Copyright

1994 by The Journal

of Bone

and Joint

Surgery.

Incorporated

Acceleration

of Tibial

Fracture-Healing

by Non-Invasive,
BY JAMES D. HECKMAN. M.D.t, JOHN P. RYABYt,

Low-Intensity
JOAN MCCABE, R.N.I, JOHN

Pulsed
J. FREY.

Ultrasound*
PH.D1. AND RAY F. KILCOYNE. M.D.#.

SAN investigation performed at The University

ANTONIO. of Texas Health

TEXAS

Science

Center

at San

Antonio,

San

Antonio

ABSTRACT: tures of the tibial

Sixty-seven shaft were

closed

or grade-I

open

frac-

examined

in a prospective,

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 healing (86 5.8 days in the active-treatment

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.
These relatively high ultrasound intensities are em-

ployed which
tions

to generate the ultrasound

of ultrasound

heat within the tissues, signal passes5. Diagnostic

include examination The of vital diagnostic

through applicaorgans,

evaluation
ies, and

of fetuses,
ophthalmic

vascular
echography.

and peripheral

flow

stud-

applica-

group group)
time

compared with 114 10.4 days in the (p = 0.01) and also a significant decrease
to over-all (clinical and radiographic)

control in the
(96

healing

4.9 days in the active-treatment 154 13.7 days in the control

patients compliance with the

group compared group) (p = 0.0001).

use of the device

with The
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 stimulation in the acceleration of

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
a rabbit, Duarte demonstrated acceleration of the nor-

the normal
Ultrasound

fracture-repair
has many

process.
medical applications, includ-

ing therapeutic, Both ultrasound

ject tissue

operative, therapy
levels

and diagnostic procedures. and operative ultrasound subthat are capable of causing

to power

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 muscle mobility. The operative applica-

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

*One

or more

of the authors

have

received

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. 810 White Passaic New Avenue, York West 10607. 1853 of Colorado Colorado William Health 80262. Caldwell,

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

Plains,

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
in Israel.

lHealth
Penn
Science #Department Center,

Products

Development,

Incorporated,

Way, Lancaster, 4200

Pennsylvania
of Radiology, East Ninth

17601.
The University Avenue, Denver,

An fered

opportunity to participate in the study was to all skeletally mature men and non-pregnant
THE JOURNAL OF BONE AND JOINT SURGERY

of-

26

ACCELERATION

OF

TIBIAL

FRACTURE-HEALING

BY

NON-INVASIVE.

LOW-INTENSITY

PULSED

ULTRASOUND

27

women and old and

seen who spiral

reduction

at our 1990 had that and was

and after

institutions who were

between at most transverse, be treated radiographs open

September seventy-five tibial short effectively

in a cast.

1986 years diaphysoblique, with made

December

a closed that and

or grade-I could lateral

eal fracture or short

closed immediately

primarily
immobilization

Anteroposterior if either
showed

were

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)
had the had injury the an operative because procedure of severe within angulation six weeks of the after fracture

investigator, nal fixation not complied

the that

the reduction. We excluded patients anteroposterior or the lateral radiographs the the length of the of the
fracture),

fracture

line

was

more (a long was or the

after
cause

treatment
fracture

had
did

begun,
not

seven
meet the

were
inclusion

excluded
criteria

beof

than
spiral

twice
or

diameter
oblique

long

diaphyseal shaft the displacement width of the shaft,

more

than

50 per

cent

of the

fracture gap sion criteria fined than not tion with with by one
metaphysis;

was more than 0.5 centimeter. were open fractures, except and Anderson; fractures
fractures

Other exclugrade I as deof the that tibial were

Gustilo centimeter

with
after

persistent
reduction; or

shortening
fractures persistent

of more
angula-

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 fractures in patients who adhered had sufficient follow-up data. to the study protocol It is this group from and which

sufficiently

stable

(recurrent

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 fractures; with fragwas had acceptthat antior stated

the diameter of the tibial shaft); pathological and comminuted fractures (comminution ments able).
they

of less Patients
could not

than were

one also

centimeter excluded

in length if they

comply

with

the protocol:
calcium-channel

were

receiving

steroids, inflammatory

anticoagulants, medication,

prescription

non-steroidal blockers,

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
active

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 and surface alignment fixture cast, at the made of molded plastic

was
medial

inserted

into

a window

centered
site

over
of the

the
tibial

anterofrac-

of the

gave into
or

informed consent, the patients were randomgroups of four at each study site to receive an
a placebo-treatment device according to a pre-

determined broken only completed.

