Tibial shaft fractures - University College Londonucgatma/Anat3048/LECTURES/Marsh...Natural healing...

$: Tibial shaft fractures - University College Londonucgatma/Anat3048/LECTURES/Marsh...Natural healing mechanisms in conservatively treated fractures • 43 isolated, low energy tibial$
Fracture HealingFracture Healing

David MarshProfessor of Clinical Orthopaedics, UCL Royal National Orthopaedic Hospital, Stanmore

David MarshProfessor of Clinical Orthopaedics, UCL Royal National Orthopaedic Hospital, Stanmore

Musculoskeletal disease –

the impact of fractures

Musculoskeletal disease –

the impact of fractures

http://whqlibdoc.who.int/trs/WHO_TRS_919.pdf

DALYsDALYs

• Disability adjusted life years• Combines impact of mortality and morbidity• Allows comparison of impact of disparate diseases

WHO: The World Health Report2002


Group Subgroup % total DALYs

Communicable diseases 42Malaria 2.9AIDS 6Respiratory infections 6.4

Non-communicable 45.9Neoplasms 5.2Neuropsychiatric 13.0Cardiovascular 9.8Musculoskeletal 2.0

Injuries 12.2OA 1.1



Group Subgroup % total DALYs

Injuries 12.2- unintentional 8.9

RTA 2.6Falls 1.1Other Injuries 3.1

- intentional 3.3Self-inflicted 1.4Violence 1.4War 0.6

20002000

20252025

2050205020

25

30

35

40

45

1995 2000 2005 2010 2015 2020 2025 2030

GermanyUK

Source: Eurostat

Number aged 65 and over as a percentage of those aged 20-64

Osteoporosis and fragility fracturesOsteoporosis and fragility fractures

• The only clinical manifestation of osteoporosis is fracture

Osteoporotic fracturesOsteoporotic fractures

• 52.1% of all fractures are potentially osteoporotic• 30.1% of fractures in males• 66.3% of fractures in females• 34.7% of outpatient fractures• 70.4% of inpatient fractures

Why focus on hip fracture?Why focus on hip fracture?

Hip Fracture IncidenceForecast in European Community

0100200300400500600700800900

1000

2000 2010 2020 2030 2040 2050

MenWomen

thou

sand

s

2020--30% excess mortality at 1 yr30% excess mortality at 1 yr

25% never get back to own home25% never get back to own home

80% elderly women would rather 80% elderly women would rather die than have a hip fracturedie than have a hip fracture

Tests the whole system:Tests the whole system:

OrthopaedicsOrthopaedics

Geriatrics Geriatrics

Social servicesSocial services

European Commission, 1998European Commission, 1998European Commission, 1998

Projected osteoporotic hip fractures worldwideProjected osteoporotic hip fractures worldwide

Adapted from Cooper C et al, Osteoporosis Int, 1992;2:285-289

Projected to reach 3.250million in Asia by 2050

1990 2050

600

3250

1990 2050

668

400

1990 205074

2

378

1990 2050

100

629

Total number ofhip fractures:1990 = 1.66 million2050 = 6.26 million

The fracture problemThe fracture problem

• High energy fractures– Normal bone– Violent injury

• Low energy fractures– Weak bone– Minimal injury– Frail patients

Bone regenerationBone regeneration

organorgan

• healing of fractures• distraction osteogenesis• failure of healing• stimulation of healing• elderly, osteoporotic bone

tissuetissue

moleculemolecule

Natural healing mechanisms in conservatively treated fracturesNatural healing mechanisms in conservatively treated fractures

• 43 isolated, low energy tibial shaft fractures• all treated in functional brace,

applied at 3-5 weeks• leg stiffness measurements (LSM)

and standard X-rays at 5,10,14 weeks• continued LSM to union (15Nm/°)

• SF36 ‘pre’-injury, 3, 6 and 12 months

43 isolated low energy 43 isolated low energy tibial shaft fracturestibial shaft fractures

