LOW INTENSITY ULTRASOUND (EXOGEN) THERAPY FOR
NON UNION OF FRACTURES
BACKGROUND
The treatment of non union or delayed union of fractures includes a growing number
of approaches and techniques, one of which is bone growth stimulation using lowintensity ultrasound (LIUS). Fracture non-union is likely to occur when there is
limited blood supply to the specific bone, or if there is severe trauma. Bones such as
the femur head and neck and the scaphoid, have a limited blood supply, which can be
destroyed if the bones are broken. The tibia has a moderate blood supply, however,
severe trauma and injury can destroy the internal blood supply or the external supply
from overlying skin and muscle. Fracture of the fifth metatarsal (i.e., Jones fracture)
also frequently results in delayed healing and non-union, despite surgical treatment,
generally due to poor blood supply of the proximal metaphyseal diaphyseal region. 1
THE TECHNOLOGY
Ultrasound bone growth stimulation is a non-invasive intervention, designed to
transmit low-density, pulsed, high-frequency acoustic pressure waves to accelerate
healing of fresh fractures and to promote healing of delayed unions and non-unions
that are refractory to standard treatment. Low-intensity ultrasound has also been
suggested to enhance healing of fractures that occur in patients with diseases such as
diabetes, vascular insufficiency, and osteoporosis, and those taking medications such
as steroids, non-steroidal anti-inflammatory drugs (NSAIDs), or calcium channel
blockers. 2
Currently, Exogen, a technology from the Smith and Nephew Corporation, is the only
device marketed worldwide that uses LIUS to influence the fracture healing process.
The Exogen bone growth stimulator uses ultrasound, the energy level of which is
close to that of diagnostic ultrasound machines. The device is intended to be used by
the patient at home and is applied 20–30 minutes daily until healing occurs
According to the manufacturer, the safety and effectiveness of LIUS has only been
established for fractures of the distal radius or tibial diaphysis; fractures with postreduction displacements of more than 50%; fractures that are open Grade II or III;
fractures that require surgical intervention or external fixation; or for fractures that are
not sufficiently stable for closed reduction and cast immobilization. Individuals who
are not skeletally mature, or who are pregnant/nursing are not candidates for this
therapy. LIUS is also not indicated for fractures related to bone pathology or
malignancy. 3
THE PATIENT GROUP
A considerable number of treatments are provided annually to adults in Wales for the
treatment of fresh fractures of the tibia, radius, scaphoid and fifth metatarsal.
Treatments include cast immobilisation and closed or open reduction, with or without
internal fixation. Closed and Grade I open fractures, for which LIUS is indicated, are
Dr M Webb, version 1, October 2008
1
most often treated with cast immobilisation, although the use of intramedullary rods is
relatively common for tibial fractures. Failure to respond to treatment can result in
non-union with implications for the patient’s quality of life and functional capacity,
together with financial costs to both patient and the NHS. The patient factors that
may inhibit bone healing are the presence of diabetes, smoking or nicotine in any
form, older age, severe anaemia, diabetes and drugs such as NSAIDs. 4
TREATMENT ALTERNATIVES
Currently, a variety of invasive and noninvasive interventions are used to treat nonunions, including immobilisation/casting, open or closed reduction, pins, screw
fixation, intramedullary rods and bone grafting. Immobilisation is considered the
primary treatment for any non-union. Bone growth stimulators (noninvasive or
invasive), may be used instead of or in addition to other interventions to promote bone
healing. Implantable devices may be used as an adjunct to planned surgical treatment
(e.g., bone grafts, internal/external fixation) of an established non-union. 5
RESEARCH EVIDENCE
See Table 1 for search terms and results
Table 1
DATABASE
SEARCH TERM/S
OVID Medline 1966-2006
Cochrane DSR
ACP Journal Club
DARE
CCTR
EMBASE
CINAHL
Sumsearch
Ultrasound, low intensity, Exogen, fractures,
orthop$edics, pulsed ultrasound, bone growth
stimulator
Google scholar
Google
HMIC
TRIP
UpToDate
National Electronic Library
for Health
INAHTA
NICE
National Horizon Scanning
Centre
National Research Register
Current Controlled Trials
NUMBER OF
HITS/NUMBER
RELEVANT
168/9
Ultrasound, low intensity, Exogen, fractures,
orthop$edics, pulsed ultrasound, bone growth
stimulator
Exogen, low intensity ultrasound, fractures
Exogen, low intensity ultrasound, fractures
16,100/14
46,232/ 24
Exogen, low intensity ultrasound, fractures
low intensity ultrasound, fractures
low intensity ultrasound, fractures
10/1
4/2
low intensity ultrasound, fractures
10/4
2/2
0
0
0
5/2
The National Public Health Service produced policy advice on electrical and
electromagnetic field treatment for non-union of bones in 2005, which was updated in
2008; this advice considered non-invasive electrical bone growth stimulators such as
Dr M Webb, version 1, October 2008
2
the Exogen and concluded that the efficacy was still uncertain but some studies are
beginning to show statistically significant effects. 6
There have been several good quality systematic reviews and meta-analyses on the
evidence for effectiveness of LIUS in different fracture situations. One performed in
2001 in Australia 5 concluded that it is not possible to state irrefutably that LIUS is
more effective than other treatments for fresh fractures. The authors identified only 2
