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]. This success led to clinical trials and the 1994 approval of LIPUS in the United States for the accelerated healing of certain fresh fractures. LIPUS was approved in the US for the treatment of established non-unions in 2000, and is also approved around the world. In this article, we present relevant literature on the effect of LIPUS on bone healing in patients with acute fractures and non-unions and provide a molecular explanation for the effects of LIPUS on bone healing. Data on LIPUS accelerated fracture repair is controversial with many controlled studies showing a positive effect. However, the largest trial in acute tibial fractures stabilized with an intramedullary nail failed to show significant differences in accelerated healing and in functional outcomes. Uncontrolled data from prospective case series suggest a positive effect of LIPUS in non united fractures with healing rates of around 85%. Evaluation of results from studies, both positive and negative, has enabled an understanding that the patient population with potentially the greatest benefit from receiving LIPUS are those at-risk for fracture healing, e.g. diabetic & elderly patients. The elucidation of a pathway to activate the Rac-1 pathway by LIPUS might explain this beneficial effect. Overall, there is a strong need for further clinical trials, particularly for acute fractures at risk of progressing to non-union and in established non-unions including a comparison to the current standard of care.
], the rate of non-union may be increasing as the survival rate for patients with severe injuries improves. Risk of non-union is related to the severity of injury resulting in fracture, and randomized clinical trials have shown that variations in non-union rates are associated with different surgical treatments [
Ultrasound is an oscillating longitudinal pressure wave with a frequency that cannot be detected by human auditory systems with frequency generally greater than 20 kHz. Ultrasound is used in numerous medical applications, including low intensity bursts of ultrasound for diagnostic imaging, medium intensity ultrasound used in physical therapy, and high intensity focused ultrasound for surgical excision. Despite their similar intensities, diagnostic and therapeutic ultrasound and low-intensity pulsed ultrasound (LIPUS) have different biological effects. LIPUS treatment for bone repair utilizes a transducer that is placed on the surface of the skin over the fracture site for a 20 minute period once a day. The LIPUS signal constitutes ultrasound at 1.5 MHz and pulsed at 1 kHz and 30 mW/cm2 (SATA) [
]. LIPUS has been used clinically for over 20 years and over that time the key points for success have been evaluated by researchers and clinicians. A number of LIPUS devices are available in the European Union (EU) with various studies supporting their use (Table 1).
Table 1Approved devices of LIPUS in EU and available clinical data.
Studies on distraction osteogenesis, joint fusion and bone transport have been excluded from this table. Studies are comprised of greater than 5 subjects.
Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion.
Ist niedrig-intensiver Ultraschall bei der Behandlung von Frakturheilungsstörungen wirksam? [Is low intensity ultrasound effective in treatment of disorders of fracture healing?].
Clinical and patient-reported outcomes following Low Intensity Pulsed Ultrasound (LIPUS, Exogen) for established post-traumatic and post-surgical nonunion in the foot and ankle.
Efficacy of low-intensity pulsed ultrasound treatment for surgically managed fresh diaphyseal fractures of the lower extremity: multi-center retrospective cohort study.
Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study.
Does pulsed low intensity ultrasound allow early return to normal activities when treating stress fractures? A review of one tarsal navicular and eight tibial stress fractures.
], 767 chronic fractures, not healed at 12 months, were identified in a non-controlled cohort study with four data points; date the fracture occurred, a date when LIPUS treatment was started, a date when LIPUS treatment was terminated and a decision on fracture healing described as healed/failed as determined by the treating physician. Patients had an average of 3.1 surgical procedures before starting LIPUS therapy. Overall, the heal rate in the 767 fractures was 86.2%, 98 patients in the cohort had a fracture of greater than five years and the heal rate in these fractures was 82.7%. A small number of patients had a fracture greater than 10 years old and 63.2% of these fractures were shown to have healed with LIPUS therapy. Overall, this data demonstrates that LIPUS has the potential to positively affect healing of chronic non-union fractures, even if prior surgical procedures have failed. The overall conclusions, however, are limited by the uncontrolled design of the study.