Ninety-six fractures, were

computer-generated after
patients, entered

code.

The

code had

was been

the

radiographic
who into

reviews a total study.

had the

of ninety-seven Forty-eight of

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 the day. window and The consisted treatment after removal of head one of the twenty-minute was plug positioned and the applifelt period in module

the fractures group and group. cent]) tients healing seventeen were from ment follow-up the and were

were forty-nine, lost to

randomized to the patients follow-up, fractures

to the active-treatment placebo-treatment control (thirteen leaving [88 was per cent]) known. because fractures eighty-four in whom An [18 of additional per cent]) deviations [13 per pathe

Thirteen (eighty-five status excluded protocol. patients

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 circuitry to drive the treatment head module and to mon-

of the from

fracture (seventeen the

fractures study

Of the thirteen
nine, and

patients
placebo the site seven

(four
treatment) final

who
healing

had
who

active
were status

treatlost was to not

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 integral ically timer turned that monitored the unit treatment off after twenty times and automatA visual minutes.

for whom

known,
been died

seven
withdrawn of unrelated

had
by

withdrawn
the causes

from
investigator, weeks

the
after

study,
and the

five
one

had
had

and audible signal alerted the patient that was complete. The patients compliance
tions inside for use of the device the main operating was unit

the treatment with instruc-

fracture.

Of the
VOL. 76.A,

five
NO.

patients
1. JANUARY

who
1994

were

withdrawn

by the

site

measured by both a timer and a patient-maintained

28 daily treatment log. The active and placebo identical in every way (they had the same and auditory signals) was except continued for for the twenty that the emitted. Treatment

J.

D.

HECKMAN

ET

AL.

devices were visual, tactile, signal

TABLE
ASSESSMENT OF TREATMENT-GROUP

I
COMPARABILITY

ultrasound weeks

Treatm Parameter Active 33

ent

Group Placebo 34 0.37* P Value

or until was plaultra-

No. Sex

of fractures

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

the fracture active or the an

Male Female Fracture Closed grade

25 8

29 5

delivered

0.64*
31 2 33

200 microseconds with a repetition

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

Grade-I
Type Transverse

open

rate

of one

kilohertz

and

a spatial
milliwatts was iden-

of fracture 4 17 11
15

0.49*
8 11

average-temporal average per square centimeter.

intensity of the

of thirty fracture in an

Short Short
Location Proximal Middle Distal Comminuted No

oblique spiral

The
tical for

regimen all

for

treatment Immobilization

Comminuted of fracture

0
0.60* 3

patients.

above-the-

knee cast was maintained until that the fracture was sufficiently

the investigator thought stable for application of

15
17 fracture 31

15 16 0.43* 29 5 0.77*

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
changes were permitted as clinically indicated.

Yes
Butterfly fracture

2
26 7 fracture 9 24 (yrs.) (per cent) 33 4.7 (n = 30) 23 2.5 36 2.3

Weightpatient. The man-

bearing clinical only agement forty-two

study eight

was difference

controlled and

on the the

basis protocol

of the of the

investigators

No Yes Fibular No Yes

Aget

28 6 0.13* 4 30 31 1.8 0.091

judgment was the patients

were weeks instructed after

tolerance

in the common initiation (forty-two

not

of fracture

of weight-bearing. The first fractures) enrolled in the to bear weight during the first and the were remaining allowed fiftyto bear

Displacement

four weight

patients

the (fifty-five

fracture, fractures)

Before
After Angulation

reductiont
reductiont (degrees) reductiont reductiont

38 4.9 (n=31) 23 2.7

0.481 0.981

as tolerated.

