This is an enhanced PDF from The Journal of Bone and Joint Surgery The PDF of the article you requested follows this cover page.

Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound JD Heckman, JP Ryaby, J McCabe, JJ Frey and RF Kilcoyne J Bone Joint Surg Am. 1994;76:26-34.

This information is current as of May 11, 2009 Reprints and Permissions

Click here to order reprints or request permission to use material from this article, or locate the article citation on jbjs.org and click on the [Reprints and Permissions] link.

Publisher Information

The Journal of Bone and Joint Surgery 20 Pickering Street, Needham, MA 02492-3157 www.jbjs.org

1994 by The Journal

Copyright

Acceleration

by Non-Invasive, BY

JAMES

D.

HECKMAN.

M.D.t,

JOHN

P.

ABSTRACT:

Sixty-seven

of the

shaft

tures

tibial

closed

or grade-I

were

examined

Pulsed

MCCABE,

University

group group) time

healing

(86 ± 5.8 days

of Texas

open

frac-

in a prospective,

in the

to over-all

(clinical

and

radiographic)

± 4.9 days in the active-treatment 154 ± 13.7 days in the control patients’

compliance

with

control in the

healing

(96

group compared group) (p = 0.0001).

the

use

of

the

with The

device

was

excellent, and there were no serious complications related to its use. This study confirms earlier animal and clinical studies that demonstrated the efficacy of lowintensity

ultrasound

the normal Ultrasound

has

ing therapeutic, Both ultrasound ject

tissue

stimulation

fracture-repair

acceleration

of

process.

many

medical

operative, therapy

to power

in the

that

applications,

are

includ-

capable

of causing

considerable heating and biological effects. In conventional ultrasound therapy, ultrasonic intensities of one to three watts per square centimeter are used to decrease joint stiffness, reduce pain and muscle spasms, and

improve

*One

muscle

or more

mobility’.

of the authors

The

have

operative

received

applica-

or will receive

ben-

efits for personal or professional use from a commercial party related directly or indirectly to the subject of this article. In addition, benefits have been or will be directed to a research fund or foundation, educational institution. or other non-profit organization with which one or more of the authors are associated. Funds were received in total or partial support of the research or clinical study presented in this article. The funding source was Exogen, Incorporated. tDepartment of Orthopaedics. The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7774. New

lExogen, Incorporated. Jersey 07006-6489. §38 Randolph Road.

‘lHealth Penn Science

26

Products

Way, Lancaster, #Department Center,

810 White

of Radiology, East Ninth

4200

Plains,

Development,

Pennsylvania

Passaic

Avenue, New

Health

Science

York

Incorporated,

West

Caldwell,

10607. 1853

These

The University Avenue, Denver,

of Colorado Colorado

FREY.

PH.D1.

Center

at San

relatively

ployed which

AND

Antonio,

tions

high

to generate the ultrasound

RAY

F.

KILCOYNE.

M.D.#.

San

Antonio

ultrasound

intensities

are

heat within the tissues, signal passes5. Diagnostic

of ultrasound

evaluation

include

of fetuses, ophthalmic

examination

vascular

of vital

and peripheral

echography.

The

organs,

flow

diagnostic

em-

through applicastud-

applica-

tions of ultrasound use much lower intensities, typically five to fifty milliwatts per square centimeter, to avoid excessive heating of tissues’. Xavier and Duarte2 reported the acceleration of the normal fracture-repair process in humans with use of low-intensity (diagnostic-range) ultrasound and also indicated that low-intensity ultrasound can induce healing of ununited diaphyseal fractures22. With use of a rabbit fibular osteotomy model and a second model that employed a drill-hole in the cortex of the femur of Duarte

demonstrated

acceleration

of the

nor-

mal fracture-repair process with use of ultrasound. Pilla et a!., with use of a slightly different fibular osteotomy model, also demonstrated that non-invasive, lowintensity pulsed ultrasound accelerated fracture-healing in the rabbit. Klug et al. used a scintigraphic technique to demonstrate quicker maturation of the callus and earlier healing in experimentally induced closed fractures in a rabbit model after ultrasound stimulation with intensity

levels

that

were

an order

of magnitude

higher

than those used by Duarte or by Pilla et al. Because we believe that these preliminary studies clearly showed a positive effect of ultrasound on the rate of osseous repair, we designed the present study to investigate the effect of specifically programmed, low-intensity pulsed ultrasound on the rate of healing of cortical fractures when used in patients as an adjunct to conventional orthopaedic

management. Materials

and

Methods

The study was multi-institutional, prospective, randomized, double-blind, and placebo-controlled. There were co-investigators from sixteen sites in various geographical areas of the United States and from one site

William

in Israel.

Health 80262.

fered

17601.

J.

tion of ultrasound employs intensity levels of five to more than 300 watts per square centimeter to fragment calculi and to ablate diseased tissues such as cataracts20.

a rabbit,

and diagnostic procedures’. and operative ultrasound sub-

levels

JOHN

Ultrasound*

TEXAS

ies, and

active-treatment

compared with 114 ± 10.4 days in the (p = 0.01) and also a significant decrease

R.N.I,

ANTONIO.

randomized, double-blind evaluation of use of a new ultrasound stimulating device as an adjunct to conventional treatment with a cast. Thirty-three fractures were treated with the active device and thirty-four, with a placebo control device. At the end of the treatment, there was a statistically significant decrease in the time to clinical

Incorporated

Low-Intensity JOAN

at The

Surgery.

Fracture-Healing

RYABYt,

performed

and Joint

of Tibial

SAN investigation

of Bone

An

opportunity to participate in the study was to all skeletally mature men and non-pregnant THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY

of-

ACCELERATION

women

seen

and

December

old

and

at our

who

had

closed

who

was

September open

and

1986

be treated

years

tibial

diaphys-

short

oblique,

transverse,

could

BY

seventy-five

effectively

immobilization

Anteroposterior

with

in a cast.

lateral

radiographs

were

made

the reduction. We excluded patients anteroposterior or the lateral radiographs after

if either

the

showed

that

than

twice

spiral

or

more

than

the the

length

fracture),

cent

of the

line

width

of the

Gustilo

and

Anderson;

with

fractures

centimeter

after stable

reduction; or

tibial

that

persistent

were

not

sufficiently

tion with with

of 10 degrees or more in any plane) for treatment immobilization in an above-the-knee cast; fractures a large butterfly fragment (larger than two times

ments

of less

able).