randomised controlled trials (RCTs) concerned with distal radius and tibial fractures
and the results were contradictory. 7 8 There was no RCT data for non-union fractures
and only poorly controlled registry data and case series evidence was available. The
authors considered however, that this represented minimally acceptable low-level
evidence to support the efficacy of LIUS for treatment of non-unions. This
conclusion was restricted to patients with radiologically confirmed fracture non-union
who have failed previous treatment. Importantly this conclusion is valid only for
comparison with no further treatment, which is an inappropriate comparator for usual
orthopaedic practice.
A subsequent American technology assessment 9 considered the data for non-union
of fractures. Three separate studies with a total of 1446 patients reported data
concerning ultrasound treatment of non-unions. All studies were case series using the
Exogen system and examined the responses of multiple bone types. Nolte et al.10
examined 29 patients and included both radiographic evidence and clinical assessment
in determining healing. No differences in healing rates were found for the 8 patients
treated by casting, 12 patients treated by osteosynthesis, 6 with intramedullary rods,
and 3 with external fixators. Even if this analysis were adequately powered to detect
a difference, it would not rule out a role for fixation and stabilisation in the healing
process, only that each method of fixation worked equally well with ultrasound. Not
including the 12 patients excluded from their analysis, all 10 tibias healed and 4/5 of
the femurs, radii, and scaphoids healed. Response to treatment was monitored with
clinical and radiographic examinations at 6 to 8-week intervals, and treatment was
continued until the treating surgeon declared the non-union healed. This study was not
of good quality because it did not mask patient assessment. Results for 12 patients
enrolled but excluded from the analysis were also presented in the article. It was clear
that some of the patients who had undergone surgery within the 90-day period prior to
use of ultrasound were still considered to be ultrasound “successes.” And this could
inflate the effect of ultrasound, if the prior treatment effect was still ongoing. The
healing rate as reported in the study was 86% (25 of 29 non-unions) healed excluding
the 12 patients described above. It is not clear whether the stratified analyses
presented were planned before the study began or were post hoc analyses and could
therefore be considered as data dredging. Among the patients that completed the
study, 18 had no treatment other than the initial procedures used to treat the fracture.
Fourteen of these patients (78%) healed during the study. All 11 of the patients who
received a secondary procedure prior to ultrasound therapy healed. 10
Mayr et al. examined data on 1317 patients from a registry maintained by Smith and
Nephew, the manufacturer of the ultrasound device. 11 Patients were described as
having “delayed union” (951 cases) if a fracture remained unhealed for 3 to 9 months
following fracture, and “non-union” (366 cases) if the time since initial fracture was
greater than 9 months. The percentage of patients healed and the time to healing for
delayed union and non-union in this prescription-based registry were compared with
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results obtained for 42 patients in the authors’ clinic, but no other validation of the
registry is mentioned in the article. The authors found very similar rates of healing
and time to healing in their clinic population as in the registry population, based on
lack of a statistically significant difference. It cannot be concluded however, that the
two groups are the same based on non-significant results. Among the non-unions in
this study, 314 of 366 (86%) fractures healed, including 105 of 120 (88%) tibias and
57 of 66 (86%) femurs. Among the 951 “delayed unions,” 862 (91%) healed,
including 350 of 380 (92%) tibias and 85 of 98 (87%) femurs.(10) Given the
requirement that non-unions be diagnosed at 9 or more months following injury
(mean 24.9 months), these results suggest that the ultrasound therapy contributed to
healing. Of note, the mean time to healing in the non-union patients was 152 (S.E.:
5.3) days versus 129 (S.E.: 2.7) days in the delayed union group. 11
The size of the registry population does improve the generalisability of the results;
however, retrospective data collection and post-hoc analyses of registry data generally
raise concerns about the potential for bias in patient selection and analysis. Outcome
assessments in the Mayr et al. study 11 were not blinded and may not have been
consistently applied across all patients. Compliance was not reported, and clinical
examination (pain and weight-bearing) was not used as part of the assessment of
healing. The study was therefore considered to have low internal validity. The study
also failed to consider the effect of concurrent immobilisation or other treatments in
the assessment of healing rates. The other study by Mayr describes 100 patients
treated with ultrasound. 12 Healing rates were 55/64 (86%) for delayed unions, which
healed in an average of 142 days, and 31/36 (86%) for non-unions, which healed in an
average of 171 days. Inclusion of the 21 patients who discontinued treatment reduces
the overall healing rate to 86 of 121 (71%). The internal validity of the study was
considered low because the outcome assessment was not blinded, pain and weightbearing outcomes were not reported, and statistical analysis was not reported.
