Description: 　
Low-intensity pulsed ultrasound (LIPUS) has been investigated as a technique to accelerate healing of fresh fractures, surgically treated closed fractures, delayed unions, nonunions, stress fractures, osteotomy sites, and distraction osteogenesis. LIPUS is administered using a transducer applied to the skin surface overlying the fracture site.

For individuals who have fresh fractures (surgically or nonsurgically managed) who receive LIPUS as an adjunct to routine care, the evidence includes randomized controlled trials (RCTs) and several meta-analyses. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence base has recently evolved with the publication of a large RCT and meta-analysis significantly shifting the weight of the evidence. Conclusions based on several earlier and small RCTs, rated at high risk of bias, showed a potential benefit of LIPUS; however, the large RCT published in 2016, rated at low risk of bias, showed no benefit. A 2017 meta-analysis including only trials with low risk of bias found no difference in days to full weight bearing, pain reduction, or days to radiographic healing. Similarly, the overall results of the meta-analysis found no significant difference in return to work, subsequent operations, or adverse events. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have fracture nonunion or delayed union fracture who receive LIPUS as an adjunct to routine care including surgery, if appropriate, the evidence includes only lower quality studies consisting of a small systematic review in scaphoid nonunions, a meta-analysis of nonunion in various locations, 3 low-quality RCTs, and observational studies. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Reported outcomes in this subgroup of fractures does not include functional outcomes. A wide range of healing rates has been reported across the observational studies with a lack of comparison with routine surgical care, limiting any meaningful interpretation of these results. Additionally, the evidence base on the use of LIPUS in the management of fresh fractures has evolved as described above, and there is no demonstrated physiologic mechanism suggesting differential results of LIPUS in fracture nonunion or delayed union. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have stress fractures, osteotomy sites, or distraction osteogenesis who receive LIPUS as an adjunct to routine care, the evidence includes only lower quality studies consisting of small RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Results do not generally include functional outcomes and results across various outcomes, primarily time to radiographic healing, are inconsistent. Additionally, the evidence base on the use of LIPUS in the management of fresh fractures has evolved as described above and there is no demonstrated physiologic mechanism suggesting differential results of LIPUS in stress fractures, osteotomy sites, or distraction osteogenesis. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
BONE FRACTURES
An estimated 7.9 million fractures occur annually in the United States. Most bone fractures heal spontaneously over several months following standard fracture care (closed reduction if necessary, followed by immobilization with casting or splinting). However, approximately 5% to 10% of all fractures have delayed healing, resulting in continued morbidity and increased utilization of health care services.¹ Factors contributing to a nonunion include which bone is fractured, fracture site, the degree of bone loss, time since injury, the extent of soft tissue injury, and patient factors (e.g., smoking, diabetes, systemic disease).¹  

Fracture Nonunion
There is no standard definition of a fracture nonunion.² The Food and Drug Administration has defined nonunion as when "a minimum of 9 months has elapsed since injury, and the fracture site shows no visibly progressive signs of healing for a minimum of 3 months." Other definitions cite 3 to 6 months of time from the original injury, or simply when serial radiographs fail to show any further healing. These definitions do not reflect the underlying conditions in fractures that affect healing, such as the degree of soft tissue damage, alignment of the bone fragments, vascularity, and quality of the underlying bone stock.  

Delayed Union
Delayed union is generally considered a failure to heal between 3 and 9 months post fracture, after which the fracture site would be considered a nonunion. The delayed union may also be defined as a decelerating bone healing process, as identified in serial radiographs. (In contrast, nonunion serial radiographs show no evidence of healing.) It is important to include both radiographic and clinical criteria to determine fracture healing status. Clinical criteria include the lack of ability to bear weight, fracture pain, and tenderness on palpation.

Treatment
Low-intensity pulsed ultrasound (LIPUS) has been proposed to accelerate healing of fractures. LIPUS is believed to alter the molecular and cellular mechanisms involved in each stage of the healing process (inflammation, soft callus formation, hard callus formation, and bone remodeling). The mechanism of action at the cellular level is not precisely known, but it is theorized that LIPUS may stimulate the production or the activities of the following compounds that contribute to the bone healing process: cyclooxygenase-2, collagenase, integrin proteins, calcium, chondroblasts, mesenchymal cells, fibroblasts, and osteoblasts.

LIPUS treatment is self-administered, once daily for 20 minutes, until the fracture has healed, usually for 5 months.

Regulatory Status 
In 1994, the Sonic Accelerated Fracture Healing System (SAFHS^®; currently called Exogen 2000^®; Bioventus) was initially approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process for treatment of fresh, closed, posteriorly displaced distal radius (Colles) fractures, and fresh, closed, or grade I open tibial diaphysis fractures in skeletally mature individuals when these fractures are orthopedically managed by closed reduction and cast immobilization. In February 2000, the labeled indication was expanded to include the treatment of established nonunions, excluding skull and vertebra. FDA product code: LPQ. 

Policy: 
Low-intensity pulsed ultrasound may be considered NOT MEDICALLY NECESSARY as a treatment of fresh fractures (surgically managed or nonsurgically managed).

Low-intensity pulsed ultrasound may be considered NOT MEDICALLY NECESSARY as a treatment of fracture nonunion and delayed union fractures.

Low-intensity pulsed ultrasound may be considered NOT MEDICALLY NECESSARY as a treatment of stress fractures, osteotomy, and distraction osteogenesis.  

Policy Guidelines: 
FRESH (ACUTE) FRACTURE
There is no standard definition for a "fresh" fracture. A fracture is most commonly defined as fresh for 7 days after the fracture occurs (Heckman et al., 1994; Kristiansen et al., 1997; Emami et al., 1999), but there is definitional variability. For example, 1 study defined fresh as less than 5 days after fracture (e.g., Lubbert et al., 2008), while another defined fresh as up to 10 days postfracture (Mayr et al. [Does low intensity, pulsed ultrasound speed healing of scaphoid fractures?] [German]. Handchir Mikrochir Plast Chir. Mar 2000;32(2):115-122). Most fresh closed fractures heal without complications using of standard fracture care (i.e., closed reduction and cast immobilization).

