Introduction Fracture is a disease with a high incidence worldwide. Foot and ankle fractures are common among fractures of the lower extremities. Foot and ankle fractures usually require surgical fixation and a period of fixed treatment, which can lead to decreased bone density. Although transcutaneous electrical acupoint stimulation (TEAS) is widely used for movement system diseases, there is minimal evidence to show the effectiveness of TEAS on patients after surgical fixation of ankle and foot fractures. This trial aims to evaluate whether TEAS can reduce bone loss in patients with immobilisation after ankle and foot fractures.
Methods and analysis A randomised controlled trial will be conducted in which 60 patients will be randomly divided into two groups: (a) the control group will be treated according to the routine procedures of basic orthopaedics treatment; (b) in the treatment group, bilateral SP36, BL23 and ST36 will be performed on the basis of the control group, and the test will be performed for 30 min every other day for a total of 8 weeks. Bone turnover markers will be used as primary outcome. Secondary outcomes are composed of blood phosphorus, blood calcium and bone mineral density. Treatment safety will be monitored and recorded.
Ethics and dissemination This trial is approved by the Ethics Committee of Beijing University of Chinese Medicine (2020BZYLL0611) and the Ethics Committee of Beijing Luhe Hospital (2020-LHKY-055-02), and inpatients who meet the following diagnostic and inclusion criteria are eligible to participate in this study.
Trial registration number ChiCTR 2000039944.
- rehabilitation medicine
- foot & ankle
- aviation medicine
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Strengths and limitations of this study
This study is the first randomised controlled trial of transcutaneous electrical acupoint stimulation (TEAS) in the treatment of bone loss in patients after surgical fixation of ankle and foot fractures.
This study will provide evidence on the optimal option for external non-interventional therapy in the treatment of patients after surgical fixation of ankle and foot fractures.
The patients cannot be blinded due to the particularity of TEAS treatment.
We cannot judge the subjective feelings of patients due to the lack of subjective outcomes.
This is an exploratory study with a small sample size which has not been calculated.
Fracture is one of the most common clinical diseases in the world, with an annual incidence rate of at least 5 per 10 000 people.1 2 When the fracture is healing, patients with foot and ankle fractures will receive surgical fixation and a period of fixation treatment. This process will reduce the mechanical stress of patients and cause bone loss.3–7 Studies have suggested that patients who are bedridden after fractures may experience bone mineral loss in their lower extremities, which is related to the reduction in weight bearing.8–11 Other studies have shown that in individuals with lower extremities injuries, a significant correlation exists between the decrease in bone density and the acceleration of bone turnover.12 13 Although there are several methods to prevent bone loss, such as hormone replacement therapy, bisphosphonates, denosumab and parathyroid hormone (PTH), the inherent side effects of their long-term use have drawn attention.14 Therefore, it is necessary to find a safe and reliable method to treat bone loss. With an appropriate stimulation frequency, physiotherapy electrical stimulation can cause passive contraction of muscles, promote osteoblast activity and inhibit bone absorption.15
Electrical stimulation can provide local irritation for bone-forming cells and reduce bone loss. As we all know, bone is a mechanical sensory organ that requires continuous strain to maintain its functional structure and prevent bone loss.16–18 Transcutaneous electrical acupoint stimulation (TEAS) is derived from acupuncture, which bears the advantages of high safety and low risk, and it also can replace electric acupuncture. TEAS is becoming increasingly popular around the world.19 20 It has been used in many diseases.21–26 The therapeutic effect of TEAS is similar to that of acupuncture. Meanwhile, it has long been regarded as a potentially effective non-drug therapy for the treatment of fractures. TEAS can reactivate the biological process of bone regeneration, simplify fracture regeneration and shorten the duration of treatment.27 It uses works by using pulsed electromagnetic fields (PEMF) together with traditional Chinese medicine acupoints.28 To date, a large number of studies have suggested that PEMF can regulate bone metabolism in patients with fractures, enhance bone formation, increase bone density and reduce patients’ pain.29–32 Although it has been proved that the postoperative fixation of ankle and foot fractures can affect bone metabolism and lead to bone loss,33 34 there is little evidence to show that TEAS can treat postoperative fixation of ankle and foot fractures.
