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Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): A systematic review and meta-analysis

Open AccessPublished:May 15, 2017DOI:https://doi.org/10.1016/j.injury.2017.05.016

      Abstract

      Introduction

      Bone fractures fail to heal and form nonunions in roughly 5% of cases, with little expectation of spontaneous healing thereafter. We present a systematic review and meta-analysis of published papers that describe nonunions treated with low-intensity pulsed ultrasound (LIPUS).

      Methods

      Articles in PubMed, Ovid MEDLINE, CINAHL, AMED, EMBASE, Cochrane Library, and Scopus databases were searched, using an approach recommended by the Methodological Index for Non-Randomized Studies (MINORS), with a Level of Evidence rating by two reviewers independently. Studies are included here if they reported fractures older than 3 months, presented new data with a sample N ≥ 12, and reported fracture outcome (Heal/Fail).

      Results

      Thirteen eligible papers reporting LIPUS treatment of 1441 nonunions were evaluated. The pooled estimate of effect size for heal rate was 82% (95% CI: 77–87%), for any anatomical site and fracture age of at least 3 months, with statistical heterogeneity detected across all primary studies (Q = 41.2 (df = 12), p < 0.001, Tau2 = 0.006, I2 = 71). With a stricter definition of nonunion as fracture age of at least 8 months duration, the pooled estimate of effect size was 84% (95% CI: 77%–91.6%; heterogeneity present: Q = 21 (df = 8), p < 0.001, Tau2 = 0.007, I2 = 62). Hypertrophic nonunions benefitted more than biologically inactive atrophic nonunions. An interval without surgery of <6 months prior to LIPUS was associated with a more favorable result. Stratification of nonunions by anatomical site revealed no statistically significant differences between upper and lower extremity long bone nonunions.

      Conclusions

      LIPUS treatment can be an alternative to surgery for established nonunions. Given that no spontaneous healing of established nonunions is expected, and that it is challenging to test the efficacy of LIPUS for nonunion by randomized clinical trial, findings are compelling. LIPUS may be most useful in patients for whom surgery is high risk, including elderly patients at risk of delirium, or patients with dementia, extreme hypertension, extensive soft-tissue trauma, mechanical ventilation, metabolic acidosis, multiple organ failure, or coma. With an overall average success rate for LIPUS >80% this is comparable to the success of surgical treatment of non-infected nonunions.

      Abbreviations:

      LIPUS (low-intensity pulsed ultrasound), RCT (randomized clinical trial), MINORS (methodological index for non-randomized studies), PRISMA (preferred reporting items for systematic reviews and meta-analyses), CINAHL (cumulative index to nursing and allied health literature), AMED (allied and complementary medicine database), EMBASE (excerpta medica database), CI (confidence interval), PWSI (prior-without-surgery-interval), ICMJE (International committee of medical journal editors)