] was conducted which identified 13 clinical studies reporting the effects of LIPUS on 1441 non-unions. When a definition of non-union being set as fracture age of at least 8 months duration, the pool estimate of effect size was 84%, in 9 studies with 239 participants for any anatomical site. In January 2013, the National Institute for Health and Care Excellence (NICE) in the UK, evaluated the data for LIPUS treated for non-union fractures, the studies evaluated were specific to the product Exogen. This Institute produced medical technology guidance (MTG-12) that stated in clause 1.1 ‘The case for adopting the Exogen ultrasound bone healing system to treat long bone fractures with non-union is supported by the clinical evidence, which shows high rates of fracture healing’ and in clause 1.2 ’The Exogen ultrasound bone healing system to treat long bone fractures with non-union is associated with an estimated cost saving of £1164 per patient compared with current management, through avoiding surgery’ [
]. In a study that evaluated LIPUS for the treatment of delayed-union of fifth metatarsal fractures, it was demonstrated that appropriate use of LIPUS equates to a cost saving of £7765 a year [
] if there was a lack of clinical and radiologic evidence of union, bony continuity or bone reaction after a fracture of the tibia for no less than 16 weeks from the index injury or the most recent intervention. Patients were treated for 16 weeks with either an active or sham device, then evaluated for signs of healing. The primary outcome measure was achieved with a significant increase in bone mineral density at the fracture site in the active group (p = 0.002) and a mean reduction in bone gap area also favored LIPUS treatment (p = 0.014). Although the study was not powered to show a difference in healing, there was an improvement in the LIPUS group, but this did not achieve significance (healing rates: LIPUS: 65% [33/51] sham device: 46% [23/50] p = 0.07).
There is a perception that LIPUS is ineffective in atrophic non-unions. Heal rates in hypertrophic non-unions are generally higher, however, there is still a positive effect in atrophic non-unions. In the Leighton meta-analysis over all studies, hypertrophic healed at 84.7% (139/164) and atrophic/oligotrophic at 76.9% (291/378) [
], the data on acceleration of acute fracture repair is not as clear and reported outcomes are also conflicting.
A prospective, randomized, double-blinded trial in the early 90s looked at the effects LIPUS in tibia shaft fractures as an adjunct to conventional treatment with a cast. The LIPUS group (33 patients) showed a statistically significant increased time to complete healing (96 ± 4.9 days) compared to the cast alone, control group (154 ± 13.7 days) (34 patients) (p = 0.0001) [
]. Another placebo controlled clinical trial from Leung et al. on complex tibial fractures also showed in surgically fixed tibial fractures treated with LIPUS had 40% acceleration in full weight bearing and 42.5% acceleration of radiographic third cortices bridged [
] with an enrollment of 501 tibial shaft fracture patients treated with an intramedullary nailing failed to show significant differences between patients treated with LIPUS vs. sham treatment. There were neither significant differences in time to radiographic healing (p = 0.55) nor in the SF-36 physical component scores between LIPUS and control groups (p = 0.41). However, observations of this study showed that the average age of patients in this study was 38 years, they few had comorbidities (diabetics 6% compared to the US mean of 14% [
]). The fractures were simple (Transverse) and mostly closed (77%) and there was poor compliant use of the device, which will be addressed later in this article. These fractures were stabilized with a locked intra medullary nail. It is hypothesized that tibial shaft fractures in young and healthy patients stabilized with a locked intramedullary nail, might not have room for acceleration by LIPUS, as they were potentially at optimum healing capacity.
The fact that clinical trials with relatively healthy patients with few co-morbidities were not able to replicate the earlier level 1 studies [
] showed that older patients had a greater acceleration of fracture healing than that of younger patients after LIPUS treatment. Patients aged 30 or less had an average acceleration of their fractures by 33%, whereas individuals greater than 30 had an average acceleration of fracture repair of 45%, which in turn brought their healing times down 23 days earlier than the younger cohort without LIPUS treatment [
], showed that by re-analysing level-1 clinical trial data, there were no incidences of delayed-union in patients with a fracture who smoked and treated with LIPUS compared to the smoking group in the placebo arm of the studies where 36% were considered to have developed a delayed-union.
This hypothesis of LIPUS being more beneficial to less heathy patients was also replicated in registry data of acute fractures treated with LIPUS, which reported a healing rate of 95.3% in patients with diabetes mellitus (n=224/235) [
]. For patients ≥60 years of age with diabetes mellitus treated with LIPUS the heal rate was 96.5% (n=110/114). This is compared to 96.2% (n=4,032/4,190) for all fractures in the database treated with LIPUS [
] the data from the registry also demonstrated that increasing age was not a risk factor when fractures are treated with LIPUS. Throughout each decade of life there was no significant decrease in heal rate in fractures treated with LIPUS. This means that patients whose age is between 30-39 have the same healing profile as those greater than 80 years old, if the fracture is treated with LIPUS. The heal rate was significantly higher than the overall heal rate only in patients age 20–29 years of age (p < 0.003). This data suggests that patients with co-morbidities might benefit from LIPUS treatment.
