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. 2020 Nov 21;13:147–155. doi: 10.1016/j.jcot.2020.11.013

Can low intensity pulsed ultrasound (LIPUS) be used as an alternative to revision surgery for patients with non-unions following fracture fixation?

Vidhi Adukia 1,1,∗, Zahra Al-hubeshy 1,1, Jitendra Mangwani 1,2
PMCID: PMC7920105  PMID: 33717887

Abstract

Background

Non-union is a significant complication of fracture fixation surgery, and can negatively impact a patient’s quality of life. Low intensity pulsed ultrasound (LIPUS) has been used to treat delayed or non-unions previously in the literature. The aim of this study was to determine the success rate of LIPUS treatment in patients with chronic fracture non-unions, and to establish the effect of systemic or local factors on its success.

Methods

This was a retrospective, observational study which included all patients undergoing LIPUS treatment in a single institution. Patients deemed suitable for LIPUS underwent treatment for a period of 6 months from initiation. They were followed up with sequential radiographs to assess union at intervals of 6 weeks, 3 months, 6 months and 1 year. LIPUS treatment was considered to be successful when patients achieved clinical and radiological union, without the need for revision surgery.

Results

A total of 46 patients were included in the study; 8 were lost to follow – up, leaving 38 patients for the final analysis. The mean age of patients was 47.03 ± 19.7 with a male to female ratio of 1.2:1. Union was achieved in 57.89%; the rest underwent revision surgery. There was no significant association between outcomes after LIPUS treatment and patients’ age, gender, smoking status or type of non-union. Patients with a small inter-fragment bone gap were more likely to have a successful outcome after LIPUS (p = 0.041). Time to treatment did not have a statistically significant impact on outcomes after LIPUS. Interestingly, all 6 patients with diabetes in the study managed to achieve union after LIPUS.

Conclusions

This study demonstrates that LIPUS is not successful in a large proportion of patients with established fracture non-unions. However, it does represent a low risk treatment modality as an alternative to revision surgery, especially for patients with diabetes who have a small inter – fragment bone gap. More research in the form of large randomised controlled trials needs to be carried out to further assess the role of LIPUS in the treatment of non-unions.

Keywords: Low intensity pulsed ultrasound, Exogen, Delayed union, Non-union, Fracture, Smoking, Diabetes, Inter-fragment bone gap

1. Introduction

Non-union remains a significant complication after surgery for fracture fixation and is often associated with pain and a poor quality of life.1,2 Depending on the operative site and patient factors such as age, smoking or concurrent active infection, the incidence of non-union after fracture fixation is estimated to be around 2–10%.3,4 Conventionally, these patients undergo revision surgery, often with the use of bone graft to achieve union.5 However, revision surgery is in itself associated with significant complications, morbidity and increased costs.6,7 Therefore, the National Institute for Health and Care Excellence (NICE) recommends the use of low intensity pulsed ultrasound (LIPUS) as an alternative treatment for patients with non-union of long bone fractures.8

LIPUS has been used to treat fresh fractures as well as delayed or chronic non-unions, with varying success rates.5,9, 10, 11, 12, 13, 14 It does this by causing micro-motion at the fracture site, which results in increased production of cyclo – oxygenase 2 (COX2). This in turn leads to upregulation of genes responsible for augmentation of endochondral ossification and angiogenesis.15, 16, 17, 18 Animal – model studies have demonstrated that LIPUS not only accelerates the process of callus formation, but also improves the quality of the callus in terms of stiffness and strength.19,20 Other experimental studies suggest that whilst LIPUS is effective in enhancing bone formation, it cannot initiate the fracture repair process and is therefore less likely to be successful in chronic non-unions when compared with fresh fractures.13,21

1.1. Aims

The aim of this study was to determine the success rate of LIPUS therapy in patients diagnosed with a non-union following surgery for fracture fixation. Furthermore, we assessed patient or fracture characteristics that could attribute to the success or failure of LIPUS therapy.

2. Methods

This was a retrospective, observational study carried out in a single institution. All patients who underwent LIPUS therapy between May 2011 to May 2019 were identified from a patient database and included in the study. Non-union was defined as a lack of bony continuity in 2 or more cortices on 2 views in plain radiographs taken at least 3 months after the surgical procedure. The decision to start LIPUS therapy was made by the treating clinician after a peer review. Patients were fitted with Exogen (Bioventus LLC Durham), and the site of treatment was marked in clinic at the time of the first treatment. Exogen generated 200-ms duration pulses at a 30 mW/cm2 intensity and a 1.5 MHz frequency. Patients were directed to self – administer LIPUS for 20 min daily, for a total period of 6 months from the time of initiation. The follow-up was at 6 weeks, 3 months, 6 months and 1 year, with clinical assessment and repeat radiographs to assess bony union. Union was defined as the time when the patient reported no functional pain and there was cortical continuity in a minimum of 3 cortices out of 4 on orthogonal views in radiographs. LIPUS therapy was deemed to be successful when patients achieved radiological and clinical union without having to undergo revision surgery.