      Keywords

      Introduction

      Bone fractures fail to heal and become nonunion in roughly 5% of patients [
      • Zura R.
      • Xiong Z.
      • Einhorn T.A.
      • Watson J.T.
      • Ostrum R.F.
      • Prayson M.J.
      • et al.
      Epidemiology of fracture nonunion in 18 human bones.
      ]. Nonunions have no expectation of spontaneous healing [
      • Bhandari M.
      • Fong K.
      • Sprague S.
      • Williams D.
      • Petrisor B.
      Variability in the definition and perceived causes of delayed unions and nonunions: a cross-sectional, multinational survey of orthopaedic surgeons.
      ] and require intervention—surgical or otherwise—to revive the healing process. What remains contentious is the time point at which a non-healing fracture can be termed a nonunion. A survey of 335 practicing orthopedic surgeons [
      • Bhandari M.
      • Fong K.
      • Sprague S.
      • Williams D.
      • Petrisor B.
      Variability in the definition and perceived causes of delayed unions and nonunions: a cross-sectional, multinational survey of orthopaedic surgeons.
      ] reported that surgeons define nonunion at a range of fracture ages, but there was a mode at 3 months and a second mode at 6 months.
      A nonunion can unite when adequate stability is provided in an osteogenic environment. These conditions are generally achieved by operative means, including some form of bone fixation to provide adequate stability, decortication of bone ends, and application of bone graft material to enhance healing capacity [
      • Bell A.
      • Templeman D.
      • Weinlein J.C.
      Nonunion of the femur and tibia: an update.
      ]. Depending on nonunion location and the type of revision surgery, the success rate ranges from 68% to 96% [
      • Gebauer D.
      • Mayr E.
      • Orthner E.
      • Ryaby J.P.
      Low-intensity pulsed ultrasound: effects on nonunions.
      ]. However, revision surgery for established nonunions is technically difficult and carries risk of complications. Certain conditions at the nonunion site render operative intervention inevitable (e.g., gross instability, malalignment, or limb-length discrepancy). When surgery is optional, more conservative modalities have been proposed to promote healing and avoid potential risks of revision surgery [
      • Goldstein C.
      • Sprague S.
      • Petrisor B.A.
      Electrical stimulation for fracture healing: current evidence.
      ,
      • Ebrahim S.
      • Mollon B.
      • Bance S.
      • Busse J.W.
      • Bhandari M.
      Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis.
      ,
      • Assiotis A.
      • Sachinis N.P.
      • Chalidis B.E.
      Pulsed electromagnetic fields for the treatment of tibial delayed unions and nonunions: a prospective clinical study and review of the literature.
      ,
      • Aleem I.S.
      • Aleem I.
      • Evaniew N.
      • Busse J.W.
      • Yaszemski M.
      • Agarwal A.
      • et al.
      Efficacy of electrical stimulators for bone healing: a meta-analysis of randomized sham-controlled trials.
      ]. Among such options, low-intensity pulsed ultrasound (LIPUS) has been evaluated in clinical studies, and has demonstrated a positive effect on delayed unions and nonunions [
      • Ebrahim S.
      • Mollon B.
      • Bance S.
      • Busse J.W.
      • Bhandari M.
      Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis.
      ,
      • Nolte P.A.
      • van der Krans A.
      • Patka P.
      • Janssen I.M.
      • Ryaby J.P.
      • Albers G.H.
      Low-intensity pulsed ultrasound in the treatment of nonunions.
      ,
      • Nandra R.
      • Grover L.
      • Porter K.
      Fracture non-union epidemiology and treatment.
      ,
      • Griffin X.L.
      • Parsons N.
      • Costa M.L.
      • Metcalfe D.
      Ultrasound and shockwave therapy for acute fractures in adults (Review).
      ,
      • Bashardoust Tajali S.
      • Houghton P.
      • MacDermid J.C.
      • Grewal R.
      Effects of low-intensity pulsed ultrasound therapy on fracture healing: a systematic review and meta-analysis.
      ,
      • Busse J.W.
      • Kaur J.
      • Mollon B.
      • Bhandari M.
      • Tornetta 3rd, P.
      • Schünemann H.J.
      • et al.
      Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials.
      ,
      • Busse J.W.
      • Morton E.
      • Lacchetti C.
      • Guyatt G.H.
      • Bhandari M.
      Current management of tibial shaft fractures: a survey of 450 Canadian orthopedic trauma surgeons.
      ,
      • Griffin X.L.
      • Costello I.
      • Costa M.L.
      The role of low intensity pulsed ultrasound therapy in the management of acute fractures: a systematic review.
      ,
      • Mollon B.
      • da Silva V.
      • Busse J.W.
      • Einhorn T.A.
      • Bhandari M.
      Electrical stimulation for long-bone fracture-healing: a meta-analysis of randomized controlled trials.
      ,
      • Busse J.W.
      • Bhandari M.
      Therapeutic ultrasound and fracture healing: a survey of beliefs and practices.
      ,
      • Busse J.W.
      • Bhandari M.
      • Kulkarni A.V.
      • Tunks E.
      The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis.
      ].
      We undertook a systematic literature review and meta-analysis to obtain a summary estimate of effect size for the heal rate following LIPUS treatment of delayed unions and nonunions. We also sought to assess any factors that could affect the results of LIPUS treatment of delayed unions and nonunions.

      Methods

      This systematic review of the literature and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ,
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      • PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].

      Eligibility criteria and literature search

      Eligibility criteria were defined before a comprehensive search of the relevant literature. Studies were considered eligible if they met the following inclusion criteria:
      • LIPUS was used as an alternative to surgery for non-healing fractures.
      • LIPUS treatment was applied at least 3 months after the last surgical procedure.
      • At least one outcome of interest was provided (Heal/Fail).
      • A clear definition of delayed union or nonunion was included.
      The following exclusion criteria were used:
      • Experimental and animal studies.
      • Review papers, case reports, and letters to editors.
      • Papers dealing with fresh fractures (less than 3 months old).
      • Papers with fewer than 12 patients.
      An electronic search of the MedLine database via the PubMed search machine was initially undertaken using the following search strategy: (((ultrasound[All Fields] AND bone[All Fields] AND stimulation[All Fields]) OR LIPUS[All Fields] OR PLIUS[All Fields] OR EXOGEN[All Fields] OR SAFHS[All Fields]) OR (Low[All Fields] AND Intensity[All Fields] AND pulsed[All Fields] AND (“ultrasonography”[Subheading] OR “ultrasonography”[All Fields] OR “ultrasound”[All Fields] OR “ultrasonography”[MeSH Terms] OR “ultrasound”[All Fields] OR “ultrasonic”[MeSH Terms] OR “ultrasonics”[All Fields])))
      The search was further extended to the Ovid MEDLINE, CINAHL, AMED, EMBASE, Cochrane Library, and Scopus databases. No language restrictions were imposed. Manual searches were done of the reference section of 10 recent LIPUS reviews [
      • Ebrahim S.
      • Mollon B.
      • Bance S.
      • Busse J.W.
      • Bhandari M.
      Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis.
      ,
      • Nandra R.
      • Grover L.
      • Porter K.
      Fracture non-union epidemiology and treatment.
      ,
      • Griffin X.L.
      • Parsons N.
      • Costa M.L.
      • Metcalfe D.
      Ultrasound and shockwave therapy for acute fractures in adults (Review).
      ,
      • Bashardoust Tajali S.
      • Houghton P.
      • MacDermid J.C.
      • Grewal R.
      Effects of low-intensity pulsed ultrasound therapy on fracture healing: a systematic review and meta-analysis.
      ,
      • Busse J.W.
      • Kaur J.
      • Mollon B.
      • Bhandari M.
      • Tornetta 3rd, P.
      • Schünemann H.J.
      • et al.
      Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials.
      ,
      • Busse J.W.
      • Morton E.
      • Lacchetti C.
      • Guyatt G.H.
      • Bhandari M.
      Current management of tibial shaft fractures: a survey of 450 Canadian orthopedic trauma surgeons.
      ,
      • Griffin X.L.
      • Costello I.
      • Costa M.L.
      The role of low intensity pulsed ultrasound therapy in the management of acute fractures: a systematic review.
      ,
      • Mollon B.
      • da Silva V.
      • Busse J.W.
      • Einhorn T.A.
      • Bhandari M.
      Electrical stimulation for long-bone fracture-healing: a meta-analysis of randomized controlled trials.
      ,
      • Busse J.W.
      • Bhandari M.
      Therapeutic ultrasound and fracture healing: a survey of beliefs and practices.
      ,
      • Busse J.W.
      • Bhandari M.
      • Kulkarni A.V.
      • Tunks E.
      The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis.
      ], to yield articles that might have been missed, and co-authors contributed articles that might still have been missed. Reviewers independently assessed titles and abstracts of the retrieved articles. The full text was obtained for potentially eligible articles and evaluated against eligibility criteria. Disagreement between reviewers was resolved by discussion. Demographic and baseline characteristics and outcome data were extracted from eligible papers and tabulated in a predefined spreadsheet. Titles of journals, names of authors, and institutions were not masked to avoid duplication.