Mechanism of action
The mechanism of action of LIPUS has been explored using basic science methodology with academic groups around the world. One strand of this research at the University of Bristol [
] identified that LIPUS treatment could restore healing times in diabetic and aged animals (18 months old) back to the healing profile of non-comorbid, three month old, wild type animals. Further research at the University of Ulm [
] strongly implicated the role of integrins in the formation of focal adhesions on the surface of LIPUS stimulated cells, which was subsequently validated at the University of Manchester [
]. The group at Manchester showed that LIPUS was able to cause the formation of focal adhesions in the absence of syndecan-4, which are a requirement for formation of focal adhesions in all other systems. Syndecans are type I transmembrane proteins with a core protein modified with glycosaminoglycan chains. There are four members of the syndecan family in mammals, of which three (syndecan 1, 2 and 3) have a restricted tissue distribution, but the fourth (syndecan‑4) is expressed ubiquitously [
]. A pathway linking the formation of focal adhesions to the GTPase, Rac1 has been identified. Two independent groups at the University of Manchester [
] were able to confirm that Rac1 was central to the effect of LIPUS and that pharmaceutical blockage of Rac1 signaling could nullify the effects of LIPUS in an animal model in which LIPUS was demonstrated to accelerate healing [
]. The current working hypothesis is that there are two pathways to activate Rac-1 in order to get healing, the traditional way and through using LIPUS with syndecan 4 involvement (Figure 1).
Figure 1Mechanical (LIPUS) and chemical (fibronectin) stimuli activate Rac1 by different pathways. LIPUS, low intensity pulsed ultrasound; GEF, guanine nucleotide exchange factor; PKC, protein kinase C; CamKII, Calmodulin kinase II; GTP, Guanosine-triphosphate.
Ultrasound stimulates cyclooxygenase-2 expression and increases bone formation through integrin, focal adhesion kinase, phosphatidylinositol 3-kinase, and Akt pathway in osteoblasts.
], resulting in a number of growth factors such as bone morphogenetic proteins (BMPs), transforming growth factor – beta (TGF-B) and vascular endothelial growth factor (VEGF) to be significantly enhanced in fractures [
]. VEGF, a potent angiogenic agent, has been shown to be increased in a diabetic animal model of fracture repair and this was correlated with a significantly greater number of blood vessels in fractures stimulated by LIPUS [
]. LIPUS not only increases growth factors local to the fracture and increases vascularization, but also can also positively enhance the number of CXCR4 positive mesenchymal cells honing to the fracture site compared to controls [
]. It has been demonstrated there is altered expression of stromal derived factor 1 (SDF-1) and CXCR4 during fracture healing diabetes mellitus. In closed transverse fractures in femurs of rats with diabetes mellitus, SDF-1 expression was significantly lower than in the healthy group. However, there was no significant difference in CXCR4 expression levels between the healthy and diabetes mellitus groups at any time point [
]. This would indicate that in diabetes mellitus there is not only an insufficiency in adequate vascular supply to injured tissues but that these tissues also have reduced capacity to recruit cells from the circulating population of mesenchymal cells in which to initiate a repair.
The discovery that LIPUS can signal through alternative pathways to achieve healing is an attractive option for patients with pre-existing medical conditions who have sustained a fracture.
Discussion
The concept of fracture related factors and patient related factors are captured in the Diamond concept of fracture repair as described by Giannoudis, Einhorn and Marsh [
], where 2 of the 4 factors for good fracture repair, providing an osteoconductive matrix and mechanical stability, are directly related to good orthopaedic practice of stabilisation and reduction. In case of obvious unstable fixation or insufficient fracture reduction with a persisting facture gap > 10 mm [
Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion.
], revision surgery should be considered as these cannot be significantly improved by ultrasound treatment. However, the other two factors, growth factors and osteogenic cells, are effected by the patient's own biology. The past decade has seen the rise and decline of the exogenous application of growth factors such as BMPs [
]. Neither of these exogenous applications can guarantee to provide the fracture site with a continuous biological stimulus over the weeks and months it will take the fracture to heal. Ideally, what is required is to stimulate the fracture biologically on a daily basis when the orthopaedic surgeon can see that normal healing is compromised. It is this circumstance where LIPUS can be utilized.
There are three basic issues when considering the clinical data for LIPUS. 1) There is ‘big data’ available on both acute fracture treatment (n = 4,190) and on chronic, greater than 12 month old fractures (n = 767) with healing rates of 96.5% [
] respectively. However, this data is from an uncontrolled cohort registry and must be treated appropriately. 2) There are data on non-union fractures treated with LIPUS, in which 13 eligible papers reporting LIPUS treatment of 1441 non-unions demonstrated a pooled estimate of effect size for heal rate of 82% [
], however all of these studies did not include a placebo arm. This might be associated with the fact that placebo treatment with a sham device can be considered unethical. However, standard of care of an established non-union includes surgical revision, e.g. with bone grafting procedures. Therefore, controlled studies for LIPUS treatment in established non-unions could consider a surgically treated patient as an appropriate control arm. 3) The variability of acute fracture studies to uniformly show an acceleration of fracture repair. It seems that acute noncomplex fractures in young and healthy patients with stable fixation of their fracture cannot be accelerated from additional LIPUS treatment as all four requirements of the Diamond Bone Concept are met.
In patients-at-risk for fracture healing, e.g. diabetic patients, the fact of a potential alternative pathway to activate Rac-1 might be beneficial. This is supported by data from a registry showing healing rates in acute fractures of 96.5% in diabetic patients older than 65 years [
There are a number of parameters that need addressing in order to achieve optimum healing with LIPUS (Table 2). Regarding the clinical application of LIPUS, the number of days of LIPUS use is an important consideration. If, after four months of compliant treatment, any progression of fracture repair can be seen radiologically then the patient's fracture has a 92% chance of union if treatment is continued. However, if after four months of compliant treatment there is no radiological progression it is likely these fractures will fail to heal [
]. Transducer placement should also be considered in deep-seated fractures of the humerus and femur. In cases such as these, the use of ultrasonography to identify and target the fracture should be considered. In a clinical study of delayed unions of the humerus and femur where fracture location was identified with ultrasonography in addition to standard radiographic identification, results showed that the “ultrasonography + x-ray group” had a statistically significantly higher heal rate compared to those who had “x-ray targeting alone” [
]. Patient adherence to usage of the device, or what is commonly known as patient compliance, has been shown to have an effect on the efficacy of LIPUS. In a clinical study of delayed or non-union after femoral and tibial fracture, an LIPUS compliance of ≥80% resulted in a heal rate of 86%, whereas a patient compliance of <80% resulted in a heal rate of 58% [
]. Compliant use of LIPUS devices was also shown to be an issue in a multi-center study of acute fracture where the compliance rate was 43%. The Treatment Compliance [Time Frame: Treatment period: Days from randomization to day of x-ray assessed healed or, if not heal, day of premature withdrawal/study termination or day 365 (end of study visit)], demonstrated that the percent of subjects who used the device greater than or equal to 18 minutes per day over 80% of the days in their treatment period was LIPUS: 44.6% and Placebo: 42.3% [
]. In response to this failure of patients to correctly use the LIPUS devices some manufacturers have developed technology to check the patients use of the device.
Table 2Key considerations for successful treatment with LIPUS.
In this review, we have explained the clinical results for acute fractures and non-unions treated with LIPUS and have provided a molecular explanation of the effects of LIPUS on bone healing. Registry data suggest a positive effect in non-unions and acute fractures, but this data is mainly derived from uncontrolled cohort studies. Randomized controlled trials to evaluate acceleration of fracture repair remain controversial and variable in their outcomes. Non-union studies have the issue of mainly utilizing a self-paired design and do not have a control arm. In patients-at-risk for fracture healing, e.g. diabetic patients and the elderly, a potential alternative pathway to activate Rac-1 might be beneficial.
Overall, there is a strong need for further clinical trials with LIPUS, especially to examine acute fractures at risk of progressing to non-union through issues due to poor biology. Further controlled non-union studies should be designed to compare LIPUS to the current standard of care i.e. surgical intervention.
Declaration of interest
Andrew Harrison is a paid employee of Bioventus who sell and market a LIPUS device known as EXOGEN.
Volker Alt has no conflict of interest.
References
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Duarte LR.
Ultrasonic stimulation of bone callus: clinical applications.
Ultrasound stimulates cyclooxygenase-2 expression and increases bone formation through integrin, focal adhesion kinase, phosphatidylinositol 3-kinase, and Akt pathway in osteoblasts.
Three key factors affecting treatment results of low-intensity pulsed ultrasound for delayed unions and nonunions: instability, gap size, and atrophic nonunion.
Ist niedrig-intensiver Ultraschall bei der Behandlung von Frakturheilungsstörungen wirksam? [Is low intensity ultrasound effective in treatment of disorders of fracture healing?].
Clinical and patient-reported outcomes following Low Intensity Pulsed Ultrasound (LIPUS, Exogen) for established post-traumatic and post-surgical nonunion in the foot and ankle.
Efficacy of low-intensity pulsed ultrasound treatment for surgically managed fresh diaphyseal fractures of the lower extremity: multi-center retrospective cohort study.
Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study.
Does pulsed low intensity ultrasound allow early return to normal activities when treating stress fractures? A review of one tarsal navicular and eight tibial stress fractures.
Consider surgery to address poor reduction and inadequate fixation.
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