NONUNION
There is no consensus on the definition of nonunions. One definition is a failure of progression of fracture healing for at least 3 consecutive months (and at least 6 months postfracture) accompanied by clinical symptoms of delayed/nonunion (pain, difficulty weight bearing; Buza & Einhorn, 2016).

The definition of nonunion used in U.S. Food and Drug Administration labeling suggests that nonunion is considered established when the fracture site shows no visibly progressive signs of healing, without providing guidance on the timeframe of observation. The following patient selection criteria are consistent with those proposed for electrical stimulation as a treatment of nonunions (see evidence review 70107):

• At least 3 months have passed since the date of the fracture.
• Serial radiographs have confirmed that no progressive signs of healing have occurred.
• The fracture gap is 1 cm or less.
• The patient can be adequately immobilized and, based on age, is likely to comply with non-weight-bearing.

DELAYED UNION
Delayed union is defined as a decelerating healing process as determined by serial radiographs, together with a lack of clinical and radiologic evidence of union, bony continuity, or bone reaction at the fracture site for no less than 3 months from the index injury or the most recent intervention.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

The transducer used for ultrasound treatment is categorized as durable medical equipment.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Low-Intensity Pulsed Ultrasound
Systematic Reviews
A systematic review by Schandelmaier et al. (2017) provides the most comprehensive and rigorous overview and analysis of the existing evidence, including 26 RCTs that used low-intensity pulsed ultrasound for bone healing.³ Additional systematic reviews or meta-analyses are listed in Table 1. However, because there is a substantial degree of overlap in the studies included in these reports (Table 2), we will primarily focus on the findings of Schandelmaier et al. (2017), which include analyses that highlight the results of RCTs identified as of higher quality. The meta-analysis by Seger et al. (2017) analyzed healing index and average time to union following use of low-intensity pulsed ultrasound in cases of scaphoid nonunion, but it did not report control group comparisons.⁴ The systematic review by Lou et al. (2017)⁵ focused on fresh fractures and the review by Leighton et al. (2017)⁶ focused on nonunions. All systematic reviewers acknowledged that the evidence for the use of the positions on low-intensity pulsed ultrasound has methodologic limitations (Table 1).

Table 1. Systematic Reviews Assessing Use of Low-Intensity Pulsed Ultrasound To Treat Fractures

Study	No. of Studies	Study Designs	No. of Subjects	Types of Fractures	Main Conclusions on Low-intensity Pulsed Ultrasound
Schandelmaier et al. (2017)3	26	RCT	1,593	Multiple types	Based on moderate- to high-quality evidence in fresh fracture, low-intensity pulsed ultrasound does not improve outcomes important to patients and is unlikely to affect radiographic bone healing
Seger et al. (2017)4	5	CS Registry	166	Nonunion	Encouraging results for consideration as nonoperative alternative in select cases
Lou et al. (2017)5	12	RCT; Quasi-RCT	1,099	Fresh fracture	Positive results though strength of the evidence is limited
Leighton et al. (2017)6	13	RCT; CS Cohort Registry	1,441	Nonunion	Potential benefit of low-intensity pulsed ultrasound; however, no evidence that low-intensity pulsed ultrasound can be used instead of surgery. May be useful in patients for whom surgery is high-risk.
Griffin et al. (2014)7	12	RCT; Quasi-RCT	648	Multiple types	Cannot rule out potential benefit but evidence insufficient
Busse et al. (2009)8	13	RCT	563	Multiple types	Promising results but moderate- to low-quality evidence

CS: case series; RCT: randomized controlled trial.

The study populations in RCTs included by Schandelmaier et al. (2017) examined multiple types of fractures including fresh fractures surgically managed (n = 7), fresh fractures not surgically managed (n = 6), distraction osteogenesis (n = 5), nonunion fractures (n = 3), osteotomy (n = 3), and stress fractures (n = 2). The RCTs had a median population size of 30 patients (range, 8 to 501 patients).

The outcomes examined by this systematic review emphasized those reported by patients to be most important: functional recovery (e.g., time to return to work, time to full weight-bearing); pain reduction; and number of subsequent operations. Additional outcomes included time to radiographic healing, because this may be used by physicians to influence clinical decision making and adverse events associated with low-intensity pulsed ultrasound.

In this systematic review, 2 reviewers independently assessed the quality of selected RCTs, using GRADE, a modified Cochrane risk of bias tool. Generation of randomization sequence, concealment of allocation, and blinding of patients, caregivers, and outcome reporting were evaluated in each trial. Each outcome within each trial was assessed for blinding of outcome assessors, loss to follow-up, and additional limitations. Trial authors were contacted if there was uncertainty in the quality assessment. Of the 26 included trials, 6 were considered to have a low-risk of bias, with the remaining 20 trials considered to have a high-risk of bias. Reasons for a high-risk of bias designation included failure to report a method for allocation concealment (15 trials), high or unclear numbers of patients excluded from the analysis (13 trials), unblinded patients (10 trials), and unblinded caregivers or outcome assessors (10 trials). Of the 6 trials rated to be at low-risk of bias, 4 were conducted in individuals with fresh fracture, 3 of which were operatively managed tibial fractures.^9,10

Schandelmaier et al. (2017) acknowledged that their findings could be less applicable to underrepresented clinical subgroups. However, they noted that in subgroup analyses, the effect of low-intensity pulsed ultrasound on days to radiographic healing did not differ significantly across clinical subgroups (interaction p = .13) or between high and moderate compliance with treatment (interaction p = .99). They also noted that qualitative subgroup effects (such as no benefit in 1 subgroup and important benefit in another) are unusual.