      Quality assessment

      The methodological quality of the primary studies was evaluated with the Methodological Index for Non-Randomized Studies (MINORS) [
      • Slim K.
      • Nini E.
      • Forestier D.
      • Kwiatkowski F.
      • Panis Y.
      • Chipponi J.
      Methodological index for non-randomized studies (MINORS): development and validation of a new instrument.
      ]. This instrument consists of eight methodological items for non-randomized studies, each receiving a maximum of 2 points, so the ideal score is 16 for non-randomized studies. Each primary study was assigned a score independently by two reviewers [CP, PVG]. Studies were also evaluated by these assessors with a level of evidence rating [
      • Wright J.G.
      • Swiontkowski M.F.
      • Heckman J.D.
      Introducing levels of evidence to the journal.
      ]. Disagreements were resolved by consensus.

      Statistics

      The main outcome of interest (heal rate) was a proportion. Binary outcomes were expressed as odds ratios with 95% confidence intervals (CIs). Heterogeneity was assessed using Cochran χ2 test and Higgin’s I2 statistic [
      • Cochran W.
      The combination of estimates from different experiments.
      ,
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. Heterogeneity was considered significant at p < 0.1, while an I2 value greater than 50% was thought to represent significant heterogeneity. Pooling of proportions was done with OpenMeta[Analyst] software (accessed at www.cebm.brown.edu/openmeta) using the DerSimonian and Laird random effects model. For binary data (expressed as odds ratios) the Mantel-Haenszel statistical method was used with either fixed or random effects, depending on the degree of statistical heterogeneity present (when I2 was above 50, a random effects model was used). RevMan (5.3) software (Review Manager, Nordic Cochrane Centre, Copenhagen, Denmark) was used to process binary data, produce pooled estimates of effect size, and test for presence of statistical heterogeneity. Comparison of heal rates between two groups was conducted with the Wilcoxon rank sum test.

      Subgroup analysis

      Subgroups were decided a priori based on anatomic location of the nonunion. Additional sub-groups were created based on factors that were thought to potentially impact treatment, including patient age, smoking status, fracture age, prior-without-surgery-interval (PWSI, defined as the time elapsed from the last surgical procedure until the commencement of LIPUS treatment), and number of prior surgeries.

      Sensitivity analysis

      We planned a priori to repeat our analysis after excluding studies of dubious eligibility, poor methodological quality, or outlying results. Confidence in the robustness of our findings would increase if this process did not produce materially different results compared with those of the original analysis.