Patients

they

could

than

not

steroids,

one

were

centimeter

also

with

comply

anticoagulants,

inflammatory

if they

prescription

was had

the protocol:

medication,

fractures; with frag-

in length

excluded

accept-

stated

were

that

receiving

non-steroidal

calcium-channel

anti-

blockers,

or

diphosphonate therapy; had a history of thrombophlebitis or vascular insufficiency; or had a recent history of alcoholism or nutritional deficiency, or both. After they had agreed to participate in the study and ized

gave into

active

informed consent, the patients were randomgroups of four at each study site to receive an

or

a placebo-treatment

determined broken only completed.

after

Ninety-six were

the fractures group and group.

the

Thirteen

to

(eighty-five

healing

patients

were

excluded

from

the

(seventeen

and

follow-up

known,

nine, and

had

been

withdrawn

died

of unrelated

VOL.

76.A,

study

[13

per

eighty-four

cent])

pa-

in whom

known.

fractures

five NO.

patients placebo

because

(four the

final

withdrawn by

the

causes

patients 1. JANUARY

were 1994

the

investigator,

seven

who

healing

from

site

had who

weeks

withdrawn

procedure of severe

had

fracture

begun,

did

not

the

within

six weeks

angulation

seven meet

of the

were

the

after fracture

excluded

inclusion

be-

criteria

of

the protocol, and four were withdrawn by the investigator because of failure to comply with the treatment protocol. These seventeen patients were still followed and the outcomes of treatment were obtained. The remaining sixty-seven fractures (thirty-three that were treated with an active unit and thirty-four, with a placebo unit) represent the core group of fracto the study protocol It is this group from

and which

the clinical and statistical inferences were drawn. There were sixty-four closed fractures (thirty-one in the active-treatment group and thirty-three in the placebo-treatment group) and three grade-I open fractures (two in the active-treatment group and one in the placebo-treatment group). The fractures were treated conventionally with closed reduction and immobilization in an above-the-knee cast. The three grade-I open fractures were treated with initial d#{233}bridement, and the wounds were allowed to heal by secondary intention. A retaining

was

and

alignment

inserted

medial

into

surface

fixture

a window

of the

made

centered

cast,

at the

of molded

over

site

plastic

the

of the

antero-

tibial

frac-

ture. This fixture held the treatment head module in place during the daily twenty-minute treatment period. Between treatment periods, a circular, felt plug was inserted in the fixture and a cap was placed over it to maintain an even pressure on the skin and to minimize the risk of edema at the site of the window. Treatment was started within seven days after the fracture each

day.

the

window

and

consisted

of

The

treatment

head

after

removal

one

twenty-minute

module

of the

felt

was plug

period positioned and

the

in appli-

cation of a small amount of ultrasonic coupling gel to the surface of the head. It was attached to a portable main operating unit that contained the necessary cir-

additional

cuitry

[18

per

itor the proper attachment of the module in the cast fixture. A warning signal was sounded by the main opcrating unit if there was not proper coupling to the skin. In addition, the main operating unit contained an inte-

cent])

deviations

active were

treatlost

to

gral

to drive

timer

that

treatment

monitored

treatment

study,

five

had

one

had

and audible signal alerted the patient that was complete. The patients’ compliance

site

tions inside

off after

for use of the device the main operating

was unit

twenty

times

ically

by the

unit

module

not

fracture.

the

head

was

the

turned

the

status and

after

because

An of

who

treatment)

for whom

seven

Of the

of

protocol.

Of the thirteen ment

fractures

per

was

the

been

Forty-eight

leaving [88

fracture

from

was

had

of ninety-seven

study.

(thirteen

follow-up,

of the

code

to the active-treatment placebo-treatment control

fractures

status

seventeen

randomized to the patients

lost

a total

the

into

to a pre-

The

reviews

had

who

entered

were forty-nine,

were

tients

according

code.

radiographic

patients,

fractures,

cent])

device

computer-generated

an operative

injury

tures in patients who adhered had sufficient follow-up data.

angula-

the diameter of the tibial shaft); pathological and comminuted fractures (comminution

had

the

the

of more

fractures

(recurrent

had

treatment

of the

27

ULTRASOUND

one had had an open reduction and interof the fracture and the remaining four had with the outlined treatment protocol. Of the seventeen patients (eleven who had active treatment and six, placebo treatment) who were cxcluded because of deviations from the protocol, six (two who had active treatment and four, placebo treatment)

after

or the

PULSED

investigator, nal fixation not complied

cause

shaft,

shortening

LOW-INTENSITY

more

Other exclugrade I as de-

fractures

persistent

NON-INVASIVE.

(a long was

was

diaphyseal shaft the displacement

was more than 0.5 centimeter. were open fractures, except

metaphysis;

one

fracture

of the

oblique

50 per

by

of the

diameter

long

fracture gap sion criteria

than

or grade-I

that and

immediately

fined

between at most

primarily

and

reduction

FRACTURE-HEALING

were

a closed

that spiral

TIBIAL

institutions

1990

eal fracture or short

OF

and

and

minutes.

to mon-

automatA visual

the treatment with instruc-

measured by both a timer and a patient-maintained

28

J.

daily treatment log. The active and placebo identical in every way (they had the same and

auditory

signals)

emitted. Treatment

except

for

the

was

signal

continued

that

for

rate

regimen

for

all

ultrasound

twenty that the

TABLE

weeks

or until

the fracture active or the

No.

was pla-

an

for

kilohertz

intensity

treatment

patients.

and

was

in an

were

permitted

bearing

was

clinical

judgment

controlled

difference

agement forty-two

the

basis

initiation (forty-two

study

were

instructed

eight

weeks

after

four

patients

protocol

fracture, fractures)

and

the were

man-

remaining allowed

up radiographs teen, twenty,

were

scheduled

at four, thirty-three,

six, and

to return

for

the

at each

x-ray

setting,

and

machine

a leg-positioning

site,

the

to each site investigator. were performed by the

Clinical follow-up site investigator

any

at six

cast

change

follow-up that

the

moval

(usually

visit

when

fracture

had

healed

ten

exposure

was

furnished

The

end-point

graphic

examination

addition

on

weeks)

study

clinical

between groups.