Data collection involved reviewing the clinical notes of all patients to identify their demographics, co-morbidities, date of surgery and whether any revision surgery was required after undergoing treatment with Exogen. Patients’ radiographs were also reviewed by two authors (ZA and VA), to assess inter-fragment bone gaps (measured in mm) and to confirm whether radiological union was achieved.

Statistical analysis was carried out using SPSS software version 21.0. Normality of data was tested by the Kolmogorov-Smirnov test. Quantitative variables were tested using the independent t-test/Mann-Whitney U test. For all qualitative variables, Chi-square test/Fisher’s exact test were used. A p value of <0.05 was considered to be statistically significant.

3. Results

Out of the 55 patients that were identified as having undergone LIPUS therapy, 46 patients met our inclusion criteria, with the exclusion criteria described in Fig. 1. Of these, 8 were lost to follow up, resulting in a total of 38 patients for whom data was analysed. The mean age was 47.03 ± 19.7 years with a male to female ratio of 1.2:1. Half (50%) of the patients had at least one co-morbidity. The socio-demographic characteristics of the patients and non-union characteristics are shown in Table 1, Table 2 respectively. The majority of patients (68.42%) underwent CT scan, to confirm the diagnosis of non-union and type of non-union, prior to starting treatment with Exogen. Over 70% of patients (27 out of 38) had an atrophic non-union. The mean inter-fragment bone gap was 4.79 ± 4.4 mm with a range of 1–17 mm. The average time to LIPUS therapy after surgery was 7.41 ± 2.96 months (range 3–14 months).

Fig. 1.

Fig. 1

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Inclusion and exclusion criteria for patients in our study. 6 patients who underwent LIPUS had missing serial radiographs and were therefore excluded from the study.

Table 1.

Socio-demographic characteristics of patients in the study.

Socio-demographic characteristics Union achieved after LIPUS therapy (n = 22) Required revision surgery after LIPUS (n = 16) P value
Age (years)
≤25 4 4 0.491
26–50 7 4
51–75 9 7
≥76 2 1
Mean 47.43 ± 20.17 49.52 ± 18.49 0.676
Range 17–84 19–87
Gender
Male 10 11 0.154
Female 12 5
Smoking status
Current smoker 1 2 0.507
Non smoker 17 13
Unknown 4 1
Diabetes
Yes 6 0 0.03∗
No 16 16
Other co-morbiditiesa
Yes 11 6 0.861
No 11 10
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∗ indicates a significant p – value.

a

Other co-morbidities included one or more conditions such as hypothyroidism, ischaemic heart disease, rheumatoid arthritis, osteoporosis, asthma and mental health disorders. None of the patients included in this study had peripheral vascular disease.

Table 2.

Non-union characteristics.

Non – union characteristics Union achieved after LIPUS (n = 22) Required revision surgery after LIPUS (n = 16) P value
Site
Foot 1 0 0.455
Tibia/Fibula 9 3
Femur 3 6
Carpal bones 1 1
Radius/ulna 5 3
Humerus 2 3
Clavicle 1 0
Type of non – union
Atrophic 13 14 0.078
Hypertrophic 9 2
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57.89% of patients (22 out of 38) achieved union within a year of starting LIPUS therapy. Fig. 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6 are radiographs of the same patient’s femoral fracture, taken at different stages, from the time of presentation [Fig. 2], to starting LIPUS treatment [Fig. 4], and at the final 1 – year follow up [Fig. 6]. The patient underwent LIPUS treatment for 6 months and had a successful outcome as shown in Fig. 6. The remaining 42.11% of patients (16 out of 38) underwent further revision surgery, of which a further 56.25% of patients (9 out of 16) went on to achieve union by the time data was collected for this study.

Fig. 2.

Fig. 2

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Antero-posterior (AP) and lateral radiographs of the right femur of an adult male who was involved in a road traffic collision, taken at the time of presentation to hospital. The radiographs demonstrate a displaced mid-femoral shaft fracture which has been temporarily immobilised in a splint.

Fig. 3.

Fig. 3

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AP and lateral radiographs taken immediately post-operatively after fixation of the right femoral shaft fracture with an intramedullary nail.

