Fracture healing Thanks to: Matthew Porteous Henry Wynn Jones Mr Lee Van Rensburg FRCS Basic...
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Transcript of Fracture healing Thanks to: Matthew Porteous Henry Wynn Jones Mr Lee Van Rensburg FRCS Basic...
Fracture healing
Thanks to:Matthew PorteousHenry Wynn Jones
Mr Lee Van Rensburg
FRCS
Basic sciences course
2014
FEBRUARY 2008 · VOLUME 90-A · SUPPLEMENT 1
Subject Bone Structure - Done Indirect healing Direct healing Strain theory Blood supply Inhibition/ Augmentation What’s new? Approach to Non union
Fracture Healing
Indirect healing (Secondary, Callus) Direct healing (Primary)
Fracture Healing
Indirect healing (Secondary, Callus)
Formation of bone via tissues which undergo change in material
structure until skeletal continuity is restored
Direct healing (Primary)
Indirect Fracture Healing
Impact
Indirect Fracture Healing
Impact Haematoma
Haemopoetic cells secrete growth factors Fibroblasts, osteoprogenitor cells,
mesenchymal cells
Indirect Fracture Healing
Impact Haematoma Inflammation
Granulation tissue 100% strain at failure
Indirect Fracture Healing
Impact Haematoma Inflammation Soft Callus
2 weeks 10% strain at failure
Indirect Fracture Healing
Impact Haematoma Inflammation Soft Callus Hard Callus
2% strain at failure
Indirect Fracture Healing
Impact Haematoma Inflammation Soft Callus Hard Callus Remodeling
Years Wolff’s law
Indirect Healing
time
strength
Movement at fracture site
VOL. 84-B, No. 8, NOVEMBER 2002
Perren’s Strain theory(interfragmentary strain theory) Interfragmentary strain determines the
subsequent differentiation of fracture gap tissue
10 to 100% fibrous tissue 2 to 10% - cartilage and enchondral
ossification < 2% - bone
Indirect Healing - Movement
Movement is desirable Provided the movement does
not disrupt the healing cells10m 5m5m40m 10m
Resorbtion
Small gap with movementHigh strain stimulates resorbtion
Resorbtion increases gap decreases strain
Comminuted fragment
Indirect Fracture Healing
Intramembranous Osification(Periosteal boney callus)
Formation of bone on, or in, fibrous connective tissue(formed from condensed mesenchyme cells)
Vs
Enchondral ossificationHyaline cartilage first
Direct Fracture Healing
Fracture stable No movement under physiological load
Bone ends compressed Can occur in cortical and cancellous bone
Direct Fracture Healing
No callus Cutting cones cross
fracture site Lay down new
osteones directly
Direct Healing
Movement Undesirable Even small amounts likely to disrupt
healing
Absolute stability
Wrong
Relative stability
Complete instability
Fractures MUST have a
blood supply to heal
Bone blood supply
Endosteal Inner 2/3rds
Periosteal Outer 1/3rd
Disrupted by a fracture Further damaged by
surgery
Bone blood supplyReaming
Damages endosteal blood supply
Blood flow reverses
BUT Stimulates callus
Bone blood supply Plates
Damage periosteal blood supply
Causes underlying necrosis
Bone blood supply - plates
Can be reduced by LCDCP Locking plate
Augmentation of fracture healing
Inhibition Augmentation
VOL. 89-B, No. 12, DECEMBER 2007
VOL. 89-B, No. 12, DECEMBER 2007
Inhibition Patient
Age - Some evidence (skeletally mature) Clavicle, NOF
Gender - No (male higher energy) Diabetes – Yes double time to union Anaemia – Some, Chronic iron defficiency Nutrition – If malnourished yes PVD – Not directly assesed but if injure vessel
40% longer to unite Hypothyroidism – Yes at risk Postmenopausal
female
Inhibition Medication
NSAID
VOLUME 88-A · SUPPLEMENT 3 · 2006
NSAIDs reduce vascularity around fracture.