Therefore, we have designed an open label, randomised, controlled trial to examine the effect of TEAS on patients with immobilisation after foot and ankle fractures. Our aim is to evaluate whether TEAS can reduce bone loss in patients with immobilisation after foot and ankle fractures.
Study design and setting
The open-label and randomised controlled trial will be conducted from November 2020 to November 2021. The hospital will assign a multidisciplinary team (including acupuncturists, rehabilitative physicians, orthopaedic surgeons, nurses and physical therapists) to conduct the trial. Participants will receive transportation and blood sample subsidies during the trial, and all TEAS treatments, blood and urinary tests, dual energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) examinations are free of charge. This trial has to follow Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines35 and will conform with Consolidated Standards of Reporting Trials guidelines.36 A SPIRIT checklist is provided as online supplemental file 1 . This trial was approved by the ethical committees of relevant hospitals and registered on www.chictr.org. The study was approved by the ethics committee of our institution and obtained the informed consent of all participants. The planned start date is April 2021 and end date is April 2022.
The flowchart of the study is presented in figure 1.
Given that this is a pilot trial, a formal sample size calculation will be not necessary. Therefore, the sample size of 60 participants (30 persons per group) is determined to be sufficient for the purpose of the trial (preliminary verification of the effectiveness of TEAS treatment in terms of bone loss relief in patients with immobilisation after ankle and foot fractures after 8-week treatment). Due to the COVID-19 epidemic, we designed the 25% dropout rate to ensure the aimed sample size, so we plan to recruit 80 participants.
According to the Guidelines for the Diagnosis and Treatment of Common Diseases in Orthopedics and Traumatology of Traditional Chinese Medicine,37 all cases will be diagnosed with foot and ankle fractures by imaging and related orthopaedics diagnosis in tertiary hospitals. Imaging examination: X-ray (CT or MRI can be used if necessary) diagnosed patients as foot and ankle fractures of the distal tibia, fibula, talus, metatarsal and ankle.
Satisfaction with the above-mentioned key diagnosis points and immobilisation needs of foot and ankle injury.
The patient is aged 18–45 years old.
The patient has a clear consciousness.
The length of internal fracture fixation does not exceed 15 cm above ankle joint.
The patient is informed and agrees to sign an informed consent form.
Patients with endocrine diseases (thyroid, parathyroid, gonad, adrenal diseases and etc) that affect bone metabolism, immune diseases (such as rheumatoid arthritis, digestive tract, liver and kidney diseases) that affect calcium and vitamin D absorption, and malignant diseases (such as multiple myeloma).
Long-term use of glucocorticoids, antiepileptic drugs, oestrogen, heparin, progesterone and other drugs affecting bone metabolism; various congenital and acquired bone metabolic disorders.
Patients who have taken calcium, calcitonin, vitamin D and other drugs affecting bone metabolism within 30 days.
Patients with severe infection of the limbs, or pathological, old fractures, or other fractures of the limbs, and severe heart, liver, kidney, lung, blood and endocrine system diseases.
Patients with histories of severe digestive system disease, kidney disease, connective tissue disease, or malignant tumour, or other disease affecting bone metabolic.
Pregnant or lactating women.
Patients with a stent implanted in their body or a history of joint replacement.
Patients with known heart disease and patients with pacemakers.
Patients who have been treated by this study within the past 30 days.
Patients with allergies, poor compliance or mental disorders who cannot cooperate with the study.
Newly diagnosed patients who need calcium intervention.
Randomisation and allocation concealment
The trial will adopt computer software named SPSS V.26.0 to generate a random number table and put the random numbers and grouping information in an opaque, sealed and sequentially coded envelope, which will be kept by a dedicated person. Patients will receive corresponding envelopes in order of their enrolment. Random numbers ending in an odd number will be included in the treatment group, and those ending in an even number will be included in the control group. Because it is difficult to implement a blinding principle in clinical research involving TEAS, special personnel will be responsible for grouping, treatment operation and data collection during the implementation process of this project; At the same time, as the outcome indicators of this trial are all objective indicators obtained from laboratory tests and machine measurement, the absence of blinding will not be considered as a factor affecting the results of the study.
