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Journal of Clinical Orthopaedics and Trauma logoLink to Journal of Clinical Orthopaedics and Trauma
. 2020 Apr 21;11(Suppl 4):S500–S505. doi: 10.1016/j.jcot.2020.03.009

Low Intensity Pulsed Ultrasound Therapy (LIPUS): A review of evidence and potential applications in diabetics

Reshid Berber a, Sheweidin Aziz a, Joanna Simkins a, Sheldon S Lin b, Jitendra Mangwani a,∗
PMCID: PMC7394837  PMID: 32774018

Abstract

Low Intensity Pulsed Ultrasound Therapy (LIPUS) is a non-invasive treatment and aims to reduce fracture healing time and avoid non-union by delivering micro-mechanical stress to the bone to stimulate bone healing. In 2018, the National Institute for Health and Clinical Excellence (NICE) recommended that the evidence for LIPUS to promote healing of delayed-union and non-union fractures raised no major safety concerns, but the current evidence on efficacy is inadequate in quality. Little is known about the potential benefits of LIPUS for fracture healing in diabetic patients. In this article, we review the current evidence of LIPUS therapy both in animal and human studies and its possible application on fractures in diabetics.

Keywords: Low intensity pulsed ultrasound, Fracture healing, Diabetic

1. Introduction

Fractures are a frequent result of trauma and usually have a predictable healing time based on age, extremity and fracture characteristics. However, diabetic patients pose a problem for orthopaedic surgeons given their unique characteristics, which include delayed fracture healing, vasculopathy, and neuropathy.1,2 These characteristics should be considered when devising a plan for treatment.3 As the prevalence of diabetes mellitus increases, the number of fractures in this patient group will increase too.

Low Intensity Pulsed Ultrasound (LIPUS) is a non-invasive therapy with a body of evidence supporting its role in accelerating fracture healing. Ultrasound waves induce micromechanical stress at a fracture site; stimulating molecular and cellular responses involved in fracture healing.4 The Food and Drug Administration (FDA, USA) approved the use of LIPUS in 1994 to prevent delayed healing or non-unions in at-risk patients.4 In 2018, the National Institute for Health and Clinical Excellence (NICE) recommended that the evidence for LIPUS to promote healing of delayed-union and non-union fractures had no major safety concerns, but the current evidence on efficacy is inadequate in quality.5 Therefore, this procedure should only be used with special arrangements for research.5,6 However, little is known about the potential benefits of LIPUS for fracture healing in diabetic patients. In this article, we review the current evidence of LIPUS therapy both in animal and human studies and its possible application on fractures in diabetics.

2. Fractures

Fracture healing is a complex biological process. Standardtreatment achieves union in the majority of cases; however, some fractures may develop symptomatic non-union requiring secondary interventions. This invariably involves surgery, which has associated risks and adverse events including infection, soft tissue injury, post-operative pain, blood clots and anaesthetic complications. In addition to such morbidity, non-unions can result in loss of independence and productivity leading to an economic burden to both the patient and the state.7 Approximately 1 in 4 diabetic patients have been shown to have 1 or more comorbidities influencing bone healing. A history of diabetes related peripheral neuropathy and haemoglobin A1c levels >7% leads to an increased likelihood of complications with bone healing8

3. Fracture healing

The physiology of fracture healing involves four temporal stages: inflammation, soft callus formation, hard callus formation and bone remodeling. The inflammatory phase involves the disruption of blood vessels, periosteal tissue, osteon units and perforating canals. This is associated with the formation of a fracture haematoma. The associated stasis in local blood flow results in aggregation of platelets and necrosis of bone with the subsequent release of inflammatory cytokines. Platelets release multiple growth factors, such as transforming growth factor beta or platelet derived growth factor. Cytokines attract mesenchymal stem cells to migrate to the fracture, to proliferate number of pluripotent cells and begin to express a multitude of bone morphogenic proteins. This stimulates the products of insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF).9 Ultimately these induce angiogenesis, chemotaxis, differentiation and proliferation towards the next stages of bone healing.10

Over the subsequent 2–5 days following fracture in a human, the healing process begins the phase of soft fibrocartilaginous callus with the arrival of osteogenic cells and fibroblasts. These cells lay collagen and form soft callus between fracture fragments. Cell proliferation is at a peak up to day-20 post injury, at which point the soft callus calcifies and hardens. This process involves the differentiation of osteogenic cells into osteoblasts, which in turn initiate intramembranous ossification to create woven bone. Osteoblasts and osteoclasts then work simultaneously to remodel bone as the final phase of fracture healing.9,10

Bone healing is influenced by multiple variables: 1) Systemic or patient related variables including age, activity level, and medical conditions such as Diabetes Mellitus and anaemia. In addition, nutritional status and vitamin (A, C, D and K) deficiencies, hormone level variation (Growth hormone) and habits (smoking and alcohol use). 2) Bone related variables including size of the gap as well as location of fracture within the bone and abnormal bone environment secondary to infection or prior radiation. 3) Injury related factors including degree of local damage to surrounding soft tissue, blood vessels and nerves. Open fractures, degree of comminution, bone or soft tissue loss and periosteal stripping. Diabetes mellitus disturbs several processes of fracture healing, leading to a deleterious effect on bone healing. These disruptions yield a high prevalence of delayed/non-union of fractures in patients undergoing elective or trauma foot and ankle surgery.11

4. Diabetes Mellitus

Diabetes is a metabolic disorder that in 2015 affected approximately 415 million adults aged 20–70 worldwide.12 It is expected to rise and affect one person in 10 by 2040–642 million.12 Diabetes manifests itself primarily as hyperglycaemia. The diagnosis is subject to a fasting blood glucose level of ≥7 mmol/L measured on 2 separate occasions with associated symptoms of polydipsia, polyuria or weight loss.3 Type 1 diabetes (T1DM) is a result of autoimmune destruction of insulin producing β-cells in the pancreas, therefore, creating a shortage of circulating insulin. This lack of insulin and the inability of the pancreas to respond to elevated glucose levels necessitate the patient to administer exogenous insulin to achieve glycaemic control. Type 2 diabetes (T2DM) is much more prevalent compared to T1DM and tends to arise later during adulthood. Peripheral resistance to insulin and defective insulin secretion characterizes the pathophysiology of T2DM by pancreatic β-cells.