Additional reduction in healing independent of blood flow.
Best to avoid in fractures prone to non union or poor vascularity.
COX 2 NSAIDS inhibit fracture-healing more than non-specific NSAIDS.
Magnitude of effect is related to duration of treatment.
On discontinuation, prostaglandin E2 levels are gradually restored.
VOLUME 89-A · NUMBER 1 · JANUARY 2007
Inhibition Medication
NSAID – Yes Corticosteroids – Appears to be longer Statins – Conflicting animal, no human?
beneficial Smoking – Yes for tibia 40% more likely non
union Nicotine replacement – conflicting high dose
no, low dose may improve, better than smoking Alcohol – Yes dose dependent
Inhibition Medication
Antibiotics Quinolones Rifampicin High dose local Gentamycin
Anticoagulants (hep and warfarin) Yes animal model No human studies
Bisphosphonates
Bisphosphonates – inhibit Osteoclasts.
Standard doses (osteoporosis), do not inhibit healing.
Do delay remodeling of callus. Higher doses eg. for Pagets or
metastatic bone disease not clear.
VOLUME 87-A · NUMBER 7 · JULY 2005
Inhibition
Timing Viz NSAIDS and steroids more effect in
inflammatory phase
Augmentation of fracture healing
Bone Grafts Bone Graft Substitutes Osteo-inductive agents Mechanical methods Ultrasound Electromagnetic fields
Bone Graft Properties
Osteoconduction 3D scaffold
Osteo-induction Biological stimulus
Mesenchymal cells Osteoprogenitor cells
Osteogenic Contains living cells that
can differentiate to from bone
Structural
Osteo-inductive agents
Transforming growth factor Superfamily BMPs GDFs (growth differentiation factors) Possibly TGF-β 1, 2, and 3.
Demineralized bone matrix
Acid extraction of allograft type-1 collagen non-collagenous proteins osteoinductive growth factors: BMP, GDFs,
TGF1,2 + 3
Different companies , processing differentALLOGRAFT, no reported infection transmission
BMP 7 (OP-1)
Tibial non-unions RCT OP1 v autogenous graft No difference in union rate Less infections Friedlaender et al J Bone Joint Surg Am. 2001;83
Suppl 1(Pt 2):S151-8.
Open Tibia OP1 v control Less secondary interventions McKee et al Proceedings of the 18th Annual
Meeting of the Orthopaedic Trauma Association; 2002 Oct 11-13
OP 1 653 cases, overall
success rate 82%
Injury, Int. J. Care Injured (2005) 36S, S47—S50
BMP £ 3000 per vial Mean number of operations
Pre BMP 4.16 Post BMP 1.2
Hospital stay and cost Pre BMP 26.84 days and £ 13,844.68 Post BMP 7.8 days and £ 7338.40
Overall cost using BMP-7 - 47.0% less.
Injury, Int. J. Care Injured (2007) 38, 371—377
BMP 2
BESTT Open tibial fractures
Control v 6mg v 12mg Higher dose
Fewer secondary procedures accelerated time to union improved wound-healing Reduced infection rateGovender et al Recombinant human bone morphogenetic protein-
2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123-34.
Osteoconductive
Making the break. Karin Hing's fellowship has brought independence to pursue her work on bone graft substitutes.
Osteoconductive RCT’s osteoconductive materials Vs autograft
encouraging. Calcium sulfate
Predictable resorption Resorbs a little too fast
Calcium phosphates Tricalcium phosphate TCP Hydroxyapatite TCP is more rapidly absorbed than hydroxyapatite,
TCP inadequate when structural support is desired Injectable osteoconductive cements
Several variations
Concentrated bone marrow aspirate
Non union – 75-95% success Aseptic non-unions
Only works if adequate cell concentration
Hernigou Pet al Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005;87:1430 -7
Concentrated BM aspirate Ongoing multicentre RCT in
France Open tibial fractures
Composite synthetic graft
Prospective multicenter RCT 249 long-bone #, min two years FU Bone graft v biphasic calcium phosphate mixed with
bovine collagen + autogenous bone marrow
No sig. diff. More infections with bone graft (22 v 9 p=0.008)
Chapman MW et al. Treatment of acute fractures with a collagen-calcium phosphate graft material. A randomized clinical trial. J Bone Joint Surg Am. 1997;79:495-502.
