Low intensity pulsed ultrasonography for fractures: Systematic review of randomised controlled trials

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DOI: 10.1136/bmj.b351 · Source: PubMed
Abstract
To determine the efficacy of low intensity pulsed ultrasonography for healing of fractures. Systematic review of randomised controlled trials. Electronic literature search without language restrictions of CINAHL, Embase, Medline, HealthSTAR, and the Cochrane Central Registry of Controlled Trials, from inception of the database to 10 September 2008. Review methods Eligible studies were randomised controlled trials that enrolled patients with any kind of fracture and randomly assigned them to low intensity pulsed ultrasonography or to a control group. Two reviewers independently agreed on eligibility; three reviewers independently assessed methodological quality and extracted outcome data. All outcomes were included and meta-analyses done when possible. 13 randomised trials, of which five assessed outcomes of importance to patients, were included. Moderate quality evidence from one trial found no effect of low intensity pulsed ultrasonography on functional recovery from conservatively managed fresh clavicle fractures; whereas low quality evidence from three trials suggests benefit in non-operatively managed fresh fractures (faster radiographic healing time mean 36.9%, 95% confidence interval 25.6% to 46.0%). A single trial provided moderate quality evidence suggesting no effect of low intensity pulsed ultrasonography on return to function among non-operatively treated stress fractures. Three trials provided very low quality evidence for accelerated functional improvement after distraction osteogenesis. One trial provided low quality evidence for a benefit of low intensity pulsed ultrasonography in accelerating healing of established non-unions managed with bone graft. Four trials provided low quality evidence for acceleration of healing of operatively managed fresh fractures. Evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results. Although overall results are promising, establishing the role of low intensity pulsed ultrasonography in the management of fractures requires large, blinded trials, directly addressing patient important outcomes such as return to function.
RESEARCH
Low intensity pulsed ultrasonography for fract ures:
systematic review of randomised controlled trials
Jason W Busse, scientist, assistant professor,
1,2
Jagdeep Kaur, student,
2
Brent Mollo n, st udent,
3
Mohit Bhandari, associate professor,
2
Paul Tornetta third, professor,
4
Holger J Schu
¨
nemann, prof essor ,
5
Gordon H Guyatt, professor
2
ABSTRACT
Objective To determine the efficacy of low intensity pulsed
ultrasonography for healing of fractures.
Design Systematic review of randomised controlled trials.
Data sources Electronic literature search without
language restrictions of CINAHL, Embase, Medline,
HealthSTAR, and the Cochrane Central Registry of
Controlled Trials, from inception of the database to 10
September 2008.
Review methods Eligible studies were randomised
controlled trials that enrolled patients with any kind of
fracture and randomly assigned them to low intensity
pulsed ultrasonography or to a control group. Two
reviewers independently agreed on eligibility; three
reviewers independently assessed methodological
quality and extracted outcome data. All outcomes were
included and meta-analyses done when possible.
Results 13 randomised trials, of which five assessed
outcomes of importance to patients, were included.
Moderate quality evidence from one trial found no effectof
low intensity pulsed ultrasonography on functional
recovery from conservatively managed fresh clavicle
fractures; whereas low quality evidence from three trials
suggests benefit in non-operatively managed fresh
fractures (faster radiographic healing time mean 36.9%,
95% confidence interval 25.6% to 46.0%). A single trial
provided moderate quality evidence suggesting no effect
of low intensity pulsed ultrasonography on return to
function among non-operatively treated stress fractures.
Three trials provided very low quality evidence for
accelerated functional improvement after distraction
osteogenesis. One trial providedlowquality evidence for a
benefit of low intensity pulsed ultrasonography in
accelerating healing of established non-unions managed
with bone graft. Four trials provided low quality evidence
for acceleration of healing of operatively managed fresh
fractures.
Conclusion Evidence for the effect of low intensity pulsed
ultrasonography on healing of fractures is moderate to
very low in quality and provides conflicting results.
Although overall results are promising, establishing the
role of low intensity pulsed ultrasonography in the
management of fractures requires large, blinded trials,
directly addressing patient important outcomes such as
return to function.
INTRODUCTION
Each year in North America about 6 million people
experience a fracture, of whom 5-10% show delayed
healing or non-union.
12
Clinicians can utilise several
options to promote healing of fractures, including bone
stimulators. A recent Canadian survey of 450 trauma
surgeons (response rate 60%) found that 45% of
respondents were using bone stimulators to manage
tibial fractures, with use evenly divided between low
intensity pulsed ultrasonography and pulsed electro-
magnetic field therapy.
3
The Food and Drug Administration approved the
use of low intensity pulsed ultrasonography for
accelerating conservatively managed fresh fracture
healing in 1994, and for treatment of established non-
unions in 2000.
4
Basic science research suggests that
beneficial effects of low intensity pulsed ultrasonogra-
phy on bone healing may include a positive impact on
signal transduction, gene expression, blood flow, and
tissue modelling and remodelling.
5
Sales of bone
stimulators in the United States alone represented a
$500m (£351m; 380m) market in 2006, with projec-
tions of 6% or 7% growth per year.
6
Based on data that
suggested low intensity pulsed ultrasonography may
reduce time to healing of operatively managed tibial
fractures by a mean of 32 days (154 v 122 days), one
study estimated savings of $13 259 per fracture.
7
This
economic analysis considered both direct and indirect
costs;however, datafor this model were based ona case
seriesof 60 patients and an ultrasound registry and used
radiographic healing as a surrogate for functional
recovery.
In the absence of high quality evidence of improved
patient important outcomes such as decreased time to
weight bearing and earlier return to function, the
widespread use of bone stimulators represents an
uncertain investment of limited healthcare resources.