Table 2. Studies Included in Systematic Reviews

		Systematic Reviews by Fracture Type
Studies	N	Study Design	Schandelmaier et al. (2017),3 Multiple	Seger et al. (2017),4 Nonunion	Lou et al. (2017),5 Fresh	Leighton et al. (2017),6 Nonunion	Griffin et al. (2014),7 Multiple	Busse et al. (2009),8 Multiple
Busse et al. (2016)	51	RCT	⚫		⚫
Busse et al. (2014)	501	RCT	⚫		⚫
Dudda et al. (2011)	36	RCT	⚫
El-Mowafi et al. (2005)	20	RCT	⚫					⚫
Emami et al. (1999)	32	RCT	⚫		⚫		⚫	⚫
Exogen et al. (1994)	85	RCT
Farkash (2015)	29	CS		⚫		⚫
Gan et al. (2014)	30	RCT	⚫
Gebauer et al. (2005)	66	CS		⚫		⚫
Handolin et al. (2005a)	22	RCT	⚫		⚫		⚫	⚫
Handolin et al. (2005b)	30	RCT	⚫		⚫		⚫	⚫
Heckman et al. (1994)	97	RCT	⚫		⚫		⚫	⚫
Hemery et al. (2010)	14	CS				⚫
Jingushi et al. (2007)	72	CS				⚫
Kamath et al. (2015)	60	RCT	⚫
Kristiansen et al. (1997)	85	RCT	⚫		⚫		⚫	⚫
Lerner et al. (2004)	17	CS				⚫
Leung et al. (2004)	30	RCT	⚫		⚫		⚫	⚫
Liu et al. (2014)	81	RCT	⚫		⚫
Lubbert et al. (2008)	120	RCT	⚫		⚫		⚫	⚫
Mayr et al. (2002)	100	CS				⚫		⚫
Mayr et al. (2000)	30	RCT	⚫		⚫		⚫
Nolte et al. (2001)	28	CS		⚫		⚫
Patel et al. (2014)	28	RCT	⚫
Pigozzi et al. (2004)	15	CS		⚫		⚫
Ricardo (2006)	21	RCT	⚫					⚫
Roussignol et al. (2012)	60	CS				⚫
Rubin et al. (2001)	118	Reviewa		⚫
Rue et al. (2004)	40	RCT	⚫				⚫	⚫
Rutten et al. (2007)	20	RCT	⚫			⚫
Salem et al. (2014)	21	RCT	⚫
Schofer et al. (2010)	101	RCT	⚫			⚫
Schortinghuis et al. (2008)	9	RCT	⚫
Schortinghuis et al. (2005)	8	RCT	⚫					⚫
Strauss et al. (1999)	20	RCT			⚫		⚫
Tsumaki et al. (2004)	42	RCT	⚫					⚫
Urita et al. (2013)	27	RCT	⚫
Wang et al. (2007)	59	RCT					⚫
Watanabe et al. (2013)	151	Cohort				⚫
Yadav et al. (2008)	67	RCT					⚫
Zacherl et al. (2009)	52	RCT	⚫
Zura et al. (2015)	767	Registry				⚫
No. of studies			26	5	12	13	12	13

CS: case series; RCT: randomized controlled trial.
^a This review contained data from a registry analysis.

Meta-analysis results are summarized in Tables 3 and 4. Variation in results was observed for days to full weight-bearing, pain, and radiographic healing. When only trials with low risk of bias were included, there was no difference between treatment and control groups (Table 3).

Table 3. Summary of Low-intensity Pulsed Ultrasound Results from the Schandelmaier Meta-Analysis

Outcomes	No. of Trials and Results (95% CI)						Heterogeneity
	High Risk of Bias		Low Risk of Bias		Total		p	I2
	n	Results	n	Results	n	Results
Percent difference in days to return to work	Not reported separately		Not reported separately		3	2.7 (-7.7 to 14.3)	.76	0%
Percent difference in days to full weight-bearing	1	-40.0 (-48.4 to -30.3)	2	4.8 (-4.0 to 14.4)	3	-16.6 (-44.9 to 26.1)	<.001	95%
Mean difference in pain reduction on 1-100 VAS (follow-up, 4 to 6 wk)	1	-28.1 (-37.1 to -19.2)	3	-0.9 (-2.5 to 0.6)	4	-6.9 (-15.4 to 1.6)	<.001	91%
RR of subsequent operations (follow-up, 8 wk to 44 mo)	Not reported separately		Not reported separately		7	0.8 (0.6 to 1.2)	.67	0%
Percent difference in days to radiographic healing	12	-32.8 (-39.5 to -25.3)	3	-1.7 (-11.2 to 8.8)	15	-27.3 (-34.7 to -19.0)	<.001	85%
Risk difference in adverse events	Not reported separately		Not reported separately		9	0.0 (-0.0 to 0.03)	.40	4%

CI: confidence interval; RR: relative risk; VAS: visual analog scale.
Adapted from Schandelmaier et al. (2017).³

Table 4. Summary of Findings and Quality of Evidence

Outcomes	QOE	Low-intensity Pulsed Ultrasound Effect on Outcome
1	Percent difference in days to return to work	Moderatea	Probably little or no impact
2	Percent difference in days to full weight-bearing	High	No impact
3	Mean difference in pain reduction on 1-100 VAS (follow-up, 4 to 6 wk)	High	No impact
4	Relative risk of subsequent operations (follow-up, 8 wk to 44 mo)	Moderatea	Probably little or no impact
5	Percent difference in days to radiographic healing	Moderatea	Probably little or no impact
6	Risk difference in adverse events	High	No impact

Adapted from Schandelmaier et al. (2017).³
QOE: quality of evidence: VAS: visual analog scale.
^a Due to serious imprecision.

Fresh Fractures
Clinical Context and Therapy Purpose
The purpose of low-intensity pulsed ultrasound in patients who have fresh fractures (either surgically managed or non-surgically managed) is to provide an adjunctive treatment option to standard of care.

The question addressed in this evidence review is: Does the use of low-intensity pulsed ultrasound improve net health outcomes in patients with fresh fractures (either surgically or non-surgically managed) compared with standard care without the adjunctive use of low-intensity pulsed ultrasound?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with fresh fractures (either surgically or non-surgically managed). A fracture is most commonly defined as fresh for 7 days after the fracture occurs.

Interventions
The therapy being considered is low-intensity pulsed ultrasound. Low-intensity pulsed ultrasound is believed to alter the molecular and cellular mechanisms involved in each stage of the healing process (inflammation, soft callus formation, hard callus formation, and bone remodeling). The mechanism of action at the cellular level is not precisely known, but it is theorized that low-intensity pulsed ultrasound may stimulate the production or the activities of the following compounds that contribute to the bone healing process: cyclooxygenase-2, collagenase, integrin proteins, calcium, chondroblasts, mesenchymal cells, fibroblasts, and osteoblasts. Low-intensity pulsed ultrasound would be an adjunctive therapy following setting and immobilizing the bone. The patient takes the low-intensity pulsed ultrasound device home and self-administers the treatment. Recommended time of treatment administration is 20 minutes/day.