Injury severity vs outcomeInjury severity vs outcomep values for Spearman rank correlationp values for Spearman rank correlation

tim e to u n io n P C S d efic ita t 3 m o n th s

P C S d efic ita t 6 m o n th s

P C S d efic ita t 1 2 m o n th s

d isp lacem en t .002 .02 .00 1 N S

sh o rten in g .01 .02 .00 1 N S

co m m in u tio nsco re

N S .01 N S N S

G u stilo sco re .004 .09 .1 0 N S

displacement indexes severitydisplacement indexes severity

Displacement vs time to unionDisplacement vs time to union

Rsq = 0.1705 Variance explained

Initial displacement (ninths)

1086420

Wee

ks to

clin

ical

uni

on

60

50

40

30

20

10

0

43 functionally43 functionally--braced braced tibial shaft fracturestibial shaft fractures


Initial displacement vs function at 6 months

Initial displacement vs function at 6 months

Initial displacement (ninths)

1086420

PCS

defic

it at

6 m

onth

s

40

30

20

10

0

-10 Rsq = 0.4855 Variance explained

worsening worsening disabilitydisability

Leg stiffness measurementLeg stiffness measurement

FourFour--point bending testpoint bending test

Four-point bending testFour-point bending test

Three displacement transducers Three displacement transducers distinguish bending from translationdistinguish bending from translation

lengthlength

absolute stiffness valueabsolute stiffness valuein Nm/degin Nm/deg

forceforce displacementdisplacement

laptop laptop

Leg stiffness measurementLeg stiffness measurement

Test protocolTest protocol

• in two tested planes– five readings taken– highest and lowest values discarded– mean of remaining three taken as result

• lower of two plane results taken as final


44 66 88 1010 1212 1414 1616 1818 202000

55

1010

1515

2020Nm/degdeg (mean +/- SE)

weeks from fractureweeks from fracture

Three healing groupsdefined by bending stiffness


N10N102525

N20N201414

SlowSlow 44

criterion valuecriterion value7 Nm/deg7 Nm/deg

3/4 healed 3/4 healed within 1yrwithin 1yr

speed of recovery of leg stiffness

speed of recovery speed of recovery of leg stiffnessof leg stiffness

displacement on presenting X-raydisplacement on displacement on presenting Xpresenting X--rayray

Severity vs healing groupSeverity vs healing group

healing group

slown201.00

initi

al d

ispl

acem

ent (

nint

hs) 10

8

6

4

2

0n10

• injury severity similar in N20 and Slow groups


Outcome measured by SF36(deficit in Physical Component Summary score)

Outcome measured by SF36(deficit in Physical Component Summary score)

PCS defic it at:

3 m on ths

6 m on ths

12 m on ths

healing group

slown20n10

PCS

defic

it

40

30

20

10

0

-10

-20

worsening worsening disabilitydisability

• Outcome similar in n10 and n20 groupsdelayed union group greatly different


Healing groups Healing groups

Similar Similar severityseverity

Similar Similar outcomeoutcome

N %N10(fast normal)

25 58

N20(slow normal)

14 33

Slow(delayed union)

4 9

TOTAL 43


Healing groups Healing groups

N % N10 (fast normal) 25 58

N20 (slow normal) 14 33

Slow (delayed union) 4 9

TOTAL 43

Less severe injury - good healingLess severe injury - good healing

More severe injury - good healingMore severe injury - good healing

More severe injury - deficient healingMore severe injury - deficient healing




weeks from fractureweeks from fracture44 66 88 1010 1212 1414 1616 1818 2020

00

55

1010

1515

2020Nm/degdeg (mean +/- SE)

N10N10N10

SlowSlowSlow

N20N20N20

Callus indexCallus index

• callus index = callus width

bone width

• larger of AP and lat views

periosteal new bone onlyperiosteal new bone onlyOni et al, 1991Oni et al, 1991


Prediction of healing group by callus index at 10 weeksPrediction of healing group by callus index at 10 weeks

Healing group

SlowN20N10

callu

s in

dex

at 1

0 w

eeks

2.0

1.8

1.6

1.4

1.2

1.0

.8

• delayed union cases had significantly less periosteal callus at 10 weeks

At 10 weeks: LSM and X-rays together predict healing groupAt 10 weeks: LSM and X-rays

together predict healing group


healing groupslow

n20

n10

callus index at 10 weeks

2.01.81.61.41.21.0.8

stiff

ness

at 1

0 w

eeks

25

20

15

10

5

0

• delayed unions have no periosteal callus


Slow healer patternsSlow healer patterns

0

5

10

15

20

0 20 40 60

weeks from fracture

stiffn

ess

Nm/°

healedhealed

healinghealing

Slow endosteal healingSlow endosteal healing


LSM and X-rays togetherpredict healing group


healing groupslow

n20

n10


2.01.81.61.41.21.0.8

stiff

ness

at 1

0 w

eeks

25

20

15

10

5

0

• some of the fastest healers have little periosteal callus

Rapid endosteal healingin a functional brace

Rapid endosteal healingin a functional brace

United, clinically and on United, clinically and on stiffness measurementstiffness measurement

