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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.
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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
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