Previous systematic reviews on the clinical effective-
ness of low intensity pulsed ultrasonography and
pulsed electromagnetic field therapy have proved
inconclusive and in the case of low intensity pulsed
1
Institu te for Work and Health,
Toronto, Canada
2
Department of Clinical
Epidemiology and Biostatistics,
McMaster University, Hamilton,
ON
3
Schulich School of Medicine and
Dentistry, University of Western
Ontario, London, ON
4
Boston University School of
Medicine, MA, USA
5
Unit of Clinic al Research
Dev elopment and INFORMAtion
Translation/CLARITY Research
Tea m, Department of
Epidemiology, Italian National
Cancer Institute Regina Elena,
Rome, Italy
Correspondence to: J W Busse,
Institute for Work and Health, 481
University Avenue, Toronto, ON,
Canada M5G 2E9
jbusse@iwh.on.ca
Cite this as:
BMJ
2009;338:b351
doi:10.1136/bmj.b351
BMJ | ONLINE FIRS T | bmj.com page 1 of 9
Table 1
|
Characteristics of included trials
Trial
Fracture
location
No of patients randomised
(No analysed)
Mean (SD) age
Duration of low
intensity pulsed
ultrasonography Outcome measures recorded
Treatment
group Control group
Non-operative management
Fresh fracture:
Kristiansen et al
1997
w2
Distal radius 40 (30) 45 (31) Treatment: 54 (3*);
control: 58 (2*)
70 days Time to early trabecular bridging
; time to cortical bridging (first,
second,third,andfourth)
; timeto organised trabecular bridging
Mayretal2000
w3
Scaphoid 15 (15) 15 (15) 37 (14) Until cast was removed Time to cast removal
; % of patients with bridging of fracture at 4,
6, 8, 10, and 12 weeks
†‡
;timeto
70% bridging of fracture
Heckman et al
1994
w1
Tibia 48 (33); 31
closed,
2gradeI
open
49 (34); 33
closed, 1 grade I
open
Treatment: 36 (2.3*);
control: 31 (1.8*)
140 days, or until study
investigator deemed
fracture was healed
Time to bridging of three cortices
;timetobridgingoffour
cortices
; time to endosteal healing
; time to clinical healing
(fracture stable and not painful to manual stress)
;timetocast
removal
; days to start of weight bearing
Lubbert et al
2008
w15
Clavicle 61 (52) 59 (49) Treatment: 38 (13);
control: 37 (12)
28 days Fracture consolidation according to patient; need for operative
fixation; analgesic use; pain; adverse events; non-union;
resumption of sport, professional, or household activities
Stress fracture:
Rue et al 2004
w4
Tibia 14 (14) 12 (12) Treatment: 18.6 (0.8);
control: 18.4 (0.8)
Until fracture was
asymptomatic and
healed on x ray film
Return to full participation and duty
Operative management
Distraction
osteogenesis:
Schortinghuis et
al 2005
w5
Mandible 4 (4) 4 (4) 65 (8.8) From first day of
distraction until implant
inserted (mean 13.0 (SD
1.5) hours)
Microradiographygap fill area; gap grey percentage;histology gap
fill length; histological score; patient ease of use questionnaire
El-Mowafi and
Mohsen 2005
w6
Tibia 10 (10) 10 (9) 35 (range 18-45) Until removal of external
fixator
Healing index (duration of external fixation divided by length of
distraction gap)
Tsumaki et al
2004
w14
Tibia 21 (21) 21 (21) 68 (range 53-78) Until removal of external
fixator
Bone mineral density in distraction callus
; bone mineral density
distal to distraction gap; consolidation period; duration of fixator
use
Bone graft for non-
union:
Ricardo 2006
w10
Scaphoid 10 (10) 11 (11) 26.7 (range 17-42) Until fracture healed
clinically and
radiographically
Overall time to clinical (no pain or tenderness) and radiographic
healing
Fresh fracture:
Handolin et al
2005
w7
Lateral
malleolus
11 (10) 11 (11) Treatment: 37.5 (range
18-54); control: 45.5
(range 26-59)
42 days Prevalence of fracture line visualisation at 2, 6, 9, and 12 weeks;
prevalence of externalcallusformationat 2, 6, 9, and 12 weeks; %
of bone healing at 2 and 9 weeks
Handolin et al
2005
w8 w9
Lateral
malleolus
15 (15)
§
15 (15)
§
Treatment: 41.4 (range
19-65); control: 39.4
(range 18-59)
42 days Prevalence of callus formation at 2 ,6, 9, and 12 weeks;
radiographic healing at 72 weeks; Olerud-Molander score at
72 weeks;clinical examinationof ankleat 72 weeks;bonemineral
density at 12 and 72 weeks
Emami et al
1999
w11 w12
Tibia 15 (15)
;12
closed, 3 open
17 (17)
;16
closed, 1
open
Treatment: 39.9;
control: 34.3
75 days Time to appearance of first callus; time to bridging of three
cortices; time to full weight bearing; level of cross linked
telopeptide over one year
**; level of bone specific alkaline
phosphatase over one year; level of osteocalcin
Leung et al
2004
w13
Tibia 16 (16); 7
closed, 9 open
14 (14); 6
closed, 8
open
35.3 (range 22-61) 90 days Disappearance of tenderness at fracture site
††
;timetopartial
weight bearing; time to full weight bearing
;durationofexternal
fixator use
; timeto appearanceof first, second,and third callus
;
% change in bonemineral content at fracturesite at 11 time points
over 30 weeks
†‡‡
; % change in bone specific alkaline
phosphatase at 13 time points over 30 weeks
§§
*Standard error
Difference between groups was statistically significantly (P<0.05) in favour of low intensi ty pulse d ultrasonography.
Significant differences were reported at weeks 4, 6, and 8.
§
Only eight in each group were available for 17 w eek follow-up.
One patient was excluded from the study, but authors did not clarify from which group. For laboratory blood assays, only 30 patients were analysed (15 per group).
**Differences were only significant (lower level o f cross linked telopeptide in low i ntensity pulsed ultra sonography group) at week 1.
††
Leung et al
w13
reported a significant difference in favour of low intensity pulsed ultrasonography, but reanalysis of their data with two sided t test showed non-significant difference
between treatment and control groups (P
=
0.09 ).
‡‡
Significant differen ces reported at weeks 6, 15, 18, and 21.
§§
Significant differen ces reported at weeks 12, 18, and 27.
RESEARCH
page 2 of 9 BMJ | ONLI NE FIRST | bmj.com
ultrasonography focused exclusively on trials pub-
lished before 2001 that utilised radiographic healing as
the end point.
8-10
We carried out a systematic review
and meta-analysis of randomised controlled trials to
determine the effect of low intensity pulsed ultrasono-
graphy on bone fractures, focusing on patient impor-
tant outcomes, in particular functional recovery.