With

to the

was

of four

a healed

process

of

re-

15

15

17

16

31

29

2

5

26

28

Comminuted

site

amination,

the

to manual

stress,

fracture

the

intermediate

investigator fracture and

thought was

the

time

stable

assessed

that,

for

and

clinical

and

In

intermediate

active-treatment

Yes fracture

to discontinuation

0.77*

Fibular No Yes

7

6

9

4

fracture

0.13*

(yrs.)

Aget

Displacement

(per

30 31 ± 1.8

0.091

33 ± 4.7 (n = 30)

38 ± 4.9 (n=31)

0.481

23 ± 2.5

23 ± 2.7

0.981

6 ± 1.0 (n=30)

6 ± 0.8

0.741

4 ± 0.5

4 ± 0.4

0.801

4 ± 0.3

4 ± 0.3

0.921

4 ± 0.2

4 ± 0.2 4 ± 0.3

0.551

cent)

reductiont reductiont (degrees) reductiont

After

reductiont

Maximum Length

fracture

gapt

of fracturet

Days

24 36 ± 2.3

until

start

(mm)

(cm) of treatmentt

4 ± 0.3

0.891

of follow-upt

(days)

250±

284±19.2

18.1

92-438

Days to start bearingt

of weight-

45

*With

the

tThe

values

Fisher

exact

are

given

test

= ±

(n

mean

49 ±

4.9 33)

or chi-square

as the

0.211

142-586

and

0.621

5.9

test. the

standard

error

of the

mean. analysis

of variance.

the

cast was documented as the time at which the site investigator discontinued use of the cast. With regard to the intermediate radiographic signs of healing, two parameters were evaluated. The first, cortical bridging, was defined as the gradual disappearance of the interruption of the cortex at the fracture site

stages

of

the time at which

to the

bridging was quantified as none (no change tical interruption compared with that seen

cx-

graph

made

initial ruption

(when a periosteal reaction at the cortical interof the fracture site was first noted), intermedi-

on was

0.43*

No

as

radio-

bridged).

were

0.60* 3

Range

allow

on

cortices

two parameters were evaluated: healing was defined as the time

individual

0 of fracture

Duration

fracture,

and

end-point,

fracture-healing

regard

11

Distal

indicated to

examination

(three

the difference placebo-treatment healing, clinical

15

11

at the

and

sufficiently

to the healed-fracture of the

17

spiral

IWith

of the

both

oblique

(n = 33)

evaluations at the time

evaluation

0.49*

Middle

of the cast.

judged

stages

and

radiographic

were use of

same

that

device

8

open’

Before

eight, ten, twelve, fourfifty-two weeks after the

and lateral radiographs whenever possible, with

4

0.64*

of fracture

After

follow-

fracture. Anteroposterior made and standardized same

Grade-I Type

Angulation

patients

33

Closed

Before

fiftyto bear

as tolerated.

All

31 2

5

grade

No Yes

The

of fracture

29

P Value

0.37*

Butterfly

investigator’s patient.

25 8

Proximal

Weight-

of the

34

Male Female

Location

of weight-bearing. The first fractures) enrolled in the to bear weight during the first

not

the (fifty-five

of the

tolerance

in the common

was the patients

weight

on the

and

Placebo

Comminuted

iden-

above-the-

indicated.

Group

Sex

Short Short

the investigator thought stable for application of

as clinically

ent

33

Transverse

milliwatts

fracture

Immobilization

COMPARABILITY

Active

of fractures

Fracture

ultra-

a spatial

of thirty

of the

I

TREATMENT-GROUP

Treatm

a short cast or a brace. After immobilization in a cast was discontinued, additional protection with either a splint or a brace was at the discretion of the investigator. Cast

only

OF

signal

delivered

of one

knee cast was maintained until that the fracture was sufficiently

changes

AL.

ASSESSMENT

composed of a burst width of containing 1 .5 megahertz sine waves,

average-temporal average per square centimeter. tical

ET

devices were visual, tactile,

was

200 microseconds with a repetition

The

HECKMAN

Parameter

the clinical investigator believed healed sufficiently to discontinue cebo ultrasound therapy. The treatment head module sound

D.

clinical not

painful of the

as a result

of callus

in the

THE

formation.

The

immediate

JOURNAL

amount

of cortical

at the coron a radio-

post-reduction

OF

BONE

AND

period),

JOINT

SURGERY

ACCELERATION

OF

TIBIAL

FRACTURE-HEALING

BY

NON-INVASIVE.

TABLE INTERMEDIATE

P Valuet

ANOVA

0.0001 0.0001

0.0001 0.0001

0.0001

190 ± 18.3

I 14 ± 7.5

182 ± 15.8

0.0002

0.0001

0.0001

136

± 9.6

243

± 18.4

0.0001

0.0001

0.0001

117

± 8.5

167

± 13.9

0.002

0.0004

0.0004

271

± 19.6

0.0001

0.0001

0.()001

investigator

Independent

Placebo Treatment (N = 34)1

33)

=

89 ± 3.7

radiologist

Complete

cortical

(4 bridged

102

Log-Rank

Independent Endosteal

148 ± 13.2

± 4.8

0.00()l

bridging

cortices) investigator

Principal

radiologist

healing

Principal

investigator

Independent

radiologist

*The

values

are

tANOVA INo

(an

given

data

as the

completely

available

or

density

the

radiograph)

as the ture

line

density

formed

dosteal

healing

fracture line radiograph), distinct), been

the

as calculated

On

fragment;

each

with

analysis

of variance.

the

amount

of

defined

of the of

frac-

increased of enin the

on the post-reduction line had become

was

marked

complete

fracture

of increased

density

line

radiographs

at each

the

radiographs

effect by

follow-up

the

of the

and

the

the presence analysis

fracture;

presence

of a fibular

was

the

pres-

of a butterfly

fracture

performed

by the

(Table

analysis

of

number to the

of days start

of follow-up,

and

of weight-bearing

mean

(Table

number

of days

I).