All

patients

were

scheduled
six, and

to return

for

follow-

Before

up radiographs teen, twenty,

at four, thirty-three,

eight, ten, twelve, fourfifty-two weeks after the were use of

6 1.0 (n=30) 4 0.5

6 0.8

0.741

After

4 0.4
4 0.3

0.801
0.921 0.551 0.891 0.211

fracture. Anteroposterior made and standardized the same x-ray

and

and lateral radiographs whenever possible, with at each site,

device

Maximum
Length Days Duration until

fracture
of fracturet start

gapt
(cm)

(mm)

4 0.3 4 0.2 4 0.3 250 92-438 18.1

of treatmentt (days)

4 0.2 4 0.3
(n = 33)

machine

the

same

exposure

setting,

a leg-positioning

that

was

furnished
of

of follow-upt

28419.2
142-586 49
5.9

to each site investigator. were performed by the

any cast change (usually

Clinical follow-up site investigator

at six and ten

evaluations at the time

and

Range
Days to start bearingt
*With

of weight-

45

(n the Fisher are exact given test

weeks)

at the
tThe

4.9 33) test. the

0.621

follow-up
that the The judged graphic

visit
fracture

when
had

radiographic
healed study

evaluation
sufficiently was a healed and cortices were to

indicated
allow fracture, on bridged). radioIn for the reas
mean.

or chi-square mean and

values analysis

as the

standard

error

of the

moval

of the cast.
end-point both on examination
of the

IWith

of variance.

of the clinical (three

examination of four process the

addition
stages

to the healed-fracture
fracture-healing between groups.

end-point,
active-treatment

intermediate
assessed and

the difference placebo-treatment

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
as a result of callus formation. The amount of cortical

With
healing, clinical individual amination, to manual

regard

to the

intermediate

clinical

stages

of
to the cx-

two parameters were evaluated: healing was defined as the time site the stress, investigator fracture and the was time thought stable that, and was

the time at which on clinical not

bridging was quantified as none (no change tical interruption compared with that seen
graph made in the immediate post-reduction

at the coron a radioperiod),

painful of the

to discontinuation

initial ruption

(when a periosteal reaction at the cortical interof the fracture site was first noted), intermediTHE JOURNAL OF BONE AND JOINT SURGERY

ACCELERATION

OF

TIBIAL

FRACTURE-HEALING

BY

NON-INVASIVE.

LOW-INTENSITY

PULSED

ULTRASOUND

29

TABLE
INTERMEDIATE RADIOGRAPHIC

II
HEALING STAGES

Days Active Treatment*

afte r Fracture Placebo Treatment (N = 34)1

P Valuet Kruskal-Wallis Rank ANOVA

(N
3 bridged Principal Independent Complete cortical cortices investigator radiologist bridging

33)

ANOVA

Log-Rank

89 3.7 102 4.8

148 13.2

190 18.3

0.0001 0.0001

0.0001 0.0001

0.0001 0.00()l

(4 bridged
Principal Independent Endosteal Principal Independent *The INo

cortices) investigator radiologist

I 14 7.5 136 9.6

182 15.8 243 18.4

0.0002 0.0001

0.0001 0.0001

0.0001

0.0001 0.0004
0.()001

healing investigator radiologist values clinical are data given were as the available mean and for one the 117 8.5 167 271 of the with mean, the 13.9 19.6 as calculated placebo device. with

0.002
0.0001 analysis of variance.

0.0004
0.0001

171 13.6 standard that deviation was treated

tANOVA

= analysis

of variance. fracture

ate

(an

increase

in the

density cortical at each

or size (the

of the peniosteal

initial On four

peneach

(proximal,
ence

middle, and

or distal)

of the
the

fracture; fracture
by the

the

pres(Table
of

osteal completely

reaction) bridged

or evaluation

complete the

reaction cortices of

of minor

comminution;

presence

of a butterfly analysis

interruption). time-point,

fragment;
I). Statistical

the presence
analysis was

of a fibular
performed

radiographic

(two
lateral

on the anteropostenior
radiograph) were bridging. other parameter, gradual line and
formed

radiograph
evaluated endosteal by for healing, a zone

and
the

two on the
amount was of defined fracof enin the less had by increased

cortical The as the ture

density

disappearance its replacement by endosteal was quantified

on obliteration

of the

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
number to the of days start of follow-up, and mean I). number of days of weight-bearing (Table

dosteal

healing

callus. The amount as none (no change on the post-reduction line had become
marked consolidation

fracture line radiograph),

distinct),

compared with that initial (the fracture

(there was

intermediate

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
by the the internal device Adverse clock reactions, and a written log complaints, kept by and patient. patients

of the
been

fracture
replaced

line),

and

complete of increased

(the

fracture density

line formed

by a zone

endosteal callus). teal healing was the of lateral the

A judgment as to the extent of endosmade on both the antenopostenior and at each follow-up visit.

complications
vestigator

were
at each

specifically
visit effect and were

sought
recorded

by each

site

in-

if found.

radiographs

Previous
showed all
osseous repair.

animal
Therefore,

and

clinical
an

studies5222
on the
time

clearly
rate
to

To minimize
radiographs

the

effect
by the

of subjective
individual

interpretation
investigators,

a positive the

of ultrasound
accelerated

of at p

heal-

radiographs were assessed in independent, blind neviews by the principal investigator (J. D. H.) and, separately, by the independent radiologist (R. F. K.). The principal investigators assessment of radiographic ing was used for purposes of statistical analysis pare the efficacy of treatment with the results healto comof use of

ing

for

active-treatment

group

was

hypothesized

the

protocol-design
statistical

phase
tests

of this
of hypothesis

study.

