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The Journal of TRAUMA Injury, Infection, and Critical Care

The Role of Low Intensity Pulsed Ultrasound Therapy in the Management of Acute Fractures: A Systematic Review
Xavier L. Griffin, MA, MRCS, Isabel Costello, BM, BS, and Matthew L. Costa, PhD, FRCS (Tr&Orth)
Background: The aim of this study was to review the evidence regarding the use of low intensity pulsed ultrasound (LIPUS) in the management of acute long bone fractures. Methods: Systematic review of Medline, Embase, and CINAHL databases. Further published studies were retrieved by hand searching bibliographies of relevant articles. Retrieved studies were limited to English-language studies published
since 1956. Retrieved studies were excluded from review using the following criteria: case reports, exclusively pathologic fractures, treatment of therapeutic osteotomies and arthrodesis, initiation of ultrasound therapy after the first month following injury, no reporting of assessment of time to fracture healing, cellular studies, and nonclinical articles. Studies were reviewed independently by two reviewers using the CONSORT score. No statistical analysis was performed as the data from the studies were not suitable for pooled analysis. Results: Seven randomized controlled trials and two meta-analyses were retrieved using the search strategy. Conclusion: The literature supports the use of LIPUS in the treatment of acute fractures treated with plaster immobilization. Key Words: Fracture healing, Ultrasound, Ununited fracture.
J Trauma. 2008;65:1446 1452.

ong-bone fractures are a leading cause of morbidity and socioeconomic cost in the developed world. Furthermore, between 5% and 10% of long-bone fractures are associated with delayed healing and these ununited fractures cause considerable morbidity, loss of independence, and loss of productivity.1 The length of time to healing is in itself an important factor in determining the success of the outcome after fracture.2 In an effort to reduce the morbidity and socioeconomic costs associated with fractures, a number of interventions have been proposed, including ultrasound therapy, to enhance and accelerate bone healing. Ultrasound is a form of mechanical stimulation that is delivered to the fracture as high-frequency acoustic pressure waves. It is speculated that ultrasound promotes fracture healing by inducing low-level mechanical forces at the fracture site, reproducing the effect of functional loading. The mechanisms through which the mechanical signal is translated into a biochemical signal have not been fully elucidated but ultrasound is likely to influence multiple points in the fracture healing cascade. Many animal and human studies have demonstrated enhanced callus formation with low intensity pulsed ultrasound treatment (LIPUS). Early evidence of the efficacy of LIPUS therapy in treating fractures in humans was reported by

Xavier and Duarte3 in 1983 with 70% of nonunions healing after treatment. The aim of this study is to review the evidence regarding the use of ultrasound in the management of acute long bone fractures.

MATERIALS AND METHODS


We searched Medline, Embase, and CINAHL using the National Library of Health Datastar search engine. The search strategy used for Medline and CINAHL was: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. fracture-healing bone-remodelling bony-callus fractures-ununited# nonunion 1 OR 2 OR 3 OR 4 OR 5 ultraso$ ultrasonography-interventional ultrasonics pulsed ADJ ultrasound 7 OR 8 OR 9 OR 10 6 AND 11 AND human yes AND LG ENG The search strategy used for Embase was: fracture-healing#.de. fracture-nonunion#.de. bone-remodeling#.de. pseudarthrosis#.w.de 1 OR 2 OR 3 OR 4 ultrasound#.w.de. pulse-wave#.de. ultrasound-therapy#.de. 6 OR 7 OR 8 5 AND 9 AND human yes AND LG ENG December 2008

Submitted for publication June 1, 2008. Accepted for publication July 7, 2008. Copyright 2008 by Lippincott Williams & Wilkins From the Warwick Orthopaedics, Clinical Sciences Research Institute, Coventry, United Kingdom. Presented at the 9th EFORT Congress, Nice. Address for reprints: Xavier L. Griffin, MA, MRCS, Warwick Orthopaedics, Clinical Sciences Research Institute, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom; email: x.griffin@warwick.ac.uk. DOI: 10.1097/TA.0b013e318185e222

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A Review of LIPUS in the Management of Acute Fractures


