Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis
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* Shanil Ebrahim
* Brent Mollon
* Sheena Bance
* Jason W. Busse
* Mohit Bhandari

## Abstract

**Background:** To best inform evidence-based patient care, it is often desirable to compare competing therapies. We performed a network meta-analysis to indirectly compare low intensity pulsed ultrasonography (LIPUS) with electrical stimulation (ESTIM) for fracture healing.

**Methods:** We searched the reference lists of recent reviews evaluating LIPUS and ESTIM that included studies published up to 2011 from 4 electronic databases. We updated the searches of all electronic databases up to April 2012. Eligible trials were those that included patients with a fresh fracture or an existing delayed union or nonunion who were randomized to LIPUS or ESTIM as well as a control group. Two pairs of reviewers, independently and in duplicate, screened titles and abstracts, reviewed the full text of potentially eligible articles, extracted data and assessed study quality. We used standard and network meta-analytic techniques to synthesize the data.

**Results:** Of the 27 eligible trials, 15 provided data for our analyses. In patients with a fresh fracture, there was a suggested benefit of LIPUS at 6 months (risk ratio [RR] 1.17, 95% confidence interval [CI] 0.97–1.41). In patients with an existing nonunion or delayed union, ESTIM had a suggested benefit over standard care on union rates at 3 months (RR 2.05, 95% CI 0.99–4.24). We found very low-quality evidence suggesting a potential benefit of LIPUS versus ESTIM in improving union rates at 6 months (RR 0.76, 95% CI 0.58–1.01) in fresh fracture populations.

**Conclusion:** To support our findings direct comparative trials with safeguards against bias assessing outcomes important to patients, such as functional recovery, are required.

Fractures are associated with considerable socioeconomic burden1 and may be associated with delayed union and nonunion.2 Delayed union and nonunion can result in loss of function and significant pain and are associated with increased treatment costs and reduced quality of life.2 Factors contributing to delayed union and nonunion include fracture characteristics (e.g., fracture displacement, severity of injury to the soft tissue envelope, infection at the fracture site), iatrogenic factors (e.g., medications, such as anticoagulants, steroids, anti-inflammatory drugs, radiotherapy) and patient characteristics (e.g., vitamin deficiencies, smoking habits).3

The standard care for delayed union and nonunion include nonsurgical (e.g., cast immobilization) and surgical treatment (e.g., external fixation, plating, internal intramedullary nail fixation). Adjunct interventions, such as bone stimulators, are commonly used to facilitate fracture healing. A 2008 survey of 450 Canadian trauma surgeons (79% response rate) showed that 45% of surgeons used bone growth stimulators as part of their treatment strategies for managing fractures.4 Of these, an equal number used low-intensity pulsed ultrasonography (LIPUS) and electrical stimulators (ESTIM).

The US Food and Drug Administration approved LIPUS in 1994 for accelerating fresh fracture healing and in 2000 for the treatment of existing nonunions.5 The technique is non-invasive, and its waves induce micromechanical stress in the fracture site, stimulating molecular and cellular responses involved in fracture healing.6,7 Previous systematic reviews evaluating the effectiveness of LIPUS have suggested a moderate effect on surrogate end points (e.g., reducing time to radiographic union), but inconsistent effects on measures of direct importance to patients, such as return to function.8–11

The use of ESTIM is another noninvasive technique marketed for improving fracture healing. It is believed to affect many cellular pathways, including growth factor synthesis, cytokine production, proteoglycan and collagen, which ultimately stimulate pathways that enhance fracture healing.12–14 Previous systematic reviews evaluating ESTIM for healing existing nonunions concluded that the current evidence is inconsistent — neither showing a significant impact nor confidently rejecting the therapeutic effect of ESTIM.3,15

There have been no comparative studies evaluating LIPUS versus ESTIM for fracture healing. Although the clinical effectiveness for both LIPUS and ESTIM is inconsistent, use of these modalities remains high. In 2012, sales of bone stimulators in the United States were approximately $700 million annually, with a projected growth of 6% per year.16

To best inform evidence-based patient care, it is often desirable to compare competing therapies. Network meta-analysis techniques are powerful approaches that allow for indirect comparison of interventions that have not been directly compared.17,18 The main purpose of this study was to systematically review the LIPUS and ESTIM literature and perform a network meta-analysis of these 2 treatments for accelerating fracture healing in both fresh fracture and nonunion populations.

