1 Inclusion and exclusion criteria
1.1 Sample size estimation
The main effect index measured in patients with KOA was the Lequesne index efficiency following general hospital treatment. According to a literature review, the effective rate of the conventional treatment regimen adopted in the control group for improvement of motor dysfunction in patients with KOA was approximately 70%. Preliminary experiments showed that the effective rate of TCM involving triple rehabilitation therapy for KOA in improving motor dysfunction in patients with KOA could reach 82.3%. Taking α = 0.05 and β = 0.10, it was expected that each group (community) should include at least 17 qualified cases (m = 17) based on the results of previous epidemiological investigations. Meanwhile, the individual correlation coefficient in the 0.02 allele group was estimated according to the sample content formula:
This can be calculated as n ≈ 326.17, taking n = 327; therefore, the number of communities to be observed in each group is n = n/17 = 327/17 ≈ 19, for a total of 38 in the two groups. After considering the shedding factor, the number of cases was appropriately increased by 10%, and the total number of cases needed in the two groups was approximately 722.
1.2 Sources of patients
From March 2013 to March 2017, 722 patients with KOA with motor dysfunction who met the inclusion criteria participated in this study. The patients were recruited from 38 community health service centers in Fuzhou, Guangzhou, Foshan, and Chengdu, with 19 patients from each community.
1.3 Patient inclusion and exclusion criteria
1.3.1 Diagnostic criteria based on Western medicine
Please refer to the Chinese Medical Association orthopedics chapter, “Guidelines for the diagnosis and treatment of osteoarthritis (2007)” [3].
1.3.2 X-ray staging standard
Please refer to the Kellgren-Lawrence staging standard [4].
1.3.3 Clinical staging criteria
Please refer to Yicong Wang, Editor-in-Chief, Bone and Joint Injury (2007 Edition)[5].
1.3.4 TCM diagnostic criteria
Refer to the syndrome differ classification for KOA in the “Guidelines for Clinical Research of New Drugs of TCM” [6], and “Diagnostic and Efficacy Standards for TCM Syndrome” [7]; after repeated discussions, the research group reached a consensus that currently, the most common TCM syndromes in patients with KOA are liver and kidney deficiencies, and stagnation of wind, cold, and dampness. The accompanying clinical manifestations are sore waist and knees, hidden joint pain that worsens with weather changes, unfavorable joint flexion and extension, favoring heat over cold temperatures, light-red tongue with thin or thick-white coating, and a taut and thin pulse.
1.3.5 Inclusion criteria
① KOA met the diagnostic criteria.
② Patients were aged 40 to 75 years old.
③ KOA was diagnosed as an early or mid-stage disease.
④ KOA was accompanied by knee pain, swelling, stiffness, or a decline in the strength and endurance of muscles around the knee leading to motor dysfunction.
⑤ KOA was in line with the TCM syndrome of liver and kidney deficiency, stagnation of wind, cold, and dampness.
⑥ Patients agreed to participate in this study and provided informed consent.
1.3.6 Exclusion criteria
① Severe knee swelling.
② naided muscle strength was rated as grade 2 or lower.
③ History of knee trauma or knee surgery.
④ Patients with heart, liver, and kidney failure, diabetic gangrene of the lower limbs, and neurological diseases.
⑤ Patients with lower extremity dysfunction caused by spinal diseases or hip and ankle diseases, and patients who had undergone joint replacement.
⑥ Patients with a malignant tumor or a local benign tumor of the knee joint.
⑦ Patients with cognitive and psychological dysfunction.
⑧Performed traditional exercises or received massage therapy in the past month.
⑨ Underwent arthroscopic treatment or articular cavity injection treatment within the last 6 months.
⑩ Patients attending other clinical trials.
1.3.7 Suspension criteria
① The occurrence of serious adverse reactions or other serious disease requiring a different treatment.
② A sudden deterioration of the patient’s condition.
③ Patients withdrew from the study for their own reasons.
④ Patients who were unable to comply after enrolling.
1.3.8 Provision for shedding cases
Patients who met the inclusion criteria and were included but then later withdrew owing to personal reasons or adverse reactions, those who had serious adverse reactions, or those who failed to complete the whole follow-up process, were considered as shedding cases.