The selected search terms were derived from the key word databases of each resource. Searches of bibliographies and texts were conducted to identify additional studies. This strategy returned 267 studies (July 2007). Studies were then excluded independently by two researchers on the basis of the following criteria:

of the effect size. The data from a subgroup analysis10 of two other studies8,9 was also included in the pooled analysis. The statistical outcome of the meta-analysis may therefore also be distorted as data has been entered twice. The potential for systematic error in this study is therefore high.

case reports exclusively pathologic fractures treatment of therapeutic osteotomies and arthrodesis initiation of ultrasound therapy after the first month following injury no reporting of assessment of time to fracture healing cellular studies nonclinical articles animal studies

Busse et al
Busse et al.18 performed a meta-analysis to assess the effect of LIPUS on time to fracture healing. One hundred thirty-eight studies were identified from clinical databases. Inclusion criteria applied were random treatment allocation, skeletally mature patients with one or more fractures, doubleblinding, use of LIPUS, and radiographic assessment of time to fracture healing. Six studies met the selection criteria applied by two independent reviewers8 10,16,17,20 and results from three studies were pooled in a meta-analysis.8,9,20 The pooled studies used the same LIPUS unit and defined a healed fracture radiographically as one in which three of four cortices was bridged on orthogonal plain radiographs. One hundred fifty-eight patients were included in the pooled analysis. The time to healing was significantly shorter in the groups receiving LIPUS treatment with a weighted average effect size of 6.41(95% CI 1.0111.81) converting to a mean difference in healing time of 64 days (CI not reported) in favor of LIPUS treatment. The thorough search strategy described by the authors included efforts to retrieve unpublished data and hand searching of key journals. The review only included high-quality RCTs. Three trials with a total of 158 fractures were entered into the final meta-analysis, which was therefore comparatively small. The authors acknowledge that the analysis is limited by the heterogeneity of fracture sites included (scaphoid, tibia, and distal radius), although the three trials demonstrated consistent treatment effects. Two studies where operative treatment was used before ultrasound were excluded from the pooled data so that the results cannot be generalized to this patient group. Interestingly, these two trials were unable to demonstrate a treatment effect of LIPUS.

Any discrepancies in study selection was highlighted and discussed between the researchers. There were no studies upon which agreement could not be reached. Because of the variability among the studies selected, it was not appropriate to attempt a meta-analysis. The studies were critically appraised independently by two researchers. The CONSORT score4 was used to assess the reports of the randomized clinical trials (RCT) and the QUOROM score5 the meta-analyses. Because of the limitations of such scoring systems6 the important methodological aspects of each study were assessed individually.

RESULTS
Of the 267 citations identified, one meta-analysis7 and nine reports on primary research8 16 met the criteria for review. Hand searching of study bibliographies revealed three further eligible studies.1719 On review of the study populations, four articles were found to report on the same patients as another study.10,13,16,19 A summary of the RCTs is shown in Table 1 and the meta-analyses in Table 2.

Bhandari and Schemitsch


Bhandari and Schemitsch7 performed a meta-analysis of the effect of LIPUS therapy on time to fracture healing. Seventyfive studies published since 1999 were identified from clinical databases using search terms ultrasound and fracture healing. Six studies met the eligibility criteria and the results from four studies were pooled in the meta-analysis. The inclusion criteria and outcome measures are not reported. Two hundred ninety-three patients were included in the pooled analysis. The weighted average effect size was 4.7 (95% CI 4.15.3) converting to a mean difference in healing time of 22 days (95% CI 19 24) in favor of LIPUS treatment. Although this meta-analysis has the advantages associated with a large sample of patients, the search strategy and eligibility criteria were not clearly reported and therefore it is impossible to assess the reliability of the review. One study was excluded from the pooled analysis because no treatment effect was demonstrated. This may lead to an overestimation Volume 65 Number 6