## Methods:

### Eligibility criteria

All published randomized controlled trials (RCTs) enrolling patients with a fresh fracture or an existing delayed union or nonunion who were randomly assigned to LIPUS or ESTIM as well as a control group were eligible for inclusion in our review and meta-analysis.

### Information sources and search

We identified relevant RCTs in any language by examining 2 recent Cochrane systematic reviews evaluating the effectiveness of LIPUS and the effectiveness of ESTIM in fracture healing.3,11 Authors of the LIPUS and ESTIM reviews searched (to November 2011 and April 2011, respectively) the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register, the Cochrane Central Register of Controlled Trials, Medline, Embase, trial registers and reference lists of all eligible articles. We updated these searches to April 2012 to identify additional trials. The medical subject headings used to capture the trials are listed in the Appendix, available at [canjsurg.ca](http://canjsurg.ca).

### Study selection

One team consisting of 2 reviewers (S.E., S.B.) screened, independently and in duplicate, titles and abstracts of identified citations. All citations flagged by either reviewer as potentially eligible in the title and abstract screening were reviewed in full text. The same reviewers independently applied the eligibility criteria to the full text of potentially eligible studies. Using the guidelines proposed by Landis and Koch19 for assessing interrater agreement for categorical data, we measured agreement for the full text review stage.

### Data collection process and data items

Two pairs of reviewers (S.E. and S.B., and S.E. and B.M.) extracted data, independently and in duplicate, from each eligible study. The data extracted included patient characteristics, intervention and control device details, union rates, and frequency and timing of outcomes. Reviewers resolved disagreements by discussion, and arbitrators (J.W.B. and M.B.) adjudicated unresolved disagreements. We made contact with 1 author directly, as the union rates were not reported in the published study,20 and the author provided this data.

### Risk of bias in individual studies

Two pairs of reviewers (S.E. and S.B., and S.E. and B.M.) assessed risk of bias using a modified Cochrane risk of bias instrument.21 Reviewers used modified response options of “definitely yes,” “probably yes,” “probably no” and “definitely no” for each risk of bias component, with “definitely yes” and “probably yes” ultimately assigned low risk of bias and “definitely no” and “probably no” assigned high risk of bias. Reviewers resolved disagreements by discussion, and arbitrators (J.W.B. and M.B.) adjudicated unresolved disagreements.

### Summary measures

We completed pooled analyses for every common time point. To compare and pool data across trials for outcomes that measured fracture healing, we calculated risk ratios (RRs) and the associated 95% confidence intervals (CIs).

### Synthesis of results

We completed standard meta-analyses to compare LIPUS with the control arm and ESTIM with the control arm. We excluded trials that reported zero events if they were the only trials reporting a given time point, as they would not produce a summary effect and the use of correction factors would provide no additional meaningful data. This resulted in the exclusion of 1 trial from the analysis, as it reported zero events at the end of 4 years.22

The author we contacted for unpublished data provided data for patients with unions (bridging at all 4 cortices by radiographic imaging), possible unions (bridging at 3 cortices) and nonunion (bridging at ≤ 2 cortices). For the purposes of our analyses of dichotomous outcomes, we merged possible union and nonunion into 1 category (nonunion) after consulting with an orthopedic surgeon in our research team in order to be conservative with respect to our treatment effect estimates.

For our network meta-analysis, we used a frequentist approach.17 A network meta-analysis was performed only if 2 conditions were satisfied: 1) the common comparator (control arm) in both trials evaluating LIPUS and trials evaluating ESTIM were considered similar to conduct an indirect comparison of the 2 bone stimulation therapies, and 2) the standard meta-analysis of each bone stimulation therapy versus standard care showed either significant benefit, or the point estimates of the bone stimulation therapies were in opposite directions (e.g., 1 suggesting potential benefit and the other suggesting potential harm).

