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

Who needs acceleration of Who needs acceleration of fracture repair?fracture repair?

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 could ‘medication’ What could ‘medication’ achieve?achieve?

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.

Should we medicate all Should we medicate all fractures?fractures?

The ‘fracture at risk’The ‘fracture at risk’

Lateral clavicleLateral clavicle

Clavicle diaphysisClavicle diaphysis

ScaphoidScaphoid

HumerusHumerus

TibiaTibia

Intracapsular neck of Intracapsular neck of femurfemur

                                               

‘‘Other’Other’

• Neck of talusNeck of talus• Medial malleolusMedial malleolus• Base of 5Base of 5thth metatarsal metatarsal

Can we quantify the risk?Can we quantify the risk?

The ‘Prognostic Index’The ‘Prognostic Index’

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.

What to inject and when?What to inject and when?

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

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

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

Thank youThank you