Heckman et al
Heckman et al.8 performed a multicenter, randomized, double-blind, placebo-controlled trial to investigate the effect of LIPUS on the rate of cortical bone healing in closed tibial diaphysial fractures. Ninety-six adult patients under the age of 75 were recruited over 4 years from 17 centers. All adult patients, under the age of 75, with closed or Gustillo and Anderson (G&A) grade I open, transverse, short oblique, or short spiral fractures of the tibial diaphysis were included. Initial management was by closed reduction and above knee cast. Patients were excluded if the fracture line was longer than twice the diameter of the diaphysis, displacement was more than 50%, or the fracture gap was greater than 0.5 cm. Other exclusion criteria were persistent shortening, treatment with steroids, anticoagulants, NSAIDs, calcium 1447

1448
Patient Demographics Entry Criteria Bone/s Mean Age (range) M:F Ratio Primary Outcome Measure Secondary Outcome Measures Principal Conclusion CONSORT Score (4)

Table 1 Summary of Randomized Controlled Trials of Ultrasound Therapy in the Management of Acute Fractures of Long Bones

Study

Design

Size

Emami et al.17 37 (1773) 3:1 Tibia Radiographic union: 3 of 4 cortices

RCT

32

No difference on X-ray

15

Handolin et al.14

RCT

22

41.5 (1859)

2:1

Fibula

Fracture line visualization on interval X-ray Fracture line on X-ray Clinical and radiographic union: 3 of 4 cortices BMD at 12 wk

Time to full weight bearing, first evidence of callus MDCT at 9 wk

15

RCT 4.2:1 Tibia

30

40.4 (1865)

1:1.3

Fibula

11 15

Handolin et al.15 Heckman et al.8

RCT

67

Adults with closed or grade I open fractures fixed with IM nail Adults with closed Weber B fractures with no widening of mortice Adults, Weber B, normal mortice Adult, closed diaphyseal fractures

No difference on X-ray, difference in MDCT 0.04 No difference on X-ray 86 5.8. vs. 154 10.4 d in favor of LIPUS*

Kristiansen et al.9

RCT

60

56 (n/r)

1:5.1

Radius

Clinical and radiographic union: 3 of 4 cortices Clinical and radiographic union: 3 of 4 cortices

End of casting, 4 cortices bridged, endosteal healing Loss of reduction

61 3 vs. 98 d in favor of LIPUS*

17

Leung et al.11 35 (2261) 8.3:1 Tibia

RCT

28

Adults with dorsally angulated fractures of metaphysis Adult, high energy fractures fixed with IM nails or external fixator New midshipmen with stress fractures on X-ray or bone scan

11.5 3.0 vs. 20 4.4 d in favor of LIPUS*

10

Rue et al.12 n/r 1:1 Tibia

RCT

26

Return to duty

No tenderness, time WB, external fixator removal, %BMD BALP Nil

No difference between LIPUS and placebo

* Significant difference. n/a indicates not applicable; n/r not reported.

The Journal of TRAUMA Injury, Infection, and Critical Care

December 2008

A Review of LIPUS in the Management of Acute Fractures

Table 2 Summary of Meta-Analyses of Ultrasound Therapy in the Management of Acute Fractures of Long Bones
Patient Demographics Study Design Size Mean Age (Range) Entry Criteria M/F Ratio Bone/s Primary Outcome Measure Principal Conclusion QUOROM Score (5)

Bhandari and Schemitsch7 Busse et al.18

Meta-analysis Meta-analysis

293 158

n/r n/r

n/r 1.3:1

Tibia, radius, scaphoid Tibia, radius, scaphoid

LIPUS shortens healing time* LIPUS shortens healing time*

n/r Radiographic union: 3 of 4 cortices

LIPUS shortens healing time* LIPUS shortens healing time*

3 8

* Significant difference. n/a indicates not applicable; n/r not reported.

