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Classificazione e indicazione all’uso dei fattori di crescita in Traumatologia G.M. Calori

ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO. Classificazione e indicazione all’uso dei fattori di crescita in Traumatologia G.M. Calori Biella, 5 Giugno 2009. Clinical Evidence vs Clinical Experience.

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Classificazione e indicazione all’uso dei fattori di crescita in Traumatologia G.M. Calori

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  1. ISTITUTO ORTOPEDICO G. PINI UNIVERSITA’ DEGLI STUDI DI MILANO Classificazione e indicazione all’uso dei fattori di crescita in Traumatologia G.M. Calori Biella, 5 Giugno 2009

  2. Clinical Evidence vs Clinical Experience G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita • Levels of evidence • PRCT (14%) • Cohort studies (20%) • Case control (10%) • Retrospective case series (56%) • Experience/Opinion (0%)

  3. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Dott. Marshall R. Urist Bone: Formation by Autoinduction. Science. 1965 Nov 12;150(698):893-9.

  4. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita OSTEOINDUCTION Is the ability to stimulate bone tissue formation in a non-bone site and can be distinguished in: 1) CELL-MEDIATED 2) GF-MEDIATED

  5. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita OSTEOINDUCTION CELL-MEDIATED In cell-mediated osteogenesis cell precursors are harvested from bone marrow, concentrated and grafted

  6. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita OSTEOINDUCTION GF-MEDIATED In GF-mediated osteoinduction growth factors stimulate resident mesenchimal cells to differentiate in a chondro and osteblastic lineage

  7. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS TGF-ß(1-5) andBMPs(1-16) belong to a family of proteins with similar amino-acidic sequences called TGF-ß superfamily They are the main regulators of osteoblastic feedback

  8. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS TGF- ß TGF-ß controls the repairing process throughtout deposition of extracellular matrix with a mitogenic and chemotactic action Joyce ME et al. J Cell Biol 110:2195-2207, 1990 Noda M, Camilliere JJ. Endocrinology 124:2991-2994, 1989

  9. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita GROWTH FACTORS TGF- ß Concentration of TGF- ß in bone tissue and in platelets is 100 times greater than in the other tissues Joyce ME et al. J Cell Biol 110:2195-2207, 1990 Noda M, Camilliere JJ. Endocrinology 124:2991-2994, 1989

  10. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Mesenchymal stem cell Osteo- progenitor cell Pre-osteoblast Transition- osteoblast Secreting osteoblast Osteozytic osteoblast Osteocyte • IGF-I / IGF-II Growth Factors have a combined, sequencial and stadium-specific action • aFGF / bFGF • TGF-B1 / TGF-B2 • LIF • BMP-2 / BMP-3 • PDGF • BMP-7 • Osteonectin • BDGF • Collagen type I • Vitamin D • sialoprotein • Osteocalcin GROWTH FACTORS

  11. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Proliferative effect Differentiative effect Mesenchimal stem cell BMP TGF-ß Cellula osteoprogenitrice BMP TGF-ß BMP TGF-ß TGF-ß IGF PDGF FGF Osteoblast GROWTH FACTORS Mohan S, Baylink DJ. Clin Orthop 263:30-48, 1991

  12. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita The meeting between biotechnologies and the muscoloscheletal system involves many fields: • scaffolds for bone defects treatment • scaffolds for cartilage defects treatment • synthetic growth factors • platelets concentration systems • marrow inhaled concentration and adsorbment systems • stem cells in vitro expansion systems (?)

  13. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita The meeting between biotechnologies and the muscoloscheletal system involves many fields: • scaffolds for bone defects treatment • scaffolds for cartilage defects treatment • synthetic growth factors • platelets concentration systems • marrow inhaled concentration and adsorbment systems • stem cells in vitro expansion systems (?)

  14. BMP genes identified Sampath & Reddi Commercial rights to molecules established Creative Biomolecules (later Stryker Orthobiologics) get OP1 (BMP-7) for bone Wyeth get BMP-2 for bone Both Boston - based Companies G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 1980 - 2000

  15. Many BMPs are recognised (?up to 40) Related by cysteine knot structure High amino acid sequence homology Share property of producing bone in non-osseous sites Genes found on different chromosomes Little difference between species (so human molecules can ligitimately and effectively be used on different lab animals) All members of TGFbeta superfamily of proteins G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 1980 - 2000

  16. Human genome identified Plasmids manufactured containing gene sequences for BMPs Development of technology to produce rhBMP in cultured CHO cells G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 1980 - 2000

