1. Use of bioactive protein factors in accelerating fracture repair M. Phillips Consultant Orthopaedic and Trauma Surgeon King’s College Hospital London, UK

2. Who needs acceleration of fracture repair?

3. Where are we with this? Public just waking upPublic just waking up Sports professionals interestedSports professionals interested Orthopaedic surgeons only just ahead of clients?Orthopaedic surgeons only just ahead of clients?

4. Has ‘medication’ of fractures only just appeared? Pulsed electromagnetic field (PEMF)Pulsed electromagnetic field (PEMF) Capacitative couplingCapacitative coupling Low Frequency Ultrasound (LFUS)Low Frequency Ultrasound (LFUS) Extracorporeal Shockwave Therapy (ECSWT)Extracorporeal Shockwave Therapy (ECSWT) Fracture ‘medication’Fracture ‘medication’

5. What has been the thrust of these therapies? To treat non-unionTo treat non-union To avert non-union in cases of delayed unionTo avert non-union in cases of delayed union

6. What could ‘medication’ achieve?

7. What does fracture medication achieve in practice?

8. BESTT Study Group J. Bone Joint Surg. Am., Dec 2002; 84: 2123 - 2134.J. Bone Joint Surg. Am., Dec 2002; 84: 2123 - 2134.

9. Should we medicate all fractures?

10. The ‘fracture at risk’

11. Lateral clavicle

12. Clavicle diaphysis

13. Scaphoid

14. Humerus

15. Tibia

16. Intracapsular neck of femur

17. ‘Other’ Neck of talusNeck of talus Medial malleolusMedial malleolus Base of 5 th metatarsalBase of 5 th metatarsal

18. Can we quantify the risk?

19. The ‘Prognostic Index’

20. Predicting the risk of clavicular delayed union and non-union Robinson, Court-Brown McQueen and Wakefield The Journal of Bone and Joint Surgery (American) 86:1359-1365 (2004)

21. Towards Trials How can we calculate the effect size?How can we calculate the effect size? Need preclinical data / pilot studiesNeed preclinical data / pilot studies

22. Rabbit ulna study

23. Rat femurs –BMP2 vs buffer only open fractures created by guillotine injected after closure. Einhorn et al J. Bone Joint Surg. Am., Aug 2003; 85: 1425 - 1435.

24. What to inject and when?

25. Seeherman trials (Wyeth) CarrierCarrier SpeciesSpecies Timing of injectionTiming of injection Dose rangingDose ranging

26. Fracture healing acceleration with BMPs works in Monkeys: Seeherman et al JBJS(Am) Sep 2004 1961-1972

27. Timing of delivery: BMP2 1 week delay produced best acceleration (40-50%)1 week delay produced best acceleration (40-50%) 8 week biomech data approx 2x as strong as controls (NB 1.5 > 4.5 > 0.5)8 week biomech data approx 2x as strong as controls (NB 1.5 > 4.5 > 0.5) Recommend 1.5 to be injected at 1 weekRecommend 1.5 to be injected at 1 week

28. Blokhuis et al (2001) Biomaterials 22:725-730

29. The case for open fractures seems clear, now need to focus on… Injected growth factors in the fresh closed fractureInjected growth factors in the fresh closed fracture Interaction of growth factors with external stimulationInteraction of growth factors with external stimulation Combinations of growth factors…etcCombinations of growth factors…etc

30. We have chosen to start with the fresh tibia: why? Common fracture – at least 1 per week per hospitalCommon fracture – at least 1 per week per hospital In UK = 1 x 52 x 200 hospitals ~ 10 000 paIn UK = 1 x 52 x 200 hospitals ~ 10 000 pa High morbidity: excess 10 weeks labour lostHigh morbidity: excess 10 weeks labour lost High risk of delayed or non-union or need for re- intervention (?10%)High risk of delayed or non-union or need for re- intervention (?10%) 10% of 10 000 is 1000 adverse outcomes10% of 10 000 is 1000 adverse outcomes Aim: halve it, and save 500 procedures, costing £10 000 each (=£5m) at a cost of £3000 x 10 000 (£30m)Aim: halve it, and save 500 procedures, costing £10 000 each (=£5m) at a cost of £3000 x 10 000 (£30m) Need to look again at the business case?Need to look again at the business case?

31. End points / outcome measures Choosing the best measuresChoosing the best measures

32. Summary Many patients will benefit from medication of fresh fractures to enhance healingMany patients will benefit from medication of fresh fractures to enhance healing Growth factors have a major roleGrowth factors have a major role These treatments are expensive and so fractures at risk will be treated firstThese treatments are expensive and so fractures at risk will be treated first There is an urgent need for well designed trials, which will involve multicentre collaborationThere is an urgent need for well designed trials, which will involve multicentre collaboration Current unit costs of commercial growth factors should reduce as economies of scale are realised if they are used more frequentlyCurrent unit costs of commercial growth factors should reduce as economies of scale are realised if they are used more frequently

33. Thank you