Meißner-Weigl
• S. Jatzke
• M. Regensburger
• D. Schneider
• J. Schneidereit
• S. Zeck

PhD MD
Science
Medicine