"Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has."
Cureus is on a mission to change the long-standing paradigm of medical publishing, where submitting research can be costly, complex and time-consuming.
The SIQ for this article will be revealed
low-intensity pulsed ultrasound, delayed union, non-union, lipus, exogen
Jacques Pretorius , Yousif Mohamed, Ahmed Mustafa, Nouman Nemat, Prasad Ellanti, Yasir Hammad, Tony Shaju, Sayed Nadeem
Cite this article as: Pretorius J, Mohamed Y, Mustafa A, et al. (September 16, 2022) A Retrospective Study: Is Low-Intensity Pulsed Ultrasound (LIPUS) an Effective Alternate Treatment Option for Non-union?. Cureus 14(9): e29230. doi:10.7759/cureus.29230
There is ongoing controversy regarding the use of low-intensity pulsed ultrasound (LIPUS) therapy in patients with delayed union or non-union. Exogen (Bioventus, Durham, NC) is a well-known brand of LIPUS, and according to their data, 86% of non-union fractures will heal without the need for surgery. A few independent retrospective studies reported much lower healing rates.
A retrospective observational study was performed assessing all the patients who underwent Exogen therapy in a single centre. All patients who were initiated on Exogen after three months with radiographic signs of the delayed union were included in the study. Routine follow-up appointments were organised until clinical and radiological healing could be confirmed. Daily 20-minute Exogen sessions were continued until the fracture was healed or up to a maximum of four months as recommended by the manufacturer.
A total of 37 patients received Exogen therapy from 2012 to 2021, of which only 28 patients met our inclusion criteria and were subsequently analysed. The mean age of the patients was 52.0 (SD ± 20.2) with a male to female ratio of 1.7:1. The average time to healing was 115 (±51.2) days with a success rate of 82.14%. The average interfragmentary gap was 7.5 mm (±5.8) for the fractures that healed whereas the failed treatment was 16.1 mm (±13.8). There was no obvious association between outcomes after Exogen therapy and the patient’s age, sex, time to initiate Exogen, diabetes, and smoking status.
This study demonstrated a high success rate of LIPUS therapy for patients with delayed union and non-union. LIPUS represents a safe, non-invasive alternative to revision surgery. An independent risk factor for a potentially poor outcome is an increased interfragmentary gap.
Fracture non-union can lead to significant patient morbidity with poor quality of life. This remains a significant complication for fractures managed surgically or even conservatively [1,2]. Risk factors for delayed union/non-union can be classified as either patient dependent or independent. The patient-dependent risk factors include advanced age, gender, smoking, non-steroidal anti-inflammatory drugs (NSAIDs) use, metabolic disease, and nutritional deficiencies. Whereas patient independent factors include injury factors (fracture pattern, location, alignment, associated soft tissue injury, and degree of bone loss) and surgical factors (surgical technique and presence of infection) [3-5]. The definitive treatment for patients with non-union would be surgical management with osteosynthesis and autologous bone grafting; however, this can be associated with significant morbidity, a wide range of complications, and increased cost [6]. Therefore, there has been an increase in popularity in the use of alternative osteogenesis stimulation devices, which accelerates and promotes bone consolidation. These devices include induced currents, pulsed electromagnetic fields, and low-intensity pulsed ultrasound (LIPUS) [5].
LIPUS produces low-frequency pulsed ultrasound waves that act on the osteoprogenitor cells, which then produce more Cbfal/Rnx2 and osteocalcin, which is essential for osteogenesis [7]. Simultaneously it causes an increase in prostaglandin E2 and nitric oxide production, which encourages the tracking of inflammatory cells to the site of injury. This will subsequently stimulate osteoblast differentiation and proliferation, which will lead to new bone formation and increased bone healing [8].
The potential of these devices has been recognised by the National Institute for Health and Care Excellence (NICE), which states that it may be beneficial as an alternative treatment option for delayed union or non-union and has a potential for accelerating bone healing, while also admitting that there is still a lack of high-quality evidence available [9]. Exogen (Bioventus, Durham, NC) is a well-known brand of LIPUS, and according to their data, they have an 86% healing rate for fracture non-union [10]. A few independent retrospective studies reported much lower healing rates with rates as low as 47% [11,12]. With this uncertainty regarding the efficacy of LIPUS therapy still prevalent and the need for further evidence as highlighted by NICE, we assessed the efficacy of Exogen use for delayed union and non-union in our centre.