      Results

      Search process

      A total of 4611 references were evaluated (Fig. 1) to yield 10 eligible references on LIPUS treatment of human fracture nonunions [
      • Gebauer D.
      • Mayr E.
      • Orthner E.
      • Ryaby J.P.
      Low-intensity pulsed ultrasound: effects on nonunions.
      ,
      • Nolte P.A.
      • van der Krans A.
      • Patka P.
      • Janssen I.M.
      • Ryaby J.P.
      • Albers G.H.
      Low-intensity pulsed ultrasound in the treatment of nonunions.
      ,
      • Mayr E.
      • Möckl C.
      • Lenich A.
      • Ecker M.
      • Rüter A.
      [Is low intensity ultrasound effective in treatment of disorders of fracture healing?].
      ,
      • Lerner A.
      • Stein H.
      • Soudry M.
      Compound high-energy limb fractures with delayed union: our experience with adjuvant ultrasound stimulation (exogen).
      ,
      • Jingushi S.
      • Mizuno K.
      • Matsushita T.
      • Itoman M.
      Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures.
      ,
      • Rutten S.
      • Nolte P.A.
      • Guit G.L.
      • Bouman D.E.
      • Albers G.H.
      Use of low-intensity pulsed ultrasound for posttraumatic nonunions of the tibia: a review of patients treated in the Netherlands.
      ,
      • Schofer M.D.
      • Block J.E.
      • Aigner J.
      • Schmelz A.
      Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial.
      ,
      • Hemery X.
      • Ohl X.
      • Saddiki R.
      • Barresi L.
      • Dehoux E.
      Low-intensity pulsed ultrasound for non-union treatment: a 14-case series evaluation.
      ,
      • Roussignol X.
      • Currey C.
      • Duparc F.
      • Dujardin F.
      Indications and results for the exogen ultrasound system in the management of non-union: a 59-case pilot study.
      ,
      • Watanabe Y.
      • Arai Y.
      • Takenaka N.
      • Kobayashi M.
      • Matsushita T.
      Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion.
      ]. Three references [
      • Pigozzi F.
      • Moneta M.R.
      • Giombini A.
      • Giannini S.
      • Di Cesare A.
      • Fagnani F.
      • et al.
      Low-intensity pulsed ultrasound in the conservative treatment of pseudoarthrosis.
      ,
      • Farkash U.
      • Bain O.
      • Gam A.
      • Nyska M.
      • Sagiv P.
      Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series.
      ,
      • Zura R.
      • Della Rocca G.J.
      • Mehta S.
      • Harrison A.
      • Brodie C.
      • Jones J.
      • et al.
      Treatment of chronic ( >1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS).
      ] were obtained outside the scope of the PubMed search, while 4608 references were found by PubMed. Two references that emerged in the PubMed search were excluded because they reported a registry [
      • Mayr E.
      • Frankel V.
      • Rüter A.
      Ultrasound—an alternative healing method for nonunions?.
      ,
      • Frankel V.H.
      • Mizuno K.
      Management of non-union with pulsed low-intensity ultrasound therapy—international results.
      ]; both papers were superseded by a recent report about the same registry that included more patients and had fewer methodological flaws, but did not appear in the PubMed search [
      • Zura R.
      • Della Rocca G.J.
      • Mehta S.
      • Harrison A.
      • Brodie C.
      • Jones J.
      • et al.
      Treatment of chronic ( >1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS).
      ]. Most references excluded from meta-analysis did not report on human bone fractures (Fig. 1). The treatment group of a randomized controlled trial (RCT) dealing with tibial delayed unions treated with either LIPUS or sham device [
      • Schofer M.D.
      • Block J.E.
      • Aigner J.
      • Schmelz A.
      Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial.
      ] was used as a prospective cohort, and only data related to LIPUS were extracted for the pooled analysis.
      A range of different definitions of fracture nonunion were used by authors of primary studies. All definitions were similar in that nonunion was defined as diagnosable at no less than 3 months post-fracture, and all definitions required radiological confirmation.
      Tables 1–3 list basic demographic and baseline characteristics as well as follow-up details of component studies. All data reflect the potential presence of clinical diversity across included studies.
      Table 1Demographic and baseline characteristics of included studies.
      StudyYearStudy typePeriod of studyStudy NMale: FemalePatient age yrs, mean (range)BoneCriterion for defining nonunionFracture ave. age, months (range)
      Nolte

      et al.
      2001P, multi-center1995–19972816:1247 (18–90)Mix of bones6 mo14.2

      (5.8–32)
      Mayr

      et al.
      2002P1995–199910063:3744 ± 2Mix of bones8 mo

      (nonunion), 4 mo

      (delayed)
      11.6 ± 2.4
      Lerner

      et al.
      2004R1997–20011714:332.7

      (19–63)
      Mix of long bones6 mo?11

      (1–40)
      Two cases were excluded from the pooled analysis, as respective fracture age was <3months.
      Pigozzi

      et al.
      2004P2000–20021512:335.5 ± 12.9 (18–60)Mix of bones9 mo11 ± 2
      Gebauer et al.2005P1995–19976640:2646 ± 1.9

      (14–86)
      Mix of bones8 mo39 ± 6.2

      (8–198)
      Jingushi

      et al.
      2007P, multi-centernr7252:2040.4

      (14–83)
      Mix of long bones3 mo18.9

      (3–159)
      Rutten

      et al.
      2007P, multi-center2000–20037156:1540

      (17–89)
      Tibia6 mo8.4 ± 0.48 (6–25.7)
      Hemery

      et al.
      2010R2006–20081411:339

      (16–62)
      Tibia/Femur6 mo≥ 6
      Schofer

      et al.
      2010RCT, multi-center2002–20055136:1542.6 ± 14.6Tibia4 mo

      (del un)
      14

      (all >4 mo)
      Roussignol

      et al.
      2012R2004–20096042:1743

      (17–85)
      Mix of bones6 mo9

      (5.4–45.8)
      Watanabe

      et al
      2013R, cohort1998–2007151110: 4136.3

      (16–82)
      Mix of long bones3mo

      (delayed) 6 mo

      (nonunion)
      NR
      Farkash

      et al
      2015R2011–201329
      A group of 13 cases was excluded from the final analysis as it represented in essence fresh scaphoid fractures diagnosed within 17days from injury and treated conservatively for 3 months before commencing LIPUS treatment.
      29:0(18–34)Scaphoid3 mo7

      (3–12)
      Zura

      et al.
      2015R, cohort1994–1998767
      A subgroup of 91 cases with PWSI≥3 mo included in pooled analysis.
      408: 35945.8 [SD,16.5]Mix of bones12mo30 [SD:31.5]
      Prospective, R: retrospective, RCT: randomized control trial, NR: not reported, M: male, F: female, frx age: fracture age (time interval from the occurrence of fracture till the start of LIPUS treatment), SD: standard deviation.
      a Two cases were excluded from the pooled analysis, as respective fracture age was <3 months.
      b A group of 13 cases was excluded from the final analysis as it represented in essence fresh scaphoid fractures diagnosed within 17 days from injury and treated conservatively for 3 months before commencing LIPUS treatment.
      c A subgroup of 91 cases with PWSI ≥ 3 mo included in pooled analysis.
      Table 2Baseline characteristics of component studies and potential sources of clinical diversity.
      StudyPrior without surgery interval (PWSI), moInitial treatmentType of nonunionSmoking habitPrior surgeries, mean (range)Previous history of infection
      ConsOperAtrophicHypertActive smokersNon smokers
      Nolte et al.12