METHODS
Two reviewers (JWB and JK) independently identified
relevant randomised controlled trials, in any language,
by a systematic search of CINAHL, Embase, Medline,
HealthSTAR, and the Cochrane Central Registry of
Controlled Trials, from inception of the database to 10
September 2008, with the following terms: (fracture
healing or bony callus or bone remod* or fracture*,
closed or fracture*, open) AND (ultrasonic therapy or
ultrasonography). We used the wild card term * to
increase the sensitivity of our search strategy.
Reviewers scanned the bibliographies of all retrieved
trials and othe r relev ant pu blica tions , inclu ding
reviews and meta-analyses, for additional relevant
articles. We contacted Smith and Nephew, the
manufacturer of the low intensity pulsed ultrasono-
graphy devices used in most trials, to inquire about any
additional unpublished trials or trials in progress.
Eligibility criteria
Two reviewers (JWB and JK) screened the titles and
abstracts of identified citations independently and in
duplicate and acquired the full text of any article that
either judged potentially eligible. These reviewers
independently applied eligibility criteria to the meth-
ods section of potentially eligible trials. Eligible trials
had to have randomly allocated patients presenting
with any form of fracture to low intensity pulsed
ultrasonography or to a control group. We resolved
disagreements by discussion.
Data abstraction and analysis
Three reviewers (JWB, BM, and JK) extracted data
from each eligible study independently and in
triplicate. Data included personal information, meth-
odology, details on interventions, and reported out-
comes. Reviewers assessed study validity and
applicability by appraising concealment of allocation,
blinding, handling of withdrawals, cointerventions,
compliance, similarity of timing of outcome assess-
ment, and adherence to the intention to treat
principle.
11 12
The reviewers resolved disagreement
by discussion. We attempted to contact study authors
to settle any uncertainties.
Among eligible trials we found substantial diversity
in the types of fractures targeted for treatment and the
outcome measures used (table 1). Two experienced
trauma surgeons (MB and PT third) grouped the
participants into the five clinical categories of non-
operatively managed fresh fractures, non-operatively
managed stress fractures, distraction osteogenesis,
bone grafting for non-union, and operatively managed
fresh fractures (table 1). We separated trials according
to clinical presentation but not the bone involved.
Although baseline healing time differs by size of bone
and the site of fracture, the process of healing is
consistent across all fractured bones
13
and the effect of
low intensity pulsed ultrasonography compared with
controlon the time to fracture healing is therefore likely
to be similar. We reasoned that pooling trials with the
same intervention directed towards clinically similar
fractures of different bones w ould increase t he
generalisability of our results.
14
To facilitate pooling of trials that explored the effect
of low in tensity pulsed ultrasonography on non-
operatively managed fresh fractures, we considered
the time to bridging of three cortices to be equivalent to
the time to achieve 70% or more bridging of fracture.
We considered the time to bridging of three cortices
and time to appearance of the third callus as equivalent.
In one trial in which the principal investigator and an
independent radiologist assessed radiographic hea-
ling
w1
we used data from the radiologist.
We used random effects meta-analyses, which are
conservative as they consider differences both within
and among studies in calculating the error term used in
the analysis.
11
For the outcomes of time to return to
active duty and time to full weight bearing we
presented pooled data in the original units of measure-
ment. For the outcome of time to radiographic healing
we carried out meta-analyses by using the inverse
variance method to combine the natural logarithms of
the ratio of the mean time to healing in the treatment
group to the mean time to healing in the placebo group.
We then converted the resulting combined estimate
and presented it as a percentage decrease in time to
healing in the treatment group compared with the
placebo group.
15
Meta-analyses of small trials can provide evidence of
benefit with what seem to be narrow estimates of
precision; however, such reviews have often been
subsequently refuted by large trials. To address this
potential concern we determined that in cases in which
our meta-analysis suggested benefit with an associated
narrow measure of precision, if the sample size was less
Abstracts acquired from search (n=564)
Citations screened (n=391)
Duplicate articles (n=173)
Articles did not meet eligibility criteria (n=373)
Potentially relevant studies retrieved in full text (n=18)
Trials included in systematic review* (n=13)
Trials were re-analysis of primary trials (n=2)
Trial applied high intensity continuous
ultrasonography (n=1)
Fig 1
|
Flow of trials through study. *Two sets of trials reported
on common patient samples and were considered as single
studies
RESEARCH
BMJ | ONLINE FIRS T | bmj.com page 3 of 9
than the optimal information size (the number of
patients generated by a conventional sample size
calculation for a single trial)
16
then we would consider
the result imprecise. For the purposes of calculating the
optimal information size we assumed a treatment effect
(Δ) of 20%, an α of 0.05, and a β of 0.20. Our choice of Δ
was based on a recent survey of orthopaedic trauma
surgeons (268 respondents) in which 80% reported that
a reduction of six weeks in healing of tibial fractures,
attributed to a bone stimulator, would be important to
patients
3
and the assumption that a typical course of
healing for tibial fractures is about seven months.
We examined heterogeneity using both a χ
2
test and
the I
2
statistic, the percentage of variability among
studies that is due to true differences between studies
(heterogeneity) rather than sampling error (chance).
17
We considered an I
2
value greater than 50% to reflect
substantial heterogeneity.
18
We generated three a
priori hypotheses to explain variability between
studies: fracture location, clinical category, and the
technical specifications and application of ultrasound
devices used. We did tests of interaction
19
to establish if
subgroups differed significantly from each other and
used the criteria of the Grading of Recommendations
Assessment, Development and Evaluation (GRADE)
to evaluate the quality of evidence by outcome.
20
RESULTS
Overall, 564 potentially eligible studies were identified
and 18 retrieved in full text.
21-23w1-w15
Two trials were
not original
21 22
and one made use of high intensity,
continuous ultrasonography,
23
leaving 15 eligible trials
(fig 1).
w1-w15
After adjustment for chance the agreement
between reviewers (κ) on full text eligibility was 0.81
(95% confidence interval 0.68 to 0.94).
Two trials
w11 w12
seemed to report on a shared group
of 30 participants as the participants had an identical
match for age. In addition, according to the methods
sections these participants were recruited at the same
institution over the same period. Attempts to contact
the authors of these trials for clarification were
unsuccessful. The data from both studies are consid-
ered as one trial for reporting purposes (fig 1).
