The Use of Ultrasound to Accelerate Fracture Healing

http://www.ortho.hyperguides.com/index.php?option=com_content&view=article&id=1938

David J. Hak, MD, MBA
Denver Health 
University of Colorado
Denver, CO

Numerous studies in animals and humans have shown that low-intensity pulsed ultrasound accelerates fracture healing. The characteristics of the commercially available low intensity pulsed ultrasound device to aid fracture healing (Exogen, Smith and Nephew. Memphis, TN) are a frequency of 1.5 MHz, a signal burst width of 200 microns, a signal repetition frequency of 1 kHz, and an intensity of 30 mW/cm2.  

Mechanism of Action

Although the exact mechanism of action has been debated, it is theorized that ultrasound pressure waves influence biologic activity either directly by deformation of the cell membrane or extracellular matrix, or indirectly through an electrical effect caused by cell deformation. Low-intensity pulsed ultrasound has been shown in vivo to accelerate all stages of the fracture repair process - inflammation, soft callus formation, hard callus formation. Ultrasound treatment also has been shown to accelerate mineralization in vitro with increases in osteocalcin, alkaline phosphatase, VEGF and MMP-13 expression.¹

Human clinical studies

Among the clinical trials of low-intensity pulsed ultrasound on fracture healing conducted in humans are several small prospective randomized studies. Heckman et al performed a prospective, randomized, double blind, placebo-controlled study of 67 closed or type I open tibial fractures.²Â Patients were randomly assigned either an active ultrasound device or a placebo device. The device was applied for 20 minutes per day for 20 weeks or until the investigator felt the fracture had healed. All patients were treated by closed reduction and cast immobilization. The acceleration of fracture healing seen in patients treated with the active ultrasound device was statistically significant when measured by both clinical and radiographic criteria. The overall time to healing, including both clinical and radiographic criteria, was 96 days (standard deviation ± 4.9 days) in the patients treated with the active ultrasound device compared with 154 days (SD ± 13.7 days) in the patients treated with the placebo device (P=.0001).

Kristiansen et al performed a multicenter, prospective, randomized, double blind, placebo-controlled study of 61 patients with distal radius fractures treated by closed reduction and short arm cast.³Â Patients were again randomly assigned either an active ultrasound device or a placebo device. The device was applied for 20 minutes per day for 10 weeks. Time to healing in the fractures treated with the active ultrasound device was significantly shorter than those treated with the placebo device. The mean time to healing in the ultrasound treatment group was 61 days (SD ± 3 days) compared with 98 days (SD ± 5 days) in the patients treated with the placebo device (P<.0001). In addition, there was a significant decrease in volar angulation reduction loss in patients treated with ultrasound (P<.01). 

Because smoking has been shown to slow fracture healing, Cook et al performed a subgroup analysis of these two studies, comparing the results of patients who were smokers with those that were nonsmokers.⁴ The researchers reported that the use of low-intensity ultrasound accelerated both tibial and distal radius fracture healing in patients who smoke. Tibial fracture healing time was decreased by 41% in smokers and by 36% in nonsmokers compared with the placebo group. In patients with distal radius fractures, treatment with ultrasound reduced the healing time by 51% in smokers and by 34% in nonsmokers.  

Emami et al performed a prospective, randomized, double blind, placebo-controlled study of 30 patients with tibial shaft fractures treated with a reamed intramedullary nail.⁵ Patients were randomly assigned either an active ultrasound device or placebo. The investigators found that ultrasound had essentially no effect on fracture healing. In fact, the results of this study have lead some surgeons to speculate that the presence of an intramedullary nail attenuates the ultrasound waves, diminishing any beneficial effects.  One criticism of this study is the small number of patients, which may have reduced the power and increased the risk that their nonsignificant result may be due to a statistical Type II error.