Over time uncontrolled glycemia leads to AGE products forming and accumulate in the extracellular matrix in various tissues of diabetic patients. This accumulation causes the alteration of the function of endothelial cells, smooth muscle cells and macrophages in a number of end organs by the process of microangiopathy and macroangiopathy. These changes lead to the complications associated with diabetes, which include peripheral neuropathy, nephropathy, retinopathy and arthropathy. The resultant ischaemia coupled with altered cellular function leads to changes in the response to fractures and subsequent bone healing.1,11

5. Fracture healing in diabetes

Few human clinical studies have reported on time to fracture union in diabetic populations. In 1972, fracture healing was noted to be delayed in diabetic patients after it was observed that fracture callus was slow to appear and calcify.13 Subsequently, Loder et al., completed a retrospective analysis of 31 fractures treated within their unit; they demonstrated that union was prolonged in closed fractures of 28 adult diabetic patients, irrespective of the type of diabetes, using radiographic and clinical chart review.14 The time to union was compared to an expected time to union for similar fractures established by literature review. The overall delay in fracture healing seen in this modest patient group was at a magnitude of 1.63 times longer.14

To understand the effect on fracture healing, it is important to understand the effects of diabetes on normal bone morphology. The gold-standard technique for estimation of BMD is the dual X-ray absorptiometry (DXA) technique because of its reproducibility, large normative data, non-invasive nature, little time requirement for procedure, and minimal radiation exposure.15 Correct interpretation of BMD requires attention to detail in anthropometric information, patient positioning, correct scan analysis, BMD pattern of individual vertebrae, and identification of artefacts.16

A meta-analysis demonstrated that type-1 diabetes is associated with reduced bone density and a higher risk of fracture.17 The converse is true in type-2 diabetics, where bone density is increased; the difference is thought to arise from the discrepancy in insulin concentrations.17 The lack of insulin translates to suppressed bone turnover due to a lack of osteoblastic activity and reduced levels of osteocalcin and insulin-growth-factor-1 (IGF-1).18,19 Such effects on bone have been shown in bone biopsy specimens from patients with type-1 diabetes.20 Given the synergistic activities of osteoclasts and osteoblasts, generally it is the suppressed activity of osteoblasts that account for the reduced bone density seen in patients with type-1 diabetes.18 In addition to the reduction in bone mineral density, the morphology of bone has been shown to transform to that of increased porosity and poor trabecular connectivity. As a result the biomechanical properties of bone deteriorate. This has been demonstrated by quantitative bone histomorphometry in experimentally induced diabetes using a rat model.21

Various animal studies have demonstrated impaired intra-membranous ossification using osteotomy or fracture models with experimentally induced diabetes, particularly in larger defects. One study using skull fractures demonstrated reduced marrow space in addition to suppressed cellularity and vascularisation after 14 days of healing.22 In addition, diminished osteoid deposition within periosteal callus and delayed maturity of woven bone were demonstrated in histological reports of femoral fracture models.23 The most profound of these studies include those using distraction osteogenesis models, which demonstrated a difference in bone bridging of 19.3 ± 12.5% (diabetic model) vs. 52.4 ± 6.2% (control) after 15 days of healing.24

In addition to intra-membranous ossification, endochondral ossification is also affected in diabetes and in particular fracture healing. Beam et al., investigated the effects of blood glucose control on Type I DM rat fracture healing; they demonstrated a reduction in the amounts of undifferentiated mesenchymal cells, cartilage formation, and proliferating chondrocytes.23 This study in particular demonstrated the importance of glycaemic control; they compared fracture healing in a control group, a spontaneously diabetic group, and a diabetic group treated with an insulin regimen. The insulin treated rats with systemic blood glucose <250 were shown to have a restored level of cellular proliferation, bone content within the callus, and biomechanical properties comparable to the control group.23 These findings were concluded by similar studies using rat models, and were shown to affect healing at various time points up to 4 weeks.25,26 These studies also concluded that poorly controlled diabetes correlated with suppressed mineralization leading to reduced apposition, diminished bridging, and remodeling; which in turn are detrimental to the biomechanical properties of the fracture callus.

Recent studies have attempted to explain the molecular mechanisms behind impaired bone healing in diabetic patients. Kayal et al., demonstrated decreased bone volume, callus size, and cartilage content towards the latter stages of bone healing that corresponded with an increased number of osteoclasts and consequently bone resorption.27 Kayal et al. used fracture models in mice with induced diabetes to demonstrate that the effect of diabetes on fracture healing increased chondrocyte apoptosis and osteoclastogenesis that accelerates the loss of cartilage and reduces the anlage for endochondral bone formation during fracture repair. That insulin reverses these effects demonstrates that they are directly related to the diabetic condition.28 Increased expression of chemokines, including the importance of TNF-alpha, by chondrocytes may contribute to the accelerated loss of cartilage observed in diabetic fracture healing.29