Fig. 4.

Fig. 4

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AP and lateral radiographs taken 3 months post-operatively. The distal locking screws have broken, and the fracture remains non-united although there is callus formation at the fracture site.

Fig. 5.

Fig. 5

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AP and lateral radiographs taken 3 months after starting LIPUS therapy. The amount of callus surrounding the fracture site has increased, with the fracture beginning to unite.

Fig. 6.

Fig. 6

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AP and lateral radiographs taken 1 year after starting LIPUS therapy. The fracture appears to have united radiologically.

No significant association was seen between success of LIPUS therapy and the age, gender or smoking status of patients. All patients with diabetes achieved union in this study after LIPUS. LIPUS was also found to be significantly more successful in treating patients with a smaller inter – fragment bone gap (p = 0.041). Furthermore, no significant association was seen with the success or failure of LIPUS in relation to the type of non-union, site of treatment or the timing of LIPUS therapy (in months) after definitive surgery [Table 2, Table 3].

Table 3.

The success of LIPUS was significantly associated with the inter-fragment bone gap, however no significant association was seen between the success of LIPUS and the time after which LIPUS treatment was commenced post definitive surgery.

Variable Union achieved after LIPUS therapy (n = 22) Required revision surgery after LIPUS (n = 16) Total (n = 44) P value
Inter-fragment bone gap (mm)
Mean 3.26 ± 2.29 6.9 ± 5.67 4.79 ± 4.4 0.041∗
Range 1–9 1–17 1–17
Time to treatment (months)
Mean 7.67 ± 3.21 7.1 ± 2.70 7.41 ± 2.96 0.54
Range 3–14 3–12 3–14
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∗ indicates a significant p – value.

4. Discussion

Non-union following fracture fixation surgery can occur as a consequence of several biological and/or mechanical causes. These include systemic factors such as advanced age, co-morbidities, concurrent medications, smoking, and site specific factors such as blood supply to the bone(s), comminution, bone gap and inadequate fixation.2,4,11,22, 23, 24 Traditionally, treatment is usually in the form of revision surgery with the use of bone graft in order to improve the stability of the fracture site and stimulate new bone formation.25 This can be technically challenging and is often associated with complications, especially for patients with diabetes.26,27 LIPUS therapy therefore provides an alternative, non – invasive way of treating non-unions, with multiple studies suggesting that it is not only successful, but is also a more cost – effective method of treatment in such cases.12,28,29

Numerous systematic reviews and meta-analyses have found the success rate of LIPUS to range from 65 to 100%, with the average being above 80%.14,30,31 However, contrary to published evidence, only 57.89% of patients (22 out of 38) in our study achieved a successful outcome following LIPUS treatment. Several patient and site-specific factors could account for this discrepancy.

4.1. Age

The detrimental effect of advanced age on fracture healing is well documented in the literature.32, 33, 34 A study by Zura R et al.5 found that patient age was correlated with the fracture healing rate in patients treated with LIPUS for chronic non-unions. Other studies, however, have disputed this correlation.13,14,26,35,36 A retrospective, observational cohort study looked at over 4000 patients who had LIPUS treatment within 90 days of sustaining a fracture.35 Whilst it found that patients had union rates that were largely independent to their age, it demonstrated that patients aged between 20 and 29 years had a significantly better fracture healing rate than their older counterparts. Our study showed no statistically significant association between age and success or failure of LIPUS (p = 0.491). It is important however to note that the mean age of our patients was 47.03 ± 19.7, with 50% of our patients being over the age of 50 (19 out of 38), which may have had an impact on the lower than average union rate following LIPUS therapy.

4.2. Smoking

Although smoking has been shown to have a negative impact on bone healing,2,37 its effect on the outcome of LIPUS treatment is still not clear. Studies by Nolte PA et al.38 and Teoh KH et al.,12 have both demonstrated that smoking is significantly associated with failure of LIPUS in patients with delayed or established non-unions. On the other hand, studies by Zura R et al.,5 Mirza YH et al.,11 and Watanabe Y et al.,39 as well as a meta-analysis by Leighton R et al.,14 have reported no demonstrable effect of smoking on the outcomes of LIPUS therapy. In this study, smoking status was known for approximately 86% of patients (33 out of 38), with 8% (3 out of 38) being listed as active smokers. 2 out of the 3 actively smoking patients went on to have failure of LIPUS treatment and required further revision surgery. Whilst no significant effect of smoking on the outcome of LIPUS was seen in this study (p = 0.507), patients should still be counselled on the overall deleterious effect smoking has on bone healing, prior to consenting them for LIPUS.