Comparators
The comparator is standard fresh fracture management without low-intensity pulsed ultrasound as an adjunctive therapy.

Outcomes
The general outcome of interest is time to healing, which may be measured radiologically and assessed by an orthopedic surgeon. Clinically meaningful measures for healing would involve functional outcomes such as assessment of pain, use of analgesics, the need for secondary procedures, and ability to return to activities of daily living.

Follow-up should extend for months, the duration of time required for fracture healing.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Lou et al. (2017) conducted a meta-analysis focusing on fresh fractures.⁵ The literature search, conducted through November 2016, included 12 studies, all of which were included in the Schandelmaier et al. (2017) meta-analysis, except for a small study (n = 20) by Strauss et al. (1999), which only appeared in a conference abstract.¹¹ Studies included patients that had been surgically and conservatively managed. Results from the Lou et al. (2017) meta-analysis showed that time to fracture union was significantly lower in patients receiving low-intensity pulsed ultrasound than in patients not receiving low-intensity pulsed ultrasound (standard mean difference, -0.65; 95% confidence interval [CI], -1.13 to -0.17). However, subgroup analysis showed that this significant reduction in healing time with low-intensity pulsed ultrasound was seen only among patients conservatively managed, while there was no difference in healing time among patients surgically managed. Reviewers concluded that patients with fresh fractures might benefit from the use of low-intensity pulsed ultrasound but warned that there were methodologic limitations in the trials. Separate analyses using only low-risk of bias trials were not conducted in the Lou et al. (2017) meta-analyses.

Surgically Managed — Randomized Controlled Trials
Busse et al. (2016) reported on results from a concealed, blinded, sham-controlled, randomized Trial to Re-evaluate Ultrasound in the Treatment of Tibial Fractures (TRUST) evaluating low-intensity pulsed ultrasound for the treatment of patients who underwent intramedullary nailing for fresh tibial fractures.¹² This is the largest RCT to date, enrolling 501 patients; 250 received a low-intensity pulsed ultrasound device, and 251 received a sham device. Treatment was self-administered for 20 minutes a day until there was radiographic evidence of healing. Coprimary endpoints were radiographic healing and return to function (as measured by the 36-Item Short-Form Health Survey [SF-36] Physical Component Summary score). Both radiographic and functional assessments had to show a clinically important effect for the results to be considered positive. All patients, clinicians, investigators, data analysts, and the industry sponsor were blinded to allocation until data analysis was complete. Patient compliance was considered moderate, with 73% of patients administering over half of all recommended treatments. There was no difference in time to radiographic healing between the treatment groups (hazard ratio, 1.07; 95% CI, 0.86 to 1.34; p = .55). Additionally, there was no difference in the SF-36 Physical Component Summary scores (mean difference, 0.55; 95% CI, -0.75 to 1.84; p = .41). A previously conducted pilot, double-blind, RCT by Busse et al. (2014), including 51 subjects not assessed in the 2016 study, also did not find any statistically significant differences in pain reduction, number of subsequent operations, or radiographic healing time.¹²

Tarride et al. (2017) provided additional analyses using data from the TRUST trial, comparing health care resource use among patients using low-intensity pulsed ultrasound with patients using the sham device.¹³ There were no significant differences between groups (11% in patients receiving low-intensity pulsed ultrasound vs. 10% in patients receiving sham) in need for secondary procedures (e.g., removal of lock screw, implant exchange or removal). There were also no statistically significant differences in use of physical therapy (44% vs. 46%), use of anticoagulants (42% vs. 36%), or use of nonsteroidal anti-inflammatory drugs (28% vs. 35%) among patients receiving low-intensity pulsed ultrasound compared with patients receiving sham, respectively.

Emami et al. (1999) conducted a double-blind, sham-controlled trial that randomized 32 patients who had a fresh tibial fracture fixed with an intramedullary rod to additional treatment with an active (n = 15) or inactive (n = 17) low-intensity pulsed ultrasound device.¹⁴ Low-intensity pulsed ultrasound treatment began within 3 days of surgery (1 patient began treatment within 7 days of injury) and was self-administered for 20 minutes a day for 75 days. Radiographs were taken every third week until healing. Results showed that low-intensity pulsed ultrasound did not shorten healing time based on any of the following measures: time to first visible callus (mean, 40 days for low-intensity pulsed ultrasound vs. 37 days for sham; p = .44); time to radiographic healing assessed by radiologist (mean, 155 days [median, 113 days] for low-intensity pulsed ultrasound vs. mean, 125 days [median, 112 days] for sham; p = .76); and time to radiographic healing assessed by orthopedic surgeon (mean, 128 days, for low-intensity pulsed ultrasound vs. mean, 114 days for sham; p = .40).

Gopalan et al. (2020) conducted a single-blind RCT of low intensity pulsed ultrasound plus open reduction and internal fixation compared to surgery alone in 40 patients with mandibular fracture at a single surgical center in India.¹⁵ Patients who were randomized to the intervention group received low intensity pulsed ultrasound therapy at 4, 8, 14, and 20 days postoperatively, for 20 minutes daily. Postoperative examinations were performed at 5, 9, 15, and 21 days to assess wound healing, pain, and teeth mobility. Assessment of orthopantomograms and ultrasound scans were blinded. Patients were not blinded, and it is unclear whether pain assessments were conducted by blinded outcome assessors. Pain scores were significantly lower in the treatment group compared to the control group at all assessment time points. Ultrasound assessments of fracture healing were significantly better in the treatment group at weeks 4, 8, and 12, but radiographic assessments of fracture healing did not differ between groups at any time point. Wound healing was significantly greater in the intervention group on postoperative days 5 and 9, but the difference was not significant on day 21. This study was limited by its small sample size, single center design, and lack of blinding of patients.

Nonsurgically Managed — Randomized Controlled Trial
Lubbert et al. (2008) performed a multicenter, double-blind RCT (n = 101) of low-intensity pulsed ultrasound treatment of fresh (< 5 days) clavicle shaft fractures.¹⁶ Patients used the low-intensity pulsed ultrasound devices for 20 minutes once daily for 28 days and recorded their subjective feeling as to whether the fracture healed (the primary outcome measure), pain on a visual analog scale (VAS), level of daily activities (hours of work, household work, sport), and analgesic use. Patient perception of the day the fracture healed was determined in 92 patients (47 active, 45 placebo); mean time to heal was 26.77 days in the active group and 27.09 days in the placebo group (p = .91). Between-group differences regarding analgesic use and mean VAS scores for pain also did not differ significantly.