Furthermore, decreased cellular proliferation rates were explained by a decrease in local platelet derived growth factor levels,30 and decreased gene expression for the regulation of osteoblast differentiation.31 Suttapreyasri et al. carried out a study to identify bone morphogenetic proteins (BMPs) expressed in normal human bone. They also investigated the specific pattern of BMP-2 to BMP-9 expression in normal human intramembraneous and endochondral bone to maintain homeostasis as well as in ex vivo primary cell culture of human osteoblasts from intramembraneous and endochondral bone. BMP3, 4, 7 and 8 were strongly expressed in normal intramembraneous bone compared to endochondral bone, whereas BMP2 and 5 were highly expressed in endochondral bone. They have concluded that from the very similar expression patterns of BMPs in fresh human bone and ex vivo osteoblastic cell culture, it can be proposed that the different proportions of BMPs in human intramembraneous and endochondral bone are needed to maintain normal homeostasis.32

6. Adjuncts to fracture healing

Studies to assess the potential use of adjuncts to enhance diabetic fracture healing in rat models have highlighted the importance of insulin in its protective role in osseous development. Deficient osseous healing in experimental diabetes is reversible by systemic insulin treatment, which improves biomechanical parameters particularly in the late stages of fracture healing.33 Furthermore, Gandhi et al., highlighted that local insulin delivery (therefore not affecting systemic hyperglycaemia) normalized properties of early and late fracture healing in rat models.34 Due to these findings, it was concluded that insulin plays an important role in fracture healing.

The same group also assessed the application of platelet rich plasma (PRP) by local administration, which similar to insulin also normalized both early and late parameters of fracture healing in diabetic rat models.35 PRP is derived from autologous blood and contains a concentrated volume of platelets, growth factors, and bioactive proteins that can influence osseous healing.35 Such growth factors include platelet-derived growth factor (PDGF), transforming growth factor (TGF), and insulin like growth factor (IGF).

Biophysical stimulators have also been utilized to promote fracture healing and union in elective arthrodesis procedures. These devices include low intensity pulsed ultrasound (LIPUS) and pulsed electromagnetic fields (PEMF). Almost half of trauma surgeons reported the use of such stimulators in the management of complicated tibial shaft fractures with the majority feeling there is a reduction in healing time of 6 weeks or more.36 We focus on the uses of LIPUS in the remainder of this review.

7. Low intensity pulsed ultrasound (LIPUS)

Ultrasound is a propagating pressure wave that transmits mechanical energy into tissues.37 Ultrasound can have diagnostic and therapeutic applications in medicine including imaging and treatment of cancers. The ultrasound intensity is set at 30 mW/cm2 (1.5 MHz frequency pulsed at 200 μs durations), and is delivered through an ultrasound probe, which is coupled to the skin overlying the fracture with a water-based gel. Typical application of the device is for 20 min on a daily basis for the duration of treatment.36 Longitudinal pressure waves are emitted from a piezoelectric crystal transducer, which pass through the soft tissues to the bone. Upon interaction with the bone the longitudinal pressure waves undergo mode conversion into shear waves that can cause particle movement.37 This motion occurs on a nanometric scale with displacements to the magnitude of 0.55 nm.38 A further study reports the motion caused to be at a higher magnitude (up to 2 mm), with the micromotion seen to occur at the junction between soft and hard callus.39 The motion stimulates molecular and cellular pathways involved in cellular signaling and osteogenic differentiation seen in fracture healing.38,39 This response is akin to that of the bones reaction to mechanical stress as proposed by Wolff’s law.

8. LIPUS induced molecular and cellular mechanisms

LIPUS has been shown to enhance enchondral ossification leading to an increase in bony callus formation with increased mineral deposition and cortical bone mass; this translates to an accelerated callus formation and a smaller fracture gap.39

A potential mechanism for the increase in strength seen as a result of accelerated callus mineralization is that LIPUS plays a role in stimulating differentiation of cells responsible for fracture healing. These include osteoblasts, chondroblasts, mesenchymal cells and fibroblasts.37,39 To support this, studies have shown that LIPUS stimulates the expression of aggrecan, one critical matrix protein. Aggrecan leads to accelerated chondroblast differentiation into chondrocytes, which are critical in the formation of chondroitin - a structural macromolecule of cartilage.40

Bone marrow is an important source of undifferentiated progenitor cells, contributing to both chondrocytic and osteoblastic lineages. As demonstrated above, LIPUS stimulation of site leading to integrin activation lead to increased gene expression of osteogenic growth factors and markers of osteogenesis from the bone marrow. These include osteonectin, osteopontin, and insulin growth factor-1.41 This response suggests a mechanism by which LIPUS stimulates undifferentiated mesenchymal stem cells to ultimately differentiate into osteoblasts at an increased rate; thus enhancing bone healing and remodeling.42 The periosteal response to LIPUS has also been documented. Leung et al., demonstrated a response of periosteal tissue to LIPUS that included increased expression of osteocalcin, alkaline phosphatase, and Vascular Endothelial Growth Factor. These resulted in an increase in mineralization (demonstrated by alizarin red staining) and enhanced angiogenesis.43 Despite the breadth of research documenting the cellular and molecular response to LIPUS significant uncertainty remains as to the exact mechanism by which LIPUS enhances fracture healing. Below we discuss the effects of LIPUS as reported in pre-clinical and also clinical studies.

9. Pre-clinical studies

Several studies have described accelerated healing following LIPUS treatment in an animal model with a controlled fibular osteotomy.44,45 Wang et al., conducted an experiment on 22 rats with bilateral closed femoral fractures, treating one limb with LIPUS and compared to the untreated contralateral limb. Radiographic, histological, and biomechanical factors were all enhanced in the LIPUS treated limb; with significantly improved torsional and torque stiffness.46

More recently the use of LIPUS in diabetic animal models have drawn interesting conclusions. Coords et al. and Gebauer et al. both conducted a study on Wistar rats with and without diabetes. In both studies mid-shaft femur fractures were utilized. The diabetic group demonstrated reduced growth factor expression, cartilage formation, and angiogenesis as seen in various models of diabetic fracture healing. LIPUS significantly increased all parameters, so the diabetic group resembled the control group. Subsequently improved biomechanical properties were seen in the late stages of healing in both populations when LIPUS was used.47,48 Both studies concluded that up-regulation of growth factor expression, cartilage formation, and angiogenesis were seen within the callus with the addition of LIPUS.