      (3.5–32)
      8/2921/2917/2912/2911/2918/291.52

      (0−6)
      2/29
      Mayr et al.≥3 moNRNR84/10016/10028/8961/89NR0/100
      Lerner et al.11

      (1–40)
      Cases with PWSI <3months excluded from the pooled analysis.
      0/1818/18NRNRNRNRNRNR
      Pigozzi et al.NR7/158/15NRNRNRNR0.6

      (0–2)
      NR
      Gebauer et al.24.2 ± 4.9

      (4–197)
      6/6357/6335/4611/4623/6441/641.6

      (0–7)
      0/67
      Jingushi et al.11.5

      (3–68)
      0/7272/7232/7240/72NRNR1.7

      (1–8)
      10/72
      Rutten et al.6.4

      (3–23.6)
      18/7253/7154/7117/7124/5531/551.2

      (0–5)
      3/71
      Hemery et al.12

      (6–38)
      0/1414/143/1411/14NRNR1.7

      (1–3)
      6/14
      Schofer et al.≥4 mo0/5151/51NRNR19/5132/5120/51
      Roussignol et al.> 6 mo0/6060/6058/591/5917/5942/591.7

      (1–4)
      NR
      Watanabe et alDelayed 3.6

      (3–6)

      Nonunion: 9.3 (6–32)
      17/

      151
      134/

      151
      95/15156/10197/15154/101NRNR
      Farkash et al≥3 mo
      13 cases excluded from the final analysis as they were fresh scaphoid fractures diagnosed within 17days from injury and treated conservatively for 3 months before commencing LIPUS treatment.
      29/290/29NANANRNR00/16
      Zura et al.3 mo
      A subgroup of 91 cases with PWSI ≥3 mo included in pooled analysis.
      88/

      767
      679/

      767
      NRNR593/

      767
      174/

      764
      3.1 ± 2.3 (SD)NR
      Atr.: atrophic, Hypert: hypertrophic, NR: not reported, NA: not applicable (scaphoid).
      a Cases with PWSI <3 months excluded from the pooled analysis.
      b 13 cases excluded from the final analysis as they were fresh scaphoid fractures diagnosed within 17 days from injury and treated conservatively for 3 months before commencing LIPUS treatment.
      c A subgroup of 91 cases with PWSI ≥3 mo included in pooled analysis.
      Table 3Treatment details, follow-up characteristics, and methodological quality of studies.
      StudyUltrasound device/Daily stimulation timeDuration of LIPUS treatment, mo

      mean

      (range)
      Follow-up, mean (duration) moDrop out rateMINORS rateLevel of evidence
      Nolte et al.Exogen

      20 min
      5 mo

      (1.7–13)
      NR29.2%9II
      Mayr et al.Exogen

      20 min
      5.1 moNR17.3%10II
      Lerner et al.Exogen

      20 min
      6.6mo

      (3–12)
      52 mo

      (15–72)
      5.8%6IV
      Pigozzi et al.Exogen

      20 min
      3.1 mo

      (1.6–4.6)
      (4.6–5.8) mo010II
      Gebauer

      et al.
      Exogen

      20 min
      4.7 ± 0.3mo13.2 ± 0.68 mo5.9%12II
      Jingushi

      et al.
      NR7.9 mo

      (2–21)
      NRNR8II
      Rutten et al.Exogen

      20 min
      6.2 mo

      (1.7–24.3)
      32.4 mo

      (13.2–55.2)
      010II
      Hemery

      et al.
      Exogen

      20 min
      ≥3moNR06IV
      Schofer

      et al.
      Exogen

      20 min
      3.7 mo4 mo9.8%11II
      Roussignol et al.Exogen

      20 min
      5 mo

      (3–8)
      6 mo1.6%9III
      Watanabe et alExogen

      20 min
      NR12 mo011III
      Farkash

      et al
      Melmak

      20 min
      2.3mo (1–4)NR05IV
      Zura et al.Exogen

      20 min
      5.9 mo [SD,4.2mo]NR40.3%6III

      Publication bias

      We did not set any language restriction during the search process. In addition, we evaluated publication bias by generating funnel plots for the outcomes of interest. The distributions of data points within the funnel plots were symmetrical, indicating that publication bias was unlikely (Fig. 2).
      Fig. 2
      Fig. 2Funnel plot of heal rate between hypertrophic and atrophic nonunions.

      Quality assessment

      MINORS scores ranged from 5 to 12 (mean: 8.7, median: 9) across primary studies (Table 3). The only RCT was rated as a prospective study, but only one arm of this study (treatment group) was used as a prospective cohort of cases [
      • Schofer M.D.
      • Block J.E.
      • Aigner J.
      • Schmelz A.
      Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial.
      ]. More than half of the primary studies were Level II (Table 3).