1.3.9 Provision for adverse reactions and serious adverse reactions
Reactions such as subcutaneous hematoma; cutaneous pruritus; and rashes that coincided with the intervention, disappeared after the cessation of intervention, and reoccurred after the intervention was reinitiated were considered adverse reactions. Events such as syncope caused by needle insertion, blood phobia, skin infection, or traumatic arthritis that coincided with the intervention, disappeared after the intervention was terminated, and then reoccurred after the intervention was reinitiated were defined as serious adverse reactions. Subcutaneous hematoma, cutaneous pruritus, or rashes that only occurred once and were unrelated to treatment were only described and not listed as adverse reactions.
2 Study Design
2.1 Research Group
The study was a randomized controlled clinical cohort study. Residents within the service scope of each community health service center were allocated to one group. The 38 communities were randomly grouped according to the study area, and the experimental and control groups were divided 1:1; there were 19 communities in each group. Nineteen patients from each community health center who met the inclusion criteria for KOA were recruited, with a total of 722 patients.
2.2 Research Blinding
A single-blind method was used to blind the outcome evaluators and statistical analysts by substituting letters A and B for the groups in the report form. After the statistical analyses were completed, the project manager revealed the group codes.
2.3 Intervention Methods
2.3.1 Basic Treatment
Patients in both groups received basic treatment such as health education and drug therapy.
(1) Health Education: Face-to-face teaching between the doctors and patients and educational pamphlets were used to eliminate the fear of disease, establish correct living habits, and avoid further aggravation of the disease; topics included the incidence, potential causative factors, standardized clinical diagnosis, treatment, and rehabilitation of KOA.
(2) Drug therapy: Pain was assessed in both groups during treatment. If the visual analog scale (VAS) was ≥ 4 points, dispersible oral meloxicam tablets (7.5 mg/once a day) were administered. The drug was discontinued when the VAS was < 4 points.
2.3.2 Experimental group
Patients received basic treatment combined with TCM involving triple rehabilitation therapy for KOA (a combination of electro-acupuncture, Chinese medicinal herb fumigation-washing, and traditional exercise).
(1) Electro-acupuncture: Patients were placed in a comfortable position after which the lower limb of the affected side was routinely disinfected. The acupuncture points were selected as dubi (ST-35), neixiyan (EX-LE-4), liangqiu (ST-34), zusanli (ST-36), xuehai (SP-10), yanglingquan (GB-34), yinlingquan (SP-9), and ashi points. Sterile disposable steel needles (φ0.3 × 40 mm, Suzhou Medical Appliance Factory, Suzhou, China) were then inserted at the above acupoints. After reaching a certain depth, an even reinforcing-reducing method was used, along with twirling, lifting, and thrusting the needles to induce the Deqi sensation. After this, the needles were linked as pairs in GB-34, ST-34, SP-10, and SP-9 with an electronic acupuncture apparatus (SDZ-II Huatuo, Suzhou Medical Appliance Factory, Suzhou, China). The program followed was using a dilatational wave for 30 minutes of treatment, once every other day, 3 times a week for 4 weeks.
(2) Chinese medicinal herb fumigation-washing: The prescription was changed by addition and removal of Haitongpi decoction (volume 88 of Yi Zong Jin Jian). Patients fumigated and washed the affected knee joint at home after receiving acupuncture therapy. After wrapping the TCM with gauze, it was added to a container with 3 liters of water, soaked for 30 minutes, and cooked for an additional 30 minutes to obtain about 2 liters of medicinal juice. The affected knee was fumigated with the medicine juice vapor and washed once the juice reached a suitable temperature of 40℃. The knee joint was repeatedly covered with a towel soaked with the medicinal juice; this action was repeated until the liquid turned cold. Fumigation and washing were performed twice a day, in the morning and afternoon, for 6 days a week over a total of 4 weeks.
(3) Traditional Exercises: Based on Tai Chi, Baduanjin, and Yijinjing, an exercise named “three-step-six-style knee exercise”[8] was designed and practiced once a day, 6 days a week, for 4 weeks.
2.3.3 Control Group
Patients were treated with standard non-TCM therapy combined with KOA conventional rehabilitation therapy with physical factor therapy, joint activity training, and muscle strength training as outlined in the “Guidelines for the diagnosis and treatment of osteoarthritis”[3], Practical Rehabilitation Medicine[9] and “Consensus of rehabilitation experts on osteoarthritis”[10].