Consequently,
and one-sided

one-sided

the placebo device. The site investigators assessment of clinical healing was used for analysis of the clinical cornponents of fracture-healing. Time to response was calculated first as the number of days after the fracture to 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 square for
VOL.

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
response
tested

for
against

those superior

treated

with

the fractures

placebo

device

was

the alternate
for the

hypothesis was defined

that
treated

the time
with

to
the

response groups were characteristics of analysis7 was pertest (or the chicategory and levels) location type,

was

active
(shorter)

device.
time

Superior
to the

as an accelerated
of a specific healing

attainment

test sex

if there of the
NO.

were patient;

more the
1994

than grade,

two

the
76-A,

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

I. JANUARY

30
TABLE
NUMBER AND CUMULATIVE NUMBER

J.

D.

HECKMAN

ET

AL.

III
OF FRACTURES FOR DAYS

scheduled
OF WEIGHT-BEARING

follow-up

visit

(for

example,

at ten,

twelve,

AFTER

THE

FRACTURE

TO

THE

START

fourteen, interim
a healing

twenty, thirty-three, or fifty-two weeks) and no visit (planned or otherwise) was used to assign
time. The number of days to the last completed

Active Days after Fracture No. 5 5 6 3 7 3 4 were available on the group. Cumulative 5 10 16 19 26 29 33 start No. 4 4 7 5 5 1 7

Placebo* Cumulative 4 8 15 20 25 26 33 for one

0-14 15-28 29-35 36-49 50-63 64-77 >77

follow-up examination for the fractures that

the last follow-up whether analysis evaluated in the

was used for the time to healing had not reached a healed status by
This intention-to-treat of the withdrawn analysis and in the noncore exclusion

visit.

protocol-compliant
of the

patients
time

biased
that the

the results
fractures

obtained

group

took

to heal.
Results

*No data
fracture in the

of weight-bearing

placebo-treatment

With
parameters
was used to calculate

regard
that

to the
were in the

seventeen
studied

patient
(Table

and the

fracture
could not

I), we

analyses.

Analysis

of variance

mean

time

and

the

standard

error

of the

mean,

the in days,

detect
three

any
fractures

appreciable

differences
active-treatment

between
core

thirtyand

group

to the attainment active-treatment

sis of variance, and ranks32,

of a healed fracture and placebo-treatment

Kruskal-Wallis analysis analysis43t4 was used life-table

status groups.
were because

for the Analyby to used

of variance

log-rank

compare
The

the mean

times
analysis

to healing

for the two

groups.
it does

Kruskal-Wallis

not make tribution

life-table censored
uses days

the statistical or homogeneity

analysis observations
to the

assumptions of a Gaussian disof variances. The log-rank

used as because censored visit active had it analyzes observations as the time-to-event treatment and right censored right and one esti-

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
clinical visits for each cent group. of the of 283 The patients who received

was last

active
up visits

treatment
89 per

returned were
(256 core

for
time visits).

the
(245

scheduled
of 276 Usage

followvisits), and

value that

(one had the

fracture placebo

follow-up that had treatment

the patients
cent of the

who
time

treated the
groups,

with

the placebo,
of the

90 per
device

was
device

comparable
timer and

between
the patient

active-treatment
as recorded log, and all of the

and
by both patients

the
the

mated values for the time to a healed fracture). In addition, Cox regression analysis was
assess whether potential covariates, such

placebo-treatment

used to as the sex

of weight-

in the active-treatment
thirty-six treatment

group
sessions.

used

the

unit

for at least
was error compagroups; it of the

and

age

of the

patient,

the

days

to the

start

bearing, and the ture, had an effect compared fect was with observed the

grade, type, or location on the healing response placebo-treatment because of the covariate,

of the fracin the active group. the If an results ef-

The total duration of follow-up, in days, rable in the active and the placebo-treatment was 250
for