10. Clinical studies - acute fractures

In 1983 Xavier and Duarte were the first to demonstrate successful human application of LIPUS for the treatment of non-unions, reporting a success rate of 70%.49 Heckman et al., conducted a multicentre, prospective, randomised, double-blind, placebo-controlled study to evaluate the effect of LIPUS on the healing of 33 tibia fractures, which were compared to 34 controls treated with a sham device. A significant improvement in the time to fracture union (clinical and radiographic) was seen in the LIPUS group compared to the controls (96 ± 4.9 days vs. 154 ± 13.7 days respectively).50 This study was the foundation for the FDA approval for the use of LIPUS in the treatment of acute fractures in 1994. A subsequent prospective, randomized, placebo-controlled, double-blind, multicenter study by Kristiansen et al., concluded similar findings in distal radius fractures (61 days vs. 98; p < 0.0001) and a greater than 50% improvement in loss of reduction rates (based on change in volar angulation; p < 0.01).4 Despite these significant landmarks, the use of LIPUS still remains undecided.

In an earlier study, Busse et al. performed a meta-analysis of randomized controlled trials for fracture healing. The study demonstrated a mean difference in healing time of 64 days in favour of LIPUS treatment compared to control groups.51

Several years later, the same group conducted an up-to-date systematic review and meta-analysis; they concluded that the evidence for the effects of LIPUS on fracture healing provides conflicting results and is moderate to very low in quality.52 Watanabe et al. and Mundi et al. both reported similar results from their respective systematic reviews, both of which highlighted the heterogeneity of results in clinical trials for fresh fractures.53,54

Studies negating the effects of LIPUS in the management of fresh fractures have also been published. Schandelmaier et al. conducted a systematic review looking at the efficacy of LIPUS for healing of fracture or osteotomy; a total of 26 randomized controlled trials with a median sample size of 30 were included. They concluded based on moderate to high quality evidence of fresh fractures LIPUS does not improve outcomes that are important to patients and probably has no effect on radiographic bone healing.55 In a follow up to the 2009 TRUST trial (a multicentre randomized, blinded, placebo/treatment controlled trial) a re-evaluation to evaluate the effects of LIPUS on validated functional outcomes and healing was conducted. It was concluded from the 501 patients with (14 open and 387 closed) tibial fractures treated with intra-medullary nailing enrolled in the study that LIPUS did not result in improved functional outcomes or time to union.56

11. Clinical studies - non-union

In cases of non-union, two studies have demonstrated excellent heal rates following the application of LIPUS. Overall heal rates were 86% in both studies in patients with established non-union (36 patients with average fracture age of 1.9 years57; 29 patients with average fracture age of 1.2 years.58 Gebauer et al. assessed studied 67 patients with a minimum fracture age of 8 months. Inclusion criteria included no surgical intervention during 4 months before US treatment and radiographically ceased healing for 3 months before US. The mean fracture age of the 67 patients was 39±6.2 months. After a daily 20-min LIPUS treatment at home for an average of 168 days, 85% (57 of 67) of the nonunion cases were clinically and radiographically healed.59

It is apparent that studies where a positive difference was demonstrated have been mainly low quality studies. The current paucity of data from methodologically sound randomized controlled trials makes it hard to recommend the use of LIPUS use in everyday circumstances. Rather it should be targeted to certain fracture types, in particular delayed or non-union fractures may benefit from LIPUS, as demonstrated by Schofer et al..60 This group undertook a multi-centre randomized sham-controlled trial across Germany; with participants randomized to LIPUS (n = 51) or sham (n = 50) device after a confirmed delayed union of at least 4 months. A significant mean improvement in bone mineral density to the order of 1.34 (1.14–1.57) and a reduction in bone gap was seen in the LIPUS treated patients.60

Zura et al., conducted an observational cohort study that included a total of 767 patients with established non-union (≥1 year); all fractures and fixation methods, patient age and co-morbidities were included, 50% of the cohort were smokers. Overall heal rate was 86.2%. Subgroup analysis demonstrated that those with a fracture age of less than 2 years had a heal rate of 87.9%, compared to 82.7% in those with fracture age over 5 years. There was no significant difference between closed or open fractures, nor fracture location. The use of LIPUS resulted in a heal rate of 80% when used alone without further surgery in tibial or femoral fractures.61

There is some radiological evidence of healing being improved when LIPUS is used for long bone fractures with delayed healing (no radiological evidence of healing after approximately 3 months). There are uncertainties about the rate bone healing progresses without adjunctive treatment between 3 and 9 months after fracture, and about whether surgery is necessary or not.62

A recent Cochrane review of 12 studies involving 622 patients with 648 fractures was conducted.63 The included studies spanned both upper and lower limb injuries, varied in terms of study design (randomized control trial with or without placebo control), and fracture type (conservatively vs. surgically treated). The authors commented on the poor reporting of methods, which potentially led to reporting bias. Pooled data from eight of these studies (446 fractures) showed no statistically significant reduction in time to union of complete fractures (standardized mean difference = −0.47, 95% CI = −1.14 to 0.20). Subgroup analysis was performed due to the significant heterogeneity seen, which showed a potential benefit in conservatively managed fractures over surgically treated fractures; however, this difference was not significant.63 Once more though, the authors concluded that the available evidence was heterogeneous and insufficient to support LIPUS in standard clinical practice for all fractures.