4.3. Non-steroidal anti-inflammatories (NSAIDs)

NSAIDs are commonly used as analgesics in patients with fractures and/or in the perioperative period. They work predominantly by inhibiting the cyclo-oxygenase 2 (COX2) enzyme that is induced by inflammatory cells.40 The COX2 enzyme is known to play an important role in the process of fracture healing by enhancing osteogenic gene expression through prostaglandin production, ultimately resulting in increased endochondral ossification.16 It is therefore no surprise that NSAIDs demonstrate a detrimental effect on bone healing.41, 42, 43 Li J et al.44 used rat ulna models to determine the effect celecoxib, a COX2 – selective NSAID drug, had on the union rate of stress fractures whilst undergoing LIPUS treatment. They found that whilst LIPUS significantly improved new bone formation rate, celecoxib was able to counteract its effects, although this did not reach statistical significance. Similarly, a study by Teoh KH et al.,12 showed no significant correlation between NSAID use and the success/failure of LIPUS treatment in patients with delayed union of fifth metatarsal fractures. On the other hand, Zura R et al.35 demonstrated that regular NSAID use reduced the healing rate in patients with fresh fractures. In our study, we were unable to determine the number of patients who were using NSAIDs regularly whilst undergoing LIPUS treatment, although it is routine practice in our unit to prescribe NSAIDs in conjunction with paracetamol as first-line analgesia if there are no contra-indications to its use. On the basis of this common practice, an assumption can be made that a number of patients in the study might have used regular NSAIDs, contributing to the poor healing rate.

4.4. Obesity

Although obesity in itself is a risk factor for developing a non-union,45,46 Majeed H et al.28 suggested that increased adiposity results in attenuation of the ultrasound signal, leading to failure of treatment with LIPUS. Interestingly, one of the few randomised, sham controlled, double blinded studies that demonstrated favourable outcomes with LIPUS, found that patients in the LIPUS treatment group had a statistically significant lower body mass index (BMI) than the sham – controlled group of patients.10 This study did not take into consideration patients’ BMI, weight or adipose tissue thickness. Interestingly, patients who had LIPUS treatment to a relatively superficial bone (such as the tibia), had a better union rate (9 out of 12 or 75%) when compared with those who had treatment to a generally deeper located bone such as the femur (3 out of 9 or 33.33%). By the same reasoning, patients who had LIPUS to the carpal bones should have all had successful outcomes, however this was not the case for one of our patients who needed revision surgery. Therefore, more research needs to be carried out to assess the impact of obesity and adipose tissue thickness on the outcomes of LIPUS.

4.5. Diabetes

Whilst there have been animal model studies that have demonstrated effectiveness of LIPUS treatment in the presence of diabetes,47 there is paucity in the published literature looking specifically at the success rate of LIPUS in humans diagnosed with diabetes. Bawale R et al.48 did not find any association between diabetes and the success or failure of LIPUS in their case series of 66 patients. However, no information was given either about the number of patients with diabetes in their study, or about the number of patients with diabetes who had a successful outcome after LIPUS. In our study, all six patients with diabetes went on to achieve union after LIPUS therapy. These patients did not have to undergo revision surgery, and therefore avoided the risks associated with surgery such as wound healing problems. This would therefore favour LIPUS being trialled as an alternative to revision surgery in such cases where there is an increased risk of post-operative complications.

4.6. Type of non-union

In our study, the majority of patients had atrophic non-unions (27 out of 38). No significant association was seen between the success or failure of LIPUS with the type of non-union (p = 0.078). In the literature however, other studies have demonstrated higher healing rates and significantly shorter healing times, with hypertrophic non-unions after LIPUS treatment.14,26,28,39 Traditionally, hypertrophic non-unions are said to occur due to poor mechanical stability, and therefore the mechanism through which LIPUS helps with bone healing in such cases is still unclear.49