      Overall heal rate (all anatomical sites)

      All 13 component studies (1441 nonunions) provided relevant data. The fracture age (time interval from fracture occurrence to commencement of LIPUS treatment) across all primary studies was at least 3 months. Three studies [
      • Lerner A.
      • Stein H.
      • Soudry M.
      Compound high-energy limb fractures with delayed union: our experience with adjuvant ultrasound stimulation (exogen).
      ,
      • Farkash U.
      • Bain O.
      • Gam A.
      • Nyska M.
      • Sagiv P.
      Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series.
      ,
      • Zura R.
      • Della Rocca G.J.
      • Mehta S.
      • Harrison A.
      • Brodie C.
      • Jones J.
      • et al.
      Treatment of chronic ( >1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS).
      ] included some patients who received an operative intervention within 3 months of commencement of LIPUS treatment, so the PWSI was <3 months. In order to avoid bias (contribution of the recent surgery to the final outcome) such cases were excluded from the pooled analyses. The pooled estimate of effect size for the heal rate, for any anatomical site of the nonunion and fracture age of at least 3 months was 82% (95% CI: 77–87%). Significant statistical heterogeneity was detected across primary studies (Q = 41.2 (df = 12), p < 0.001, Tau2 = 0.006, I2 = 71) (Fig. 3). Considering a stricter definition of nonunion as fracture age of ≥8 months, the calculated pooled estimate of effect size for the heal rate was 84% (95% CI: 77%–91.6%) and was derived from 9 studies (239 participants). Again, significant statistical heterogeneity was present: Q = 21 (df = 8), p < 0.001, Tau2 = 0.007, I2 = 62) (Fig. 4).
      Fig. 3
      Fig. 3Forest plot of heal rate across all primary studies.
      Fig. 4
      Fig. 4Forest plot of heal rate across primary studies where nonunion was defined at 8 months.

      Subgroup analysis

      We investigated the potential effect of patient age, fracture age, smoking habit, gender, type of nonunion, PWSI, and number of prior surgeries on outcome. Only type of nonunion and PWSI seemed to have an impact on final outcome. The odds of healing were twice as large in hypertrophic nonunions, compared to atrophic nonunions (Fig. 5). A PWSI <6 months was associated with a more favorable result (Fig. 6).
      Fig. 5
      Fig. 5Forest plot of comparison of hypertrophic vs atrophic nonunions in terms of heal rate.
      Fig. 6
      Fig. 6Forest plot of heal rate according to prior without surgery interval (PWSI).
      We further stratified nonunions by anatomical site and calculated heal rate (Table 4). No statistically significant difference was detected between upper and lower extremity long bone nonunions in heal rate (Table 5).
      Table 4Heal rates per anatomical site (subgroup analysis).
      Fracture siteNumber of referencesPatient NHeal Rate (Weighted mean)[
      DerSimonian and Laird, random effect model.
      ]
      95% CIHeterogeneity
      Tibia1035486%79%–93%Q = 47, df = 9, p < 0.001, I2 = 81
      Femur911080.4%70.6%–90.3%Q = 14, df = 8, p = 0.08, I2 = 42.6
      Scaphoid66178%62.6%–93.5%Q = 16, df = 5, p = 0.007, I2 = 68.5
      Humerus64474%61.4%–86%Q = 4, df = 5, p = 0.54, I2 = 0
      Radius + Ulna51877.5%60%–95%Q = 0.096, df = 4, p = 0.99, I2 = 0
      a DerSimonian and Laird, random effect model.
      Table 5Comparison of heal rates of long bones in upper and lower extremities (subgroup analysis).
      Fracture siteNHR (95% CI)Medianp
      Wilcoxon rank sum test.
      Tibia35486%

      (79%–93%)
      87%Tibia vs humerus: p = 0.3
      Humerus4474%

      61.4%–86%
      75%Humerus vs femur: p = 0.3
      Radius + Ulna1877.5%

      60%–95%
      100%Tibia vs radius + ulna: p = 0.09
      Femur11080.4%

      70.6%–90.3%
      92%Femur vs radius + ulna: p = 0.19
      * Wilcoxon rank sum test.

      Sensitivity analysis

      We repeated the pooled analysis after excluding studies that were regarded as weaker in methodological quality [
      • Lerner A.
      • Stein H.
      • Soudry M.
      Compound high-energy limb fractures with delayed union: our experience with adjuvant ultrasound stimulation (exogen).
      ,
      • Hemery X.
      • Ohl X.
      • Saddiki R.
      • Barresi L.
      • Dehoux E.
      Low-intensity pulsed ultrasound for non-union treatment: a 14-case series evaluation.
      ,
      • Farkash U.
      • Bain O.
      • Gam A.
      • Nyska M.
      • Sagiv P.
      Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series.
      ,
      • Zura R.
      • Della Rocca G.J.
      • Mehta S.
      • Harrison A.
      • Brodie C.
      • Jones J.
      • et al.
      Treatment of chronic ( >1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS).
      ]. These studies had been assigned a score ≤6 in the MINORS scale. We also repeated the pooled analysis after excluding the study by Pigozzi [
      • Pigozzi F.
      • Moneta M.R.
      • Giombini A.
      • Giannini S.
      • Di Cesare A.
      • Fagnani F.
      • et al.
      Low-intensity pulsed ultrasound in the conservative treatment of pseudoarthrosis.
      ], as it did not accurately report the PWSI. All above procedures did not substantially change results compared with the original procedure (Table 6).
      Table 6Results of the sensitivity analysis.
      Fracture siteN of studiesN of casesHR

      (95% CI)
      MedianP
      Wilcoxon rank sum test.
      All studiesAll 1375382%

      (77%–87%)
      85%
      Exclusion of low quality studies9 [
      [9 studies include: Nolte, Mayr, Pigozzi, Gebauer, Jinguishi, Rutten, Schofer, Roussignol, Watanabe].
      ]
      61581.5%

      75%–88%
      85%0.97
      Additional exclusion of study with dubious eligibility8 [
      [8 studies include: As above, excluding Pigozzi].
      ]
      60080%

      74%–85.5%
      80%0.74
      * Wilcoxon rank sum test.
      a [9 studies include: Nolte, Mayr, Pigozzi, Gebauer, Jinguishi, Rutten, Schofer, Roussignol, Watanabe].
      b [8 studies include: As above, excluding Pigozzi].