18.1 the

days

(mean

and

standard

mean
days)

[analysis

of variance])
active-treatment 142
=

(range,
586

ninety-two

to 438
with 284 placebo-

of active treatment

treatment compared with were statistically adjusted

determine group was whether compared maintained the

those of placebo for the covariate

superiority with the presence of the placeboof the

in order to active-treatment treatment covariate file and fully ough

analyses

19.2 days (range, treatment group (p

active-treatment

to

group compared days) for the I). One a fracture

group

0.21) (Table sustained

patient in the in the same

group effect.

in the

area
was

of the tibia
considered

seven
to be

months
healed

after
both kicks

the initial
clinically and

fracture
radio-

All data
then

observations
the computer

were

entered
was

into

a computer
care-

graphically.
cer game,

The
from

second
simultaneous

fracture healed

occurred
to the

during
tibia

a socby two

printout

proofread

against the case-record comparison of all

form. An independent, thordata used in the statistical

other

players.

This

fracture

four

months

later.

with
the further.

those
All

in the
analysis, analyses

case-record
to ensure were

form
the performed

was
accuracy with

done
of the

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

done at the to deter-

before the data

statistical

mine
study the

whether
remained injury.

all healed
healed Fifty-five

fractures
at a minimum

in both

groups
years

in the
after of the

of two fractures)

Statistical Analysis System software North Carolina) on an IBM 3081

(SAS Institute, Cary, mainframe computer.

patients

(fifty-six

All of the fractures

study group were analyzed

that

were
for the life-table

randomized

into

each
in an fracof a

intention-to-treat ture was considered

log-rank to be

time to healing analysis. Each only at the time

healed

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

FRACTURE-HEALING

BY

NON-INVASIVE,

LOW-INTENSITY

PULSED

ULTRASOUND

31

TABLE
SUMMARY OF THE

IV
FOR TIME ASSESSMENT TO A HEALED OF THE FRACtURE SIGNIFICANCE OF

Cox

REGRESSION COVARIATES

ANALYSES ON ThE

POTENTIAL

Core-Group Potential Sex Age Days Adjusted Fracture Type Location *The variance to start of weight-bearing Covariate Log-Likelihood 0.01 1.78 4.55 17.97 1.38 0.10 1.27 with the placebo p value, when adjusted for the start Chi-Square P Value 0.92 0.18 0.03 0.0001 0.24 0.76 0.26 of weight-bearing,

Fractures Significant No No Yes

-

Covariate

difference* grade of fracture of fracture active and compared

No No No compared favorably with the analysis of

log-rank

p values

of 0.0001.

Analysis

of

variance

showed

the
judged

end-point both

of clinically
(three

the
of

study by
was

(a site

that the healed

mean time fracture), and

to as ra-

placebo-treatment The time to clinical patient The

were sixty-seven

group (p = 0.008, healing was not group. stages of the principal

Analysis

0.005, recorded

and for

0.01). one

the
four

investigator

in the
determined

placebo-treatment by for

diographically principal treatment placebo-treatment ance, Kruskal-Wallis group

investigator, compared group

bridged cortices) 96 4.9 days for the

by the active-

intermediate
patients.

radiographic investigator third, rate

with
(p analysis

154 13.7 days

[analysis At 120 days
of variance,

for the
of vanand log-

of variance

healing for all of the time to and fourth in in the inanalysis in the

< 0.0001

complete cortices

healing demonstrated

the an group group.

first,

second,

rank

increased compared There was

of bridging with that a significant

rank

rank the
cent per were treatment

life-table fracture,
in cent group

analysis]) 88 per cent

were fractures

(Fig. of the
healed in the

1).

after active-

fractures
compared

in the at

the active-treatment placebo-treatment

crease of ferences (according and between to variance,

the
of

placebo-treatment
the

group; 62 per cent

with 44 per 150 days, 94 group placeboby activefor the [analto dislog-rank

analysis

of variance, life-table analysis)

log-rank

dif-

active-treatment in the as

healed The

treatment the site

compared group (Fig. time to

with 2). clinical was

of days
these days tively The for

after
differences the

the
second,

the groups with regard fracture that bridging

were thirty, fifty-nine,

to the number had occurred;

and sixty-eight

mean
group

healing,

assessed

third,

and

fourth
of the

cortices,
principal

respecinves-

investigator,

treatment placebo-treatment

compared group

86 5.8 days for the with 114 10.4 days

(p
=

(Fig.