This was a retrospective observational study performed in a single institution looking at all the patients who received Bioventus Exogen therapy from February 2012 to December 2021. The time to union of fractures is influenced by a variety of factors mentioned above but generally "delayed union" is said to occur when there is no radiological evidence of healing within three months of initial injury or surgery [9]. Whereas "non-union" is established when nine months have passed since the initial injury or surgery, with no visible signs of healing over the last three months [9]. Radiological evidence of non-union is defined as a lack of bridging callus in two or more cortices on two plain film orthogonal radiographs. In this study, we included all patients who received Exogen therapy for delayed union or non-union. Patients were excluded if they received Exogen before three months has passed since the initial injury or surgery, if they had pathological fractures, patients with infected cases, and patients with insufficient notes (Figure 1).
The treating orthopaedic consultant would decide to start Exogen therapy when they believe the patient will not heal due to specific risk factors or already has evidence of radiographic delayed union/non-union. The device would then be fitted in the clinic over the fracture site that is marked by the surgeon. Patients would then be directed by the Exogen representative to self-administer LIPUS daily for 20 minutes, at the same time frame until fracture union or up to four months, as advised by the manufacturer. The patients were followed up routinely until clinical and radiological union could be confirmed.
Radiological assessment was performed by two experienced orthopaedic surgeons during which the fracture gap was measured, as well as the radiological union, defined as three or more cortices bridged with a callus on two orthogonal views. The clinical union was defined as when the patient reported no functional pain, which was identified in the patient's clinical notes, along with the patient's demographics, comorbidities, date of Exogen application, and whether revision surgery was performed.
A total of 37 patients received Exogen therapy from 2012 to 2021, of which only 28 patients met our inclusion criteria. There were six patients with insufficient notes, two were lost to follow-up, and one patient started Exogen therapy for an acute fracture (Figure 1). The mean age of the patients was 52.0 (SD ± 20.2) years with a male to female ratio of 1.7:1. More than 50% of the patients had at least one comorbidity that could be a potential risk factor for developing non-union (Table 1).
The average time to healing was 115 (±51.2) days after Exogen initiation with a success rate of 82.14% (23 out of 28 patients). This was confirmed on radiological assessment whereas the documentation regarding clinically healed fractures was poorly documented. The average interfragmentary gap was 7.5 mm (±5.8) for the fractures that healed, whereas the failed treatment was 16.1 mm (±13.8 mm). Most of the patients included in this study (24 of 28) had an atrophic non-union. The most common fracture sites leading to non-union were humerus shaft (n = 9) and tibia/fibula (n = 7) fractures (Table 2).
The patients that did not show any signs of healing received revision surgery at an average of 81.51 (±44.64) days. An average of 9.5 fracture clinic visits was recorded. Only seven patients received a computed tomography (CT) scan to confirm non-union and classify the sub-type. Initial surgical management was only performed in 50% of fractures, whereas the other 14 patients were treated conservatively with either casting or bracing. Patients that were treated conservatively tended to have a larger interfragmentary gap (Table 3).
DHS = dynamic hip screw; N/A = not applicable.
The healing rate of patients using Exogen for delayed union in our study was 82.14%. This included patients who were treated with initial surgical fixation (79% union) as well as patients who were managed conservatively (86% union). This is in keeping with the healing rates according to the data provided by Exogen as well as other recently published studies, whose success rates vary between 78% and 90% [10,13-15]. An example of one of the successfully managed patients with LIPUS therapy can be appreciated in Figures 2-5. It is important to recognise that two recently performed retrospective reviews reported worse union rates with the lowest reporting a success rate of 47% [4,11,12].
The importance of interfragmentary bone gap as an independent risk factor for failing LIPUS therapy as demonstrated by Watanabe et al. was reiterated in this study [16]. The average gap was 16.1 mm in the patients who failed therapy in contrast to the 7.5 mm in the fractures that united successfully. It is even recommended by NICE guidelines, as well as Exogen, that LIPUS should ideally be used on fractures with an interfragmentary gap of less than 10 mm [9].