Section Summary: Fresh Fractures
Evidence for the use of low-intensity pulsed ultrasound following fresh fracture includes 4 RCTs that evaluated patients that were surgically managed and 1 RCT that evaluated patients that were nonsurgically managed. One RCT of 40 patients with mandibular fractures reported better wound healing and pain scores in patients who received low intensity pulsed ultrasound following surgical fixation compared to those who received surgery alone. This study was limited by a lack of blinding of patients and its small sample size. The other RCTs reported no statistically significant differences in radiographic healing, physical component score of the SF-36, use of physical therapy, need for secondary procedures, use of nonsteroidal anti-inflammatory drugs, and time to first visible callus.

Fracture Nonunion or Delayed Union Fracture
Clinical Context and Therapy Purpose
The purpose of low-intensity pulsed ultrasound in patients who have fracture nonunion or delayed union fracture is to provide an adjunctive treatment option to standard of care.

The question addressed in this evidence review is: Does the use of low-intensity pulsed ultrasound improve net health outcomes in patients with fracture nonunion or delayed union fracture compared with standard care without the adjunctive use of low-intensity pulsed ultrasound?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients with fracture nonunion or delayed union fracture. There is not a consensus definition of nonunion or delayed union. In general, these conditions are considered if serial radiographs either do not show progressive healing or show a decelerating healing process after 3 months since the fracture occurrence.

Interventions
The therapy being considered is low-intensity pulsed ultrasound. Low-intensity pulsed ultrasound is believed to alter the molecular and cellular mechanisms involved in each stage of the healing process (inflammation, soft callus formation, hard callus formation, and bone remodeling). The mechanism of action at the cellular level is not precisely known, but it is theorized that low-intensity pulsed ultrasound may stimulate the production or the activities of the following compounds that contribute to the bone healing process: cyclooxygenase-2, collagenase, integrin proteins, calcium, chondroblasts, mesenchymal cells, fibroblasts, and osteoblasts. Low-intensity pulsed ultrasound would be an adjunctive therapy following setting and immobilizing the bone. The patient takes the low-intensity pulsed ultrasound device home and self-administers the treatment. Recommended time of treatment administration is 20 minutes/day.

Comparators
The comparator is standard nonunion or delayed union fracture management without low-intensity pulsed ultrasound as an adjunctive therapy.

Outcomes
The general outcome of interest is time to healing, which may be measured radiologically and assessed by an orthopedic surgeon. Clinically meaningful measures for healing would involve functional outcomes such as assessment of pain, use of analgesics, the need for secondary procedures, and ability to return to activities of daily living.

Follow-up should extend for months, the duration of time required for fracture healing.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
The meta-analysis by Seger et al. (2017) included 5 studies focused on scaphoid nonunions and analyzed healing index and average time to union following low-intensity pulsed ultrasound.⁴ Among 166 cases in the analysis, 78.6% (range, 33% to 100%) were reported to show healing following low-intensity pulsed ultrasound, with an average time to union of 4.2 months (range, 2.3 to 5.6 months). Comparative results were not conducted.

The meta-analysis by Leighton et al. (2017) included 13 studies, one of which was an RCT.⁶ The date of the literature search was not provided. Quality of the studies was assessed using the Methodological Index for Non-Randomized Studies. Quality scores ranged from 5 to 12 (an "ideal" is 16 for nonrandomized trials). While the pooled estimate of effect size for the healing rate was 82% (95% CI, 77% to 87%), significant heterogeneity was detected (I2 = 62). A separate analysis, excluding studies with quality scores of 6 or lower, resulted in a comparable heal rate of 80% (95% CI, 74% to 85%).

The systematic review by Schandelmaier et al. (2017) included 3 RCTs of nonunion fractures operatively managed. Because all the RCTs were rated at high-risk of bias, the authors could not adequately assess the efficacy of low-intensity pulsed ultrasound for nonunion fractures.3, Two of the RCTs are discussed below; one is not discussed below because it was published only as a thesis.

Randomized Controlled Trials
Schofer et al. (2010), reported on a multicenter, randomized, double-blind, sham-controlled trial of low-intensity pulsed ultrasound in 101 patients with delayed union of the tibia (Table 5).¹⁷ Delayed union was defined as a lack of clinical and radiologic evidence of union, bony continuity, or bone reaction at the fracture site for no less than 16 weeks from the index injury or the most recent intervention. Roughly one-third of patients had an open fracture. Patients were randomized to low-intensity pulsed ultrasound (n = 51) or to an inactive sham device (n = 50), to be administered 20 minutes a day for 16 weeks. The primary outcome was change in bone mineral density assessed by computed tomography attenuation coefficients. Gap area was a secondary outcome. Intention-to-treat analysis showed that low-intensity pulsed ultrasound improved mean bone mineral density by 34% (90% CI, 14% to 57%) compared with sham treatment. The mean reduction in bone gap area was -0.13 mm2 in the low-intensity pulsed ultrasound group and -0.10 mm2 in the sham group (effect size, -0.47; 95% CI, -0.91 to -0.03 mm²). At the end of 16 weeks, physicians judged 65% of patients in the low-intensity pulsed ultrasound group healed and 46% of the patients in the sham group healed (p = .07) (Table 6). This trial did not report functional outcomes or pain assessment, limiting the utility of results.

Ricardo (2006) published a blinded RCT evaluating 21 subjects with scaphoid nonunion who were treated with low-intensity pulsed ultrasound or a sham device following a pedicled vascularized bone graft (Table 5).¹⁸. Time to healing was defined as the number of days from the operation to healing both clinically (solid and not causing tenderness or pain) and radiographically (bridging cortices). Additional outcomes included pain, wrist range of motion, radiographic evidence of union, carpal height index, and scapholunate-capitolunate angles; however, the authors did not report these outcomes by treatment arm. The authors reported a statistically significant reduction in time to radiographic healing (-40.4%; 95% CI, -48.7% to -30.8%) with low-intensity pulsed ultrasound (Table 6).