      Discussion

      These findings indicate that LIPUS for nonunions can result in an increased heal rate, particularly when treatment was done within 3 to 6 months of the last revision surgery. Hypertrophic nonunions seemed to benefit more than biologically inactive atrophic nonunions. Almost one-third of the primary studies were assigned a low quality score, while the rating of the remainder was moderate in quality. The moderate rating was a result of retrospective study design, inadequate description of follow-up methodology, patient drop-outs and losses to follow-up, or lack of power analysis and sample size calculations in the primary studies. Nevertheless, we believe our included studies constitute the best available material relevant to our review question.

      Study limitations

      Systematic reviews of the literature and meta-analyses provide the strongest scientific evidence when they pool data from high quality RCTs [
      • Bhandari M.
      • Morrow F.
      • Kulkarni A.V.
      • Tornetta P.
      Meta-analyses in orthopaedic surgery: a systematic review of their methodologies.
      ]. Unfortunately, this was not possible, so we had to rely on data extracted from observational studies.
      There are several reasons that RCTs relevant to our research question are lacking. First, there is no sense that clinical equipoise exists in comparing surgery to other nonunion treatments; rather, it is assumed that surgery is required as first-line treatment [
      • Zura R.
      • Mehta S.
      • Della Rocca G.
      • Steen R.G.
      Biological risk factors for nonunion of bone fracture.
      ]. Without perceived equipoise, surgeons are reluctant to undertake an RCT treating nonunion without surgery and Institutional Review Boards may be reluctant to approve such an RCT. Second, patient recruitment for an operative versus non-operative treatment protocol has been difficult in most countries, so it would take a long time to recruit enough patients to achieve reasonable statistical power. Third, there are standardized procedures for surgical debridement, but fixation, bone grafting, and post-operative patient management are surgeon and/or institution specific. This makes it hard to adequately control an RCT to evaluate LIPUS. Fourth, surgery is hard to blind [
      • Losina E.
      • Ranstam J.
      • Collins J.E.
      • Schnitzer T.J.
      • Katz J.N.
      OARSI Clinical Trials Recommendations: key analytic considerations in design, analysis, and reporting of randomized controlled trials in osteoarthritis.
      ,
      • Katz J.N.
      • Losina E.
      • Lohmander L.S.
      OARSI Clinical Trials Recommendations: design and conduct of clinical trials of surgical interventions for osteoarthritis.
      ], which makes it challenging to objectively assess outcomes. Fifth, once an intervention is recognized as useful, there may be little impetus to characterize exactly how useful it is [
      • Smith G.C.
      • Pell J.P.
      Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials.
      ]. Mayr proposed a prospective, placebo-controlled trial of LIPUS but his proposal was rejected; study authors were forced instead to do a prospective, consecutive-observation study [
      • Mayr E.
      • Möckl C.
      • Lenich A.
      • Ecker M.
      • Rüter A.
      [Is low intensity ultrasound effective in treatment of disorders of fracture healing?].
      ]. It is our hope that this meta-analysis will stimulate interest in an RCT to test the efficacy of LIPUS versus surgery.
      Although we performed a comprehensive search of published literature without language restrictions, we acknowledge that possible errors in search strategy and failure to include unpublished reports could have resulted in missing data. However, we are confident we did not miss large reports that could have biased our estimate of effect size for several reasons. First, our results seem free of publication bias, as indicated by the relative symmetry of the respective funnel plot (Fig. 2). Second, other estimates based on binary data were also free of statistical heterogeneity. Finally, funnel plots of the intervention effect of binary outcomes against study size were uniformly symmetrical, suggesting it is unlikely we missed studies that would have had a statistically significant effect.