Due to the particularity of TEAS treatment, neither the patient nor the acupuncturist can be blinded. However, clinical assessors, rehabilitative physicians, orthopaedic surgeons, data collectors and analysts will be blinded to the treatment and grouping of patients.
Patient and public involvement
There is no patient or public involvement in study design, recruitment for or conduct of the study.
The conventional orthopaedic treatment: (a) no weight-bearing lower limb joint and muscle training for 4 weeks after operation, including active and passive exercises; (b) routine X-ray examinations 1 month and 2 months after operation would be performed to observe fracture healing and internal components (plates, screws).
Based on the conventional orthopaedic treatment in control group, TEAS treatment will be adopted bilaterally at SP36, BL23 and ST36. The acupoint locations refer to the PRC National Standard ‘Acupoint Name and Location’ (GB/T 12346-2006).38 Operation: a patient takes the supine position, the acupoint locations are wiped and disinfected with a 75% alcohol cotton ball, and, after drying, the electrode pads are pasted on. During the treatment, one set of electrodes will be applied to the BL23 on both sides, and the other set of electrodes to the SP36 and ST36 on the same side of the lower limbs. In this way, a current loop will be formed. Electrical stimulation of the lower limbs focuses on stimulating the affected limb. If it is not possible to stimulate the affected side after fixation, a contralateral acupoint can be used. The power will be turned on and the parameters adjusted. The stimulation frequency will be set to 2 Hz/100 Hz and the default value to 10 mA; its actual value (5–10 mA) will be determined by keeping the patient comfortable for 30 min at a time, every other day, for 8 weeks. Before treatment, the knob will be adjusted to the lowest position and the power gradually increased. It should not be large and then small or suddenly large and small, which would make it difficult for the patient to accept. The methods and parameters of acupoint electrical stimulation are standard parameters, which ensure the maximum safety of TEAS. The operating instrument used is the INTI brand KWD-808 I pulse therapy instrument (Su Annotation 20152261330).
Treatment during hospitalisation
The patients with foot and ankle fractures in the trial group accept surgical treatment and can be discharged after 1 week of hospitalisation in accordance with routine procedure; so, the treatment in the first week is performed by a professionally qualified acupuncturist. At the same time, basic orthopaedic treatment is jointly completed by a professionally qualified orthopaedic doctor and a professionally qualified rehabilitation therapist. Before the project is launched, acupuncturists, rehabilitation physicians, orthopaedic surgeons, nurses and physiotherapists will be trained in the operation methods and procedures for transcutaneous electrical acupuncture and basic orthopaedic therapy, to unify and standardise their operation.
Treatment after discharge
Treatment after discharge: the patients and their families will get standardised operation process training after their enrolment. The training team consists of two acupuncturists, an orthopaedic doctor and a rehabilitation specialist who perform the first week of treatment. The training includes TEAS and basic orthopaedic treatment. Training content: (a) therapeutic point selection of SP36, BL23 and ST36 acupoint positioning (each patient will have an acupoint positioning guide); (b) operation procedures of TEAS (each patient will have an instrument operation manual); (c) basic orthopaedic treatment content (such as active and passive weight-bearing lower limb joint and muscle training).
After being randomly assigned, all patients will receive a baseline assessment and bone turnover marker (BTM) content to be evaluated over 2 months, including: (a) bone formation markers: alkaline phosphatase (ALP), bone glaprotein (BGP) and procollagen type I N-terminal propeptide (PINP); (b) bone resorption markers: β-CTX, urine calcium/creatinine (Ca/Cr); (c) PTH.