(1) Physical Factor Therapy: Specific electromagnetic wave (Te Ding Dian Ci Pu, TDP) irradiation was adopted. The distance between TDP and the affected limb was maintained at 30–50 cm. It is advisable to maintain a comfortable temperature at the irradiation site. TDP was irradiated once a day for 20–30 minutes, 6 days a week, with the treatment performed for 4 weeks.
(2) Joint Movement Training: ① Drafting: After the patient was seated, a towel roll was padded under the popliteal fossa of the affected lower extremity, if necessary, to relieve discomfort. With the body slightly leaning backward and both hands on the bed for support, the therapist, standing in front of the patient, squatted slowly and held the far end of the patient’s leg with both hands, and then slowly and forcefully pulling the leg toward the foot end for about 10 seconds. The above movements were repeated 5 times. ② Passive joint movement: After the patient assumed a prone position, the therapist placed a hand on the affected side of the pelvis while holding the ankle with the other hand, causing the affected knee to bend by applying force with both arms simultaneously. This maneuver lasted for 30 seconds each time, for a total of 15 times. The range of motion (ROM) was within the range tolerated by the patient. ③ Active joint movement: The patient was seated with the knee joint bent at 90 any significant pain. Both knees were stretched in turns, with each position held for 5 seconds each time, for a total of 10 times on each side. Joint activity training was performed once a day for 6 days a week, and the treatment was performed for 4 weeks.
(3) Muscle strength training: ① Straight leg lifts: The patients were placed in the supine position, with the lower limbs flat. Patients were asked to lift their limbs straight up to about 30° and hold for about 10 seconds, for a total of 15 times in groups. A 30-second break was taken after each group before proceeding to the next group of training. The training was stopped after muscle fatigue was experienced. ② Hip muscle contraction training: The patients were placed on their sides or in a prone position and were instructed to abduct and extend their thighs for gluteal muscle contraction training, with the same frequency mentioned above. ③ Quadriceps isometric contraction training: The patients were placed in the supine position with both legs remaining flat on the bed. They performed active quadriceps contraction, which lasted for 30 seconds, followed by a rest period of 30 seconds. Contraction and relaxation were done together in sets of 15 and repeated 3 times. ④ Static training: The patients were instructed to assume a semi-squat position, with the knee and hip joints bent at no less than 90°; this posture lasted for 30 seconds and was performed l5 times for each group, followed by a rest of 30 seconds, and repeated for 3 groups. ⑤ Resistance muscle strength training: Sandbags were used for resistance muscle strength training to gradually increase the resistance with increase in muscle strength. The practice was carried out twice a day, 6 days a week, for 4 weeks.
2.4 Follow-Up Study
Outpatient and telephone follow-up were the main methods used. Appointments in the outpatient clinic were made with all patients after 1 month and 3 months of treatment. A telephone follow-up was conducted on one occasion, 2 months post-treatment, mainly enquiring patients about their current physical and mental state, rehabilitation and exercise status, and quality of life. We also learned about their compliance behavior, recorded the drugs or treatment utilized, and scheduled a follow-up appointment in the community clinic.
2.5 Outcome assessment
2.5.1 General information
Patients’ age, gender, education, occupation, height, weight, residential floor, and course of disease were included.
2.5.2 Primary Outcomes
(1) Lequesne Index：The Lequesne index was used to score the severity and functional status of KOA patients[11]; the higher the score, the more serious the clinical symptoms.
(2) Visual Analog Scale: We drew a 10 cm line with two ends indicating "painless" (0) and "extreme pain" (10), respectively, allowing the patient to draw markers consistent with the intensity of their pain.
2.5.3 Secondary outcomes
(1) Assessment of Knee ROM: A protractor method was used to measure the degree of flexion and extension of the knee joint by using the femoral external condyle as the axis, the longitudinal axis of the femur as the fixed arm, and the small head of the fibula and the external ankle.
(2) Assessment of lower limb muscle strength: The muscle strength of the knee extensor and flexor muscles was assessed by the hand muscle strength assessment method and the Lovett muscle strength classification method. The muscle strength of the extensor muscles of the knee joint was used mainly to evaluate the muscle strength of the quadriceps muscle. Muscle strength of the knee flexor muscles was mainly used to assess the muscle strength of the biceps femoris.