This study did not demonstrate any obvious association between smoking, diabetes, or age with failed LIPUS treatment, which is statistically supported by other available studies [2,12,17-19]. It has been clearly demonstrated that smoking has a definite negative impact on bone healing [2], but this does not seem to be the case when LIPUS therapy is used, as demonstrated in a meta-analysis performed by Leighton et al., who reported no association between smoking and failed LIPUS therapy [17]. A large retrospective, observational study that reviewed more than 4000 patients suggested that there is no association between healing rates in LIPUS therapy and patients' age [18]. Two recent retrospective studies performed did not demonstrate any association between the poor success rate of LIPUS therapy and the diagnosis of diabetes mellitus [12,19].
One of the major advantages of Exogen is the fact that it can be a cost-effective alternative to surgical management with the added advantage of being a non-invasive and low-risk intervention. NICE performed a literature review of Exogen therapy and established that successful treatment with Exogen instead of revision surgery can surmount cost savings of approximately £2407 per patient [9].
There are several limitations to this study, which include this being a retrospective, non-comparative study, with a small number of patients included, similar to other recently published studies (Table 4). The decision to initiate Exogen therapy, as well as subsequent follow-up visits, was not standardised, leading to a major disparity in the time to initiate Exogen therapy. The study also included multiple different fracture sites, fracture patterns, and initial treatment methods, which increases the number of variables that can influence the outcome significantly. The compliance rate of our patients was not documented, although the Exogen device routinely monitors compliance, which according to Exogen’s own available data demonstrates a high level of treatment compliance [10].
This study demonstrated a high success rate of LIPUS therapy for patients with delayed and non-union. This included a wide range of fracture sites, fracture patterns, and initial treatment options, which did not adversely affect the result. There was no association identified between union rates and diabetes, smoking, or age. An essential consideration to take into account prior to starting LIPUS therapy is the interfragmentary gap, as an increase in size is associated with poorer success rates.
Although there is still controversy regarding the effectiveness of LIPUS, it is undeniable at this point that it represents a low-risk, non-invasive alternative to revision surgery with multiple studies demonstrating promising results. Further research is nevertheless indicated in the form of high-quality large randomised controlled trials to more clearly demonstrate the role of LIPUS in delayed as well as non-union.
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedic Surgery, St. James's Hospital, Dublin, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Trauma and Orthopaedics, Letterkenny University Hospital, Letterkenny, IRL
Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Pretorius J, Mohamed Y, Mustafa A, et al. (September 16, 2022) A Retrospective Study: Is Low-Intensity Pulsed Ultrasound (LIPUS) an Effective Alternate Treatment Option for Non-union?. Cureus 14(9): e29230. doi:10.7759/cureus.29230
Peer review began: September 04, 2022 Peer review concluded: September 12, 2022 Published: September 16, 2022
© Copyright 2022 Pretorius et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
LIPUS = low-intensity pulsed ultrasound.
DHS = dynamic hip screw; N/A = not applicable.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. Learn more here.
This link will take you to a third party website that is not affiliated with Cureus, Inc. Please note that Cureus is not responsible for any content or activities contained within our partner or affiliate websites.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. SIQ™ assesses article importance and quality by embracing the collective intelligence of the Cureus community-at-large. All registered users are invited to contribute to the SIQ™ of any published article. (Authors cannot rate their own articles.)
High ratings should be reserved for work that is truly groundbreaking in its respective field. Anything above 5 should be considered above average. While all registered Cureus users can rate any published article, the opinion of domain experts is weighted appreciably more than that of non-specialists. An article’s SIQ™ will appear alongside the article after being rated twice and is recalculated with each additional rating.
Visit our SIQ™ page to find out more.
Scholarly Impact Quotient™ (SIQ™) is our unique post-publication peer review rating process. SIQ™ assesses article importance and quality by embracing the collective intelligence of the Cureus community-at-large. All registered users are invited to contribute to the SIQ™ of any published article. (Authors cannot rate their own articles.)
Already have an account? Sign in.
Please note that by doing so you agree to be added to our monthly email newsletter distribution list.
By joining Cureus, you agree to our Privacy Policy and Terms of Use.