Medullary callus

Rhinelander 1974 - earliest bridging by new capillaries and bone

McKibbin 1978 - late healing




healing groupslow

n20

n10


2.01.81.61.41.21.0.8

stiff

ness

at 1

0 w

eeks

25

20

15

10

5

0

• slow normals always have periosteal callus

In conservatively treated tibial shaft fractures:

In conservatively treated tibial shaft fractures:

• two modes of bridging are possible• periosteal healing

– delayed after deep soft tissue disruption– switches off after a time

• endosteal healing – can be very rapid if conditions are right– can occur late

Rapid endosteal healingin an Ilizarov frame

Rapid endosteal healingin an Ilizarov frame

Frame Frame removed at removed at 12 weeks12 weeks

IM nailExternal bridging callus

IM nailExternal bridging callus

6/526/52 10/5210/52 16/5216/52

Tissue levelTissue level

• initiated by inflammation• parallels, then diverges from

soft tissue healing• bone regeneration• similarities to embryogenesis• osteogenesis and angiogenesis

go hand-in-hand

Acute inflammationAcute inflammationILIL--1, IL1, IL--6, TNF6, TNFααplatelets: PDGF, platelets: PDGF, TGFßTGFßmacrophagesmacrophages

RecruitmentRecruitment

endothelial cellsendothelial cellsmesenchymal stem cells mesenchymal stem cells

ProliferationProliferation

MSC commitmentMSC commitmentMSC commitment

cartilagecartilagecartilage

bonebonebone

Haematoma Haematoma granulation tissuegranulation tissue calluscallus

? Bone Morphogenic

Proteins

? Bone Morphogenic

Proteins


GodGodGod• intramembranous• endochondral• chondroid

• primary cortical• distraction osteogenesis

Man Man Man


intramembranousendochondralchondroid

intramembranousintramembranousendochondralendochondralchondroidchondroid

I

mesenchymal stem cellsmesenchymal stem cells

woven bonewoven bone

osteoblastsosteoblasts

III

chondrocyteschondrocytes

cartilagecartilage

mineralisedmineralised cartilagecartilageII

X

lamellar bonelamellar bone

Primary callusPrimary callus

• intramembranous(direct)

Primary cortical unionPrimary cortical union

• direct remodeling

• gap healing

Bone remodellingBone remodelling

primary callusdistraction osteogenesisprimary callusprimary callusdistraction osteogenesisdistraction osteogenesismesenchymal stem cellsmesenchymal stem cells



lamellarlamellar bonebone

I

III

osteoclastsosteoclasts + osteoblasts + osteoblasts = bone remodeling unit= bone remodeling unit

primary cortical unionprimary cortical unionprimary cortical union

The only mode of healing that requires osteoclastic action to create a bridge across the fracture

Distraction osteogenesisDistraction osteogenesis

• columns of collagen I• direct bone formation in the columns• cartilage if unstable• huge increase in blood flow

- angiogenesis leads osteogenesis

New bone New bone for freefor free

Talking to cells in the Talking to cells in the language of mechanicslanguage of mechanics

create a low energy fracture or osteotomy

stabilise it and wait 7-10 days

distract it gradually, avoiding high strain rates

bone will grow and grow

How does it work?