channel blockers or bisphosphonates, alcoholism, and nutritional deficiency. Patients were then randomized to treatment with an ultrasound device or an identical placebo device. Treatment was started within 7 days of injury and continued for a maximum of 20 weeks. The principal investigator and an independent radiologist made independent assessments of all the follow-up radiographs while blind to the treatment allocation. Ninety-six patients were recruited, 13 were lost to follow-up and 17 violated the protocol. The control and treatment groups were similar in terms of baseline characteristics. The mean healing time, defined as time to healing on clinical assessment and complete bridging of three of four cortices on radiographic assessment, was significantly reduced to mean 96 SD 4.9 days in the treatment group compared with mean 154 SD 13.7 days in the placebo group (KruskalWallis and log-rank life-table tests p 0.0001). Six percent of fractures in the treatment group had not healed at 20 weeks compared with 38% in the placebo group. It is not clear if all fractures eventually healed without further treatment. This RCT scored highly on the CONSORT criteria. The study excluded patients with complex fractures or significant comorbidities that would adversely effect healing time, limiting extrapolation of the results to situations where fracture healing is favorable. Substantial numbers of enrolled patients were lost to follow-up or excluded because of deviation from the trial protocols, but an intention-to-treat analysis was performed.

Kristiansen et al
Kristiansen et al.9 performed a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of LIPUS in shortening healing time of dorsally angulated distal radial fractures. Patients were included with fractures that were within 4 cm of the tip of the radial styolid and could be satisfactorily reduced closed and treated in a below elbow cast. Patients who were younger than 20 years of age, had fractures of the ulna, other fracture patterns of the radius, required operative treatment, were treated with steroids or anticoagulants or who had nutritional deficiency or alcohol dependency were excluded. Volume 65 Number 6

Eligible patients were treated with closed reduction and a cast and then randomized to treatment group with LIPUS or placebo group with a sham device. Treatment was started within 7 days of injury and continued for 10 weeks. The principal investigator and an independent radiologist made blind independent assessments of all the follow-up radiographs. Eighty-three patients were recruited at 10 centers. Three patients withdrew from the study and 20 violated the protocol for various reasons. The outcomes from 60 patients with 61 closed fractures were analyzed. The control and treatment group demographics and fracture patterns were similar. The mean time to union, defined as time to healing on clinical assessment and complete bridging of three of four cortices on radiographic assessment, was significantly reduced to mean 61 SD 3 days in the treatment group compared with mean 98 SD 5 days in the placebo group (log-rank life-table and stratified analysis of variance p 0.0001). All fractures in both groups healed by 140 days. There was also a significant decrease in the loss of reduction in the subset of patients with fractures that had 10 degrees of negative volar angulation before reduction. Seven of 15 fractures in the treatment group had no loss of reduction compared with 3 of 17 in the placebo group (t test p 0.04). Overall this was a good quality study. However, substantial numbers of enrolled patients were excluded from the analysis and an intention-to-treat analysis was not performed. The majority of these types of fractures heal after a period of immobilization. However, it was interesting to find that loss of reduction was less common in the treatment group, perhaps because of faster healing times, although there was no clinical assessment made of what impact this or a shorter period of immobilization might have had on the functional outcome. Neither Heckman or Kristiansen report the smoking behavior of the patients entered into their studies. Smoking is clearly an important confounder. Cook et al.10 reanalyzed the data from these trials to assess the role of smoking (the majority of the data on smoking was collected retrospectively). Seven of the patients with tibial fractures and 10 with radial fractures were lost to follow-up with regard to smoking status. Only 21 and 9 patients smoked in each study, respec1449

The Journal of TRAUMA Injury, Infection, and Critical Care


tively, leaving small numbers for the analysis. Despite this, LIPUS treatment significantly reduced healing time in smokers in both populations. In the tibial fracture study, smokers healed in mean 75 SE 27 days in the treatment group compared with mean 103 SE 8.3 days in the placebo group (stratified analysis of variance p 0.006). In the radial fracture study, smokers healed in mean 48 SE 5.1 days in the treatment group compared with mean 98 SE 30 days in the placebo group (stratified analysis of variance p 0.003). Smokers with tibial fractures in the placebo group had significantly longer healing times than nonsmokers, but there was no statistical difference in healing time between smokers and nonsmokers treated with LIPUS in either study. Similar results were found when comparing groups with and without a smoking history in the past 10 years. It is therefore possible that LIPUS may mitigate the effect of smoking on delaying fracture healing in smokers. possibility of a type II error is real although there is not even a trend toward a shorter healing time with LIPUS. Otherwise the study is of high quality and the risk of bias is low. Emami et al. concluded that LIPUS does not accelerate fracture healing in tibial fractures that have been stabilized with an intramedullary nail. Given the positive effects shown in other studies, this conclusion should be limited to their specific patient group. Emami et al. postulate that the effect of reaming, which is considered osteogenic, may have influenced the result, noting that healing time in the placebo group was shorter than the corresponding healing time in the study by Heckman et al.8 In addition, treatment with a statically locked nail changes the fracture stability. Given that LIPUS may act through generating micromotion at the facture site, it is possible that the stiffness of the bone-nail construct might contribute to the different outcome in this study.