Patient compliance was measured as the adherence to the scheduled follow-up visits as dictated by the protocol and the frequency of use of the device as measured

had

by the

formed

by

the

internal

patient.

device Adverse

complications

at each

investigators,

all

clock

a positive

osseous

repair.

and effect

sought

were

log

an

studies5’’222

clearly

on

accelerated

the

rate

time

protocol-design

principal investigator’s assessment of radiographic ing was used for purposes of statistical analysis pare the efficacy of treatment with the results

values were calculated to assess the superiority of treatment with the active device compared with treatment with the placebo, control device. The null hypothesis that the time to response for fractures treated with the active device was the same or worse than the time to

the placebo device. The site investigator’s assessment of clinical healing was used for analysis of the clinical cornponents of fracture-healing. Time to response was calculated

as the

number

of days

after

the

occurrence of the specified event. The active and the placebo-treatment compared with regard to important the fractures and patients. A statistical formed with use of the Fisher exact

fracture

to the

first

square

test

if there

were

for

sex

of the

patient;

VOL.

the 76-A,

NO.

I. JANUARY

more the 1994

than grade,

response tested

response groups were characteristics of analysis7 was pertest (or the chi-

two

category

type,

and

levels) location

active (shorter)

for against

was

device. time

tests

those

was

study.

of

heal-

for

statistical

group

to

the

phase

of this

in-

ing

one-sided

active-treatment

site

if found.

of ultrasound

Therefore,

by and

by each

recorded

clinical

kept

complaints,

radiographs were assessed in independent, blind neviews by the principal investigator (J. D. H.) and, separately, by the independent radiologist (R. F. K.). The healto comof use of

the

and

a written

patients’

specifically visit

animal

showed

and

reactions,

were

vestigator

Previous

interpretation

individual

or distal)

comminution;

variance for the mean age of the patients in years, mean pre-reduction and post-reduction displacement, mean pre-reduction and post-reduction angulation in degrees, maximum fracture gap in millimeters, maximum length of the fracture in centimeters, mean number of days after the fracture before the start of treatment, mean

visit.

of subjective

middle,

of minor

less

consolidation

(the

device.

I). Statistical

two on the

a zone

placebo

ence

cortices

was

the

(proximal,

pen-

A judgment as to the extent of endosmade on both the antenopostenior and

To minimize

mean,

reaction

callus. The amount as none (no change

(there

and

by a zone

endosteal callus). teal healing was lateral

by

compared with that initial (the fracture

replaced

for

with

and

healing,

replacement

line),

four

on obliteration

by endosteal was quantified

fracture

of the

treated

initial

interruption). time-point,

endosteal

intermediate

of the

of the

was

peniosteal

evaluated

disappearance its

that

radiograph

were

and

deviation

fracture

(the

at each

bridging. other parameter, gradual

standard

or size

cortical

evaluation

cortical The

the

for one

on the anteropostenior

lateral

and

complete

bridged

radiographic

mean

of variance.

were

in the

increase

reaction)

(two

171 ± 13.6

= analysis

clinical

osteal

of

STAGES

cortices

Principal

the

HEALING

Kruskal-Wallis Rank ANOVA

(N

ate

29

ULTRASOUND

afte r Fracture

Active Treatment*

3 bridged

PULSED

II

RADIOGRAPHIC

Days

LOW-INTENSITY

of hypothesis

treated

with

the alternate superior

Superior to

the

the

was attainment

defined

one-sided

placebo

fractures

at

Consequently, and

hypothesis

for the

hypothesized

that treated

device

p

was

the time with

to the

as an accelerated of a specific

healing

response, such as a healed fracture status. The result was significant when the p value was 0.05 or less in favor of the active-treatment group. Three statistical approaches are presented for all

30

J.

TABLE NUMBER

AND

AFTER

CUMULATIVE

THE

TO

THE

after

Fracture

No.

ET

AL.

scheduled OF

FRACTURES

START

OF

FOR

DAYS

follow-up

fourteen, interim

WEIGHT-BEARING

Active Days

HECKMAN

III

NUMBER

FRACTURE

D.

Placebo*

a healing

Cumulative

No.

Cumulative

time.

5

5

4

4

5

10

4

8

the

29-35

6

16

7

15

evaluated

36-49

3

19

5

20

protocol-compliant

50-63

7

26

5

25

in the

analysis

64-77

3

29

1

26

group

took

>77

4

33

7

33

fracture

were

in the

available

on

the

placebo-treatment

start

of weight-bearing

for

last

follow-up

Analysis

mean

time

and

the

to the attainment active-treatment

Kruskal-Wallis

and

compare

error

log-rank

life-table

the mean

times

Kruskal-Wallis

of the

status groups.

for the Analy-

analysis

of variance

by

analysis43t4

were

to

to healing

analysis

mean,

the in days,

to calculate

of a healed fracture and placebo-treatment

of variance,

ranks32,

standard

used

used

for the two

was

used

groups.

because

it does

not make tribution

the statistical or homogeneity

assumptions of a Gaussian disof variances. The log-rank

life-table

analysis

used

censored

observations

uses

to the

days

value

(one

that

had

was

as

last

placebo

it analyzes

censored

follow-up that had

fracture the

because

observations

visit active

treatment

right and

had

right

censored

of the

regard

detect

any

bearing, and the ture, had an effect compared fect

with

was

group

covariate

effect.