What is needed for it to work well?

mineralisation mineralisation frontfront

corticotomy surfacecorticotomy surface

microcolumns of bonemicrocolumns of bone

fibrous fibrous interzoneinterzone

blood vesselsblood vessels

Aronson 1990Aronson 1990

proliferation of mesenchymal cellsproliferation of mesenchymal cellsformation of type I collagenformation of type I collagen

differentiation to osteoblastsdifferentiation to osteoblasts

intramembranous ossificationintramembranous ossification

mechanical stimulusmechanical stimulus mesenchymal cell proliferationmesenchymal cell proliferation

osteogenic commitmentosteogenic commitment

angiogenesisangiogenesis

chemical stimulichemical stimuli

mechanism mechanism for applying for applying controlled controlled strainstrain

osteoblasts cultured on flexible surfaceosteoblasts cultured on flexible surface

Courtesy of Professor Lutz ClaesCourtesy of Professor Lutz ClaesInstitute for Orthopaedic Research and BiomechanicsInstitute for Orthopaedic Research and BiomechanicsUniversity of UlmUniversity of Ulm

Effect of strain magnitude on cell proliferation(1 Hz, 1800 cycles)

Effect of strain magnitude on cell proliferation(1 Hz, 1800 cycles)

500 1000 3000 10.000 40.000 80.000-20

-10

0

10

20

30

40m

ean

devi

atio

n vs

. con

trol i

n %

magnitude in µstrain

*

**

500 1000 3000 10.000 40.000 80.000-20

-10

0

10

20

30

40m

ean

devi

atio

n vs

. con

trol i

n %

magnitude in µstrain

*

**

Effects of cyclic strain on cell activity(1000 µstrain, 1 Hz, 1800 cycles)

Effects of cyclic strain on cell activity(1000 µstrain, 1 Hz, 1800 cycles)

-25

0

25

50

75

100

mea

n de

viat

ion

vers

us c

ontro

l in

%

Response to strainResponse to strain

• mesenchymal cells, including osteoblasts, are programmed to respond to strain by turning on genes which produce– proliferation– angiogenesis– production of matrix

• excessive strain– overloads the cells and inhibits proliferation– thwarts angiogenesis

differentiationdifferentiation

Molecular levelMolecular level

• intercellular signalling• cell-matrix interactions• induction by morphogens

product of one cell interacts with product of one cell interacts with another cell (or same cell)another cell (or same cell)specific receptors / second messengersspecific receptors / second messengersgene inductiongene inductioneffect depends on ‘set’effect depends on ‘set’

? single molecule approach? single molecule approach

Strain transductionStrain transduction

integrinsintegrinscell - matrix interaction

gene activation via the cytoskeleton

cadherinscadherins

cell - cell signalling

When healing faltersWhen healing falters

• wake-up call to existing tissue– change mechanics

• realignment• distraction• ultrasound

– change vascular supply– re-initiate inflammation – repair– specific molecular signals

• tissue engineering approach

Tissue engineering approachTissue engineering approach

Elements of bone formationElements of bone formation

• osteoinduction• osteoconduction• osteogenesis

Elements of tissue engineeringElements of tissue engineeringcells cells

capable of proliferation and capable of proliferation and differentiation to osteoblastsdifferentiation to osteoblasts

scaffold scaffold

hospitable to osteoblasts and hospitable to osteoblasts and capable of being remodelledcapable of being remodelled

molecules molecules

signalling appropriately signalling appropriately to induce angiogenesis / to induce angiogenesis /

osteogenesisosteogenesis

SummarySummary

• fracture bridging endosteal, periosteal or intracortical

• bone formation intramembranous, endochondral or via remodelling

• intercellular signalling and gene induction underlies healing programme

• cell-matrix interactions mediate response to the mechanical environment

• possibilities for therapeutic stimulation• tissue engineering

Osteoporosis –related (low trauma or fragility) fractures in the elderly

Osteoporosis –related (low trauma or fragility) fractures in the elderly

Threat to the NHSand to patients

• Current cost of osteoporosis and fragility fractures is £2bn pa

• Bed occupancy threatens other work– Elective orthopaedics– Other specialities

In an ideal worldIn an ideal world

• Osteoporosis would be prevented

• Falls would be prevented

• Fragility fractures would be prevented

In the real worldIn the real world

• Elderly patients get fractures– Often the first evidence of tendency to fall and

osteoporosis

Get the fracture healedGet the fracture healed

Optimum rehabilitationOptimum rehabilitation

Minimise loss of QOLMinimise loss of QOL

Treat the osteoporosisTreat the osteoporosis

Treat the tendency to fallTreat the tendency to fall

Prevent another fracturePrevent another fracture

Our goalsOur goals

• Systems in which fracture reliably triggers secondary prevention– Osteoporosis treatment which also has a

facilitatory effect on fracture biology

– Rehabilitation which flows seamlessly into falls prevention

• Reliable fracture treatment despite the challenges of osteoporotic bone

Getting the fracture healed

Two issuesTwo issues

• The capacity for normal healing in osteoporotic fractures– Effect of ageing per se vs osteoporosis