Most recently Leighton et al., conducted a meta-analysis of 13 studies incorporating 1441 non-unions demonstrated an overall heal rate of 82% (77–87%). When ≥8 months was used as the definition of non-union, the heal rate was estimated at 84% (77–91.6%). They concluded that hypertrophic non-unions benefitted more than biologically inactive atrophic non-unions and that LIPUS is an alternative to surgery for the management of fracture non-unions.64

These recent studies would discourage clinicians from using LIPUS in fresh fractures, leaving its use more suitable for circumstances involving delayed or non-union. Importantly, no studies have assessed the impact of LIPUS on diabetic human subjects with fresh fractures or non-unions. This may be an important sub-group of patients in which LIPUS may also be of benefit as corroborated by our increased understanding of how diabetes effects fracture healing.

12. Economic benefits

In 1997, an economic analysis estimated savings of $13,259 per fracture following the use of LIPUS in 60 patients with delayed union of tibial shaft fractures using radiographic healing as a surrogate for functional recovery.65 A more recent comprehensive study used insurance databases to identify patients with non-unions who underwent either surgery or LIPUS treatment. The groups were retrospectively matched and all medical costs were taken into account. Surgical patients used significantly more healthcare services in treatment for fracture union compared to those receiving LIPUS therapy alone.66 It was estimated that the use of LIPUS in this group of patients could save $4 billion dollars in the United States annually, where surgery-only patients had total medical costs of $6289 higher than LIPUS-only patients.66

13. Summary

The current heterogeneity of the available supporting evidence makes it hard to justify the use of LIPUS as a standard of care. However, further work needs to be conducted, with an increasing focus on identifying sub-categories of patients that would benefit most from LIPUS treatment. One such group may be diabetic patients who frequently suffer with delayed or non-union for a variety of molecular, cellular, and biological reasons. Animal studies have highlighted the potential of LIPUS in reversing these mechanisms that lead to non-union in diabetic patients, however, no human clinical studies exist to substantiate these findings. With the population of diabetic patients set to increase, and the high rate of bone healing complications, it is more important than ever that further research is undertaken to shed light on the potential impact of LIPUS in treating fractures in diabetic patients.