All data

three

fractures

visits

active

treatment

up visits

for

of the

esti-

was

comparable

was

the data

whether compared maintained

statistical All

entered

printout

in the

were

intention-to-treat was

considered

was

presence

of the

case-record to ensure were

analyzed

log-rank to be

a computer

proofread

form

analysis,

that

into

were

was

the

accuracy

performed

with

of

(SAS Institute, Cary, mainframe computer.

randomized

into

for the life-table

time to healing analysis. Each

healed

only

at the

time

each in an fracof a

non-

in the

patient

and

I), we

core

fracture could

between

the

core

not

thirty-

group

of the

were

the

and

(245

of 276

received

followvisits),

the placebo, Usage

as recorded log,

group

and

used

250

and

the the

unit

for

the

days

active-treatment 142

active-treatment

of the tibia

seven

for at least

The

to

586

healed

second

from

group compared days) for the

with 284 placebo-

I). One a fracture

after

patient in the in the same

the initial clinically

occurred kicks

whether

study

remained

the

injury.

all healed healed

four

Fifty-five

fractures

patients

a soc-

tibia

by

months

in both

at a minimum

radio-

during

to the

healed

fracture and

A subsequent, long-term follow-up was request of the Food and Drug Administration

mine

of the

to 438

fracture

fracture

compagroups; it

ninety-two

both

simultaneous

This

standard

(range,

months

to be

players.

and

0.21) (Table sustained

=

group

considered game,

(mean

of variance])

± 19.2 days (range, treatment group (p area

patients

sessions.

± 18.1

[analysis

device

by both

all of the

the

and

90 per

of the

active-treatment

groups,

patient

treatment

scheduled

visits).

the

who

the with

of 283

core and

patients

time

treated

(256

between

timer

The

for

error

other

the

fractures

was

cer

done

the

(Table

group.

cent

time

graphically.

care-

obtained

was

days)

of the placebo-

the results

The total duration of follow-up, in days, rable in the active and the placebo-treatment

mean

form. An independent, thordata used in the statistical

analyses

All of the fractures

ture

superiority with the

in the

were

computer

those

further.

group

ef-

results

those of placebo for the covariate

the

Statistical Analysis System software North Carolina) on an IBM 3081 study

thirty-six

was

the

with

of weight-

the

biased

active-treatment

each

who

cent

If an

covariate,

and

that

returned

89 per

one

of the fracin the active

analysis

withdrawn

differences

in the

clinical

device

start

intention-to-treat

the thirty-four fractures in the placebo-treatment core group, with the numbers studied. Therefore, we believe that the placebo-treatment group was quite similar to the active-treatment group. The patients’ compliance with the follow-up protocol was analyzed by calculation of the ratio of actual clinical visits to the expected (scheduled) number of

used to as the sex

group.

of the

against the case-record comparison of all

before

to the

placebo-treatment because

observations

then

analyses

the

the

determine group

treatment

fully ough

such

days

treatment compared with were statistically adjusted

in order to active-treatment

file and

the

grade, type, or location on the healing response

observed

of active treatment

covariates,

patient,

completed

of the

studied

appreciable

in the active-treatment

potential

of the

to the last

seventeen

were

assess

whether

time

to the

that

placebo-treatment

age

This

patients

mated values for the time to a healed fracture). In addition, Cox regression analysis was and

twelve,

to heal.

the patients

as the time-to-event treatment and

at ten,

Results

With was

of days

exclusion

one

group.

of variance’

example,

was used for the time to healing had not reached a healed status by

visit.

whether

parameters analyses.

(for

number

15-28

*No data

The

The

follow-up examination for the fractures that

0-14

sis

visit

twenty, thirty-three, or fifty-two weeks) and no visit (planned or otherwise) was used to assign

done at the to deter-

groups

of two

(fifty-six

two

later.

fractures)

in the

years

after of the

sixty-six patients (sixty-seven fractures) who had been enrolled in the protocol were contacted. All fifty-six of the fractures were still healed. The duration of follow-up for twenty-three fractures was more than four years and for thirty-three fractures, it was two to four years. THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY

ACCELERATION

OF

TIBIAL

SUMMARY

OF

FRACTURE-HEALING

BY

NON-INVASIVE,

TABLE Cox

THE

REGRESSION

ANALYSES

COVARIATES

ON

POTENTIAL

ASSESSMENT

TIME

TO

A

OF

HEALED

Covariate

THE

Fractures P Value

Significant

Covariate

0.92

1.78

0.18

No

4.55

0.03

Yes

to start

Type

difference*

of fracture

0.10

0.76

No

1.27

0.26

No

of fracture active

compared

log-rank

of

study by

(three

principal

of

investigator,

treatment

group Kruskal-Wallis

rank

life-table

in

the

cent

of

healed

treatment

time

site

investigator, group

compared group

of variance,

group

cast

of weight-bearing,

in the at

62 per

cent

compared

for the

sixty-seven

log-

after

compared

favorably

with

healing,

as

active-

=

0.01,

0.03,

and

the

analysis

of

analysis, The

and

mean

cortices

demonstrated

Analysis

for

by

for

tively

the

The

to dis-

to

complete

fourth

fourth

with that a significant rank

analysis)

fifty-nine,

and

assessments

independent for three

endosteal

with

results,

flecting

thirty,

and

of bridging

of variance, life-table

third,

radiographic

and the bridging

statistical

third,

compared There was

analysis

were second,

0.01). one

in in the in-

analysis in the

dif-

to the number had occurred; and

sixty-eight

cortices,

respec-

3).

(Fig.

tigator cortical

94 ± 5.5 days for the activewith 120 ± 9.1 days for the

the

for

healing for all of the time to

rate

the groups with regard fracture that bridging

between

after

second,

increased

log-rank

differences

days

[anal-

to

and

radiographic investigator

of variance

first,

group group.

and

of days

the an

(according

variance,

ferences

log-rank

time

patients.

healing

0.005, recorded

group.

stages of the principal

by

determined

complete

of

activefor the

0.01

placebo-treatment

intermediate

crease

placebo-

assessed

group (p = 0.008, healing was not

the active-treatment placebo-treatment

group

in the

in the

The

with 44 per 150 days, 94

86 ± 5.8 days for the with 114 ± 10.4 days

was

patient

these

clinical

(p

ra-

were

days

active-treatment

respectively]).

of the

start

by the active-

and

120

fractures

Kruskal-Wallace

analysis,

continuation treatment

with 2). was

placebo-treatment

At

compared

in the

to

the

placebo-treatment The time to clinical

of van-

of variance,

1).