A current ongoing clinical study, Trial to Evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST), is being conducted to evaluate the safety and efficacy of low-intensity pulsed ultrasound applied to tibial fractures treated with intramedullary nailing.⁶ This is a randomized, placebo-controlled clinical trial that plans to enroll 500 patients.  The primary outcome measure is radiographic fracture healing, and the secondary outcome measure is the rate of tibial nonunion formation.
    
Ultrasound has also been evaluated in the treatment of scaphoid fractures, clavicle, fibula, delayed unions, and nonunions.^7-13 Although many of these studies have shown fracture healing acceleration, some have shown no effect.^5,8,9 For cases of delayed union and nonunion the reported overall success rate of ultrasound treatment in the various studies is approximately 67% in the humerus, 82% in the femur, and 87% in the tibia.¹⁴

Summary

Low-intensity pulsed ultrasound has been shown to accelerate fracture healing in several small prospective randomized studies. However, further investigation with larger scale well-designed prospective randomized clinical studies is warranted to better determine the effectiveness and optimal indication for the use of ultrasound in patients with fractures.

References

1. Pounder NM, Harrison AJ. Low intensity pulsed ultrasound for fracture healing: a review of the clinical evidence and the associated biological mechanism of action. Ultrasonics. 2008;48:330-338.

2. Heckman JD, Ryaby JP, McCabe J, Frey JJ, Kilcoyne RF. Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. J Bone Joint Surg Am. 1994;76:26-34.

3. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. 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. 1997;79:961-973.

4. Cook SD, Ryaby JP, McCabe J, Frey JJ, Heckman JD, Kristiansen TK.  Acceleration of tibia and distal radius fracture healing in patients who smoke. Clin Orthop Relat Res. 1997;337:198-207.

5. Emami A, Petrén-Mallmin M, Larsson S. No effect of low-intensity ultrasound on healing time of intramedullary fixed tibial fractures. J Orthop Trauma. 1999;13:252-257.

6. ClinicalTrails.gov. Trial to evaluate ultrasound in the treatment of tibial fractures (TRUST). http://clinicaltrials.gov/ct2/show/NCT00667849?term=TRUST&rank=6. Access June 7, 2011.

7. Mayr E, Rudzki MM, Rudski M, Borchardt B, Hausser H, Ruter A. Does low does intensity, pulsed ultrasound speed healing of scaphoid fractures? Handchir Mikrochir Plast Chir. 2000;32:115-122.

8. Lubbert PH, van der Rijt RH, Hoorntje LE, van der Werken C. Low-intensity pulsed ultrasound (LIPUS) in fresh clavicle fractures: a multi-centre double blind randomised controlled trial. Injury. 2008;39:1444-1452.

9. Handolin L, Kiljunen V, Arnala I, Pajarinen J, Partio EK, Rokkanen P. The effect of low intensity ultrasound and bioabsorbable self-reinforced poly-L-lactide screw fixation on bone in lateral malleolar fractures. Arch Orthop Trauma Surg. 2005;125:317-321.

10. Jingushi S, Mizuno K, Matsushita T, Itoman M. Low-intensity pulsed ultrasound treatment for postoperative delayed union or nonunion of long bone fractures.  J Orthop Sci. 2007 Jan;12(1):35-41.

11. Schofer MD, Block JE, 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. BMC Musculoskelet Disord. 2010;11:229.

12. Nolte PA, van der Krans A, Patka P, Janssen IM, Ryaby JP, Albers GH. Low-intensity pulsed ultrasound in the treatment of nonunions. J Trauma. 2001;51:693-702.

13. Pigozzi F, Moneta MR, Giombini A, et al. Low-intensity pulsed ultrasound in the conservative treatment of pseudoarthrosis. J Sports Med Phys Fitness. 2004;44:173-178.

14. Watanabe Y, Matsushita T, Bhandari M, Zdero R, Schemitsch EH. Ultrasound for fracture healing: current evidence. J Orthop Trauma. 2010;24 Suppl 1:S56-61.

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