Leung et al Emami et al
Emami et al. conducted a prospective, randomized, double-blind, placebo-controlled trial to analyze the effect of LIPUS on healing time in closed tibial shaft fractures. Patients, more than the age of 16 years, with either closed or Gustillo and Anderson grade I open fractures of the tibia that were fixed with an intramedullary nail were recruited. Patients were excluded if there were other injuries, a history of alcohol or drug dependency, neuropathy, arthritis, malignant disease, or radiographs that showed severe comminution or open physes. Patients receiving steroids, anticoagulants, NSAIDs, or bisphosphonates were also excluded. Thirty-three patients were entered into the study of whom 32 completed the protocol. Surgery was performed by one of six experienced trauma surgeons. All patients underwent closed reduction and fixation with a reamed, distally locked intramedullary nail. Ultrasound treatment was started within 3 days of surgery and continued for 75 days. All follow-up radiographs were assessed by independent blind review by an orthopedic surgeon and a musculoskeletal radiologist. The two treatment groups were similar. Healing time, defined as the time to bridging of three cortices on plain radiographs, was not significantly different between the two groups. The mean time to healing was 155 SE 22 days in the treatment group compared with 125 SE 11 days in the placebo group (Mann-Whitney U test p 0.76). There was also no significant difference in time to full weight bearing; 6.5 SE 0.7 weeks in the treatment group compared with 7.1 SE 0.8 weeks for placebo group (MannWhitney U test p 0.59). All of the fractures healed, but healing time exceeded 6 months in 5 patients in the treatment group and 2 patients in the placebo group, which was considered to be delayed union. The population in this study is small when compared with the studies of Heckman et al.8 and Kristiansen et al.9 and there is no reporting of a sample size calculation or the confidence intervals of the primary outcome. Therefore, the 1450
17

Leung et al.11 performed a prospective, randomized, double-blind, placebo-controlled trial to analyze the effect of LIPUS treatment on the healing of high energy tibial fractures. Patients with comminuted, segmental or open tibial shaft fractures were recruited and treated with either reamed, distally locked intramedullary nails or an external fixator. Immediately postoperatively, treatment with either an ultrasound device or a placebo machine was started and continued for 90 days. Patients were followed up until the fracture healed. Healing was assessed by clinical examination, orthogonal plain radiographs, bone mineral density (BMD) and plasma bone-specific alkaline phosphatase activity. Twenty-eight patients with 30 fractures were recruited. There were 16 patients in the treatment group with 9 open fractures and 10 were treated with an external fixator. In the control group there were 14 patients, 8 had open fractures and 9 were treated with an external fixator. The LIPUS group showed significantly faster healing at all clinical and radiologic assessments. The time to bridging of three cortices by callus was 11.5 SD 3.0 weeks in the treatment group compared with 20 SD 4.4 weeks in the control group (Mann-Whitney U test p 0.05) and the time to full weight bearing was 9.3 SD 2.1 week compared with 15.5 SD 3.0 weeks, respectively, (t test p 0.05). BMD at the fracture site was significantly more positive in the treatment group at 6, 15, 18, and 21 weeks and bone-specific alkaline phosphatase activity was significantly higher in the treatment group at 12, 18, and 27 weeks (Mann-Whitney U test p 0.05). There was one case of delayed union in each group and two cases of infected fractures, both of which were in the placebo group. Overall, this was a good quality study. All the outcome measures were concordant. Patients had undergone different surgical treatments for diverse fracture types before randomization. This is a pragmatic and robust experimental design that allows easily generalization of the results. However, there is no formal comparison between the control and treatDecember 2008