to as

and

[analysis

group;

fractures

mean

life-table

of the healed

placebo-treatment

The treatment

(Fig.

cent

compared group (Fig.

for

mean time fracture),

154 ± 13.7 days

analysis

were

the

adjusted

investigator

< 0.0001

(p

rank

88 per

site

with

compared

group

when

bridged cortices) 96 ± 4.9 days for the

analysis])

fracture,

treatment

that the healed

(a

the

group

ance,

p value,

four

was

placebo-treatment

placebo

showed

the

clinically

diographically

the

of 0.0001.

variance

of

both

judged

with

p values

end-point

were

-

No

Analysis

cent

0.0001 0.24

and

the

17.97 1.38

*The variance

of weight-bearing

No

grade

Location

ysis

Chi-Square

Age

Fracture

the

OF

0.01

Adjusted

per

SIGNIFICANCE

Sex

Days

the

Log-Likelihood

31

ULTRASOUND

FRACtURE

Core-Group Potential

PULSED

IV FOR

ThE

LOW-INTENSITY

more

of the

principal

inves-

radiologist for the time to and four cortices and the time healing

the

produced

radiologist’s

conservative

evaluations

±

.

=

comparable

assessments (Table

re-

II).

The

S.E.M.

ACTIVE

LIPLACEBO

N=33

PRINCIPAL

N=34

N=33

INVESTIGATOR

FIG.

Graph independent

VOL.

76-A,

showing the radiologist.

NO.

days to healing of S. E. M. = standard

1. JANUARY

1994

the fracture error of the

N=34

INDEPENDENT

(clinically mean.

and

RADIOLOGIST

I radiographically)

as

assessed

by

the

principal

investigator

and

the

32

J.

D.

HECKMAN

ET

AL.

ACTIVE

(N=33)

MEAN

Lu

96

-J

SEM

±

± 4.9

PLACEBO(N-34) LU

MEAN

I

154

SEM

± ±

13.7

P VaIu=O.0001

LU I-

TPLACEBO

-I

ACTIVE

-.-

U

%q

q,c

DAYS

TO HEALING

OF THE FRACTURE FIG.

Graph showing the cumulative superiority of the active-treatment placebo-treatment group, at ninety and no clinical data were available life-table analysis. SEM = standard

principal

investigator

bridging

determined

of three

cortices

active-treatment

table ment

group

with

(p

analysis,

The tices),

(p

and

log-rank

time

to complete

as assessed

182

± 15.8

0.0002, Wallace

[analysis

[analysis

log-rank The time

the

principal

investigator,

active-treatment

group

was

to the

with (p =

to the

start

117 ± 8.5 days

0.0004,

group

compared

with

fractures

in thirteen

patients

groups by

Cox

the

and

with

132 ±

the

after

in the

treated

I and

on

III) of

the

the

efficacy

difference

to the

and and

results

efficacy

of fracture

start

of weight-

placebo-treatment

on the

effect

time

for the

in the pattern

fracture

with the

statistical

the start of the active

analysis of weighttreatment

of

The Cox regresactive-treatment

and the placebo-treatment groups were statistically adjusted to a common start of weight-bearing effect, the active-treatment group maintained a significant supeniority for the time to a healed fracture (p = 0.0001) (Table

IV). in the

271 ± 19.6 days , 0.0001 , and

analysis

1) and

This

result

analysis

of variance,

confirms

a healed

that

is identical

to

of variance, and

that

did not significantly thirty-seven Among the

was

justification

identical

the

regression

only

fractures

active-treatment

(Tables

0.0001

never

were

patients

compared with the placebo treatment. sion analysis established that when the

and analysis,

had

device

The

essentially

time

the

who

active

compared

that

the of the

of weight-bearing.

was

bearing

previously,

of all core-group

mean

bearing

days

analysis]), and the independent was 171 ± 13.6 days for

for the placebo-treatment group (p = 0.0001 0.0001). A smoking history was obtained from core-group patients (thirty-eight fractures).

fourteen

for

placebo-treatment group (p = 0.002, [analysis of variance, Kruskal-Wallace

active-treatment

=

as assessed ± 13.9

life-table assessment

and

analysis,

healing, with

(p

the

eleven

management

combination analysis

136 ± with

group

period,

device (p = 0.09). As mentioned regard

167

and log-rank radiologist’s

compared

treatment

114

were compared

with

active

was

Kruskal-Wallace

analysis]). endosteal

the

the

con-

placebo-treatment

of variance, life-table to complete

patients,

treated

of 87 ± 3.9 days,

for the five that were treated with the placebo = 0.002). Among the fractures in the remaining who were ex-smokers or who were smoking

(all four compared group

were

device healed in a mean of 115 ± 11.2 days, compared with a mean of 158 ± 28.6 days for thirteen fractures that were treated with the placebo

,

for

(p

with

0.0001 and 0.0001 [analysis of variance, Kruskalanalysis, and log-rank life-table analysis]), and

days

days

device

during

assessgroup

investigator,

assessments group

nine

in a mean

11.2

of life-

Kruskal-Wallace

for the active-treatment group days for the placebo-treatment

± 18.4

the

the

healed

days

[analysis log-rank

bridging

principal

243

0.0004

smoked,

analysis]).

cortical

radiologist’s active-treatment

by the

and

for

± 13.2

for

for the placebo-treatment

life-table

the independent 9.6 days for the 0.0001

days

radiologist’s active-treatment

of variance,

by the

needed

148

0.0001

=

analysis,

190 ± 18.3 days

0.0001

=

± 7.5 days

for

with

group

Kruskal-Wallace

time

89 ± 3.7

analysis]), and the independent was 102 ± 4.8 days for the

compared

and

be

compared

for the placebo-treatment variance,

the

to

group

2

percentage of clinically and radiographically healed fractures in the core group as a function of time. The group is seen, with 56 per cent of the fractures healed compared with 18 per cent of the fractures in the days after the fracture. One fracture in the placebo-treatment group healed at 465 days after the fracture, for one fracture in this group. The p value is for analysis of variance, rank analysis of variance, and log-rank error of the mean.

the

affect

the

log-rank

life-table

day

weight-bearing

that

p value

Kruskal-Wallis

the efficacy

analysis

results

of rank (Fig.

started

of time

to

fracture.