3).
assessments

radiographic

0.01, The

0.03, analysis,

and and

0.01 time

ysis

of variance, analysis,

Kruskal-Wallace respectively]). cast was

compared of the

tigator cortical to
statistical flecting

and the bridging

results, more

independent for three

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

life-table
continuation treatment

mean

complete

endosteal

group

94 5.5 days for the activewith 120 9.1 days for the

with
conservative

the

radiologists
evaluations

assessments
(Table II).

reThe

S.E.M.

ACTIVE

LIPLACEBO

N=33

N=34

N=33

N=34

PRINCIPAL

INVESTIGATOR

INDEPENDENT FIG.

RADIOLOGIST

I radiographically) as assessed by the principal investigator and the

Graph independent

showing the radiologist.

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

the fracture error of the

(clinically mean.

and

VOL.

76-A,

NO.

1. JANUARY

1994

32

J.

D.

HECKMAN

ET

AL.

ACTIVE

(N=33)

Lu
-J LU

MEAN
96

SEM

4.9

PLACEBO(N-34)

I
LU I-I

MEAN
154

SEM

13.7

P VaIu=O.0001

TPLACEBO
-.-

ACTIVE

%q
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

q,c

DAYS

TO HEALING

OF THE FRACTURE
FIG.

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.

principal bridging active-treatment variance, table ment

investigator of three group Kruskal-Wallace

determined cortices to compared be

the with

time 148

needed days for 13.2

for the days of life-

smoked,

nine

were

treated

with

the

active

device

and

89 3.7

healed
11.2
device

in a mean
days
(p

of 87 3.9 days,

compared

with

132

for the placebo-treatment

group

(p

0.0001
and

analysis,

[analysis log-rank

patients, during

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 treatment period, eleven that were treated

analysis]), and the independent was 102 4.8 days for the with 190 18.3 days
[analysis

radiologists active-treatment
Kruskal-Wallace

assessgroup

the

with

compared

for the placebo-treatment analysis]).

group
analysis,

(p The

0.0001

of variance,

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
device (p = 0.09). As mentioned regard to the previously, the of the only patients difference was in the
pattern

the

active

and

log-rank

life-table

time

to complete
by the

cortical
principal

bridging
investigator,

(all four
was compared group

con114 with (p =

with the time

tices), 182

as assessed 15.8

management

7.5 days 0.0002, Wallace

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

,

to the
analysis

start
was

of weight-bearing.
of all core-group
the essentially

The
identical

justification

for the
efficacy
of fracture

combination and groups

by Cox

fractures to the

0.0001 and 0.0001 [analysis of variance, Kruskalanalysis, and log-rank life-table analysis]), and
radiologists active-treatment for the of variance, life-table to complete group assessments group Kruskal-Wallace healing, with 167 were compared group 136 with (p
=

mean

time

after I and
of

the III)
the

fracture and
effect

start

of weightanalysis of weighttreatment

the independent 9.6 days for the 243 0.0001 and 18.4 log-rank The time principal days [analysis

bearing

in the
(Tables
regression

active-treatment

and
on the
of

placebo-treatment
statistical

placebo-treatment analysis]). endosteal was compared

analysis, as assessed for the days 13.9

bearing

on

the

efficacy

results

the start of the active

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

The Cox regresactive-treatment

by the for the

investigator,

117 8.5 days

active-treatment

0.0004

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

0.0004,

and analysis, the

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 confirms fracture. This result
and

and log-rank radiologists

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

is identical of variance,
log-rank

to
life-table

the

p value
analysis

of rank
(Fig.

0.0001
analysis

analysis that the

Kruskal-Wallis weight-bearing

active-treatment

group

compared

with

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

271 19.6 days , 0.0001 , and

thirty-seven Among the

of variance,

1) and a healed

day

that

started

did not significantly

affect

the efficacy

results

of time

to

fourteen

fractures

in thirteen

patients

who

had

never

that

In addition, the Cox regression analysis established other clinically relevant covaniates, such as the sex
THE JOURNAL OF BONE AND JOINT SURGERY

A((ELERATION

OF

TIBIAL

FRACTURE-HEALING

BY

NON-INVASIVE.

LOW-INTENSITY

PULSED

ULTRASOUND

33

CORTEX
BRIDGED p VALUE
0.0002
-

4TH

114 7.5
.---.-

.-.