Three trials by the same group of authors, published
in three different journals in 2005, reported on the
effect of low intensity pulsed ultrasonography on
lateral malleolar fractures.
w7-w9
Contact with the lead
authorconfirmedthat therewere twodistinct trials: one
randomised trial of 22 patients
w7
and another of 30
patients.
w8 w9
This left 13 unique trials for analysis
(fig 1).
Most studies reported only surrogate end points; five
explored end points of importance to patients (table 1).
Eleven trials used imaging methods to assess bone
healing. Six studies used plain films,
w1 w2 w6 w10-w13
one
used dual energy x ray absorptiometry scans,
w14
two
used both dual energy x ray absorptiometry scans and
multidetector computed tomograms,
w7-w9
one used
high resolution microradiographs of fixed biopsies,
w5
and one used sagittal computed tomography to assess
scaphoid healing.
w3
Study quality
Eligibletrials were of limited quality (table 2). Attempts
were made to contact the authors of seven trials to
resolve uncertainties,
w3 w6-w10 w13 w15
and clarification
Table 2
|
Methodological quality of eligible randomised controlled trials
Trial
Concealment of
treatment allocation Patients blinded Caregivers blinded Outcome assessors blinded Loss to follow-up (%)
Non-operative management
Fresh fracture:
Kristiansen et al 1997
w2
Yes Yes Yes Yes 28
Mayr et al 2000
w3
Unclear No No Yes 0
Heckman et al 1994
w1
Yes Yes Yes Yes 31
Lubbert et al 2008
w15
Yes Yes Yes Yes 16
Stress fracture:
Rue et al 2004
w4
Yes Yes Yes Yes 0
Operative management
Distraction osteogenesis:
Schortinghuis et al 2005
w5
Yes Yes Yes Yes 0
El-Mowafi and Mohsen 2005
w6
Unclear Unclear Unclear Unclear 5
Tsumaki et al 2004
w14
Yes No No No 0
Bone graft for non-union:
Ricardo 2006
w10
Yes Yes Yes Yes 0
Fresh fracture:
Handolin et al 2005
w7
Yes Yes Yes Yes 5
Handolin et al 2005
w8 w9
Yes Yes Yes Yes 0% for 12 week follow-up;
47% for 18 month follow-up
Emami et al 1999
w11 w12
Yes Yes Yes Yes 3
Leung et al 2004
w13
Unclear Unclear Unclear Unclear 0
RESEARCH
page 4 of 9 BMJ | ONLINE FIRST | bmj.com
was successful in four.
w7-w10 w15
Eleven trials used a
parallel design with random allocation of sham and
active ultrasound devices; two did not use a sham
device as their control.
w3 w14
One trial
w3
randomly
assigned patients with non-operatively managed sca-
phoid fractures to usual care or to low intensity pulsed
ultrasonography in addition to usual care, whereas
another study
w14
randomly assigned one limb of
patients who had undergone bilateral tibial osteotomy
to ultrasonography and the other limb to control.
Although one trial
w13
stated that patients and care
providers were blinded, the treatment and control
devices were visually different. No study explicitly
declared an intention to treat analysis, but no trials
reported patient crossover and all patients were
analysed according to the group to which they were
randomly allocated. No trial described any cointerven-
tions to which participants were exposed. Seven trials
reported loss to follow-up, ranging from 3% to 47%
(table 2), which in all cases was dealt with by excluding
lost participants from both the numerator and denomi-
nator for all outcome calculations.
Trial ult raso und devices
In 12 of the eligible trials the treatment provided to the
control group was indistinguishable from that pro-
vided to the treatment group, the exception being the
trial in which the active and sham devices were similar
but easily visually distinguishable.
w13
In 12 of the 13
eligible studies
w1-w9 w11-w15
the investigators made use of
the Sonic Accelerated Fracture Healing System (Exo-
gen, Piscataway, NJ). The trials that used this device
required their treatment groups to receive daily
20 minute sessions with an ultrasound signal composed
of a burst width of 200 μs (SD 10%) containing 1.5 MHz
(SD 5%) sine waves, with a repetition rate of 1 kHz
(SD 10%) and a spatial average temporal intensity of
30 mW/cm
2
(SD 30%). The settings of the ultrasound
unit could not be modified and a warning signal was
sounded for active devices if coupling to the skin was
not achieved. Duration of ultrasound use varied
between trials: f ive studies instructed patients to
apply low intensity pulsed ultrasonography until their
fracture was healed,
w3 w4 w6 w10 w14
seven used a set time
that ranged from 13 hours to 90 days,
w2 w5 w7-w9 w11-w13 w15
and in one the patients applied low intensity pulsed
ultrasonography up to a maximum of 140 days until
their fracture was healed (table 1).
w1
Five trials reported on patient compliance with low
intensity pulsed ultrasonography.
w1 w2 w5 w7 w11 w12
Com-
pliance was measured by an elapsed time recorder that
provided only the total time used and not the temporal
picture of use and by a daily log book maintained by
participants. All found high agreement between the
internal device timer and patients log books, and that
use of the device between treatment and control groups
was not significantly different. One of the trials
w5
provided additional details on use of the device, noting
that although the patients applied low intensity pulsed
ultrasonography on a daily basis, treatment with the
active device was interrupted in 11% of applications
owing to disconne cted cables, improper contact
between transducer and skin, or a low battery;
however, patients successfully corrected the error and
resumed treatment in all cases but one.
One study
w10
used an alternate ultrasound device,
the Theramed 101-B ultrasound device supplied by the
Instituto Nacional de Investigaciones en Metrología
(Havana, Cuba). The signal intensity was 30 mW/cm
2
,
and the device was described as low intensity pulsed
ultrasound therapy. Patients applied this device for
20 minutes each day until radiographic healing, and
active and sham units were blinded in the same manner
as the Exogen device. None of the 13 eligible trials
reported any a dverse reactions or complications
attributable to the device.
Outcomes
When time to radiographic healing
the most com-
monly reported end point among eligible trials
was
pooled across all studies it showed a moderate effect in
favour of low intensity pulsed ultrasonography. The
pooled mean reduction in radiographic healing time
was 33.6% (95% confidence interval 21.4% to 43.8%)
but the associated heterogeneity was high (I
2
=76.9%;
heterogeneity P<0.01; fig 2). Tests of interaction
provided no evidence to support a different treatment
effect across clinical presentations. The effect of low
intensity pulsed ultrasonography was not significantly
different between conservatively managed fresh frac-
turesandoperatively managed fresh fractures (P=0.48),
between conservatively managed fresh fractures and
operatively managed non-unions (P=0.61), or between
operatively managed fresh fractures and operatively
managed non-unions (P=0.39).