The primary outcome measures mean changes in BTM (BTM) and PTH from baseline to 8 weeks. Bone density provides only static parameters, which reflect changes in bone mass over a relatively long time. In order to understand the dynamic change process of bone metabolism, we need to evaluate bone metabolism markers.39 Measuring BTMs is helpful for predicting rapid bone loss. In addition, subsequent changes in bone mineral density (BMD) can be predicted on the basis of the changes in bone turnover within 1 month, which can provide early and effective prognostic measures.40 BTM can be divided into bone formation markers and bone resorption markers. Bone formation markers can reflect the activity of osteoblasts and the state of bone formation, and bone resorption markers reflect the activity of osteoclasts and the level of bone resorption.41 Bone formation markers include serum ALP, PINP, BGP. Bone resorption markers include: β-cross-linked C-telopeptide of type Ⅰ collagen (β-CTX). The bone metabolism biochemical index can reflect the state of bone turnover over time, with high sensitivity and strong specificity.42 The International Federation of Clinical Chemistry and Laboratory Medicine also recommends using serum PINP as a bone formation marker, and serum CTX as a bone resorption marker, making it a reference analyte for BTMs in clinical research.43 44
PTH has been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodelling.45 Its target is found to be cells of the osteoblast lineage.46 In addition, the only Food and Drug Administration-approved anabolic bone agent for the treatment of osteoporosis in the USA is PTH 1-34, or teriparatide.47
Secondary results include: (a) BMD; (b) blood phosphorus and calcium in plasma. DXA and QCT will be used to measure the mean change in BMD at 8 weeks after baseline. We will use DXA to scan the participants’ L1-L4 and femurs (femoral neck, greater tuberosity, and all femurs)48 and QCT to scan the ankle of the affected limb to record and analyse changes in bone density. The measurement of BMD by DXA is the gold standard for the diagnosis of osteoporosis.49 Although DXA is simple and fast to operate and does little harm to the body, its main measurement area is BMD; that is, the sum of cortical bone and cancellous bone BMD.50 Therefore, the detection may be misdiagnosed due to tissue structure or abdominal aortic atherosclerotic and other diseases that affect the measurement accuracy.51 The DXA vertebral body BMD measurement is therefore used only to predict overall fracture risk, although it is difficult to predict the absolute risk in some individuals. In recent years, it has been discovered clinically that QCT is of great value in diagnosing osteoporosis.52 It uses phantom and analysis software to determine volume BMD on the basis of CT scans, and the measurements are not affected by cortical bone and hyperplasia.53 Bone and other influences are of great significance for physicians in analysing bone mass changes of cancellous bone and providing cross-sectional data.54
The electrochemical method will be used to detect blood phosphorus and calcium in plasma. Blood phosphorus and calcium are general biochemical markers in bone metabolism. All the assessments are presented in table 1.
Adverse events occurring during the study will be recorded in detail, including the specific time, severity, duration and relationship with transcutaneous electrical acupuncture point stimulation. Five grading criteria will be used to evaluate the relationship between adverse events and treatment: (1) certain correlation; (2) possible correlation; (3) absolutely irrelevant; (4) may not be relevant; (5) uncertainty about the countermeasures taken and the final results.
Quality control of inpatients
All practitioners, evaluators and statisticians will receive uniform training before the test. The training courses include basic orthopaedic treatment operations, inclusion and exclusion criteria, standardised operating procedures, observation time, result measurement, completion, acupoint positioning, the operation of the transcutaneous acupoint electrical stimulator and training on technical data processing. The training of patients and their families involves the operation of basic orthopaedic treatment, acupoint positioning and the operation of the transcutaneous acupoint electrical stimulator. Clinical monitors will regularly monitor the study to ensure trial quality.
Telephone interview and WeChat video will be adopted to monitor and record the patients’ feelings after treatment. The main content includes: (1) monitoring the operation process of the treatment group; (2) monitoring the accuracy of acupoint positioning; (3) inquiring about and recording of adverse reactions, and treatment instructions (severe pain: remove the electrode immediately; skin redness: reduce power or suspend use in time); (4) the use of the electrode sheet and whether it needs to be mailed; (5) re-checking time statistics.
Data collection and management
Two independent investigators will collect the baseline data, such as age, gender, height weight, cause of fracture, ankle fractured, the type of fixation (screw/plate or intramedullary nail), the severity of comminution of fractures, the use of bone graft, including autograft, allograft or artificial bone graft with/without osteoinductive activity, associated injury, for example, multiple traumas, brain injury, ambulation status (the activity limitation of included patients since weight-bearing status). All data will be carefully verified by these two investigators, then will be kept by a designated person.