We used a random-effects approach for our meta-analyses.23,24 We examined heterogeneity using a χ2 test and *I*2 and Tau2 statistics.25,26 We interpreted heterogeneity using the guidelines proposed by the *Cochrane Handbook*.27 We generated the following a priori hypothesis to explain variability between studies: studies with greater risk of bias will have larger effects than studies with lower risk of bias. This subgroup analysis was completed only on a risk of bias component × component basis if there was considerable variability within the risk of bias component. On consulting with a methodologist, we performed subgroup analyses only when there were at least 5 studies to avoid high risk of spurious subgroup findings.

We intended to assess publication bias by visually observing asymmetry of the funnel plot for each outcome. As a rule of thumb,28 one should only perform tests for funnel plot asymmetry when there are at least 10 studies included in the meta-analysis. We were underpowered to assess publication bias.

We performed all standard meta-analyses using RevMan software version 5.1.2 and the Canadian Agency for Drugs and Technology in Health indirect comparison software, and we used Microsoft Excel 2011 for our network meta-analyses.

### Confidence in estimates

Reviewers (S.E., S.B.), independently and in duplicate, evaluated the quality of the evidence for relevant outcomes analyzed in the network meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.29,30

## Results:

### Study selection

Twelve eligible trials were captured in the LIPUS Cochrane review,11 and 11 in the ESTIM Cochrane review.3 From our search update, we identified an additional 67 potentially eligible studies; we retrieved 4 of them in full text, and 2 of these were eligible for our review (Fig. 1). We also knew of 2 recent trials that were published after our updated search.20,31 Thus, 27 trials were included in our review: 12 evaluating LIPUS32–42 and 15 evaluating ESTIM.20,31,43–55 There was perfect agreement between reviewers in the full text review stage.

![Fig. 1](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F1.medium.gif)

[Fig. 1](http://canjsurg.ca/content/57/3/E105/F1)

Fig. 1 
Study eligibility. ESTIM = electrical stimulation; LIPUS = low-intensity pulsed ultrasonography.

### Study characteristics

Table 1 describes the trials included in our review. Eight trials evaluating LIPUS (7 fresh fracture and 1 nonunion populations),32–34,37–39,41 and 7 trials evaluating ESTIM (3 fresh fracture and 5 nonunion populations),43,44,49,52–54 reported union rates as one of their outcomes and were used in the network meta-analyses.

View this table:
[Table 1](http://canjsurg.ca/content/57/3/E105/T1)

Table 1 
Description of studies

### Risk of bias within studies

Fig. 2 and Table 2 present the risk of bias within included studies.

![Fig. 2](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F2.medium.gif)

[Fig. 2](http://canjsurg.ca/content/57/3/E105/F2)

Fig. 2 
Risk of bias within included studies; (+) denotes low risk of bias; (−) denotes high risk of bias.

View this table:
[Table 2](http://canjsurg.ca/content/57/3/E105/T2)

Table 2 
Risk of bias within included studies

### Effect of LIPUS on rate of fracture union

In patients with a fresh fracture, very low-quality evidence showed that LIPUS, when compared with standard care, had no significant effects on improving rates of healing at 3 months (RR 1.01, 95% CI 0.90–1.13; Fig. 3A), 6 months (RR 1.17, 95% CI 0.97–1.41; Fig. 3B) or 12 months (RR 1.06, 95% CI 0.85–1.31; Fig. 3C).

![Fig. 3](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F3.medium.gif)

[Fig. 3](http://canjsurg.ca/content/57/3/E105/F3)

Fig. 3 
Fracture union rates in low intensity pulsed ultrasound (LIPUS) versus control for fresh fractures at 3, 6 and 12 months; **(A)** 3 months; **(B)** 6 months; **(C)** 12 months; events refer to those who had a fracture union. CI = confidence interval.

### Effect of ESTIM on rate of fracture union

In patients with a fresh fracture, very low-quality evidence showed no significant effects in union rates between ESTIM and standard care at 3 months (RR 1.23, 95% CI 0.91–1.66; Fig. 4), 6 months (RR 0.89, 95% CI 0.72–1.09; Fig. 5) or 12 months (RR 1.00, 95% CI 0.88–1.14; Fig. 6).