Table 3 presents a detailed GRADE description for
the effect of low intensity pulsed ultrasonography on
return to function or acceleration of radiographic
healing of non-operatively managed fresh fractures,
non-operatively managed stress fractures, operatively
Conservatively managed fresh fractures
Heckman et al 1994
w1
Kristiansen et al 1997
w2
Mayr et al 2000
w3
Pooled estimate (n=158), I
2
=41.6%
Operatively managed fresh fractures
Emami et al 1997
w11 w12
Leung et al 2004
w13
Pooled estimate (n=62), I
2
=90.0%
Operatively managed non-union
Ricardo 2006
w10
Overall pooled estimate (n=241), I
2
=76.9%
46.3 (33.8 to 56.5)
33.8 (19.0 to 45.8)
30.3 (14.7 to 43.1)
36.9 (25.6 to 46.0)
-24.0 (-71.9 to 10.6)
42.5 (31.7 to 51.6)
16.6 (-76.8 to 60.7)
40.4 (30.8 to 48.7)
33.6 (21.4 to 43.8)
-80 -60 -40 -20 0 20
6040
Target lesion
Favours treatmentFavours control
% reduction in
healing time (95% CI)
% reduction in
healing time (95% CI)
67
61
30
32
30
21
No of patients
analysed
Fig 2
|
Effect of low intensity pulsed ultrasonography on radiographic healing of fractures
RESEARCH
BMJ | ONLINE FIRS T | bmj.com page 5 of 9
managed non-union, and operatively treated fresh
fractures. Trials addressing distraction osteogenesis are
not shown as they did not report any functional
outcomes or any common surrogate end point.
Non-operatively managed fresh fractures
One study found no effect of low intensity pulsed
ultrasonography on conservatively managed, isolated,
clavicle shaft fractures.
w15
Subjective fracture consoli-
dation among patients treated with low intensity pulsed
ultrasonography o ccurred in a mean 26.8 days
compared with 27.1 days in the control (mean
difference 0.3 days, 95% confidence interval 5.3 to
5.9), and no significant differences were found between
groups regarding the need for operative fixation,
analgesic use, pain, adverse events, or resumption of
sport, professional, or household activities. As patient
assessed fracture healing, resumption of household
activities, return to work, and resumption of sport
measure the same underlying domai n (functional
recovery), a random effects model was used to pool
data from these four end points to improve the
precision of this outcome measure. The pooled
standardised mean difference found that treatment
with low intensity pulsed ultrasonography resulted in a
non-significantly faster return to function by 1.4 days
(95% confidence interval 0.6 to 3.4; I
2
=11.4%;
heterogeneity P=0.34).
Low intensity pulsed ultrasonography significantly
accelerated radiographic healing of fractures in all
three trials that assessed this outcome.
w1-w3
One trial
found a 33.8% reduction in healing time, with distal
radial fractures healing in 51 days compared with
77 days in the control group (mean difference 26 days,
95% confidence interval 6.4 to 38.6).
w2
A second trial
found a 30.3% reduction in healing time of scaphoid
fractures; 43.2 days in the low intensity pulsed
ultrasonography group compared with 62.0 days in
the control group (mean difference 18.8 days, 7.6 to
30.0).
w3
The authors did not specify the unit of their
associated measures of variance, and for our analysis
standard deviations were assumed. A third trial found a
46.3% reduction in healing time of tibial shaft fractures:
102 days in the low intensity pulsed ultrasonography
group compared with 190 days in the control group
(mean difference 88 days, 50.4 to 125.6).
w1
This trial
also found a significant improvem ent in surgeon
assessed clinical healing (fracture stable and not painful
to manual stress) of 86 days compared with 114 days
(mean difference 28 days, 4.9 to 51.1), but not in time to
Table 3
|
GRADE evidence profile: randomised controlled trials of low intensity pulsed ultrasonography for more rapid return to function (often measured by
surrogate of radiographic fracture healing)
No of studies (No of
patients) Limitations Consistency Directness Precision Publication bias Magnitude of effect (95% CI) Overall quality
Non-operatively managed fresh fractures
Return to function:
1trial(n
=
101) No limitations No important
inconsistency
Direct Imprecise* Unlikely Faster return to function
1.40 days
(
0.56 to 3.36)
Moderate
Radiographic healing:
3trials(n
=
158) Limitations
No important
inconsistency
Indirect
§
Precision
adequate
Potential
Reduction in healing time 36.9%
(25.6% to 46.0%)
Low
Non-operatively treated stress fractures
Return to function:
1trial(n
=
26) No limitations No important
inconsistency
Direct Imprecise* Unlikely Faster return to active duty 0.4 days
(
13.1 to 13.9)
Moderate
Operatively managed non-union
Radiographic healing:
1trial(n
=
21) No limitations No important
inconsistency
Indirect
§
Imprecise** Potential
Reduction in healing time 40.4%
(30.8% to 48.7%)
Low
Operatively managed fresh fractures
Return to function:
2trials
††
(n
=
61) Serious
limitations
‡‡
Important
inconsistency
Direct Imprecise* Unlikely Faster return to full weight bearing
3.4 weeks (
2.1 to 8.9)
Low
Radiographic healing:
2trials(n
=
61) Serious
limitations
‡‡
Important
inconsistency
Indirect
§
Imprecise* Unlikely Reduction in healing time 16.6%
(
76.8% to 60.7%)
Very low
*95% confidence interval included both important benefit and harm.
As patient assessed fracture healing, resumption of household activities, return to work, and resu mption of sport measure same underlyi ng domain (functional recovery), data from these
four end points were pooled to improve precision of outcome measure.
Loss to follow-up was about 30% in two trials, and third trial did not blind participants or provi ders and it is not certain that allocation was concealed.
§
Evidence is provided by surrogate measure only (radiographic healin g).
As a result of small number of trials and inconsisten t reporting of outcomes across trials. Overall quality rating was not decreased on basis of suspicion of publication bias.