4.7. Time to treatment

In this study, no significant association was found between the success or failure of LIPUS and the timing at which LIPUS therapy was commenced following definitive surgery. This is in keeping with findings by some other studies.5,14 However, there is strong evidence in the literature which suggests that LIPUS is far more effective on fresh fractures and fractures with delayed union, than it is on chronic non – unions. In a prospective, multicentre study by Jingushi S et al.,13 the time to treatment was significantly associated with the success of LIPUS. Union rates were around 90% when LIPUS was started within 6 months of surgery, however this dropped to less than 65% when LIPUS was started after 12 months of surgery. Similarly, the randomised controlled trial by Schofer MD et al.10 demonstrated poorer radiographic outcomes in patients for whom the time to treatment was greater than 48 weeks, irrespective of whether they were in the LIPUS or sham treatment groups. This is further echoed by other studies which have confirmed higher healing rates in patients with delayed union as compared with chronic non – unions. This is likely due to the presence of cellular activity in delayed unions which can be accelerated by LIPUS, something which is lacking in non – unions.39,50 A systematic review by Rutten S et al.51 concluded that LIPUS was capable of enhancing, and not kick-starting the processes involved in fracture healing. This would explain why, in a study of patients with tibial non-unions, those who had undergone revision surgery followed by LIPUS, had a significantly higher union rate than those who had undergone LIPUS treatment alone.26 Revision surgery would involve decortication of the bone ends, effectively converting the non-unions into fresh fractures. This may also be the reason why the study by Zura R et al.,5 reported union rates as high as 86.2% in patients with chronic non-unions, as the majority of their patients underwent revision surgery followed by LIPUS treatment within a span of 3 months.

4.8. Inter-fragment bone gap

Multiple studies have suggested that the inter – fragment bone gap is a significant predictor of the outcomes of LIPUS therapy, with a gap size of 10 mm or more used as a contraindication to LIPUS treatment.12,39,52, 53, 54, 55 Watanabe Y et al.39 looked at 152 patients with delayed- or chronic non-unions and showed that an inter – fragment bone gap size of 9 mm or more was an independent predictor for determining failure of LIPUS treatment. This is probably the reason why the study by Roussignol X et al.55 had union rates of 88% in patients with non-unions undergoing LIPUS treatment, as they had a strict inclusion criterion of an inter – fragment bone gap that was less than 10 mm. It may also explain the reason why Biglari B et al.54 had a union rate of only 32.8%, which is even lower than what was seen in our study. Inter-fragment bone gap was found to be significantly associated with the success of LIPUS treatment in our study (p = 0.041), reinforcing NICE guidelines which recommend LIPUS for patients with an inter-fragment bone gap of less than 10 mm. In this study, all 4 patients who had inter-fragment bone gaps greater than 10 mm failed LIPUS treatment and needed to undergo revision surgery.

4.9. Compliance

One of the limitations of this study was the inability to measure patient compliance, and this may have had a significant impact on the relatively poor success rate seen after LIPUS therapy. A treatment protocol of 20 min daily, for a period of 6 months can be a big commitment in patients’ lives. Multiple studies looking at patient compliance with LIPUS treatment suggest that depending on the LIPUS device, compliance can range from 51 to 83.8%, which may ultimately affect clinical outcomes.56,57

4.10. Complications associated with LIPUS

As a non-invasive mode of treatment, the documented side effects of LIPUS are minimal. Studies have shown that LIPUS is a safe treatment, with very few patients developing side-effects or complications such as skin irritation or abscess formation.52,58 In this cohort, only one patient had some pain and swelling around the LIPUS treatment site which resolved when treatment was stopped for a duration of 2 weeks. The patient went on to resume LIPUS treatment, with no further reported pain, and ultimately had a successful outcome.

4.11. Limitations

In addition to the limitations described above, there are other limitations which are in line with any retrospective study. The heterogeneity of data and loss to follow – up (8 out of 46 patients) may have resulted in a type II error. A priori sample size estimation was also performed using G∗Power (version 3.1.9.7), which suggested that we would need a total of 184 patients (92 patients in each group). However, despite including patients over the last 8 years, since LIPUS therapy was initiated in our unit, we were only able to identify 55 patients who were treated with LIPUS. Our study was therefore underpowered, which could again contribute to a type II error. Moreover, the lack of a control group (i.e. patients who did not undergo LIPUS treatment), implies that we cannot reliably conclude that the patients who went on to achieve union, did so solely due to the effects of LIPUS.

5. Conclusion

This study suggests that LIPUS is not successful in a large proportion of patients with established fracture non – unions. However, it does represent a low risk alternative to revision surgery, especially in diabetic patients with hypertrophic non-unions, and inter – fragment bone gaps of less than 10 mm. This becomes especially important in recent times with the coronavirus pandemic, where there is a huge strain on healthcare services worldwide, with increasing waiting times for elective operating. Further research, in the form of large, randomised controlled trials, needs to be carried out to assess the role of LIPUS in the treatment of non-unions.

Declaration of competing interest

The authors have no conflicting interests. No funding was received for the completion of the study.

Acknowledgement

The authors would like to thank Ms. Bhawna Garg (MSc Statistics, CFA) for her help with the statistical analysis of the study.

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