Mechanical
Controlled axial micromotion Compression Distraction LIPUS Electromagnetic
Controlled axial micromotion
Prospective RCT 102 tibial fractures 1.0 mm at 0.5 Hz /30 minutes per
day Sig. reduction
Time to union Secondary surgery
Kenwright J, Goodship AE. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop 1988;241:36-47.
Low Intensity Ultrasound
Several RCTs Reduced time to union
Non-op tibia (No benefit in nailed #)
Scaphoids Impacted distal radius Jones
May reduce time to healing JW Busse et al. The effect of low-intensity pulsed ultrasound therapy
on time to fracture healing: a meta-analysis. Canadian Medical Association Journal 2002 166: 437-441
Sonic Accelerated Fracture Healing
System (SAFHS®) -Exogen 2000®
Acute fractures with ultrasound Inconsistency in evidence ? Type II failure Available evidence supports the use of ultrasound in
the treatment of acute fractures of tibia and radius treated with plaster immobilization. (non op)
No benefit of LIPUS in the treatment of fractures of the tibia managed with intramedullary fixation.
J Trauma. 2008 Dec;65(6):1446-52
Clinical relevance of any demonstrated effect is more difficult to justify.
Study may demonstrate a statistically significant effect of LIPUS, which may not be clinically relevant.
Overall low rate of nonunion in the studies raises the question of the usefulness of LIPUS in patients who have a fracture that is likely to heal anyway.
LIPUS therapy may be useful in patients with a potential for delayed union
complex fractures, significant comorbidities, smokers
J Trauma. 2008 Dec;65(6):1446-52
Evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results.
Although overall results are promising, establishing the role of low intensity pulsed ultrasonography in the management of fractures requires large, blinded trials
BMJ. 2009; 338 b351
Current evidence on the efficacy of low-intensity pulsed ultrasound to promote fracture healing is adequate to show that this procedure can reduce fracture healing time and gives clinical benefit, particularly in circumstances of delayed healing and fracture non-union.
There are no major safety concerns. Therefore this procedure may be used with normal
arrangements for clinical governance, consent and audit
Electromagnetic Fields Exact Mechanism of action unknown Research suggests pulsed EM fields affect:
Encourages mineralisation Angiogenesis Increases DNA synthesis Alters the cellular calcium content in osteoblasts
EM fields can be generated:
Direct-current stimulation using implanted electrodes Inductive coupling produced by a time-varying
magnetic field Capacitative coupling
Electromagnetic Fields Five methods for application of electromagnetic fields
Direct current (dc) delivered via a percutaneous cathode and an anode in contact with the skin
Direct current (dc) delivered by a completely implanted system
Capacitive coupled electric field (CCEF) through conductive plates attached to the skin.
Pulsed electromagnetic fields (PEMF) through externally applied coils which induce low level current
Combined electromagnetic fields (CMFs) which use both dynamic and static magnetic fields
Electromagnetic devices
In vivo Osteoblasts BMP,TGFs, IGF
Small RCT 66% vs 0 healing of tibial non-unionScott G, King JB. A prospective double blind trial of electrical capacitive
coupling in the treatment of nonunion of long bones. J Bone Joint Surg [Am] 1994;76-A:820-6.
Several series 64-87% union of tibial non-union
Small, methodologically limited trials with wide confidence intervals
Leaves impact of electromagnetic stimulation of fracture-healing uncertain.