– Problems secondary to poor fixation

• The effects on fracture healing of drugs used to treat osteoporosis and other common diseases in the elderly

Slower healing in the elderlySlower healing in the elderly

• Gene expression in older rats with delayed union of

femoral fractures. – Meyer RA Jnr et al, (2003). (Charlotte, NC)

J Bone Joint Surg 85-A; 1243-54

• 6wk-old vs 1 yr-old rats– Closed, nailed femoral shaft fracture

• BMD not considered

Meyer et al 2003

6wk6wk--old ratold rat 1yr1yr--old ratold rat

PostPost--opop

One weekOne week

6 weeks6 weeks

• Young healed in 6 weeks, old needed 26 weeksPeriosteal bridgingPeriosteal bridging

Bone-inducing genesBone-inducing genes

• Same pattern of cytokine gene expression in both groups• Lower levels of Ihh and BMP-2 in older rats

• Fall back to normal levels at same time in both groups• Despite the fact that the older rats had not healed

Why no feedback loop to Why no feedback loop to keep cytokine drive going?keep cytokine drive going?

Meyer et al 2003

Stimulated by Stimulated by micromotionmicromotion

Later Medullary CallusLater Medullary Callus

Rapid Periosteal CallusRapid Periosteal Callus

Requires mechanical stabilityRequires mechanical stability

The problemThe problem

• Initial drive to (periosteal) bone regeneration is weak in older animals

• Drive switches off before healing occurs• Slower (endosteal) healing modes will heal

the fracture eventually, given stability• But stability depends on enduring fixation• And enduring fixation is difficult

in osteoporotic bone

Anti-resorptive therapyAnti-resorptive therapy• Raloxifene, estrogen and alendronate affect the

processes of fracture repair differently in ovariectomized rats. • Yongping Cao et al, (2002). (Kagawa)

J Bone Miner Res 17: 2237-46• OVX vs sham-op in 3 month-old rats

• Closed, nailed femoral shaft fracture• OVX alone, or with E, SERM, or BP

• X-ray, QCT, biomechanical testing, histology• At 6 and 16 weeks

Vs sham control:Vs sham control:Cao et al (2002)Cao et al (2002)

At 6 weeks At 16 weeksCallus size

Ultimate load

BMC

+

-

-

Callus size

Ultimate load

BMC Lamellar/woven

Ovxalone +Ovx + EOvx + SERMOvx + BP + + + + -

• Fracture healing at least as advanced in Ovx alone vs sham (younger)• BP did prevent remodelling and material properties were inferior• But larger callus more than compensated for this biomechanically

Bone remodellingBone remodelling

primary callusdistraction osteogenesisprimary callusprimary callusdistraction osteogenesisdistraction osteogenesismesenchymal stem cellsmesenchymal stem cells



lamellarlamellar bonebone

I

III

osteoclastsosteoclasts + osteoblasts + osteoblasts = bone remodeling unit= bone remodeling unit

primary cortical unionprimary cortical unionprimary cortical union

The only mode of healing that requires osteoclastic action to create a bridge across the fracture

Anti-resorptive drugs and fracture healing

Anti-resorptive drugs and fracture healing

• Osteoclast inhibition will impair primary cortical union – rigid internal fixation not a good idea in OP#s

• All other modes as good or better with bisphosphonates• Anabolic drugs will solve the problem• Much more to lose by lack of secondary prevention

Osteoporotic fractures

Conclusions Conclusions

• Elderly, low trauma fractures, associated with osteoporosis, will form an increasing proportion of our work

• Osteoporotic bone can heal normally, but fixation may fail• We have much to learn about the effect of ageing on bone healing• Secondary prevention is absolutely necessary

– Anti-resorptive agents will not impair healing if rigid internal fixation is not used

Tibial shaft fractures - University College Londonucgatma/Anat3048/LECTURES/Marsh...Natural healing...

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