use of bioactive protein factors in accelerating fracture repair m. phillips consultant orthopaedic...
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Use of bioactive protein Use of bioactive protein factors in accelerating factors in accelerating
fracture repairfracture repair
M. PhillipsM. Phillips
Consultant Orthopaedic and Consultant Orthopaedic and Trauma SurgeonTrauma Surgeon
King’s College HospitalKing’s College Hospital
London, UKLondon, UK
Where are we with this?Where are we with this?
• Public just waking upPublic just waking up• Sports professionals interestedSports professionals interested• Orthopaedic surgeons only just Orthopaedic surgeons only just
ahead of clients?ahead of clients?
Has ‘medication’ of Has ‘medication’ of fractures only just fractures only just
appeared?appeared?
• Pulsed electromagnetic field (PEMF)Pulsed electromagnetic field (PEMF)• Capacitative couplingCapacitative coupling• Low Frequency Ultrasound (LFUS)Low Frequency Ultrasound (LFUS)• Extracorporeal Shockwave Therapy Extracorporeal Shockwave Therapy
(ECSWT)(ECSWT)• Fracture ‘medication’Fracture ‘medication’
What has been the thrust What has been the thrust of these therapies?of these therapies?
• To treat non-unionTo treat non-union• To avert non-union in cases of To avert non-union in cases of
delayed uniondelayed union
What does fracture What does fracture medication achieve in medication achieve in
practice?practice?
BESTT Study GroupBESTT Study Group
• J. Bone Joint Surg. Am., Dec 2002; 84: J. Bone Joint Surg. Am., Dec 2002; 84: 2123 - 2134.2123 - 2134.
‘‘Other’Other’
• Neck of talusNeck of talus• Medial malleolusMedial malleolus• Base of 5Base of 5thth metatarsal metatarsal
Predicting the risk of clavicular Predicting the risk of clavicular delayed union and non-uniondelayed union and non-union
Robinson, Court-Brown McQueen and WakefieldRobinson, Court-Brown McQueen and WakefieldThe Journal of Bone and Joint Surgery (American)The Journal of Bone and Joint Surgery (American)
86:1359-1365 (2004)86:1359-1365 (2004)
Towards TrialsTowards Trials
• How can we calculate the effect How can we calculate the effect size?size?
• Need preclinical data / pilot studiesNeed preclinical data / pilot studies
Rabbit ulna Rabbit ulna studystudy
Rat femurs –BMP2 vs buffer onlyRat femurs –BMP2 vs buffer onlyopen fractures created by guillotine open fractures created by guillotine
injected after closure.injected after closure.Einhorn et al J. Bone Joint Surg. Am., Aug Einhorn et al J. Bone Joint Surg. Am., Aug 20032003; 85: 1425 - ; 85: 1425 -
1435. 1435.
Seeherman trials Seeherman trials (Wyeth)(Wyeth)
• CarrierCarrier• SpeciesSpecies• Timing of injectionTiming of injection• Dose rangingDose ranging
Fracture healing acceleration Fracture healing acceleration with BMPs works in Monkeys: with BMPs works in Monkeys: Seeherman et al JBJS(Am) Sep Seeherman et al JBJS(Am) Sep
2004 1961-19722004 1961-1972
Timing of delivery: BMP2Timing of delivery: BMP2
• 1 week delay produced best acceleration 1 week delay produced best acceleration (40-50%)(40-50%)
• 8 week biomech data approx 2x as 8 week biomech data approx 2x as strong as controls (NB 1.5 > 4.5 > 0.5)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
The case for open The case for open fractures seems clear, now fractures seems clear, now
need to focus on…need to focus on…
• Injected growth factors in the fresh Injected growth factors in the fresh closed fractureclosed fracture
• Interaction of growth factors with Interaction of growth factors with external stimulationexternal stimulation
• Combinations of growth factors…etcCombinations of growth factors…etc
We have chosen to start We have chosen to start with the fresh tibia: why?with the fresh tibia: why?
• Common fracture – at least 1 per week per hospital Common 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-High risk of delayed or non-union or need for re-
intervention (?10%)intervention (?10%)• 10% of 10 000 is 1000 adverse outcomes10% of 10 000 is 1000 adverse outcomes• Aim: Aim: halvehalve it, and save 500 procedures, costing it, and save 500 procedures, costing
£10 000 each (=£5m) at a cost of £3000 x 10 000 £10 000 each (=£5m) at a cost of £3000 x 10 000 (£30m)(£30m)
• Need to look again at the business case?Need to look again at the business case?
End points / outcome End points / outcome measuresmeasures
• Choosing the best measuresChoosing the best measures
SummarySummary• Many patients will benefit from medication of Many patients will benefit from medication of
fresh fractures to enhance healingfresh fractures to enhance healing• Growth factors have a major roleGrowth factors have a major role• These treatments are expensive and so These treatments are expensive and so
fractures at risk will be treated firstfractures at risk will be treated first• There is an urgent need for well designed There is an urgent need for well designed
trials, which will involve multicentre trials, which will involve multicentre collaborationcollaboration
• Current unit costs of commercial growth Current unit costs of commercial growth factors should reduce as economies of scale factors should reduce as economies of scale are realised if they are used more frequentlyare realised if they are used more frequently