Current evidence justifies neither enthusiastic dissemination nor confident rejection of this therapeutic modality.
Mollon B. et.al. J Bone Joint Surg 2008:90:2322-2330
Clinically relevant treatment effect using electromagnetic stimulation.
Despite some methodological inconsistencies, the randomised trial evidence is consistent, and statistically significant.
Conclude - available evidence supports the use of electromagnetic stimulation in the treatment of non-union of the tibia.
Injury, Int. J. Care Injured (2008) 39, 419—429
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
• BTM’s - Bone Turnover Markers• Metabolic bone disorders• Possible use in fracture prediction
• Delayed union• Non union
• Bone formation• Osteoblastic activity
• Bone resorption• Osteoclastic activity
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
1. Bone-resorption markers2. Osteoclast regulatory proteins3. Bone-formation markers
3 Groups
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
1. Bone-resorption markers2. Osteoclast regulatory proteins
• Factors involved with fusion of mononuclear osteoclast precursors to form mature multinucleated osteoclasts
• Factors include:• Receptor activator of nuclear factor NF-kB ligand
(RANKL)
• c-fms protooncogene• Modulation of osteoclastic activity is
controlled by: osteoprotegerin (OPG)
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
1. Bone-resorption markers2. Osteoclast regulatory proteins3. Bone-formation markers
• Type-III collagen, is the initial collagen laid down during fracture healing and is replaced by type-I collagen to form bone.
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
1. Bone-resorption markers2. Osteoclast regulatory proteins3. Bone-formation markers
• Hence markers of bone healing include fragments of type-I and type-III procollagen• Type-III collagen N-terminal propeptide, (PIIINP)• Type-I collagen C-terminal propeptide, (PICP)• Type-I collagen N-terminal propeptide (PINP)
• Specific measures of osteoblastic activity include :• Osteocalcin the major non-collagenous protein of bone
matrix• Bone-specific alkaline phosphatase (BSAP)
VOLUME 92-A d NUMBER 3 d MARCH 2010
Whats new
VOL. 92-B, No. 3, MARCH 2010
G. Cox, T. A. Einhorn, C. Tzioupis, and P. V. Giannoudis
VOL 92-A ,No 3, MARCH 2010
24 year old PVA Head injury Closed humeral shaft Radial nerve intact Humeral brace 6 months
Non union
Non union approach
General Inhibition (smoking, NSAIDS)
Biology Mechanics (stability) Particular
Current Opinion in Orthopaedics 2006, 17:325–330
Non union approach
General Biology
(atrophic vs hypertrophic) Open Infected Blood supply
Mechanics (stability) Particular
Current Opinion in Orthopaedics 2006, 17:325–330
Non union approach
General Biology Mechanics (stability)
Brace (functional management) Plate Fixation Intramedullary Nail External fixation
Particular
Current Opinion in Orthopaedics 2006, 17:325–330
Non union approach
General Biology Mechanics (stability) Particular
Acta Orthopaedica 2006; 77 (2): 279–284
6 weeks 4 months
4 months post injury
40 YO male High energy MVA Open grade 2 IM nail primary Rx
Non union 2
Non union approach
General Biology
Atrophic (autograft) Avascular (nail – endosteal, cerclage periosteal) Open fracture ? Infection
Mechanics Instability No shelf viz compression (Biasetti II)
Particular No nail to nail
10 months post injury Nail removed Plate
9 hole, LC-DCP SMALL FRAGMENT Proximal – 2 ?3 cortices Distal – 4? cortices
No growth
Questions
www.easytrauma.co.ukwww.easytrauma.co.uk
Questions Gap healing AO - Metaphyseal bone fairly rigidly fixed, no callous, no
cones but strain right to convert fibrous tissue to bone (get lucky)
Implant to bone gap and filling Defect (Gap) distraction osteogenesis
Electromagnetic stimulation
BMP in tissueInjury (2008) 39, 419—429