References

  • 1.Gandhi A., Liporace F., Azad V., Mattie J., Lin S. Diabetic fracture healing. Foot Ankle Clin. 2006;11(4):805–824. doi: 10.1016/j.fcl.2006.06.009. [DOI] [PubMed] [Google Scholar]
  • 2.Wukich D.K., Joseph A., Ryan M., Ramirez C., Irrgang J.J. Outcomes of ankle fractures in patients with uncomplicated versus complicated diabetes. Foot Ankle Int. 2011;32(2):120–130. doi: 10.3113/FAI.2011.0120. PubMed PMID: 21288410. [DOI] [PubMed] [Google Scholar]
  • 3.Wukich D.K., Kline A.J. The management of ankle fractures in patients with diabetes. J Bone Jt Surg Am Vol. 2008;90(7):1570–1578. doi: 10.2106/JBJS.G.01673. PubMed PMID: 18594108. [DOI] [PubMed] [Google Scholar]
  • 4.Kristiansen T.K., Ryaby J.P., McCabe J., Frey J.J., Roe L.R. 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 Jt Surg Am Vol. 1997;79(7):961–973. doi: 10.2106/00004623-199707000-00002. PubMed PMID: 9234872. [DOI] [PubMed] [Google Scholar]
  • 5.Low-intensity pulsed ultrasound to promote healing of fresh fractures at high risk of non-healing. 2020. https://www.nice.org.uk/guidance/IPG622 Nice.org.uk.
  • 6.Poolman R., Agoritsas T., Siemieniuk R. Low intensity pulsed ultrasound (LIPUS) for bone healing: a clinical practice guideline. BMJ. 2017:j576. doi: 10.1136/bmj.j576. [DOI] [PubMed] [Google Scholar]
  • 7.Aaron R.K., Ciombor D.M., Simon B.J. Treatment of nonunions with electric and electromagnetic fields. Clin Orthop Relat Res. 2004;(419):21–29. doi: 10.1097/00003086-200402000-00005. PubMed PMID: 15021127. [DOI] [PubMed] [Google Scholar]
  • 8.Shibuya N., Humphers J.M., Fluhman B.L., Jupiter D.C. Factors associated with nonunion, delayed union, and malunion in foot and ankle surgery in diabetic patients. J Foot Ankle Surg: official publication of the American College of Foot and Ankle Surgeons. 2013;52(2):207–211. doi: 10.1053/j.jfas.2012.11.012. PubMed PMID: 23313498. [DOI] [PubMed] [Google Scholar]
  • 9.Tsiridis E., Upadhyay N., Giannoudis P. Molecular aspects of fracture healing: which are the important molecules? Injury. 2007;38(Suppl 1):S11–S25. doi: 10.1016/j.injury.2007.02.006. PubMed PMID: 17383481. [DOI] [PubMed] [Google Scholar]
  • 10.Phillips A.M. Overview of the fracture healing cascade. Injury. 2005;36(Suppl 3):S5–S7. doi: 10.1016/j.injury.2005.07.027. PubMed PMID: 16188551. [DOI] [PubMed] [Google Scholar]
  • 11.Mehta S.K., Breitbart E.A., Berberian W.S., Liporace F.A., Lin S.S. Bone and wound healing in the diabetic patient. Foot Ankle Clin. 2010;15(3):411–437. doi: 10.1016/j.fcl.2010.03.005. PubMed PMID: 20682414. [DOI] [PubMed] [Google Scholar]
  • 12.Facts and Stats. Diabetes UK. 2016. https://diabetes-resources-production.s3-eu-west-1.amazonaws.com/diabetes-storage/migration/pdf/DiabetesUK_Facts_Stats_Oct16.pdf [Google Scholar]
  • 13.Cozen L. Does diabetes delay fracture healing? Clin Orthop Relat Res. 1972;82:134–140. PubMed PMID: 5011018. [PubMed] [Google Scholar]
  • 14.Loder R.T. The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res. 1988;(232):210–216. PubMed PMID: 3289812. [PubMed] [Google Scholar]
  • 15.Blake G.M., Fogelman I. The role of DXA bone density scans in the diagnosis and treatment of osteoporosis. Postgrad Med. 2007;83(982):509–517. doi: 10.1136/pgmj.2007.057505. PubMed PMID: 17675543; PubMed Central PMCID: PMCPMC2600106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Garg M.K., Kharb S. Dual energy X-ray absorptiometry: pitfalls in measurement and interpretation of bone mineral density. Indian J Endocrinol Metab. 2013;17(2):203–210. doi: 10.4103/2230-8210.109659. PubMed PMID: 23776890; PubMed Central PMCID: PMCPMC3683192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis. Osteoporos Int. 2007;18(4):427–444. doi: 10.1007/s00198-006-0253-4. PubMed PMID: 17068657. [DOI] [PubMed] [Google Scholar]
  • 18.McCabe L.R. Understanding the pathology and mechanisms of type I diabetic bone loss. J Cell Biochem. 2007;102(6):1343–1357. doi: 10.1002/jcb.21573. PubMed PMID: 17975793. [DOI] [PubMed] [Google Scholar]
  • 19.Kemink S.A., Hermus A.R., Swinkels L.M., Lutterman J.A., Smals A.G. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. J Endocrinol Invest. 2000;23(5):295–303. doi: 10.1007/BF03343726. PubMed PMID: 10882147. [DOI] [PubMed] [Google Scholar]
  • 20.Krakauer J.C., McKenna M.J., Buderer N.F., Rao D.S., Whitehouse F.W., Parfitt A.M. Bone loss and bone turnover in diabetes. Diabetes. 1995;44(7):775–782. doi: 10.2337/diab.44.7.775. PubMed PMID: 7789645. [DOI] [PubMed] [Google Scholar]
  • 21.Suzuki K., Miyakoshi N., Tsuchida T., Kasukawa Y., Sato K., Itoi E. Effects of combined treatment of insulin and human parathyroid hormone(1-34) on cancellous bone mass and structure in streptozotocin-induced diabetic rats. Bone. 2003;33(1):108–114. doi: 10.1016/s8756-3282(03)00169-8. PubMed PMID: 12919705. [DOI] [PubMed] [Google Scholar]
  • 22.Santana R.B., Xu L., Chase H.B., Amar S., Graves D.T., Trackman P.C. A role for advanced glycation end products in diminished bone healing in type 1 diabetes. Diabetes. 2003;52(6):1502–1510. doi: 10.2337/diabetes.52.6.1502. PubMed PMID: 12765963. [DOI] [PubMed] [Google Scholar]
  • 23.Beam H.A., Parsons J.R., Lin S.S. The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. J Orthop Res: official publication of the Orthopaedic Research Society. 2002;20(6):1210–1216. doi: 10.1016/S0736-0266(02)00066-9. PubMed PMID: 12472231. [DOI] [PubMed] [Google Scholar]
  • 24.Fowlkes J.L., Bunn R.C., Liu L. Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology. 2008;149(4):1697–1704. doi: 10.1210/en.2007-1408. PubMed PMID: 18162513; PubMed Central PMCID: PMCPMC2276714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Macey L.R., Kana S.M., Jingushi S., Terek R.M., Borretos J., Bolander M.E. Defects of early fracture-healing in experimental diabetes. J Bone Jt Surg Am Vol. 1989;71(5):722–733. PubMed PMID: 2659600. [PubMed] [Google Scholar]