Table 5. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Schofer et al. (2010)17	Germany	6	2002 to 2005	Patients with tibial delayed unions	Low-intensity pulsed ultrasound (n = 51)	Sham device (n = 50)
Ricardo (2006)18	Cuba	1	1999 to 2004	Patients with scaphoid nonunion fractures treated with pedicled vascularized bone grafts from the distal radius	Low-intensity pulsed ultrasound (n = 10)	Sham device (n = 11)

RCT: randomized controlled trial.

Table 6. Summary of Key RCT Results

Study	Healing		p-value
	Low-intensity pulsed ultrasound	Sham device
Schofer et al. (2010)17	physician assessed 65% healed	physician assessed 46% healed	.07
Ricardo (2006)18	56 + 3 days	94 + 5 days	< .0001

RCT: randomized controlled trial.
The purpose of the limitations tables (Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 7. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Schofer et al. (2010)17				2. Primary outcome was bone mineral density and secondary outcome was gap area. Physicians judged patients as healed/not healed, but no description of criteria used by physician
Ricardo (2006)18

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 8. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Schofer et al. (2010)17				1. Drop out rate for low-intensity pulsed ultrasound group was 10% and drop out rate for sham device was 24%
Ricardo (2006)18	No description of randomization procedure				1. Power calculations not reported and sample size is small (N = 21)	4. Only time to healing was compared statistically; additional outcomes (pain, return to activities) were not reported by treatment group

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Observational Study
Nolte et al. (2016) conducted a retrospective comparison of patients with metatarsal fractures treated by low-intensity pulsed ultrasound and by surgical techniques.¹⁹ For the comparative analysis, patients from a U.S. Food and Drug Administration (FDA) required low-intensity pulsed ultrasound registry (n = 594) were propensity-matched 1:1 with patients treated surgically from a health claims database. The overall heal rates for all types of fractures combined were comparable for low-intensity pulsed ultrasound (97%) and surgery (95%) (p = .07). A subgroup analysis of patients with delayed or nonunion metatarsal fractures (n = 226) also showed comparable rates of healing among the low-intensity pulsed ultrasound group (96%) and the surgery group (96%).

Section Summary: Fracture Nonunion or Delayed Union Fracture
The evidence for low-intensity pulsed ultrasound treatment of fracture nonunion consists only of lower quality and uncontrolled studies. There are 2 meta-analyses (2017) without controlled comparative results. A third meta-analysis, which included all types of fractures, identified 3 RCTs of patients with nonunion; however, all 3 trials were considered at high-risk of bias (one published as a thesis). Of the 2 RCTs, the larger one had primary and secondary outcomes that were physiological assessments, rather than functional measures. It is unclear how healing status was determined in this study, as the outcome was described as "physician-assessed." Limitations of the second published RCT include no description of the randomization process and small sample size.

Stress Fractures, Osteotomy Sites, or Distraction Osteogenesis
Clinical Context and Therapy Purpose
The purpose of low-intensity pulsed ultrasound in patients who have stress fractures, osteotomy sites or distraction osteogenesis, is to provide an adjunctive treatment option to standard of care.

The question addressed in this evidence review is: Does the use of low-intensity pulsed ultrasound improve net health outcomes in patients with stress fractures, osteotomy sites, or distraction osteogenesis compared with standard care without the adjunctive use of low-intensity pulsed ultrasound?

The following PICO was used to select literature to inform this review.

Populations
The population of interest consists of patients with stress fractures, osteotomy sites, or distraction osteogenesis.

Interventions
The therapy being considered is low-intensity pulsed ultrasound. Low-intensity pulsed ultrasound is believed to alter the molecular and cellular mechanisms involved in each stage of the healing process (inflammation, soft callus formation, hard callus formation, and bone remodeling). The mechanism of action at the cellular level is not precisely known, but it is theorized that low-intensity pulsed ultrasound may stimulate the production or the activities of the following compounds that contribute to the bone healing process: cyclooxygenase-2, collagenase, integrin proteins, calcium, chondroblasts, mesenchymal cells, fibroblasts, and osteoblasts. Low-intensity pulsed ultrasound would be an adjunctive therapy following setting and immobilizing the bone. The patient takes the low-intensity pulsed ultrasound device home and self-administers the treatment. Recommended time of treatment administration is 20 minutes/day.

Comparators
The comparator is standard stress fracture, osteotomy sites, or distraction osteogenesis management without low-intensity pulsed ultrasound as an adjunctive therapy.

Outcomes
The general outcome of interest is time to healing, which may be measured radiologically and assessed by an orthopedic surgeon. Clinically meaningful measures for healing would involve functional outcomes such as assessment of pain, use of analgesics, the need for secondary procedures, and ability to return to activities of daily living.

Follow-up should extend for months, the duration of time required for fracture healing.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Stress Fractures
Rue et al. (2004) reported on a double-blind RCT that examined the effects of 20 minutes of daily low-intensity pulsed ultrasound on tibial stress fracture healing outcomes such as pain, function, and resumption of professional and personal activities in 26 military recruits.²⁰ The delay from onset of symptoms to diagnosis was 32 days in the low-intensity pulsed ultrasound group and 28 days in the placebo group. This trial found no significant difference in healing times between low-intensity pulsed ultrasound treatment and sham, with a mean time of return to duty of 56 days for both groups. The trial was rated with a high-risk of bias in the Schandelmaier et al. (2017) meta-analysis.³

Osteotomy Sites
Urita et al. (2013) published a small (n = 27) quasi-randomized study (alternating assignment) of low-intensity pulsed ultrasound after ulnar-shortening osteotomy for ulnar impaction syndrome or radial-shortening osteotomy for Kienböck disease.²¹ Patients in the low-intensity pulsed ultrasound group received daily 20-minute treatment for at least 12 weeks postoperatively. Blinded evaluation of radiographic healing showed that low-intensity pulsed ultrasound reduced the mean time to the cortical union by 27% (57 days vs. 76 days) and endosteal union by 18% (121 days vs. 148 days) compared with sham treatment. At the time of endosteal healing, the osteotomy plus low-intensity pulsed ultrasound group and the osteotomy-only group had similar results, as measured using the Modified Mayo Wrist Score and no pain at the osteotomy site. The study was rated at high-risk of bias in the meta-analysis by Schandelmaier et al. (2017).³

Distraction Osteogenesis
The Schandelmaier et al. (2017) systematic review also included 6 trials of low-intensity pulsed ultrasound for distraction osteogenesis following surgery. Four of 6 studies were rated at high-risk of bias.³ Four studies were in the tibia.^9,10 No clinically meaningful results were reported for the mandible studies in the meta-analysis.³ The remaining studies in the tibia were all unblinded. No statistically significant difference was noted in subsequent operations (relative risk, 0.63; 95% CI, 0.13 to 2.99) in the meta-analysis.³ Four of the studies^22,23,24,25 were included in the meta-analysis³ for time to radiographic healing with mixed results, 3 not reporting statistically significant results.