**Although confidence interval appears adequ ately narrow, the sample size failed to meet the optimal information size.
††
A third, negative, trial by Handolin et al
w9
reported on a functional outcome, mean Olerud-Molander score, but did not provide the associated measure of variance to allow for statistical
pool ing.
‡‡
Uncertain if, in positive trial by Leung et al
w13
, allocation was concealed or if patients, care givers, or outcome assessors were blinded. Quality was not, however, downgraded.
RESEARCH
page 6 of 9 BMJ | ONLI NE FIRST | bmj.com
partial weight bearing (45 days in the low intensity
pulsed ultrasonography group v 49 days in the control
group; mean difference 4 days, 11.0 to 19.0).
15
The pooled results from the three trials
w1-w3
found a
significant mean reduction in radiographic healing
time of 36.9% (95% confidence interval 25.6% to
46.0%; I
2
=41.6%; heterogeneity P=0.18; fig 2). Calcu-
lating a Δ of 20% relevant to the control data for each
trial (15, 12, and 38 days) and using the standard
deviation associated with fracture healing in the three
studies (31.6, 15.8, and 37.6 days) yields corresponding
required sample sizes of 140, 56, and 32. The 158
patients available for this analysis therefore meet the
optimal information size. Low quality evidence from
three trials suggests a benefit of low intensity pulsed
ultrasonography in non-operatively managed fresh
fractures (tables 2 and 3).
w1-w3
Non-operatively managed stress fractures
One study
w4
noted no improvement in return to full
participation and duty among midshipmen sick listed
because of tibial stress fractures. Patients treated with
low intensity pulsed ultrasonography returned to
active duty in a mean 55.8 days compared with
56.2 days for those receiving sham therapy (mean
difference 0.4 days, 95% confidence interval 13.4 to
14.2). This trial provided moderate quality evidence of
no effect of low intensity pulsed ultrasonography on
returnto function amongnon-operatively treated stress
fractures (tables 2 and 3).
Operatively managed distraction osteogenesis
One study
w5
found no effect of low intensity pulsed
ultrasonography in the stimulation of bone formation
in the distraction gap created in severely resorbed
mandibles, and suggested that future trials consider a
longer consolidation period than 31 days. Another
study
w6
found that low intensity pulsed ultrasonogra-
phy accelerated radiographic healing in patients with
tibial defects managed with distraction osteogenesis.
The authors used a healing index as their outcome,
which was defined as the duration of external fixation
divided by the length of distraction gap. Patients using
active low intensity pulsed ultrasonography had a
healing index of 30 days/c m compared with
48 days/cm for those exposed to a sham device
(mean difference 18.0 days/cm, 95% confidence inter-
val 11.7 to 24.3). One study
w14
administered low
intensity pulsed ultrasonography or sham treatment
to patients undergoing opening wedge high tibial
osteotomy to tackle varus deformity secondary to
osteoarthritis. The authors noted that low intensity
pulsed ultrasonography compared with sham treat-
ment resulted in a significant increase in mean bone
mineral density in the distraction callus (0.20 g/cm
2
v
0.13 g/cm
2
; mean difference 0.07 g/cm
2
, 95% con-
fidence interval 0.003 to 0.14) but not in bone mineral
density distal to the distraction gap, nor in the mean
consolidation period or duration of external fixator
use. The authors did not specify the unit of their
associated measures of variance, and for our analysis
these were assumed to be standard deviations. Three
trials provided very low quality evidence for acceler-
ated functional improvement after distraction osteo-
genesis (table 2).
w5 w6 w14
Operatively managed (bone graft) non-union
In one study
w10
the application of low intensity pulsed
ultrasonography to patients with established scaphoid
non-union and treated with vascularised pedicle bone
graft compared with those exposed to a sham device
accelerated healing by a mean difference of 38 days
(95% confidence interval 26.3 to 49.7), which repre-
sentsa 40.4% (95% confidence interval 30.8% to 48.7%)
reduction in healing time (fig 2). Communication with
the author established that the reported associated
measures of variance were standard errors of the mean,
and these were converted to standard deviations. To be
considered healed, patients had to present with no
tendernessat the scaphoid and show complete bridging
of cortices on plain radiographs. Calculating a Δ of 20%
relevant to the control data (94×0.2=19 days) and using
the standard deviation associated with fracture healing
(27 days) yielded a required sample size of 64. The 21
patients available for this analysis therefore did not
meet the optimal information size. This trial provided
low quality evidence for a benefit of low intensity
pulsed ultrasonography in accelerating healing of
established non-unions managed with bone graft
(tables 2 and 3).
Operatively managed fresh fractures
Functional outcomes were inconsistent. One trial of
patients with lateral malleolar fractures fixed using
bioabsorbable screws found no differences in function
at 18 months.
w9
One trial of operatively managed tibial
shaft fractures found no difference in time to full weight
bearing (6.5 weeks for low intensity pulsed ultrasono-
graphy v 7.1 weeks for sham therapy; mean difference
0.6 weeks, 1.5 to 2.7).
w11 w12
One trial of operatively
managed tibial fractures reported that low intensity
pulsed ultrasonography reduced average time t o
disappearance of site tenderness. Our reanalysis of
the results found that this difference was not significant
(6.1 weeks v 7.9 weeks; mean difference 1.8 weeks, 0.2
to 3.8, P=0.09). The authors did find that low intensity
pulsed ultrasonography reduced time to full weight
bearing (9.3 weeks v 15.5 weeks; mean difference
6.2 weeks, 4.4 to 8.0); there was no difference in time to
partial weight bearing.
w13
Two trials
w7-w9
of patients with lateral malleolar
fractures fixed using bioabsorbable screws and treated
with low intensity pulsed ultrasonography or a sham
device found no significant differences in visualisation
of the fracture line, external callus formation, percen-
tage of bone healing, or bone mineral density. One
study
w11 w12
found that low intensity pulsed ultrasono-
graphy had no effect on radiographic healing among
patients with operatively managed (intramedullary
nail) tibial shaft fractures. Active treatment resulted in a
non-significant mean time to bridging of three cortices
of 155 days compared with 125 days for sham
RESEARCH
BMJ | ONLINE FIRS T | bmj.com page 7 of 9
treatment (mean difference 30 days, 95% confidence
interval 16.5 to 76.5; fig 2). Leung et al
w13
explored the
effect of low intensity pulsed ultrasonography on
operatively managed tibial fractures and found that it
reduced time to removal of external fixator (9.9 weeks v
17.1 weeks; mean difference 7.2 weeks, 2.6 to 11.8) and
time to first, second, and third callus format ion;
specifically, patients receiving active treatment showed
formation of the third callus in an average of 11.5 weeks
compared with 20 weeks for those receiving sham
therapy (mean difference 8.5 weeks, 5.8 to 11.2), a
42.5% (95% confidence interval 31.7% to 51.6%)
reduction in radiographic healing time (fig 2).