  17. Animal and human studies Large scale commercial production Commercial licences granted rhBMP7 (OP1/ Osigraft) for long-bone non-union rhBMP2 (Inductos) for open fractures of the tibia rhBMP2 (Infuse) for spinal fusion G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 2000 - present

  18. Salkeld, Cook et al 2001 – dog ulna defect Mizumoto et al 2003– augmented callotasis with BMP7 Cook et al 2003– improved cartilage repair in dogs Improved tendon integration Dose ranging studies Seeherman (Wyeth – BMP2) – acceleration of fracture healing Blokhuis – (BMP7) acceleration of fracture healing Saito et al 2006 (BMP-2) - repair rabbit radial bone defect – 2009 induced periodontal regeneration in dogs G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Animal Studies since 2001

  19. Salkeld, Cook et al 2001 – dog ulna defect Mizumoto et al 2003– augmented callotasis with BMP7 Cook et al 2003– improved cartilage repair in dogs Improved tendon integration Dose ranging studies Seeherman (Wyeth – BMP2) – acceleration of fracture healing Blokhuis – (BMP7) acceleration of fracture healing Saito et al 2006 (BMP-2) - repair rabbit radial bone defect – 2009 induced periodontal regeneration in dogs G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Animal Studies since 2001

  20. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Repair of Articular Cartilage Defects with Osteogenic Protein-1 (BMP-7) in Dogs – Cook et al OP-1 After 6 weeks Control

  21. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Repair of Articular Cartilage Defects with Osteogenic Protein-1 (BMP-7) in Dogs OP-1 Control After 52 weeks

  22. Friedlaender 2001 BESTT 2003 Australian Limb Salvage Series Others - ongoing G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Human Studies for Trauma

  23. BMP-7 in Non Union - Friedlander et al. JBJS (Am) 2001;83 Suppl 1(Pt1):s151-62 PRCT (Part blinded, multi-center) 124 Tibial Non unions Excluded: Unreliable, Infected, envelope problems etc 2 groups Autograft + IM Nail (Control) BMP-7 + IM nail G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  24. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Summary of Safety*: *Friedlaender et. al, JBJS, Vol. 83-A, No. 4, April 2001.

  25. More “atrophic” (p=0.048) in OP-1 (randomisation) Comparable union rates at 9 months Concluded BMP-7 comparable to autograft 20% chronic donor pain in autograft group Osteomyelitis higher in control group (21% vs 3%) p=0.002 Potential Criticisms: 1/3 loss to follow up at 2 years Heterogenous group (50% prev IMN, 40% prev autograft) Non stratified G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Friedlander results

  26. Evidence for BMPs in Acute Fracture Care G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  27. BMP-2 Evaluation in Surgery for Tibial Trauma Trial (BESTT) - Govender et al BMP-2 for treatment of Open Tibial fractures: PRCT (450 Patients) JBJS(A) 2002 84-A(12):2123-34. 49 centres, 11 countries 450 Patients, Stratified (1, 2 and 3A) and (3B) Excluded patients in whom “bone grafting anticipated” 3 groups IM Nailing Low concentration BMP-2 (0.75mg/ml) High concentration BMP-2 (1.5mg/ml) Outcome measure 2y intervention within 12 months due to delayed or non union. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  28. No significant difference % reamed and unreamed (p=0.14) Outcome measures : Need for bone graft Control 13/65 (20%) BMP-2 1/66 (2%) p0.0005, relative risk reduction 90% Invasive secondary procedures Control 18/65 (28%) BMP-2 6/66 (9%) p=0.0065, relative risk reduction 68% Infection Control 26/65 (40%) BMP-2 13/66 (21%) p=0.02, relative risk reduction 48% Faster clinical healing 95 v 126 days in BMP-2 group G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 3B Open Tibia Subgroup

  29. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Results 6 weeks 14 weeks 52 weeks 26 weeks * BESTT Study Group