A Review of LIPUS in the Management of Acute Fractures


ment groups beyond fixation type and whether the fracture was open. Given the small numbers of patients recruited, it is possible that there was a difference in the baseline characteristics of the two groups. The authors assert that patients and assessors were adequately blinded, but the illustrations of the active and dummy devices are not identical. lateral malleolus fractures showed a slight increase in BMD at 12 weeks which was equal in both groups. The authors do not disclose the hypothesis they were trying to test in assessing the effect of ultrasound therapy on BMD or comment on its clinical importance.

Rue et al Handolin et al
Two similar studies by Handolin et al. report on the efficacy of LIPUS therapy on lateral malleolus fractures fixed with bioabsorbable screws. The population was similar in both of the studies. Patients were recruited with closed, displaced Weber B fractures. Patients were excluded if there was widening of the distal tibiofibular joint, an open fracture or a history of drug or alcohol misuse. Patients underwent ORIF with a single self-reinforced poly-L-lactide screw, followed by immobilization of the fracture in a removable softcast brace. Postoperatively, partial weight bearing was allowed at 2 weeks and full weight bearing at 4 weeks. Patients were randomized to treatment with an active ultrasound device or a sham device from 2 weeks to 8 weeks postoperatively. In the first study,15 30 patients were recruited. Fracture healing was assessed by fracture line visualization and callus formation on interval plain radiographs and BMD. There was no statistical difference between the LIPUS and placebo groups found at assessment of fracture healing by plain radiographs. The difference between mean BMD in the two groups was not significant, p 0.952 (95% CI 0.049 to 0.046). In the second study,14 22 patients were recruited and one failed to complete the protocol because of a new injury. Fracture healing was assessed by fracture line visualization and callus formation on interval plain radiographs as well as the percentage of endosteal consolidation on multiplanar reconstructions from multidetector computed tomography. There was no statistical difference between the LIPUS and placebo groups found at assessment of fracture healing by plain radiographs. The difference between mean percentage consolidation of the fracture on multidetector computed tomography at 9 weeks was not significant, p 0.812 (95% CI 0.29 to 0.37). The failure of Handolin to demonstrate a treatment effect may be due to the small study populations. No sample size calculation was reported in either of the studies. The clinical importance of these data sets is difficult to evaluate because the outcome measures do not directly correlate with clinical healing. The descriptive data for fracture line visualization was not disclosed and so cannot be compared with the reported time of 6 weeks when all fractures were clinically united. A definition of a healed fracture was not stated making it difficult to compare the results of this study with other authors. When a stable ankle fracture is treated nonoperatively, BMD decreases because of the resulting immobilization, with the maximal drop at 6 weeks.21 This study of fixed Volume 65 Number 6
14,15

Rue et al.12 performed a prospective, randomized, doubleblind, placebo-controlled clinical trial to analyze the effect of LIPUS on tibial stress fractures in midshipmen newly recruited to the US Naval Academy. Stress fractures were diagnosed based on radiographic and scintigraphic findings. Patients were offered the standard of care treatment of protected weight bearing, alternative aerobic exercise and calcium supplementation, and the possibility of LIPUS. Forty midshipmen were available for entry to the study. Of these, seven did not fulfill the inclusion criteria study and seven had fractures outside of the tibia. Twenty-six midshipmen with 43 fractures were randomized to treatment with LIPUS or placebo with a sham unit until determined fit for duty. Patients were defined as fit to return to duty when there was no pain on palpation and were able to perform a single leg hop on the affected side. If plain radiographs at that time showed any signs of healing, the midshipman was declared fit. The treatment and placebo groups were similar. Both groups mean time to return to duty was 56 days (t test p 0.05). The study population differs from the general population in demographics, premorbid characteristics, physical stressors, and functional requirements, making it difficult to extrapolate the results. The delay from onset of symptoms to initiation of treatment averaged 29 days and the most common finding at the time of diagnosis was a periosteal reaction, indicating that the healing process had already started. The study endpoint is not well defined and it is not clear if one individual assessed of all the radiographs or their level of experience. The power of the study might be too small to show a real treatment effect, but no sample size calculation is reported.