  • 26.Follak N., Kloting I., Merk H. Influence of diabetic metabolic state on fracture healing in spontaneously diabetic rats. Diabetes Metab Res Rev. 2005;21(3):288–296. doi: 10.1002/dmrr.537. PubMed PMID: 15693070. [DOI] [PubMed] [Google Scholar]
  • 27.Kayal R.A., Tsatsas D., Bauer M.A. Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res : the official journal of the American Society for Bone and Mineral Research. 2007;22(4):560–568. doi: 10.1359/jbmr.070115. PubMed PMID: 17243865; PubMed Central PMCID: PMC3109431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Kayal R.A., Alblowi J., McKenzie E. Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone. 2009;44(2):357–363. doi: 10.1016/j.bone.2008.10.042. PubMed PMID: 19010456; PubMed Central PMCID: PMCPMC2700945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Alblowi J., Tian C., Siqueira M.F. Chemokine expression is upregulated in chondrocytes in diabetic fracture healing. Bone. 2013;53(1):294–300. doi: 10.1016/j.bone.2012.12.006. PubMed PMID: 23262028; PubMed Central PMCID: PMCPMC3767396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Tyndall W.A., Beam H.A., Zarro C., O’Connor J.P., Lin S.S. Decreased platelet derived growth factor expression during fracture healing in diabetic animals. Clin Orthop Relat Res. 2003;(408):319–330. doi: 10.1097/00003086-200303000-00043. PubMed PMID: 12616077. [DOI] [PubMed] [Google Scholar]
  • 31.Lu H., Kraut D., Gerstenfeld L.C., Graves D.T. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinology. 2003;144(1):346–352. doi: 10.1210/en.2002-220072. PubMed PMID: 12488363. [DOI] [PubMed] [Google Scholar]
  • 32.Suttapreyasri S., Koontongkaew S., Phongdara A., Leggat U. Expression of bone morphogenetic proteins in normal human intramembranous and endochondral bones. Int J Oral Maxillofac Surg. 2006;35(5):444–452. doi: 10.1016/j.ijom.2006.01.021. PubMed PMID: 16513322. [DOI] [PubMed] [Google Scholar]
  • 33.Macey L.R., Kana S.M., Jingushi S., Terek R.M., Borretos J., Bolander M.E. Defects of early fracture-healing in experimental diabetes. J Bone Jt Surg Am Vol. 1989;71(5):722–733. PubMed PMID: 2659600. [PubMed] [Google Scholar]
  • 34.Gandhi A., Beam H.A., O’Connor J.P., Parsons J.R., Lin S.S. The effects of local insulin delivery on diabetic fracture healing. Bone. 2005;37(4):482–490. doi: 10.1016/j.bone.2005.04.039. PubMed PMID: 16027060. [DOI] [PubMed] [Google Scholar]
  • 35.Gandhi A., Doumas C., O’Connor J.P., Parsons J.R., Lin S.S. The effects of local platelet rich plasma delivery on diabetic fracture healing. Bone. 2006;38(4):540–546. doi: 10.1016/j.bone.2005.10.019. PubMed PMID: 16368279. [DOI] [PubMed] [Google Scholar]
  • 36.Busse J.W., Morton E., Lacchetti C., Guyatt G.H., Bhandari M. Current management of tibial shaft fractures: a survey of 450 Canadian orthopedic trauma surgeons. Acta Orthop. 2008;79(5):689–694. doi: 10.1080/17453670810016722. PubMed PMID: 18839377. [DOI] [PubMed] [Google Scholar]
  • 37.Parvizi J., Vegari D. Pulsed low-intensity ultrasound for fracture healing. Foot Ankle Clin. 2005;10(4):595–608. doi: 10.1016/j.fcl.2005.06.007. vii. PubMed PMID: 16297821. [DOI] [PubMed] [Google Scholar]
  • 38.Pounder N.M., Harrison A.J. Low intensity pulsed ultrasound for fracture healing: a review of the clinical evidence and the associated biological mechanism of action. Ultrasonics. 2008;48(4):330–338. doi: 10.1016/j.ultras.2008.02.005. PubMed PMID: 18486959. [DOI] [PubMed] [Google Scholar]
  • 39.Claes L., Willie B. The enhancement of bone regeneration by ultrasound. Prog Biophys Mol Biol. 2007;93(1-3):384–398. doi: 10.1016/j.pbiomolbio.2006.07.021. PubMed PMID: 16934857. [DOI] [PubMed] [Google Scholar]
  • 40.Parvizi J., Wu C.C., Lewallen D.G., Greenleaf J.F., Bolander M.E. Low-intensity ultrasound stimulates proteoglycan synthesis in rat chondrocytes by increasing aggrecan gene expression. J Orthop Res: official publication of the Orthopaedic Research Society. 1999;17(4):488–494. doi: 10.1002/jor.1100170405. PubMed PMID: 10459753. [DOI] [PubMed] [Google Scholar]
  • 41.Sena K., Leven R.M., Mazhar K., Sumner D.R., Virdi A.S. Early gene response to low-intensity pulsed ultrasound in rat osteoblastic cells. Ultrasound Med Biol. 2005;31(5):703–708. doi: 10.1016/j.ultrasmedbio.2005.01.013. PubMed PMID: 15866420. [DOI] [PubMed] [Google Scholar]
  • 42.Gurkan U.A., Akkus O. The mechanical environment of bone marrow: a review. Ann Biomed Eng. 2008;36(12):1978–1991. doi: 10.1007/s10439-008-9577-x. PubMed PMID: 18855142. [DOI] [PubMed] [Google Scholar]
  • 43.Leung K.S., Cheung W.H., Zhang C., Lee K.M., Lo H.K. Low intensity pulsed ultrasound stimulates osteogenic activity of human periosteal cells. Clin Orthop Relat Res. 2004;(418):253–259. doi: 10.1097/00003086-200401000-00044. PubMed PMID: 15043127. [DOI] [PubMed] [Google Scholar]
  • 44.Duarte L.R. The stimulation of bone growth by ultrasound. Archives of orthopaedic and traumatic surgery Archiv fur orthopadische und Unfall-Chirurgie. 1983;101(3):153–159. doi: 10.1007/BF00436764. PubMed PMID: 6870502. [DOI] [PubMed] [Google Scholar]
  • 45.Pilla A.A., Mont M.A., Nasser P.R. Non-invasive low-intensity pulsed ultrasound accelerates bone healing in the rabbit. J Orthop Trauma. 1990;4(3):246–253. doi: 10.1097/00005131-199004030-00002. PubMed PMID: 2231120. [DOI] [PubMed] [Google Scholar]
  • 46.Wang S.J., Lewallen D.G., Bolander M.E., Chao E.Y., Ilstrup D.M., Greenleaf J.F. Low intensity ultrasound treatment increases strength in a rat femoral fracture model. J Orthop Res: official publication of the Orthopaedic Research Society. 1994;12(1):40–47. doi: 10.1002/jor.1100120106. PubMed PMID: 8113941. [DOI] [PubMed] [Google Scholar]