The pooled results from two trials
w11-w13
showed a
non-significant mean reduction in radiographic healing
time of 16.6% (76.8% to 60.7%; I
2
=90.9%; hetero-
geneity P<0.01; fig 2). Four trials provided low quality
evidence for acceleration of healing of operatively
managed fresh fractures (tables 2 and 3).
w7-w9 w11-w13
DISCUSSION
Our systematic review and meta-analysis of eligible
randomised controlled trials found moderate to very
low quality evidence for low intensity pulsed ultra-
sonography in accelerating functional recovery among
patients with fracture; only five of 13 trials directly
assessed functional end points (time to return to active
duty,
w4
Olerud-Molander score
w9
; time to full weight
bearing
w11-w13
; time to patient reported fracture healing
and resumption of househ old activities, work, or
sports
w15
); of these, one was positive.
w13
The two trials
providing the highest quality evidence (table 3)
showed no difference in functional outcome.
w4 w15
Quality of evidence
Our findings are strengthened by the comprehensive
search and broad clinical eligibility criteria (including
trials in any language), and by including only
randomised controlled trials. In the GRADE system
of rating quality of evidence for each outcome,
20 24
randomised trials begin as high quality evidence but
may be rated down by one or more of five categories of
limitations. The eligible trials in our analysis had
methodological limitations including lack of blinding
of all relevant parties and substantial loss to follow-up
in some trials. Results were sometimes inconsistent
across trials, and most studies used surrogate end
points; larger effects were typically reported for
surrogates compared with direct measures of function.
Concerns about publication bias arose from the limited
number of small trials,
25
and the inconsistent reporting
of outcomes across trials raises the possi bility of
selective reporting bias,
26
although we did not rate
down the evidence for publication bias or selective
reporting bias. The strength of inference is therefore
limited.
Furthermore, two eligible trials did not specify the
unit of measurement for their reported measures of
vari ance
w3 w14
and we were unable to clarify this
information. We assumed that they reported standard
deviations; however, three other eligible trials in our
review reported the standard error of the mean
w1 w2 w11
w12
and clarification with the author of another trial in
which the unit of measurement was unclear established
that they reported the standard error.
w10
If our
assumption was incorrect, and the authors of the two
trials in question
w3 w14
reported the standard error, their
results would become non-significant.
Implications for clinical practice and research
Recent Canadian surveys have found that 40% of
senior residents in orthopaedic surgery (n=20) and 21%
of trauma surgeons (n=268) are currently using low
intensity pulsed ultrasonography as part of their
management of tibial fractures.
327
A 2008 narrative
review in the Journal of Bone and Joint Surgery, American
edition, that failed to include negative trials, said there
is overwhelmingly positive clinical data supporting
low-intensity pulsed ultrasound as a treatment for
fracture repair.
5
Our results, however, suggest that
despite the relatively common use of low intensity
pulsed ultrasonography to enhance the healing of
fractures the available evidence is only moderate to
very low, few trials report on patient important
outcomes (for example, time to full weight bearing or
return to function), and of the five that did
w4 w9 w11-w13 w15
only one reported a benefit.
w13
Evidence to support the
use of low intensity pulsed ultrasonography in opera-
tively managed fresh fractures is inconsistent
incon-
sistency may (or may not) be explained by differences
in the patient populations or by duration of low
intensity pulsed ultrasonography use. A negative
trial
w11 w12
enrolled almost all closed tibial fractures
and applied low intensity pulsed ultrasonography for
75 days, whereas a positive trial
w13
enrolled mostly
open tibial fractures and applied low intensity pulsed
ultrasonography for 90 days. Future trials of the effect
of low intensity pulsed ultrasonography on operatively
managed fresh tibial fractures may enhance their
usefulness by including a range of injury severity and
stratifying by open and closed fractures, an d by
instructing patients to administer low intensity pulsed
ultrasonography until their fracture is healed or until
maximum likely healing has occurred (for example, no
evidence of additional radiographic healingis apparent
on two consecutive follow-up radiographs).
Even where the evidence for accelerating radio-
graphic healing with low intensity pulsed ultrasono-
graphy is stronger, such as in conservatively managed
fresh fractures, reduction in healing time as measured
WHAT IS ALREADY KNOWN ON THIS TOPIC
Low intensity pulsed ultrasonography is commonly used to improve the healing of fractures
WHAT THIS STUDY AD DS
Evidence to support the use of low intensity pulsed ultrasonography for fracture healing is
limited and inconsistent; most trials report surrogate outcomes
Large, methodologically sound, trials on the effect of low intensity pulsed ultrasonography on
fractures, particularly operatively managed fresh fractures and non-union, and that measure
patient important outcomes are needed
RESEARCH
page 8 of 9 BMJ | ONLIN E FIRST | bmj. com
by plain films may not translate into patient important
benefit. Nevertheless, low intensity pulsed ultrasono-
graphy may provide important benefits to patients with
fracture through accelerated improvement in function.
Large trials of high methodological quality focusing on
patient important outcomes such as quality of life and
return to function are needed to establish whether this
is the case.
We thank Wolfram Bosenberg for translating web reference 3. JWB is
funded by a new invest igator award from t he Ca nadian Institutes of Health
Research a nd Canadian Chiropractic Research Foundation. MB is
supported in part by a Canada research chair, McMaster U niversity. HJS is
funded by a European Commissio n: the human factor, mo bility and Marie
Curie Actions, scie ntist reintegration grant (IGR 42192).
Contributors: JWB,MB,andGHGwereinvolvedinthestudydesignand
concept.JWB, JK, and BM collected the data. JWB and GHG did the analysis.
All authors critically revised the manuscript and approved the fina l version.
JWB is the guarantor.
Funding: None.