DISCUSSION
We have reported a systematic review of the published, English-language literature concerning the treatment of acute fractures with ultrasound. The current literature demonstrates a treatment effect of LIPUS in accelerating healing in some fracture types. The inconsistency in the evidence may be due to type II error in small studies or a real difference in some fracture groups. We conclude that the available evidence supports the use of ultrasound in the treatment of acute fractures of tibia and radius treated with plaster immobilization. However, there is no benefit of LIPUS in the treatment of fractures of the tibia managed with intramedullary fixation. The clinical relevance of any demonstrated effect is more difficult to justify. A study may demonstrate a statistically significant effect of LIPUS, which may not be clinically 1451

The Journal of TRAUMA Injury, Infection, and Critical Care


relevant to the orthopedic surgeon. The low rate of nonunion reported in the studies raises the question of the usefulness of LIPUS in patients who have a fracture that is likely to heal well anyway. LIPUS therapy may be most useful in patients with a potential for delayed healing, such as those with complex fractures, significant comorbidities, or smokers. Future studies should address whether reducing the time to fracture healing has a significant effect on the morbidity or socioeconomic costs associated with some fractures. Specifically, future research should target patients at risk of fracture healing complications, in whom nonunion is common. The most clinically relevant impact of LIPUS treatment could be a significant reduction in the proportion of patients who go on to develop a nonunion.
9. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound A multicenter, prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 1997; 79:961973. Cook SD, Ryaby JP, McCabe J, Frey JJ, Heckman JD, Kristiansen TK. Acceleration of tibia and distal radius fracture healing in patients who smoke. Clin Orthop Relat Res. 1997:198 207. Leung KS, Lee WS, Tsui HF, Liu PP, Cheung WH. Complex tibial fracture outcomes following treatment with low- intensity pulsed ultrasound. Ultrasound Med Biol. 2004;30:389 395. Rue JPH, Armstrong DW III, Frassica FJ, Deafenbaugh M, Wilckens JH. The effect of pulsed ultrasound in the treatment of tibial stress fractures. Orthopedics. 2004;27:11921195. Handolin L, Kiljunen V, Arnala I, et al. No long-term effects of ultrasound therapy on bioabsorbable screw- fixed lateral malleolar fracture. Scand J Surg. 2005;94:239 242. Handolin L, Kiljunen V, Arnala I, et al. Effect of ultrasound therapy on bone healing of lateral malleolar fractures of the ankle joint fixed with bioabsorbable screws. J Orthop Sci. 2005;10:391395. Handolin L, Kiljunen V, Arnala I, Pajarinen J, Partio EK, Rokkanen P. The effect of low intensity ultrasound and bioabsorbable selfreinforced poly-L-lactide screw fixation on bone in lateral malleolar fractures. Arch Orthop Trauma Surg. 2005;125:317321. Emami A, Larsson A, Petren MM, Larsson S. Serum bone markers after intramedullary fixed tibial fractures. Clin Orthop Relat Res. 1999:220 229. Emami A, Petren-Marianne M, Larrson S. No effect of low-intensity ultrasound on healing time of intramedullary fixed tibial fractures. J Orthop Trauma. 1999;13:252257. Busse JW, Bhandari M, Kulkarni AV, Tunks E. The effect of lowintensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ. 2002;166:437 441. Kristiansen TK. The effect of low power specifically programmed ultrasound on the healing time of fresh fractures using a Colles model. J Orthop Trauma. 1990;4:227228. Mayr E, Rudzki M, Rudzki M, et al. Beschleunight niedrig intensiver, gepulster Ultraschall die Heilung von Skaphoidfrakturen? Handchir Mikrochir Plast Chir. 2000;32:115122. Ingle BM, Hay SM, Bottjer HM, Eastell R. Changes in bone mass and bone turnover following ankle fracture. Osteoporos Int. 1999; 10:408 415.

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