Although the size of the patient populations and the methods of data collection and
analysis were very different, Nolte et al.10 and Mayr et al.11 reported 86% healing in
non-unions of all bone types at an average of 152 days and Mayr et al.12 reported 86%
healing of non-unions in 171 days. Nolte et al.10 reported that all six patients 65
years or older had healed non-unions after treatment, but Mayr et al.11 analysed the
registry data for an effect of age and reported that the healing rate for non-unions
consistently declined from 97% at 20 years to 71% at 70 years. The evidence on the
effect of age on healing was therefore inconsistent.
The authors of the AETMIS 4 study considered separately the evidence for
acceleration of healing, prevention of non-union and treatment of non-union. The
technology brief relies heavily on the evidence presented in the review from Australia
5
and the subsequent meta-analysis by Busse et al. 13 on the effect of LIUS on time to
fracture healing. The latter meta-analysis has been criticised for introducing bias in
favour of an effect by excluding one RCT 8 that did not find an effect of LIUS.
According to AETMIS’s assessment, the available studies did not mention any
adverse effects associated with this treatment modality. Given the efficacy and safety
evidence AETMIS considered that, with regard to the acceleration of healing and the
prevention of non-union, the level of evidence was insufficient to recommend the use
of low-intensity ultrasound. However, in the case of non-union of tibial fractures
however, the prognosis is often so poor that it seems reasonable to consider the use of
LIUS after failed surgical intervention and after the consolidation process, as
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measured by serial radiographs including multiple views, has ceased for several
months. Further data has confirmed the utility of LIUS for post traumatic non-unions
of the tibia 14 15 16 As for fracture sites other than the tibia, the uncertainties
concerning the efficacy of Exogen in the treatment of non-union should be assessed in
light of the prognosis specific to these fractures and of the clinical context.
The review of the literature by CIGNA 17 concluded there was sufficient evidence in
the peer-reviewed scientific literature to support the safety and efficacy of ultrasound
bone growth therapy in patients with fresh fractures of the distal radius and the tibial
diaphysis, when the patients have skeletal maturity, and when the therapy is used as
an adjunct to closed reduction and cast immobilization, or for non-union of bones
other than skull or vertebrae in skeletally mature individuals. There was also some
evidence that LIUS may enhance healing of fractures that are high risk for delayed
union or non-union, in addition to stress fracture non-union.
The authors concluded that there was insufficient evidence in the peer-reviewed,
published scientific literature to support the clinical utility of bone growth stimulation
for the treatment of any of the following non-union conditions:








fresh fractures (other than when using ultrasound bone stimulation for the
tibia, radius or other high-risk fractures)
toe fractures
sesamoid fractures
avulsion fractures
osteochondral lesions
displaced fractures with malalignment
synovial pseudarthrosis
the bone gap is either > 1 cm or > one-half the diameter of the bone
COST EFFECTIVENESS
From the health economic aspect, it is recognised that the longer the delay to union,
the greater the total cost for the treatment of this fracture. In a 1997 publication,
Heckman 18 et al estimated an overall cost savings for the use of LIUS of approx US$
13,000-15,000 /case. In the Australian review 5 the incremental costs per quality
adjusted life year (QALY) gained for LIUS treatment of fresh tibial, distal radius and
sca[phoid fractures were Au$106,601, Au$501.699 and Au$641,060, respectively.