  • 47.Coords M., Breitbart E., Paglia D. The effects of low-intensity pulsed ultrasound upon diabetic fracture healing. J Orthop Res: official publication of the Orthopaedic Research Society. 2011;29(2):181–188. doi: 10.1002/jor.21223. PubMed PMID: 20886648. [DOI] [PubMed] [Google Scholar]
  • 48.Gebauer G.P., Lin S.S., Beam H.A., Vieira P., Parsons J.R. Low-intensity pulsed ultrasound increases the fracture callus strength in diabetic BB Wistar rats but does not affect cellular proliferation. J Orthop Res: official publication of the Orthopaedic Research Society. 2002;20(3):587–592. doi: 10.1016/S0736-0266(01)00136-X. PubMed PMID: 12038635. [DOI] [PubMed] [Google Scholar]
  • 49.Watanabe Y., Matsushita T., Bhandari M., Zdero R., Schemitsch E.H. Ultrasound for fracture healing: current evidence. J Orthop Trauma. 2010;24(Suppl 1):S56–S61. doi: 10.1097/BOT.0b013e3181d2efaf. PubMed PMID: 20182238. [DOI] [PubMed] [Google Scholar]
  • 50.Heckman J.D., Ryaby J.P., McCabe J., Frey J.J., Kilcoyne R.F. Acceleration of tibial fracture-healing by non-invasive, low-intensity pulsed ultrasound. J Bone Jt Surg Am Vol. 1994;76(1):26–34. doi: 10.2106/00004623-199401000-00004. PubMed PMID: 8288661. [DOI] [PubMed] [Google Scholar]
  • 51.Busse J.W., Bhandari M., Kulkarni A.V., Tunks E. The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis. CMAJ. 2002;166(4):437–441. PubMed PMID: 11873920; PubMed Central PMCID: PMCPMC99352. [PMC free article] [PubMed] [Google Scholar]
  • 52.Busse J.W., Kaur J., Mollon B. Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials. BMJ. 2009;338:b351. doi: 10.1136/bmj.b351. PubMed PMID: 19251751; PubMed Central PMCID: PMCPMC2651102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Watanabe Y., Matsushita T., Bhandari M., Zdero R., Schemitsch E.H. Ultrasound for fracture healing: current evidence. J Orthop Trauma. 2010;24(Suppl 1):S56–S61. doi: 10.1097/BOT.0b013e3181d2efaf. PubMed PMID: 20182238. [DOI] [PubMed] [Google Scholar]
  • 54.Mundi R., Petis S., Kaloty R., Shetty V., Bhandari M. Low-intensity pulsed ultrasound: fracture healing. Indian J Orthop. 2009;43(2):132–140. doi: 10.4103/0019-5413.50847. PubMed PMID: 19838361; PubMed Central PMCID: PMCPMC2762261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Schandelmaier S., Kaushal A., Lytvyn L. Low intensity pulsed ultrasound for bone healing: systematic review of randomized controlled trials. BMJ. 2017;356:j656. doi: 10.1136/bmj.j656. PubMed PMID: 28348110; PubMed Central PMCID: PMCPMC5484179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.group TIw, Busse J.W., Bhandari M. Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial. BMJ. 2016;355:i5351. doi: 10.1136/bmj.i5351. PubMed PMID: 27797787; PubMed Central PMCID: PMCPMC5080447 at www.icmje.org/coi_disclosure.pdf and declare: TAE, ES, and MB have received consulting fees from Smith & Nephew, the manufacturer of the study device. PT receives royalties from Smith & Nephew. GJDR is a paid consultant for Bioventus LLC, which is 51% owned by Essex Woodlands and 49% by Smith & Nephew. MB is supported, in part, by a Canada research chair, McMaster University. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Mayr E., Mockl C., Lenich A., Ecker M., Ruter A. [Is low intensity ultrasound effective in treatment of disorders of fracture healing?] Unfallchirurg. 2002;105(2):108–115. doi: 10.1007/s001130100301. PubMed PMID: 11968536. [DOI] [PubMed] [Google Scholar]
  • 58.Nolte P.A., van der Krans A., Patka P., Janssen I.M., Ryaby J.P., Albers G.H. Low-intensity pulsed ultrasound in the treatment of nonunions. J Trauma. 2001;51(4):693–702. doi: 10.1097/00005373-200110000-00012. discussion -3. PubMed PMID: 11586161. [DOI] [PubMed] [Google Scholar]
  • 59.Gebauer D., Mayr E., Orthner E., Ryaby J.P. Low-intensity pulsed ultrasound: effects on nonunions. Ultrasound Med Biol. 2005;31(10):1391–1402. doi: 10.1016/j.ultrasmedbio.2005.06.002. PubMed PMID: 16223643. [DOI] [PubMed] [Google Scholar]
  • 60.Schofer M.D., Block J.E., 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 Muscoskel Disord. 2010;11:229. doi: 10.1186/1471-2474-11-229. PubMed PMID: 20932272; PubMed Central PMCID: PMCPMC2958986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Zura R., Della Rocca G.J., Mehta S. Treatment of chronic (>1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS) Injury. 2015;46(10):2036–2041. doi: 10.1016/j.injury.2015.05.042. PubMed PMID: 26052056. [DOI] [PubMed] [Google Scholar]
  • 62.EXOGEN Ultrasound Bone Healing System for Long Bone Fractures with Non-union or Delayed Healing. 2013. https://www.nice.org.uk/guidance/mtg12/chapter/1-Recommendations Nice.org.uk. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Griffin X.L., Parsons N., Costa M.L., Metcalfe D. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2014;6:CD008579. doi: 10.1002/14651858.CD008579.pub3. PubMed PMID: 24956457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Leighton R., Watson J.T., Giannoudis P., Papakostidis C., Harrison A., Steen R.G. Healing of fracture nonunions treated with low-intensity pulsed ultrasound (LIPUS): a systematic review and meta-analysis. Injury. 2017;48(7):1339–1347. doi: 10.1016/j.injury.2017.05.016. PubMed PMID: 28532896. [DOI] [PubMed] [Google Scholar]
  • 65.Heckman J.D., Sarasohn-Kahn J. The economics of treating tibia fractures. The cost of delayed unions. Bull Hosp Jt Dis. 1997;56(1):63–72. PubMed PMID: 9063607. [PubMed] [Google Scholar]
  • 66.Mehta S., Long K., DeKoven M., Smith E., Steen R.G. Low-intensity pulsed ultrasound (LIPUS) can decrease the economic burden of fracture non-union. J Med Econ. 2015;18(7):542–549. doi: 10.3111/13696998.2015.1019887. PubMed PMID: 25708448. [DOI] [PubMed] [Google Scholar]

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