Lou et al. (2018) conducted a systematic review and meta-analysis on the use of low-intensity pulsed ultrasound for the treatment of patients with distraction osteogenesis.²⁶ The literature search, conducted in May 2018, identified 7 RCTs (172 patients) for inclusion. The Cochrane risk of bias tool was used to assess trial quality. Three of the trials were considered low-risk of bias and 4 were considered to have high-risk of bias. Main limitations in the trials were related to the lack of treatment allocation details and outcome assessors' knowledge of treatment. Pooled results did not find statistically significant differences in treatment time, radiological gap fill area, histological gap fill length, or bone density.

Song et al. (2019) reported on a retrospective observational study of 30 patients who underwent tibial lengthening procedures at a single institution between October 2009 and October 2015.²⁷ Fifteen patients who received low intensity pulsed ultrasound during distraction osteogenesis were compared to 15 patients who underwent the same procedure but did not receive low intensity pulsed ultrasound. During the distraction phase, calluses of the low intensity pulsed ultrasound group were more cylindrical, more homogeneous, and denser than those of the control group. At the time of external fixator removal; however, there were no significant differences between the groups in callus shape and type. There were no significant differences in external fixation index between the groups. There were 6 complications in the group who received low intensity pulsed ultrasound and 5 in the control group. No complications related to the low intensity pulsed ultrasound procedure were reported.

Section Summary: Stress Fractures, Osteotomy Sites or Distraction Osteogenesis
The evidence for low-intensity pulsed ultrasound treatment of stress fractures, osteotomy sites, or distraction osteogenesis consists only of lower quality RCTs and a retrospective comparative observational study with a high risk of bias. Results do not generally include functional outcomes and results across various outcomes, primarily including time to radiographic healing, are inconsistent. A meta-analysis of 3 trials on the use of low-intensity pulsed ultrasound for patients with distraction osteogenesis reported no statistically significant differences in treatment time, gap fill, or bone density.

Summary of Evidence
For individuals who have fresh fractures (surgically or nonsurgically managed) who receive low-intensity pulsed ultrasound as an adjunct to routine care, the evidence includes RCTs and several meta-analyses. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence base has evolved with the publication of a large RCT and meta-analysis significantly shifting the weight of the evidence. Conclusions based on several earlier and small RCTs, rated at high-risk of bias, showed a potential benefit; however, the large RCT published in 2016, rated at low-risk of bias, showed no benefit. A 2017 meta-analysis including only trials with low-risk of bias found no difference in days to full weight-bearing, pain reduction, or days to radiographic healing. Similarly, the overall results of the meta-analysis found no significant difference in return to work, subsequent operations, or adverse events. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have fracture nonunion or delayed union fracture who receive low-intensity pulsed ultrasound as an adjunct to routine care including surgery, if appropriate, the evidence includes only lower quality studies consisting of a small systematic review in scaphoid nonunions, a meta-analysis of nonunion in various locations, 2 low-quality RCTs, and 1 observational comparative study. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Of the 2 RCTs, one did not include functional outcomes. The second RCT had a small sample size and did not describe the randomization procedure. The observational study reported similar healing rates with low-intensity pulsed ultrasound and surgery, although the retrospective nature of the study, limits meaningful interpretation of these results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have stress fractures, osteotomy sites, or distraction osteogenesis who receive low-intensity pulsed ultrasound as an adjunct to routine care, the evidence includes only lower quality studies consisting of small RCTs, a retrospective comparative observational study, and one meta-analysis for distraction osteogenesis. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Results do not generally include functional outcomes and results across various outcomes, primarily time to radiographic healing, are inconsistent. The meta-analysis of 3 trials using low-intensity pulsed ultrasound for distraction osteogenesis reported no statistically significant differences in physiological or functional outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input
In response to requests, input was received from 4 academic medical centers while this policy was under review in 2012. Input supported the use of low-intensity pulsed ultrasound for delayed unions and nonunions of bones excluding the skull and vertebra, and in fresh closed fractures at high-risk for delayed fracture healing or nonunion. Commentators agreed that other applications of low-intensity pulsed ultrasound treatment are investigational, including, but not limited to, treatment of congenital pseudoarthrosis, open fractures, stress fractures, arthrodesis, or failed arthrodesis. Additional risk factors were noted, including use of anticoagulants, immunosuppressive drugs or chemotherapy, infection at the fracture site, severe anemia, obesity, and fracture locations more prone to nonunion such as tibial and distal radial fractures.

2011 Input
In response to requests, input was received from 2 physician specialty societies and 1 academic medical center while this policy was under review in 2011. Input supported the use of ultrasound for nonunion and for fresh closed fractures at high-risk for delayed fracture healing or nonunion as described in the policy. One reviewer supported including chemotherapy, immunosuppressive agents, history of infection, Charcot neuroarthropathy, and fractures of the tibial shaft or clavicle as additional risk factors, and another supported including fractures of the talus and sesamoids as additional risk factors.

2008 Input
In response to requests, input was received from 1 physician specialty society while this policy was under review in 2008. Input obtained through the American Academy of Orthopaedic Surgeons supported the positions on the criteria for medical necessity and the conditions considered investigational (e.g., delayed union and open/unstable grade II or III fractures).