The authors considered that the cost-effectiveness of LIUS in each of the indications
reviewed did not compare favourably with a range of other common healthcare
interventions.
A 2006 study from the York Health Economics Consortium, 19 evaluated the relative
cost-effectiveness of ultrasound stimulation (Exogen) as a complement to
conservative therapy ( casting) or surgical fixation in fresh fractures in patients at risk
( e.g smokers or diabetics) of non-union (non-union is defined at six months). A costeffectiveness model estimated expected outcomes and costs in the 12-months
following first presentation for a cohort of patients with fresh fracture of the tibia.
The model allowed the probability of healing to be varied to reflect the prognosis of
patients with a higher than average risk of non-union. These groups included current
and past smokers and patients with diabetes. The higher risk of non-union is reflected
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in a percentage reduction in the probability of healing. Probabilities are derived from
the literature. The analysis reflected costs to the payer – Medicare in the US, the
National Health Service in the UK. Healthcare resources (such as physician visits,
physiotherapy sessions, X-rays) used to treat patients with fracture of the tibia were
identified through interviews with expert orthopaedic surgeons in the US and the UK.
For a population at risk of non-union whose probability of healing is 80% of the
general population (or less), Exogen was cost saving irrespective of whether the
patient was treated conservatively or with surgery. The greater the risk of non-union,
the greater the relative advantage of Exogen. In the UK adding Exogen to
conservative treatment reduced cost per patient by £1,378 (£2,415 versus £3,793) and
using Exogen as an adjunct to surgery reduced the cost of treatment by £884 per
patient (£5,578 versus £6,462). The increase in the number of fractures healed was
7.6% and 6.4% respectively.
Including lost productivity in the model the addition of Exogen to conservative
treatment was cost-saving, even for the general population of fresh fractures (cost per
patient was reduced by -$2,136). Busse et al 20 suggested that from an economic
standpoint, while reamed intramedullary nailing is the treatment of choice for closed
and open Grade 1 tibial fractures, treatment with therapeutic ultrasound and casting
may also be an economically sound intervention (for appropriate patients). The
authors concluded that in a population at risk of non-union, ultrasound was both less
expensive and led to better outcomes. Providing the risk is such that the probability of
healing is 80% of the general population or less, adjunctive ultrasound appeared to be
an effective strategy irrespective of the primary treatment choice.3-200ource
l., 1988
ONGOING RESEARCH
A search of the controlled trials meta-register and the Cochrane Library revealed the
following relevant trials
1. Trial to evaluate ultrasound in the treatment of tibial fracture- National
Institute for Health (NIH), recruiting
2. Trial to re-evaluate ultrasound in the treatment of tibial fractures (TRUST) –
NIH, completed
3. Pulsed Ultrasound to Speed-up Healing after Intramedullary nailing of Tibia
fractures Charite Hospital, Germany - ongoing
4. Busse JW, Bhandari M, Kulkarni AV, Schünemann HJ. Therapeutic
ultrasound for treating fractures in adults. (Protocol) Cochrane Database of
Systematic Reviews 2005, Issue 3. Art. No.: CD005464. DOI:
10.1002/14651858.CD005464.
CONCLUSIONS
.
 There was a lack of consistent high quality evidence from controlled trials for
the effectiveness of LIUS (Exogen) in the acceleration of healing of fractures,
the prevention of fracture non-union or the treatment of non-union. One often
quoted meta-analysis suffered from methodological problems that introduced
positive bias into the conclusions. Two reviews did however consider that
despite the lack of high level evidence, the data from poorly controlled
Dr M Webb, version 1, October 2008
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registry data and case series was adequate to recommend treatment using the
Exogen device for non-union of fractures, particularly those of the tibia.

While the results of these studies suggest that ultrasound promotes the healing
of non-union fractures, they do not rule out a role for other concurrent
treatment procedures—such as stabilization of the non-union—contributing to
the observed effects. The two studies reporting data for patients over 65 are
not in agreement as to the effect of age on response to ultrasound treatment

The cost effectiveness data did appear to suggest that adding Exogen to
conservative treatment is cost effective providing that the healing of the
population undergoing treatment is ≤80% of the general population
.
REFERENCES
1
Nunley JA. Fractures of the base of the fifth metatarsal: the Jones fracture. Orthopedic Clinic North
America. 200132:171.