Competi ng interests: JWB, MB, and GHG are currently involved in a
multicentre, randomised controll ed trial that has received pa rtial funding
from Smith and Nephew, the company that manufactures Exogen. GHG
and HJS are members of the GRADE working group.
Ethical approval: Not required.
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RESEARCH
BMJ | ONLINE FIRS T | bmj.com page 9 of 9
    • "Injury j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i n j u r y tibial fractures [17] and non-unions of various bones [18] were demonstrated clinically. A few meta-analyses also verified the different extents of positive effects of LIPUS on fracture healing [19,20]. In vivo, LIPUS was shown to increase blood flow around the fracture site [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Osteoporotic fracture is known to have impaired healing capacity and therefore takes longer time to heal, as compared with younger one. The mechanism of impaired osteoporotic fracture healing is multifactorial, where lower responsiveness to mechanical loading is generally believed to be one factor, yet not absolutely confirmed. In recent years, low intensity pulsed ultrasound (LIPUS) is demonstrated to have good efficacy in treating normal fracture healing, as proven by many randomized controlled trials, as well as in vitro and animal evidences. The effects of LIPUS on osteoporotic fracture healing was also validated in an animal study, which revealed that osteoporotic fractured bone of SD rats showed radiologically and biomechanically comparable responses to LIPUS as age-matched normal fracture healing, in terms of callus width, bridging rate, bone volume fraction, and stiffness etc. Gene expression profiling also confirmed that osteoporotic fractured bone responded to LIPUS very well by upregulating Col1 and BMP2 (osteogenesis) at early phase, VEGF (angiogenesis) at middle phase and RANKL (remodeling) at late phase. These confirm that osteoporotic bones respond well to LIPUS as good as normal bone. These findings may be associated with estrogen receptors (ERs), as estrogen depletion is sensed and relayed by ERs and ERs also function as mechano-sensors. A previous study observed a delayed ERs expression pattern in fracture callus of OVX rats, as compared with SHAM rats, which correlated well with the expression pattern of BMP-2 (callus formation-related gene). Hence, the responses of osteoporotic fractured bone to LIPUS may be related to the local ERs expression at fracture callus that needs further experiments to validate.
    Article · Jan 2016
    • "Of 268 respondents to a survey of 450 surgeon members of the Canadian Orthopedic Association (60% response rate), 45% reported use of bone stimulators for fracture healing in at least some cases, evenly split between LIPUS and electrical stimulation [8]. Although a number of randomized trials have suggested that LIPUS may improve fracture healing, inferences are limited because of small sample size, risk of bias, frequent reporting of surrogate outcomes (such as radiographic healing) but limited attention to patientimportant outcomes (functional recovery), and inconsistent results [9]. Until a large randomized controlled trial (RCT) is undertaken, the effect of LIPUS on fracture healing will remain uncertain. "
    [Show abstract] [Hide abstract] ABSTRACT: The role of low-intensity pulsed ultrasound (LIPUS) in the management of fractures remains controversial. The purpose of this study was to assess the feasibility of a definitive trial to determine the effect of LIPUS on functional and clinical outcomes in tibial fractures managed operatively. We conducted a multicenter, concealed, blinded randomized trial of 51 skeletally mature adults with operatively managed tibial fractures who were treated with either LIPUS or a sham device. All participating centers were located in Canada and site investigators were orthopedic surgeons specializing in trauma surgery. The goals of our pilot study were to determine recruitment rates in individual centers, investigators’ ability to adhere to study protocol and data collection procedures, our ability to achieve close to 100% follow-up rates, and the degree to which patients were compliant with treatment. Patients were followed for one year and a committee (blinded to allocation) adjudicated all outcomes. The committee adjudicators were experienced (10 or more years in practice) orthopedic surgeons with formal research training, specializing in trauma surgery. Our overall rate of recruitment was approximately 0.8 patients per center per month and site investigators successfully adhered to the study protocol and procedures. Our rate of follow-up at one year was 84%. Patient compliance, measured by an internal timer in the study devices, revealed that 39 (76%) of the patients were fully compliant and 12 (24%) demonstrated a greater than 50% compliance. Based on patient feedback regarding excessive questionnaire burden, we conducted an analysis using data from another tibial fracture trial that revealed the Short Musculoskeletal Function Assessment (SMFA) dysfunction index offered no important advantages over the SF-36 Physical Component Summary (PCS) score. No device-related adverse events were reported. Our pilot study identified key issues that might have rendered a definitive trial unfeasible. By modifying our protocol to address these challenges we have enhanced the feasibility of a definitive trial to explore the effect of LIPUS on tibial fracture healing. Trial registration The TRUST definitive trial was registered at ClinicalTrials.gov on 21 April 2008 (identifier: NCT00667849).
    Full-text · Article · Jun 2014
    • "encourage bone union in the clavicle still needs to be validated [42] [43] [44]. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction The aim of our study was to evaluate the results of surgical treatment of clavicle non-union after failure of conservative treatment. Our hypothesis was that stable fixation with bone graft derived from local bone stock (fracture site) or the iliac crest was essential to achieve bone union. Material and methods Twenty-one patients with a symptomatic middle-third clavicle non-union after failure of initial conservative treatment were included in the study. Delay between the initial fracture and surgery for non-union was 27 months (6–144). In five cases, the non-union was hypertrophic and bone graft was obtained locally from the callus. In 16 patients, the non-union was atrophic. Bone was harvested from the iliac crest as cortico-cancellous graft (7 patients) and cancellous graft (8 patients). One patient refused bone grafting. A 3.5-mm plate with non-locking screws was placed anterior in 12 and superior in 9 patients. Results At 41 months average follow-up (minimum of 12 months), 20 patients were available for review. Bone healing was obtained initially in 15 cases. Six complications required a revision procedure: 3 for infection and 3 for mechanical failure. At last follow-up, 19 patients were satisfied with the surgery. Average Constant score was 84 ± 26 points (7–100), and Quick DASH score 17 ± 22 points (0–91). Radiographic bone healing was obtained in 19 of the cases. Conclusion Treatment of middle-third clavicle non-union after initial failure of conservative treatment with stable fixation and bone graft is a reliable, well-suited and effective treatment. Our hypothesis was verified. Preoperative evaluation of appearance of the non-union X-rays can be used to determine the type of bone graft needed, but the final decision is often taken during surgery. Level of evidence Level IV.
    Full-text · Article · Apr 2014
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