![Fig. 4](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F4.medium.gif)

[Fig. 4](http://canjsurg.ca/content/57/3/E105/F4)

Fig. 4 
Fracture union rates in electrical stimulation (ESTIM) versus control for fresh fracture and nonunion populations at 3 months; events refer to those who had a fracture union. CI = confidence interval.

![Fig. 5](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F5.medium.gif)

[Fig. 5](http://canjsurg.ca/content/57/3/E105/F5)

Fig. 5 
Fracture union rates in electrical stimulation (ESTIM) versus control for fresh fracture and nonunion populations at 6 months; events refer to those who had a fracture union. CI = confidence interval.

![Fig. 6](http://canjsurg.ca/https://www.canjsurg.ca/content/cjs/57/3/E105/F6.medium.gif)

[Fig. 6](http://canjsurg.ca/content/57/3/E105/F6)

Fig. 6 
Fracture union rates in electrical stimulation (ESTIM) versus control for fresh fracture and nonunion populations at 12 months; events refer to those who had a fracture union. CI = confidence interval.

In patients with an existing nonunion or delayed union, very low-quality evidence showed that ESTIM, when compared with standard care, had a suggested nonsignificant benefit on union rates at 3 months (RR 2.05, 95% CI 0.99–4.24; Fig. 4) but no significant effect at 6 months (RR 1.47, 95% CI 0.85–2.54; Fig. 5) or 12 months (RR 0.89, 95% CI 0.57–1.38; Fig. 6).

### Network meta-analysis of LIPUS and ESTIM on fresh fracture union rates

Results from the network meta-analysis showed that in patients with a fresh fracture, there was a potential non-significant benefit with LIPUS at 6 months (RR 0.76, 95% CI 0.58–1.01).

### Confidence in estimates

Using the GRADE system, we rated the confidence in our estimates for the network meta-analysis to be very low (Table 3).

View this table:
[Table 3](http://canjsurg.ca/content/57/3/E105/T3)

Table 3 
GRADE evidence profile: LIPUS versus ESTIM for improvement in union rates in patients with fresh fractures

## Discussion

### Summary of findings

We found that neither LIPUS nor ESTIM (compared with standard care) were effective in improving union rates at 3, 6 or 12 months in fresh fracture populations. However, the estimates suggest a potential but nonsignificant benefit of LIPUS at 6 months. In patients with a delayed union or nonunion, ESTIM showed a borderline significant effect in improving union rates (compared with standard care) at 3 months, but not at 6 or 12 months. Data were not available to compare LIPUS with standard care in nonunion populations.

Our network meta-analysis suggested a potential but nonsignificant benefit with an average of 24% greater union rate using LIPUS at 6 months in fresh fracture populations. The wide CIs around the estimates of effect suggest considerable uncertainty about relative effects.

Our findings are consistent with those of 2 recent Cochrane reviews that showed no significant difference over standard care for either LIPUS or ESTIM in improving union rates.3,11 Our review adds 4 additional trials and, to our knowledge, presents the first network analysis to indirectly compare LIPUS and ESTIM for fracture healing.

The strengths of our study include a comprehensive and transparent search strategy, independent and duplicate eligibility assessment and data extraction, use of standard meta-analytic techniques to assess the effectiveness of LIPUS and ESTIM separately in both fresh fracture and nonunion populations, and use of network meta-analysis approaches to obtain our estimates of the improvement in union rates for the comparison between the 2 bone stimulation devices in fresh fracture populations.

Network meta-analysis has been gaining considerable attention for its ability to evaluate interventions that have never been directly compared.56 However, it is important to be cautious of the inferences made from network meta-analyses. A recent article in the *Journal of American Medical Association* provides guidance for readers to assess the strength of inferences and credibility of a network meta-analysis.57 A critical appraisal of our study using these guidelines is presented in Table 4. Based on these criteria, our review addresses a sensible clinical question for the network meta-analysis and includes all relevant studies. However, we were limited in our comparisons, and given the lack of direct comparisons, we were unable to verify whether the results would have been consistent between direct and indirect comparisons.