__x 182
158

0.0001 0.0001

0.0001

3RD

89
3.7
-

.x.-

148
13.2

0.0001 0.0001 0.02

ACTIVE (N

XPLACEBO

(N-34(

2ND

86

0.05 13.1 0.01

3.9

1ST

70
the rate
are

0.1 0.5 3.9 0.2

80

90

100

110
DAYS

120
AFTER

130

140

150

160

170

180

190

THE FRACTURE
FIG.

3
are given as the life-table analyses. mean and the standard error

Graph
of

showing

the

mean.

P values

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

and
of

age
the

of the
fracture,

patient
also

and had

the grade, type, and no significant effect

location on the

ing

of fresh
created

fractures
two very

in humans.
similar

The
groups

randomization
of patients and

process

efficacy results of time Log-rank life-table

to-treat study. the which The analysis time to for

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

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
was found to be significantly device was accelerated applied period tibial for one when the active-treatment twenty-

a healed group

active-treatment compares

0.005
the

favorably

with

probability level, analysis of variance, for time to a healed valid-

minute
in the had

period
immediate

each
or grade-I no at the

day

for as many
open

as twenty
in patients diaphyseal

weeks
who fracture.

Knuskal-Wallis,

and

log-rank

p values

post-fracture

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

patients There cation in for the clinical were two sixty-six and adverse

This result confirms the group of protocol-compliant

inferences. reactions in cramping the and core one group.

a closed

The
patients,

treatment
and

regimen
serious site
of

was

tolerated No patient
device.

well
attributable

by the
to

statistical patients

complications of the
use of

compliOne

the
able
as a

treatment
edema
consequence

were

identified.

had
The

noticeirritation patients

window the

or skin

patient
cramping

(who by
follow-up

had the

active
week. The

treatment) week. swelling

This problem

reported
resolved,

musclewithout

at one

treatment, placebo
week

second had
visit.

One

patient

(who

had sixby

found achieve and the

the

portable adequate

unit easy to use coupling contact head surface. No

and were able to between the skin specific mechanical

treatment) visit.
embolus was and remained

in the reactions

cast at the had resolved were reported.

treatment

or

technical
The specific

problems

were

encountered
by which

during
low-intensity

the

the

next

No other

adverse
the four-week successfully in the

study. mechanism
The

One
monary patient therapy

patient

who
at managed

used

a placebo

device
follow-up

had
visit.

a pul-

with

anticoagulant

pulsed ultrasound accelerates the fracture-repair process is unknown. does not forces address this by the question. Other

normal diaphyseal The present study authors have re-

study.

ported
Discussion
The ante2, intriguing supported by clinical findings of Xavier animal and Du-

on biological
and biological

effects
pressure

caused
waves

by static
of

mechaniwaves by may
de-

cal
studies

ultrasounds

mechanical
mediate

perturbation27.
activity

These
directly cell
the

pressure
by

placebo-controlled

mechanical

by

Duarte

and
bone.

by Pilla the
These

et al., demonstrated normal fracture-repair

that process

ultrain

formation
electrical
Knistiansen

of the
effect

cell
caused

membrane
by
on

or
acceleration

indirectly
of the

an

sound
diaphyseal spective, study the
VOL.

accelerates
randomized, to use assess of

deformation.
time

both

findings led us to design a prodouble-blind, placebo-controlled the safety and the effectiveness of ultrasound
1994

reported

to a healed
tens of healing

fracture

and on other
bone

radiographic
in a similar

paramedouble-

of metaphyseal

low-intensity
JANUARY

to

accelerate

heal-

blind,

randomized,

placebo-controlled

study

with

use

76-A,

NO.

I.

34

J.

D.

HECKMAN

ET

AL.

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
1

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.
Noi
Chillag. Gamwell.

of the use of ultrain the

study.

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

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

The authors thank the following site investigators: R. M. Christian. J. Cronkey. J. R. DeAndrade. J.
R. Garland. M. lusim. T. Kristiansen. P. E. Levin,

W. W.

C.

Dunlap. Thcarsal,

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

M. C. Meier.

K. J.

T. McElligot,

D. G. Kern

Ihank

pulsed
.

ultrasound

in the

acceleratlon

of the

fracture-healing

process

in humans.

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

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

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

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THE

JOURNAL

OF

BONE

AND

JOINT

SURGERY