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