In addition, the Cox regression analysis established other clinically relevant covaniates, such as the sex THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY

OF

A((ELERATION

TIBIAL

FRACTURE-HEALING

BY

NON-INVASIVE.

LOW-INTENSITY

PULSED

33

ULTRASOUND

CORTEX BRIDGED p VALUE

4TH

-

114

.-.

±7.5

0.0002

__x182

-

.---.-

0.0001

-

0.0001

±158

0.0001

3RD

-

89 ±

3.7

.x.-

148

0.0001 0.0001

±13.2

-

0.02

2ND

-

±

0.1 0.5 0.2

80

90

100

110

120

130

DAYS

AFTER

140

150

the

and

P values

age

of

the rate

showing

mean.

of the

the

patient

and had

also

efficacy results of time Log-rank life-table to-treat

analysis

study.

The

the

for

time

to

the grade, type, and no significant effect

fracture

group

compares

and

with

log-rank

for

clinical

There cation

were in

patient

the

by

placebo week

week.

No other

who

This

at

patient

was

managed

therapy

and

remained

was

one

period

had sixby

or

(who

were

device

had

treatment and

a

and

the

the

The

anticoagulant

ante2,

by

supported

Duarte

sound

and

diaphyseal

the

bone.

These

to use

76-A,

both

assess of

low-intensity

NO.

I.

JANUARY

of

Xavier animal

et al., demonstrated normal

and

fracture-repair

Du-

1994

to

process

accelerate

were at the

open

tibial

was

use

well

patient

window the

of

surface.

No

were

by the to

had

or skin

device.

head

problems

who fracture.

attributable

No

of the

of

weeks

diaphyseal

tolerated

identified.

the

twenty-

in patients

complications

site

one

as twenty

period

treatment

specific

not

noticeirritation

The

patients

and were able to between the skin specific

mechanical

encountered

in

heal-

mechanism

address

forces’

and

mechanical

by

by

the

during

which

the

effect

Knistiansen

cell caused

reported

fracture

of healing

randomized,

Other

on

waves

of

pressure

directly

by

or

cell

have

re-

mechani-

ultrasound’s

waves

may

mechanical

de-

indirectly

by

an

deformation.

the

acceleration

and on other

of metaphyseal

authors

by static

These membrane by

low-intensity

normal diaphyseal The present study

caused

pressure

activity

of the

to a healed blind,

question.

effects

perturbation2’7. biological

electrical

tens

this

on biological

formation

ultra-

findings led us to design a prodouble-blind, placebo-controlled the safety and the effectiveness of ultrasound

for as many

unit easy to use coupling contact

mediate

studies

that

and

when

for

portable adequate

The

cal

findings

placebo-controlled

by Pilla

randomized,

study

VOL.

by

accelerates

spective, the

clinical

randomization

applied

pulsed ultrasound accelerates the fracture-repair process is unknown. does

study.

Discussion intriguing

day

serious

consequence

ported The

error

of patients

accelerated

was

regimen

no

technical

a pul-

visit.

standard

study.

reported.

follow-up

the

groups

significantly

or grade-I’

edema

found achieve

cast at the had resolved

and

The

similar

post-fracture

treatment

without

patient

be

each

a closed

able

One

very

device

immediate

resolved,

with

to

in the

the

compli-

mean

in humans.

two

minute

The

group.

fractures

created

found

had

valid-

are given as the life-table analyses.

therefore permitted an unbiased assessment of the effect of the active-treatment device. When these two groups were compared, the time to a healed fracture

as

reactions

successfully in the

of fresh

muscle-

problem

four-week

ing

process

reported

in the

a placebo

the

to a healed

core

One

adverse

used

embolus

the

cramping

swelling

visit.

patient

The

had visit.

monary

in

190

3

patients,

and

treatment)

second

follow-up

next

One

the

180

active-treatment

inferences.

patients

treatment)

for time

reactions

active week.

for

This result confirms the group of protocol-compliant

adverse

had

the

statistical

sixty-six

at one

treatment,

the

two

(who

cramping

and

significant

probability level, analysis of variance,

p values

fracture in the core group. ity of the use of the core patients

was

0.005

at the

favorably

Knuskal-Wallis,

location on the

to a healed fracture (Table IV). analysis was used in an intentionall fractures randomized into the

a healed

active-treatment

which

170

of progression of healing by the amount of cortex bridged. The values given for analysis of variance, rank analysis of variance, and log-rank

are

fracture,

160

THE FRACTURE FIG.

Graph

(N-34(

0.01

13.1

± 3.9

70

of

(N

0.05

86

± 3.9

1ST

ACTIVE

XPLACEBO

bone

placebo-controlled

of the

radiographic in a similar

study

time

paramedouble-

with

use

34

J.

D.

HECKMAN

ET

of the same ultrasound treatment on Colles fractures. Knoch and Kiug reported an increased rate of healing of fractures at various locations in humans with use of ultrasound treatment with signal intensities that were one order of magnitude more than the signal intensities used

in the

present

clinical studies of Xavier and the present study, we studies that document the

1

of low-intensity .

acceleratlon

We believe that additional clinical corroboration acceleration of healing of fresh fractures with specifically programmed, pulsed, low-intensity sound treatment may lead to its useful application treatment of fractures.

of the use of ultrain the

study.

Beyond the preliminary and Duarte---, Knlstlansen, are not aware of any other effectiveness

AL.

of the

pulsed

,

ultrasound

.

fracture-healing

Noi

R. Garland.

M. lusim.

T. Kristiansen.

W.

C.

Dunlap.

W.

P. E. Levin,

Brady. D. Cahorn. Jr.. D. N. Ervin.

T. McElligot,

M. C. Meier.

Thcarsal,

in the

Charles. Roger Talish. and Arthur Lifshey Gaston. M.D.: Arthur Pilla. Ph.D.: James invUuable counsel during the preparation

.

process

The authors thank the following site investigators: R. M. Christian. J. Cronkey. J. R. DeAndrade. J.