  30. “Son of BESTT” - Swiontowski et al rhBMP-2 inopen tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am. 2006 Jun;88(6):1258-65. 450 BESTT patients plus 60 US centre patients Sub group analysis 3A/3B fractures (n=131) Reamed Nailing (n=113) Only analysed 1.5mg/ml (High dose/concentration) treatment group Trial not set up or powered for subgroup analysis. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  31. Results BESTT Secondary Intervention Control 46% 0.75mg/ml BMP-2 37% 1.5mg/ml BMP-2 26% dose/response relationship (p=0.0004) 44% reduction in 2y intervention between Control and High dose Greater overall success in BMP groups esp High Faster wound healing at 6/52 p=0.001 More healed P=0.0008 Faster Healing P=0.002 Lower infection in severe fractures (3B) in BMP groups. P=0.02 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  32. BMP-2 + Allograft vs AICBG - Jones et al rhBMP-2 and allograft compared with Autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. (BESTT ALL) Study Group 2006 JBJS (A)July 2006 RCT N=30 (2/3 IM nail), (1/3 Ex fix) 2 Groups of 15 15 Secondary autologous graft at 6-12 weeks 15 Allograft chips with BMP-2 1-7cm defects, 20% drop out rate/loss to follow up,15% violated protocol (LISS 2/IMN 1) or Demineralised Bone Matrix (1) “Success” rate in BMP-2 87%, Control 67%. (p>0.05) 13% of failures in control were broken cross screws! Suggested equivalence of Auto vs Allo+BMP-2 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  33. Healing of Fresh tibial fractures with OP-1 a preliminary report. Acta Biomed Ateneo Parmenese 2002;73:27-32. Ex fix +BMP-7 vs Ex fix + Autologous graft 2 randomised groups BMP-7 (n=7) control (n=7). No statistical difference They all healed! Involved opening closed fractures Undersized study G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Tibial fractures – Maniscalco et al

  34. BMP-7 on healing of open tibial fractures results of multicenter PRCT OTA 2002, AAOS 2003 N=62 per group Favoured early weight bearing in BMP-7 group Less painwith activity P=0.04 Reduced secondary interventionin BMP-7 group (13% vs 27%) p=0.02 G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Open Tibial Fractures – McKee et al

  35. rhBMP-7 accelerates the healing in distal tibial fractures treated by external fixation. JBJS Br 2007 Feb 89(2):265-72. 20 in each group, case control study Faster healing p<0.03 Faster return to work p<0.018 Shorter time in external fixator p<0.037 Lower secondary intervention in BMP-7 group 10% vs 35% CONCLUDED BMP-7 ACCELERATES ACUTE FRACTURE UNION G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita BMP-7 in Distal Tibial Fractures + EF – Ristinemi et al

  36. Spinal Fusion Evidence G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  37. 9 USA, 1 Sweden,1 Canada, 1 Japan/USA Ecosse 1 France 0 (Full Time) 4 Anterior, 7 Posterolateral, 1 Neck. BMP-2 n=631 More effective than autograft for radiographic fusion p<0.05 95% vs 89% Burkus 2002 99% vs 76% in Burkus 2005 BMP-7 n=56 No significant difference to autograft in fusion G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita 12 RCTs of BMPs in Spinal Fusion

  38. 163 cases 1997-1999 FU 15 mo ave. Heterogeneous group – OP1 + AutoG, AlloG, Fillers. OP1 alone: 36 cases. 40 had previous AutoG. 39 failures overall 30% failure for non union group (28/113) G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Australian Limb Salvage

  39. Bone loss - THA revision G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  40. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July 2006 - Impaction grafting review

  41. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July 2006 - Impaction grafting review

  42. GFs vs infection G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

  43. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July 2006 – Chen et al

  44. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita July 2006 – Chen et alConclusions

  45. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PRP PRP is a source of aspecific autologous GFs able to stimulate the repairing process in the application site. It has the same effects of the haematoma, empowered by high concentration of trombocites.

  46. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita PPP (Platelet Poor Plasma) PRP (Platelet Rich Plasma) Red blood cell ThroughoutcentrifugationPRP is divided from the other blood fractions PRP

  47. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Activated platelets degranulate and release various GF and cytokines: Platelet Derived Growth Factor PDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor beta TGF-ß1 TGF-ß2 Vascular Endothelial Growth Factor VEGF Epithelial Growth Factor EGF Insuline Growth Factor IGF1-2 PRP

  48. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita Activated platelets degranulate and release various GF and cytokines: INDUCE OSTEOGENESIS Platelet Derived Growth FactorPDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor betaTGF-ß1 TGF-ß2 Vascular Endothelial Growth FactorVEGF Epithelial Growth FactorEGF Insuline Growth FactorIGF1-2 PRP

  49. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita INDUCES ANGIOGENESIS PRP Activated platelets degranulate and release various GF and cytokines: Platelet Derived Growth Factor PDGF-ßß PDGF-aa PDGF-aß Transforming Growth Factor beta TGF-ß1 TGF-ß2 Vascular Endothelial Growth Factor VEGF Epithelial Growth Factor EGF Insuline Growth Factor IGF1-2

  50. G.M. CALORI Classificazione e indicazione all’uso dei fattori di crescita

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