Statistical analysis will be performed using SAS V.9.4. For continuous outcomes, the Shapiro-Wilk test will be used to test the normal distribution of data. If quantitative data follow normal distribution, described as mean±SD, we will use the t-test to compare the differences. If quantitative data do not follow normal distribution, it will be described as median (IQR), and we will use the Wilcoxon rank-sum test to compare the differences. Categorical variables will be described as percentages (n%). We will use the χ2 test to compare the differences on categorical variables (Fisher’s exact test is used where appropriate). All statistical analyses will use two-sided tests, with p<0.05 considered as the difference required to be statistically significant.
Data availability statement
Within 6 months of the trial’s completion, the original data will be shared through the ResMan platform of the Chinese Clinical Trial Registry (http://www.medresman.org.cn).
The study aims to evaluate effectiveness and safety. We hypothesised that TEAS could reduce bone loss in patients with immobilisation after ankle and foot fractures. In clinical trials of TEAS, it has been proved that the combination of PEMF and acupuncture points can promote bone formation and slow bone resorption.55 56 This study is the first randomised controlled trial of TEAS in the treatment of bone loss on patients after surgical fixation of ankle and foot fractures.
This study will provide evidence on the optimal option for external non-interventional therapy in the treatment of patients after surgical fixation of ankle and foot fractures. In addition, this is the first trial exploring whether the bone density will change after 2 months of TEAS.
Despite the potential strengths, there are some limitations in our trial. First, due to the particularity of patients hospitalised for only 1 week after orthopaedic treatment and surgery and then discharged, the post-discharge treatment can be performed only by patients and their families. In order to compensate for this limitation, professional acupuncturists and orthopaedic doctors will train patients in a rigorous and standardised method of TEAS, and basic orthopaedic treatment, during their week of hospitalisation. WeChat video and voice call will be used for quality monitoring, and questions about adverse reactions and statistical re-inspection time will be asked.
Second, the patients cannot be blinded due to the particularity of TEAS treatment. Patients will know whether they had received additional TEAS treatment, which, in some cases, may have increase the risk of dropout in control patients.
Third, we cannot judge the subjective feelings of patients due to the lack of subjective outcomes.
Finally, this is an exploratory study with a small sample size which has not been calculated. No long-term follow-up will be performed to observe long-term treatment effects and adverse reactions.
Moreover, a review of the literature found that BMD may not change within 2 months, so we used bone metabolic markers as the primary outcome indicator. On the other hand, we hope to explore whether bone density will change in 2 months. The results of this trial will help provide evidence for the efficacy of TEAS in reducing bone loss for patients after fractures.
Ethics and dissemination
All participants who meet the diagnostic, inclusion criteria and exclusion criteria will be required to sign an informed consent form prior to participating in this study. This study was approved by Beijing University of Chinese Medicine (2020BZYLL0611) and the Ethics Committee of Beijing Luhe Hospital (2020-LHKY-055-02). Study findings will be published in peer-reviewed journals and presented at national congresses.
Patient consent for publication
The authors would like to express their appreciation to Yutong Fei and Jing Hu for their wonderful design work and valuable suggestions for this trial. In addition, thanks are due to Xiaojie Wang, Qian Xu and Lin Zhou for their grammar modification, and to Siting Li for his contribution to the initial phase of the project. The authors would also like to express their appreciation to the rehabilitative physicians: Qi Wang and Qi Liu, and all the testing personnel in the bone density, CT, biochemical and endocrine laboratories.
Contributors SG is the first author. BZ, SG, XO, GZ, YH, QY and JL have made their contributions to study design. SG wrote the first draft of the protocol manuscript, and BZ, BL, CZ, QW and XC supervised the process. SG and GZ revised the manuscript. SG contributed to drafting the manuscript. YX, YL, SG, GZ, BZ and LH commented and approved the final version.
Funding This work is funded by the National Key R&D Programme of China (No. 2019YFC1711901), the National Key R&D Programme of China (No. 2019YFC1711903) and the Space Medical Experiment Project of the China Manned Space Programme.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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