2
Wood GW II. General principles of fracture treatment : In: Canale TS, editor. Canale: Campbell’s
Operative Orthopaedics, 10th ed. Copyright 2003. Cited in reference 17
3
Exogen, Inc. The Exogen 2000+ Low intensity ultrasound fracture healing system. Copyright 2000
Smith & Nephew.. Available at URL address: http://global.smithnephew.com/us/EXOGEN_BN_HEALING_SYS_OVW_7227.htm . Accessed October 6th 2008
4
Agence d’évaluation des technologies et des modes d’intervention en santé (AETMIS). Lowintensity ultrasound (Exogen TM) for the treatment of fractures. Technology brief prepared by Banken
R. AETMIS 033-05) Montreal AETMIS 2004. Available at http://www/aetmis gouv.qc.ca. Accessed
5th October 2008.
5
Medical Services Advisory Committee. Low intensity ultrasound treatment for acceleration of bone
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http://www.msac.gov.au/internet/msac/publishing.nsf/Content/MSAC%20Completed%20Assessments
%201021%20-%201040. accessed 5th October 2008.
6
National Public Health Service. Electrical and electromagnetic field treatment fro non-union of
bones. Public Health Advice 15; NPHS 2008. Unpublished draft.
7
Kristiansen T; Ryaby J; McCabe J et al. Accelerated healing of distal radial fractures with the use of
specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebocontrolled study. Journal Bone Joint Surgery. 1997;79:961.
8
Emami A; Petren-Mallmin M; Larsson S. No effect of low-intensity ultrasound on healing time of
intramedullary fixed tibial fractures. Journal of Orthopaedic Trauma,1999; 13; 252.
9
Agency for Healthcare Research and Quality . The role of bone growth stimulating devices and
orthobiologics in healing non-union fractures. AHRQ 2005. Available at:
http://www.cms.hhs.gov/mcd/viewtechassess.asp?from2=viewtechassess.asp&where=index&tid=29&.
Accessed 5th October 2008.
10
Nolte PA, van der Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. Low-intensity pulsed
ultrasound in the treatment of nonunions. Journal Trauma 2001; 51:693.
11
Mayr E; Frankel V; Ruter A. Ultrasound--an alternative healing method for nonunions. Archives
Orthopedic Trauma Surgery 2000;120:1.
12
Mayr E; Mockl C; Lenich A et al.. [Is low intensity ultrasound effective in treatment of disorders of
fracture healing?]. Unfallchirurgie 2002 ;105:108.
13
Busse J; Bhandari M; Kulkarni A et al.. The effect of low-intensity pulsed ultrasound therapy on
time to fracture healing: a meta-analysis. Canadian Medical Association Journal 2002 ;166:437.
14
Rutten S; Nolte PA; Guit G et al. use of low-intensity pulsed ultrasound for posttraumatic nonunions
of the tibia: a review of patients treated in the Netherlands. Journal Trauma 2007; 62:902
15
Walker NA; Denegar CR; Preische J. Low intensity pulsed ultrasound and pulsed electromagnetic
field in the treatment of tibial fractures: a systematic review. Journal Athletic training 2007; 42: 530
16
Gold SM; Wasserman R. Preliminary results of tibial bone transports with pulsed low intensity
ultrasound (Exogen). Journal Orthopaedic Trauma 2005; 19 10:
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17
CIGNA Medical Policy Coverage. Bone Growth Stimulators: Electrical (Invasive, Noninvasive0
Ultrasound. Coverage Policy number 0084; CIGNA 20008. available at:
http://www.cigna.com/health/provider/procedural/coveragepositions/medical/mm0084covergaeposition
criteria_bone_growth_stimulators.pdf. Accessed 5th October 2008.
18
Heckman JD; Sarasohn-Kahn; Kristiansen TK et al. The economics of treating tibia fractures. The
cost of delayed nonunions. Bulletin Hospital Joint Diseases 1997; 56: 63.
Taylor MJ; Chaplin S; Trueman P et al. Economic evaluation of the use of Exogen
for fresh fracture of the tibia in patients at risk of non-union. ISPOR 9th European
Conference, Copenhagen, October 2006. Available at:
http://php.york.ac.uk/inst/yhec/files/resources/ISPOR%20(Euro)%202006%20-%20Exogen.pdf.
Accessed 5th October 2008
19
20
Busse JW; Bhandari M; Sprauge S et al. An economic analysis of management strategies for closed
and open grade 1 tibial shaft fractures. Acta Orthopaedica. 2005; 76: 705.
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