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence
In 2013, the National Institute for Health and Care Excellence (NICE) published guidance on Exogen for the treatment of long-bone fractures with nonunion and delayed fracture healing.²⁸ The NICE concluded that use of the Exogen bone healing system to treat long-bone fractures with nonunion is supported by "clinical evidence" and "cost savings … through avoiding surgery." For long-bone fractures with delayed healing, defined as no radiologic evidence of healing after 3 months, there was "some radiologic evidence of improved healing." However, due to "substantial uncertainties about the rate at which bone healing progresses without adjunctive treatment between 3 and 9 months after fracture" and need for surgery, "cost consequences" were uncertain. In 2019, the Exogen guidance was updated with a review of studies published after June 2012.28, The review decision stated, "Overall the additional clinical evidence identified since the guidance was published in 2013 supports the current recommendations." The reviewers did not consider the Schandelmaier et al. (2017) systematic review because it pooled fresh fractures and distraction osteogenesis alongside non-unions.

In 2018, NICE published guidance on the use of low-intensity pulsed ultrasound in 3 clinical circumstances, The guidance made the following conclusions:

• To promote healing of fresh fractures at low-risk of non-healing: "Current evidence does not show efficacy. Therefore, this procedure should not be used for this indication."²⁹
• To promote healing of fresh fractures at high-risk of non-healing: "Current evidence on efficacy is very limited in quantity and quality. Therefore, this procedure should only be used in the context of research."³⁰
• To promote healing of delayed and nonunion fractures: "Current evidence on efficacy is inadequate in quality. Therefore, this procedure should only be used with special arrangements for clinical governances, consent and audit or research."³¹

American Academy of Orthopaedic Surgeons
In 2020, the American Academy of Orthopaedic Surgeons published updated guidelines on the treatment of distal radius fractures.³² Although the Academy issued a limited recommendation for the use of low-intensity pulsed ultrasound for adjuvant treatment of distal radius fractures in its prior 2009 guidelines, low-intensity pulsed ultrasound was not mentioned in the updated guidelines.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02383160a	A Randomized Controlled Trial Comparing Low-Intensity, Pulsed Ultrasound to Placebo in the Treatment of Operatively Managed Scaphoid Non-unions	154	Dec 2023
NCT03382483a	A Prospective, Patient-centric, Observational, Consecutive Enrollment, Non-interventional Study of Patients At Risk for Fracture Non-union Treated with EXOGEN Compared to a National Healthcare Claims Database Control	12,387	May 2022

NCT: national clinical trial.
^a denotes an industry-sponsored trial

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7. Griffin XL, Parsons N, Costa ML, et al. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. Jun 23 2014; (6): CD008579. PMID 24956457
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9. Schortinghuis J, Bronckers AL, Stegenga B, et al. Ultrasound to stimulate early bone formation in a distraction gap: a double blind randomised clinical pilot trial in the edentulous mandible. Arch Oral Biol. Apr 2005; 50(4): 411-20. PMID 15748694
10. Schortinghuis J, Bronckers AL, Gravendeel J, et al. The effect of ultrasound on osteogenesis in the vertically distracted edentulous mandible: a double-blind trial. Int J Oral Maxillofac Surg. Nov 2008; 37(11): 1014-21. PMID 18757179
11. Strauss E, Ryaby JP, McCabe J. Treatment of Jones' fractures of the foot with adjunctive use of low-pulsed ultrasound stimulation. J Orthop Trauma. 1999;13(4):310. https://journals.lww.com/jorthotrauma/Citation/1999/05000/Treatment_of_Jones__fractures_of_the_foot_with.76.aspx. Accessed February 2, 2022.
12. Busse JW, Bhandari M, Einhorn TA, et al. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. Oct 25 2016; 355: i5351. PMID 27797787
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14. Emami A, Petren-Mallmin M, Larsson S. No effect of low-intensity ultrasound on healing time of intramedullary fixed tibial fractures. J Orthop Trauma. May 1999; 13(4): 252-7. PMID 10342350
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17. Schofer MD, Block JE, Aigner J, et al. Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial. BMC Musculoskelet Disord. Oct 08 2010; 11: 229. PMID 20932272
18. Ricardo M. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union. Int Orthop. Apr 2006; 30(2): 123-7. PMID 16474939
19. Nolte P, Anderson R, Strauss E, et al. Heal rate of metatarsal fractures: A propensity-matching study of patients treated with low-intensity pulsed ultrasound (LIPUS) vs. surgical and other treatments. Injury. Nov 2016; 47(11): 2584-2590. PMID 27641221
20. Rue JP, Armstrong DW, Frassica FJ, et al. The effect of pulsed ultrasound in the treatment of tibial stress fractures. Orthopedics. Nov 2004; 27(11): 1192-5. PMID 15566133
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Coding Section

Codes	Number	Description
CPT	20979	Low-intensity ultrasound stimulation to aid bone healing, non-invasive (nonoperative)
ICD-9 Procedure	99.86	Non-invasive placement of bone growth stimulator
ICD-9 Diagnosis	733.82	Fracture nonunion
	810-829	Fracture code range. Even 4th digit indicates closed fracture, odd 4th digit indicates open fracture. Fifth digit subclassification is required with several of the fracture codes
	905.0-905.5	Late effects of fracture code range
	V54.10-V54.19	Aftercare for healing traumatic fracture
HCPCS	E0760	Osteogenesis stimulator, low-intensity ultrasound, non-invasive
ICD-10-CM (effective 10/01/15)	S42.00xA-S42.92xA; S49.00xA-S49.199A; S52.00xA-S52.92xA; S59.00xA-S59.299A; S62.00xA-S62.92xA; S72.00xA-S72.92xA; S79.00xA-S79.199A; S82.00xA-S82.92xA; S89.00xA-S89.399A; S92.00xA-S92.919A	Fracture codes – 7th digit “A,” as shown in the list, is initial encounter for closed fracture. The same codes with 7th digit “K” is subsequent encounter for nonunion (in forearm, femur, lower leg & ankle fractures 7th digits “M” and “N” are also nonunion for certain types of open fractures – in fractures of the shoulder, humerus, wrist, hand and foot there isn’t separation of open vs closed nonunions). 7th digit “G” represents subsequent encounter for fracture with delayed healing. This list does not include any skull or vertebral fracture codes. There are also other codes for pathological and stress fractures (M80-M84) which are not listed here.
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services.
	3E00XGC	Administration, physiological systems and anatomical regions, introduction, skin and mucous membranes, external, other therapeutic substance
Type of Service	DME
Place of Service	Outpatient, Home

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

01012024  NEW POLICY

03/27/2024 Annual review, no change to policy intent.