Chillag. Gamwell.

in humans.

for their engineering Ryabs. Ph.D.: and of this study.

K. J.

D. G.

Ihank

Kern

assistance and the late Sawnie Robert Siffert. M.D. for their

References 1. Binderman, events 2.

I.; Zor, in bone

Chapman,

I.

thymocytes

U.; Kaye,

cells

may

V.; MacNally,

in vitro.

N.

Conover, Cox, D.

R.: Regression

5.

Duane,

L. R.: The stimulation

6.

Dyson,

M:

Ziskin.

New

Fleiss,

8.

Gustilo,

York,

10.

Mug, W.; Franke, Knoch,

J. Orthop.

Lehmann,

13.

Mantel,

N.:

163-170,

1966.

Mantel,

15.

Nyborg,

N.:

L.:

H. Med.,

Mont,

M. A.;

Pollack.

San Francisco,

Scheffe,

H.:

Wells,

factor

new

restricted

P. R.; Khan, A.

beta

San

in the A.;

and

In

Francisco

Press,

of Variance.

New

B.: How

safe

is diagnostic

101:

pp.

153-159,

121-133.

thousand June

bone-fracture

of

potassium

ions

in

rat

1983.

Edited

by W. L. Nyhorg

and

M. C.

and

twenty-five

under

ultrasonic

open

fractures

of

long

1976.

healing

translated

by T. C. Telger.

on the

San Francisco, statistics

healing

stimulation:

in

its

Edited

Springer,

of fresh

an

animal

1991.

fractures

using

a Colles’

1975.

consideration.

23: 65-78,

23-33.

Berlin,

time

Holden-Day.

arising

Biometrics, pp.

Churchill

of

Wiley,

Cancer

Chemother.

Rep.,

50:

1967.

by

W.

L.

Nyborg

and

M.

C.

Ziskin.

New

York.

ultrasound.

Livingstone,

Biological

L. R.: Estimulac#{227} ultra-sonica L. R.: Treatment

Jan.

Siffert,

R. S.: Non-invasive

low-intensity

pulsed

1990.

pulsed

in Medicine

Canadian

In

Duarte, Orthopedic

J. J.; and

4: 246-253,

and

ultrasound Biology,

modulates

95-100.

pp.

adenylate Edited

cyclase

activity

by C. T. Brighton

and

and

S. R.

1959.

Duarte,

Latin-American

M.; Kaufman, Trauma,

ultrasonography?

and

Press,

efflux

1991. York,

and

Effects,

and

1981.

453-458,

P.: Low-intensity

C. A. M,

Biological

influx

Surg.,

of one

ultrasound

Ranks.

Electromagnetics

C. A. M.,

C.:

Wiley,

Ultrasound,

order

Figueiredo,

J. Orthop.

Duarte-Alves,

synthesis.

applications

S. A.;

rabbit.

Xavier,

M.

of

Ultrasound,

Xavier,

California,

biomechanical

1972.

Ultrasound,

58-A:

observation. of

22.

Ziskin,

on rank

21.

cisco,

with

Based

two

Surg.,

programmed

New

23.

into

1986.

Ziskin.

the

Joint

Healing

Effects

Analysis

P. N. T.: Surgical York,

of

Trauma

treatment

control

494-497,

Methods and

arbitrarily

healing

J.; Pilla,

growth

Brown,

of

York,

in the

and

specifically

Biological

Nasser,

bone

J. T.; Mathew,

The

187-220,

and

Effects

Ed. 2. New

Scintigraphic

11:

ofFracture

data for

B, 34:

Orthop.

In Biological

J. Bone

G.:

Statistical

In

in rates

force

1988.

1985.

accelerates

Ryaby,

19. St. John 20.

Knoch, J. Nucl.

procedures

of mechanical

42: 261-266,

1980.

Series

Arch.

of infection

analyses.

survival

Mechanisms.

Wiley,

Soc.,

Proportions.

of low power 4: 227-228, 1990.

of

Livingstone,

A. A.;

and

W.: Stimulation

Trauma,

Ranking

transforming 18.

and

transduction

Internat.,

changes

York.

Statist.

by ultrasound.

effect

Evaluation

W.

ultrasound 17.

Rates

E. L.: Nonparametrics:

Churchill

Pilla,

G.;

D.: The

Tissue

1985.

prospective

Klug,

Ed. 2. New

J. T.: Prevention

European

T. K.: The

12.

14.

W.

study.

G. H., and

model.

16.

and

Somjen, Calcif

1980.

J. Roy.

growth

Livingstone,

A2.

Ultrasound-induced

of ultrasound.

Methodsfor

A.; and

6: 47-58,

life-tables.

of bone

Anderson,

S.:

Biol., Statistics.

and

Churchill

and

‘flicker, and

applications

Retrospective

1 1 . Kristiansen,

and

Med.

Z.; Harell,

of phospholipase

Nonparametric

L.: Statistical

experimental

A.;

models

Therapeutic

R. B.,

bones. 9.

W. 3.: Practical

J.

7.

activation

Ultrasound

4.

3.

A. M.; Shimshoni,

involve

Med.

Effects

Assn.

of

J., 131: 307-311,

Ultrasound,

pp.

1984.

157-167.

Edited

by

W. L. Nyborg

and

M. C.

1985. de cab

of nonunions

Association,

at the

osseo:

by ultrasound

Annual

Meeting

applicac#{226} clinica. stimulation:

of The

Rev.

first

American

Brasi/eira

clinical

Academy

Ortop.,

applications.

18: 73-80, Read

of Orthopaedic

1983.

at the

Meeting

Surgeons,

San

of Fran-

25, 1987.

Applications and

of Hazard

ultrasound Potential,

in pp.

medicine 49-59.

-

Edited

comparison by

M.

with H.

Repacholi,

other

modalities. M.

Grandolfo,

In

Ultrasound: and

A.

Medical Rindi.

New

Applications, York,

Plenum

1987.

THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY