Ultrasound for Fracture Healing: Low Intensity Pulsed Ultrasound - LIPUS

 

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Introduction

Reviews & Clinical Evidence

Recent (2022-2022) Evidence and Reviews

References

 
Introduction

Numerous recent papers have identified the benefits of using therapeutic ultrasound for both normally healing (fresh) fractures and those that demonstrate either a delayed union or non union (e.g. Mayr et al 2000, Busse et al 2002, Warden et al 1999). Ultrasound has been historically considered to be a contraindication is these circumstances, though the exact reason for this remains unclear. Given the volume and quality of the published evidence, it would be entirely inappropriate for fractures to remain on the contraindication list.

The ultrasound application which is evidenced for this type of application is commonly referred to as LOW INTENSITY PULSED ULTRASOUND (or LIPUS). The does delivered is both SPECIFIC to this treatment and it is much LOWER than delivered from standard therapy machines.

[In recent years, the term LIPUS is being more widely employed as a way of differentiating from High Intensity Pulsed Ultrasound (HIFU) and so when searching the literature, the LIPUS term is now no longer 'exclusive' to the fracture and bone healing material on this page - just a note of caution.]

DOSE : Full details are included on the downloadable pdf file, (LINK HERE) but summarised thus :

1.5MHz
0.03 W cm-2 (sometimes described as 30mW cm-2)
Pulsed at 1:4 (20%) at 1000Hz
20 minutes, daily

It can be clearly seen this this application is not routinely available on most existing machines

Two existing machines (that I am aware of) can deliver this treatment :

Exogen series of machines which was from Smith + Nephew but is NOW available from Bioventus

OSTEOTRON device from EMS Physio (in the UK) or ITO (Japan). Sure it is available elsewhere, just that I am not aware of specific distributors.

 
Reviews & Clinical Evidence

A systematic review and meta-analysis (Busse et al 2002) has carefully considered the evidence in respect to the effect of low intensity pulsed ultrasound on the time to fracture healing. They conclude that the evidence from randomised trials where the data could be pooled (3 studies, 158 fractures) that the time to fracture healing was significantly reduced in the ultrasound treated groups than in the control groups and the mean difference in healing time was 64 days.

Warden et al (1999) published a review paper concluded that from animal and human studies, the use of ultrasound could accelerate the rate of fracture repair by a factor of 1.6. The unit utilised for this work (Sonic Accelerated Fracture Healing System – SAFHS) delivers a low intensity (0.03 W cm-2) at 1.5MHz pulsed at a ratio of 1:4. Whilst this dose may be reproducible by standard therapeutic machines, the SAFHS device has a particularly low BNR and thus is considered to be safe to apply with a stationary treatment head, unlike conventional physiotherapy ultrasound machines. This could be an important factor as treatment was for 20 minutes daily, with the patient using the device rather than attending for therapy.

Heckman et al (1994) demonstrated a 38% reduction in the healing time for tibial fractures using the SAFHS device whilst Kristiansen et al (1997) demonstrated a 30% acceleration in healing for fractures of the radius. Jensen (1998) identifies the beneficial effects of ultrasound in the treatment (as opposed to the diagnosis) of stress fractures with an overall success rate of 96%. The report fails to identify all relevant data for consideration and must therefore be considered with some caution in terms of ‘quality evidence’.

Mayr et al (2000) report a series of outcomes when using low intensity pulsed ultrasound for patients with delayed unions (n=951) and non unions (n=366). The overall success rate for the delayed unions was 91% for the delayed and 86% for the non unions.

The authors undertook an interesting stratified analysis of their patients, and identified that those who were using non steroidal anti inflammatory drugs, calcium channel blockers or steroids had a less favourable outcome, a finding that could be considered to be consistent with several research publications that have tried to identify the mechanism by which the ultrasound could bring about fracture healing acceleration and other wider research concerning the adverse influence of NSAID’s on tissue repair (e.g. Tsai et al 2004, Evans & Butcher2004).

The use of such low doses has been shown to result in non significant increases in tissue temperature. Using higher ultrasound doses could have an adverse effect on the fracture healing process and the low intensity pulsed system is considered to be effective and safe for this patient group. Reher et al (1997) demonstrated a stimulative effect at low dose (0.1 W cm-2) whilst an inhibitory effect at a higher dose (1 – 2 W cm-2). Chang et al (2002) demonstrated that the effect of low intensity pulsed ultrasound in these circumstances was achieved by non thermal mechanisms rather than as a phenomenon secondary to thermal effects.

The mechanisms by which therapeutic ultrasound can be effective for fracture repair includes nitric oxide (NO) pathways and prostaglandin (PGE2) (Reher et al 2002, Warden et al 2001, Kobubu et al 1999). This too would be consistent with other proposed mechanisms of ultrasound action (ter Haar 1999) and the relationship between the use of NSAID’s and tissue repair following injury.

Both Tis et al (2002) and Sakurakichi et al (2004) have evaluated the use of ultrasound as a component of treatment (in an animal model) during distraction osteogenesis, and both have demonstrated significant benefits. Cook et al (2001) have demonstrated similar benefits following spinal fusion surgery and Tanzer et al (2001) have shown that the use of ultrasound in combination with porous intramedullary implants is also beneficial. There are many other studies concerning the use of US and bone repair, but essentially the published work shows a consistent benefit, and the use of low intensity pulsed ultrasound for patients with bone related disorders, including normally healing fractures, stress fractures, delayed and non unions and as a post surgical intervention should be considered positively.

One study (Schortinghuis et al 2004) that employed the SAFHS ultrasound system yet failed to demonstrate a significant effect (following deliberate bone injury – rat model) is probably related to the additional inclusion of a PTFE membrane – a GoreTex® like material). This would almost certainly not enable adequate ultrasound energy transmission due to the porous nature of the material, and the consequent air trapping, leading to ultrasound energy reflection.

The SAFHS system is not the only ultrasound device employed for the clinical management of fractures, and a recent paper (Lerner et al 2004) describes the use of an alternative (Exogen) system with 17 ‘case studies’. The Exogen device is additionally described in several other review papers.

The Warden et al (1999) paper provides a useful review for therapists wishing to update their knowledge in the area and who want to go beyond the material on these pages.

 
Recent Evidence

Since initially composing this page, there have been a plethora of papers and reviews published concerning the use of LIPUS applications with frest fractures, delayed and non-unions - in fact I now have over 500 such papers in my database - and I am pretty sure that this is not a complete list.

I have identified (below) some of the key papers and reviews since 2020 for those who want to catch up with the current state of the art. The reviews will provide a swift access of many original RCT and clinical studies

Reviews

Yang, J. et al (2022) Efficacy of adjuvant treatment for fracture nonunion/delayed union: a network meta-analysis of randomized controlled trials BMC Musculoskeletal Disorders 23(1): 481

This review considers multiple interventions for fracture delayed / non-union - including LIPUS - which as an intervention, is supported
 

Palanisamy, P. et al (2022) Low-Intensity Pulsed Ultrasound Stimulation for Bone Fractures Healing: A Review J Ultrasound Med 41(3): 547

This review considers clinical effectiveness together with mechanisms of action - with fresh fractures, delayed and non-unions. The authors conclude "Overall, LIPUS has shown positive results on bone fracture healing through the molecular, biological, and biomechanical
changes around the fracture site. It has been proven to accelerate the bone formation in fresh fractures, delayed unions, nonunions, and distraction osteogenesis. LIPUS treatment is recommended as a safe therapy when compared to existing fracture treatments, and can be used as an adjunctive therapy to accelerate the bone healing process for fresh fractures, delayed fractures, and nonunions."

Elmajee, M. et al (2022) The perceptions of clinicians using low-intensity pulsed ultrasound (LIPUS) for orthopaedic pathology: A national qualitative study Injury
This review considers the results of a (UK) survey considering LIPUS use for fracture healing. The authors conclude "LIPUS technology may have a significant role to play in the treatment of orthopaedic fracture related pathology. Regular users perceived the technology to be cost-effective and efficacious."

Puts, R. et al (2021) Pulsed ultrasound for bone regeneration - outcomes and hurdles in the clinical application: a systematic review Eur Cell Mater 41: 281
This review tackles some of the controversies that have emerged in the more recent published literature - and some of the apparent discrepancies in results and conclusions reached.

Leighton, R. et al (2021) Low intensity pulsed ultrasound (LIPUS) use for the management of instrumented, infected, and fragility non-unions: a systematic review and meta-analysis of healing proportions BMC Musculoskeletal Disorders 22(1): 532
Nice review which considers 'problematic' fracture healing based on N=29 studies. The authors conclude "This study has provided a thorough overview of the current literature on LIPUS treatment for instrumented, infected, and fragility fracture non-unions. The healing rates for non-unions in these subgroups were comparable to healing rates observed with LIPUS use in general non-union literature. LIPUS treatment should be considered as a conservative non-surgical treatment option to potentially reduce the socioeconomic impact and improve the quality of life of these unfortunate patients."

Harrison, A. & Alt, V. (2021) Low-intensity pulsed ultrasound (LIPUS) for stimulation of bone healing - A narrative review Injury 52 Suppl 2: S91
The broadly scoped review also tackles some of the comtroversites and mixed results - especially regarding poor results with internally fixed fractures.

Majeed, H. et al (2020) 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 Foot Ankle Surg 26(4): 405
There are several papers which have looked at the use of LIPUS in the fott and ankle - this review provides a useful overview. The authors conclusions are positive "Exogen for established nonunion in the foot and ankle is a safe, valuable and economically viable clinical option as an alternative to revision surgery. We observed better results in the fracture and midfoot/forefoot groups and relatively poorer results in the hindfoot fusion group."

Elvey, M. H. et al (2020) The use of low-intensity pulsed ultrasound in hand and wrist nonunions J Plast Surg Hand Surg 54(2): 101
Many studies (and reviedws) only really consider lower linb fractures and unions. This paper specifically looks at wrist and hand issues. While the healing rates may not be a profound as for the lower limb, the treatment still has positive effects and clinical benefits when surgery is not a viable option.

Berber, R. et al (2020) Low Intensity Pulsed Ultrasound Therapy (LIPUS): A review of evidence and potential applications in diabetics J Clin Orthop Trauma 11(Suppl 4): S500
Interesting take on the classical review - specifically looking at LIPUS use for fractures in patients with diabetes. Actually includes both animal and human studies but provides some useful insights.

I will not go on to list all the non-review papers (would get somewhat arduous) but sure that if I can find them, then so can the interested reader

 
References:

Busse, J. W., M. Bhandari, et al. (2002). "The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis." CMAJ 166(4): 437-41.

 

Chang, W. H., J. S. Sun, et al. (2002). "Study of thermal effects of ultrasound stimulation on fracture healing." Bioelectromagnetics 23(4): 256-63.

 

Cook, S. D., S. L. Salkeld, et al. (2001). "Low-intensity pulsed ultrasound improves spinal fusion." The Spine Journal 1: 246-254.

 

Evans, C. E. and C. Butcher (2004). Journal of Bone and Joint Surgery 86-B(3): 444-449.

 

Heckman, J. D., J. P. Ryaby, et al. (1994). "Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound." J Bone Joint Surg Am 76(1): 26-34.

 

Jensen, J. E. (1998). "Stress fracture in the world class athlete: a case study." Med Sci Sports Exerc 30(6): 783-7.

 

Kristiansen, T. K., J. P. Ryaby, et al. (1997). "Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study." J Bone Joint Surg Am 79(7): 961-73.

 

Lerner, A., H. Stein, et al. (2004). "Compound high-energy limb fractures with delayed union: our experience with adjuvant ultrasound stimulation (exogen)." Ultrasonics 42: 915-917.

 

Mayr, E., V. Frankel, et al. (2000). "Ultrasound--an alternative healing method for nonunions?" Arch Orthop Trauma Surg 120(1-2): 1-8.

 

Reher, P., N. I. Elbeshir el, et al. (1997). "The stimulation of bone formation in vitro by therapeutic ultrasound." Ultrasound Med Biol 23(8): 1251-8.

 

Reher, P., M. Harris, et al. (2002). "Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts." Bone 31(1): 236-41.

 

Sakurakichi, K., H. Tsuchiya, et al. (2004). "Effects of timing of low-intensity pulsed ultrasound on distraction osteogenesis." J Orthop Res 22: 395-403.

 

Schortinghuis, J., J. L. Rubenb, et al. (2004). "Therapeutic ultrasound to stimulate osteoconduction A placebo controlled single blind study using e-PTFE membranes in rats." Archives of Oral Biology 49: 413-420.

 

Tanzer, M., S. Kantor, et al. (2001). "Enhancement of bone growth into porous intramedullary implant using non-invasive low intensity ultrasound." J Orthop Res 19: 195-199.

 

ter Haar, G. (1999). "Therapeutic Ultrsound." Eur J Ultrasound 9: 3-9.

 

Tis, J. E., R. H. Meffert, et al. (2002). "The effect of low intensity pulsed ultrasound applied to rabbit tibiae during the consolidation phase of distraction osteogenesis." J Orthop Res 20: 793-800.

 

Tsai, W.-C., F.-T. Tang, et al. (2004). "Ibuprofen inhibition of tendon cell proliferation and upregulation of the cyclin kinase inhibitor p21CIP1." Journal of Orthopaedic Research 22(3): 586-591.

 

Warden, S., K. Bennell, et al. (1999). "Can conventional therapeutic ultrasound units be used to accelerate fracture repair?" Phys Ther Rev 4: 117-126.

 

Warden, S. J., J. M. Favaloro, et al. (2001). "Low-intensity pulsed ultrasound stimulates a bone-forming response in UMR-106 cells." Biochem Biophys Res Commun 286(3): 443-50.