View this table:
[Table 4](http://canjsurg.ca/content/57/3/E105/T4)

Table 4 
Critical appraisal of the network meta-analysis57

### Limitations

Our study has limitations. First, for our pooled network meta-analysis, we used fracture union rates as our outcome. This is a surrogate for functional recovery and improvements in union rates may not necessarily translate to commensurate improvements in function.58 Only 5 trials evaluating LIPUS32,34,37,38,40 and no trials evaluating ESTIM reported functional outcomes. Second, fracture union rates may fail to take into account faster healing if the difference in fracture healing appears between reported time points. We had limited data to pool estimates of time to fracture healing in our network meta-analysis. Previous reviews evaluating the effectiveness of LIPUS that assessed time to radiographic fracture healing have shown a significant benefit.11 The 1 trial that evaluated the effectiveness of ESTIM on time to fracture healing showed no difference in time to fracture healing between ESTIM and standard care.20 Thus, it is possible that there is a difference in fracture healing time between LIPUS and ESTIM for fresh fracture populations; if a difference exists, it may be between 3 and 6 months. Third, although we intended to compare LIPUS and ESTIM in patients with an existing nonunion or delayed union, we were able to perform a network meta-analysis only for fresh fracture populations owing to the lack of available data for nonunion populations. This stresses the importance of evaluating the effectiveness of LIPUS in patients with delayed unions or nonunions on union rates, given that current recommendations support its use for this population albeit with no evidence from RCTs. The 1 trial that evaluated the effect of LIPUS on time to fracture healing in nonunion populations was different than typical nonunion populations, as the study included a surgical treatment designed to address nonunions but also administered ultra-sonography to increase bone graft uptake.22 Fourth, we analyzed only studies that provided union rates in our standard and network meta-analyses. We were unable to analyze other eligible studies that did not provide the outcome data. Thus, this may be introducing a potential bias, as there is a possibility that there could be differences between trials that reported and did not report the outcome of interest. Fifth, the confidence in our estimates was very low, as we rated down for risk of bias, imprecision and indirectness using the GRADE system for rating quality of evidence per outcome.59 Finally, our findings provide inferences on the comparative effectiveness of LIPUS and ESTIM that, to our knowledge, have never been directly evaluated in clinical trials. A head-to-head comparison would provide more credibility to our findings.57 However, as bone stimulator trials typically rely on manufacturers to supply both treatment and sham devices, this would involve agreement between industry competitors to collaborate and require investigators to implement comprehensive strategies to minimize any bias that may be introduced as a result.

## Conclusion:

The current evidence suggests that there may not be significant difference between LIPUS, ESTIM and standard care in improving union rates. There may, however, be a potential benefit to using LIPUS at 6 months for fresh fractures and ESTIM for nonunion populations at 3 months. The evidence in this area is extremely weak, as patient-reported outcomes are not reported, sample sizes are very small, and no direct comparisons of bone stimulation devices exist. Large head-to-head trials with safeguards against bias that assess outcomes inportant to patients (e.g., return to function) are required to confirm or refute the role of bone stimulation devices for fracture healing in either fresh fracture or nonunion populations.

## Acknowledgements

We thank Dr. Gordon Guyatt for his intellectual contributions on network meta-analyses and subgroup analyses, and Ms. Rachel Couban for updating the systematic search.

## Footnotes

*   **Competing interests:** J.W. Busse is the co-principal investigator of an industry-partnered trial to explore the effect of low-intensity pulsed ultrasonography on fracture healing: Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST). The TRUST trial is registered at [clinicaltrials.gov](http://clinicaltrials.gov) ([NCT00667849](http://canjsurg.ca/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00667849&atom=%2Fcjs%2F57%2F3%2FE105.atom)). No other competing interests declared.

*   **Contributors:** S. Ebrahim and M. Bhandari designed the study. S. Ebrahim, B. Mollon and S. Bance acquired the data, which S. Ebrahim, J.W. Busse and M. Bhandari analyzed. S. Ebrahim wrote the article, which all authors reviewed and approved for publication.

*   Accepted July 22, 2013.

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