      Results of analysis

      Favorable results of LIPUS intervention were obtained when LIPUS was used as an alternative rather than an adjuvant to surgery. Our results suggest that nonunions that present within 3 to 6 months of fracture are candidates for LIPUS treatment.
      Biologically active nonunions benefit more from application of LIPUS that do atrophic nonunions (Fig. 5). This is of interest because it is a common belief that the failure of hypertrophic nonunions to heal is due to mechanical instability [
      • Niikura T.
      • Lee S.Y.
      • Sakai Y.
      • Nishida K.
      • Kuroda R.
      • Kurosaka M.
      Causative factors of fracture nonunion: the proportions of mechanical, biological, patient-dependent, and patient-independent factors.
      ]. A common surgical strategy to solve this problem is therefore revision of fixation without biological stimulation. Whether and how LIPUS promotes bone healing in a hypertrophic environment, without addressing mechanical instability, remains obscure. Of interest, patient age, patient gender, smoking habit, fracture age, and number of prior procedures had no impact on outcome. Moreover, it should be appreciated that PWSI ≥3 months was used as a prerequisite of eligibility, to avoid bias from concurrent use of surgery [
      • Gebauer D.
      • Mayr E.
      • Orthner E.
      • Ryaby J.P.
      Low-intensity pulsed ultrasound: effects on nonunions.
      ,
      • Mayr E.
      • Möckl C.
      • Lenich A.
      • Ecker M.
      • Rüter A.
      [Is low intensity ultrasound effective in treatment of disorders of fracture healing?].
      ,
      • Jingushi S.
      • Mizuno K.
      • Matsushita T.
      • Itoman M.
      Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures.
      ,
      • Rutten S.
      • Nolte P.A.
      • Guit G.L.
      • Bouman D.E.
      • Albers G.H.
      Use of low-intensity pulsed ultrasound for posttraumatic nonunions of the tibia: a review of patients treated in the Netherlands.
      ,
      • Schofer M.D.
      • Block J.E.
      • Aigner J.
      • Schmelz A.
      Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial.
      ,
      • Roussignol X.
      • Currey C.
      • Duparc F.
      • Dujardin F.
      Indications and results for the exogen ultrasound system in the management of non-union: a 59-case pilot study.
      ,
      • Watanabe Y.
      • Arai Y.
      • Takenaka N.
      • Kobayashi M.
      • Matsushita T.
      Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion.
      ,
      • Pigozzi F.
      • Moneta M.R.
      • Giombini A.
      • Giannini S.
      • Di Cesare A.
      • Fagnani F.
      • et al.
      Low-intensity pulsed ultrasound in the conservative treatment of pseudoarthrosis.
      ,
      • Farkash U.
      • Bain O.
      • Gam A.
      • Nyska M.
      • Sagiv P.
      Low-intensity pulsed ultrasound for treating delayed union scaphoid fractures: case series.
      ]. This provides evidence that LIPUS can heal nonunion fractures without concurrent surgery. Nevertheless, we cannot recommend LIPUS instead of surgery for all nonunions. Such a recommendation could only be made in the context of an RCT comparing LIPUS to surgery.
      LIPUS was used as an adjunct to surgery in several studies reported here [
      • Nolte P.A.
      • van der Krans A.
      • Patka P.
      • Janssen I.M.
      • Ryaby J.P.
      • Albers G.H.
      Low-intensity pulsed ultrasound in the treatment of nonunions.
      ,
      • Lerner A.
      • Stein H.
      • Soudry M.
      Compound high-energy limb fractures with delayed union: our experience with adjuvant ultrasound stimulation (exogen).
      ]. Initial treatment was conservative in 8 cases and operative in 21 cases, with additional treatments including bone grafting, reosteosynthesis, and other surgeries an average of 52 weeks prior to LIPUS [
      • Nolte P.A.
      • van der Krans A.
      • Patka P.
      • Janssen I.M.
      • Ryaby J.P.
      • Albers G.H.
      Low-intensity pulsed ultrasound in the treatment of nonunions.
      ]. While this study has the limitation that surgery could bias the results of LIPUS treatment, it supports the view that addition of LIPUS to surgical treatment can be helpful. Because data on LIPUS used as an adjunct to surgery is scarce, no strong recommendation can be made for adjunctive LUPUS [
      • Zura R.
      • Della Rocca G.J.
      • Mehta S.
      • Harrison A.
      • Brodie C.
      • Jones J.
      • et al.
      Treatment of chronic ( >1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS).
      ].
      Overall, LIPUS may be useful in patients for whom surgery is high risk. For example, surgery is not recommended for patients at risk of delirium due to old age, or patients with dementia, extreme hypertension, extensive soft-tissue trauma, mechanical ventilation, metabolic acidosis, multiple organ failure, or coma [
      • Zaal I.J.
      • Devlin J.W.
      • Peelen L.M.
      • Slooter A.J.
      A systematic review of risk factors for delirium in the ICU.
      ]. Avoidance of surgery in such patients may mean that non-surgical techniques such as LIPUS are especially valuable.

      Conclusions

      This systematic review and meta-analysis is supportive of the use of LIPUS in patients with a nonunion. Results are better in biologically active nonunions and when the modality is applied 3–6 months after the last revision surgery. Given an overall average success rate for LIPUS of better than 80% this rivals the success of surgical treatment of non-infected nonunions. An RCT of LIPUS versus surgery should be conducted so surgeons will be able to compare the success of surgical treatment with LIPUS treatment for nonunions.

      Competing interests

      All authors have completed the ICMJE uniform disclosure form. We declare that 4 authors had financial relationships with Bioventus LLC (summarized below) that could constitute a competing interest. However, neither Dr. Giannoudis nor Dr. Papakostidis had any relationships or activities with Bioventus that could have influenced the submitted work. None of the authors had non-financial competing interests. Conflicts of interest are summarized as follows:

      Ethics approval and consent to participate

      Not applicable; this is a literature review.

      Consent for publication

      Not applicable; this is a literature review.

      Availability of data and material

      All data generated or analyzed during this study are included in this published article and its Supplementary information files.

      Paid consultants to bioventus

      Ross Leighton, J. Tracy Watson.

      Employees of bioventus

      Andrew Harrison, R. Grant Steen.

      Funding

      All financial and material support for this research was provided by Bioventus LLC.

      Authors’ contributions

      All authors made substantive intellectual contributions to this study, according to the guidelines of the International Committee of Medical Journal Editors (ICMJE). No medical writers were involved in the completion of this manuscript. RL contributed to the study design, checked the citations, and drafted the manuscript; JTW checked the citations, and drafted the manuscript; PG checked the citations, graded the studies, performed the meta-analysis, and drafted the manuscript; CP checked the citations, graded the studies, performed the meta-analysis, and drafted the manuscript; AH contributed to the study design, screened the literature, and drafted the manuscript; RGS contributed to the study design, screened the literature, and drafted the manuscript. All authors read and approved the final manuscript.

      Acknowledgements

      None at present.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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