(3) Measurement of the knee joint circumference: A tape was used to measure the circumference of each knee 10 cm above the lower border of the patella, the midpoint of the patella, and 10 cm below the upper border of the patella. This corresponded to the upper, middle, and lower circumferences of the knee joint, respectively.
(4) KOA symptom score: The KOA symptom classification and quantification table score, according to the “Guidelines for Clinical Research of New Drugs of TCM” [6], consists of a total of 10 items, including pain, the relationship between activity and pain, and special examination items related to dysfunction. The scoring method has 0-6 points for each item, and the sum of the points of each item is calculated. The higher the score, the more serious the clinical symptom.
(5) Quality of life assessment: SF-36[12] was used to assess the patients’ quality of life, including physical and mental health, with a total of eight dimensions.
2.5.4 Safety Index
Incidence of adverse reactions and serious adverse reactions: Adverse reactions and serious adverse reactions were recorded and their relevance to treatment was evaluated.
2.6 Statistical Analyses
The statistical analysis software, SAS 8.2, was used. All statistical tests were performed on both sides. A value of P < 0.05 was considered to be significant, and P < 0.01 was considered to be extremely significant. Qualitative indicators were described by composition ratio, frequency, and frequency description. The mean and standard deviation were calculated for each measurement, and the paired t-test was used to evaluate the differences before and after treatment. The t-test (including a calculation of the 95% confidence interval) was used for comparison between small sample data sets. The rank-sum test (Wilcoxon method) was used when the variance was uneven. If the baselines between the groups were inconsistent, covariance analysis and other appropriate methods were used. The rank-sum test (Mann-Whitney method) was used for comparisons between graded data sets. Longitudinal follow-up data were obtained by using a mixed linear model.
For analysis of the main outcome indicators, we took the multi-level characteristics of the data into account and set the measurement time points as level 1, individuals as level 2, and communities as level 3. A 3-level random intercept model with the nested design longitudinal data was fitted along with a random slope model. Calibrated covariates included age, gender, community type, and severity of illness. The statistical model was also used to analyze secondary outcome indicators of the same data type. Other analytical methods for outcome measures included two groups of t-tests, the rank-sum test (Wilcoxon method), and the Chi-square test.
Missing values in this data corresponded with completely random missing (Missing Completely at Random) and the random missing (Missing at Random) descriptions. The data were filled and statistically analyzed by using the method of multiple filling (Multiple Imputation).
2.7 Quality Control Measures
(1) Strict implementation of the test principles of multi-center, random, controlled, and blind methods.
(2) Coordination of the research plan, process, and research organization implementation before the study, preparation of a unified research plan, research work manual, and case report form, filling in the instructions and filling out the sample form. Training and assessing specific programs and standard operating procedures for personnel participating in clinical research.
(3) Strict implementation of the inclusion and exclusion criteria for determining the final sample; implementation of interventions was strictly regulated following the uniform standards specified by each collaboration unit;
(4) Completion of the medical records required authenticity, timeliness, and completeness, ensuring that important information was not missed; the combined use of drugs should be recorded truthfully; research related documents should be standardized; adverse events should be reported promptly. During the implementation process, the procedures for signing all case report forms, training certificates and laboratory consumables were implemented, and the test was consistent with the original test draft; the auditors monitored the consistency of the test every 2 weeks. At the same time, the community physicians conducted a spot check on the relevant technologies used in the implementation plan.
2.8 Flowchart of cases（Figure 1）
Figure 1 Flowchart of cases
Note ◆: Two patients gave up on treatment due to relocation from their original home address; three patients gave up on treatment for being afraid of acupuncture; three patients believed that Chinese medicinal herb fumigation-washing was too time-consuming and troublesome, and therefore decided to quit.
Note ★: One patient gave up on treatment due to traveling abroad with family members; one patient had an accidental fall that resulted in bone fracture and could not go on with the treatment.
Note ▲: Two patients gave up on treatment due to the loss of a close relative; one patient was unable to continue treatment due to visiting relatives abroad; three patients gave up on treatment due to private personal reasons; one patient was unable to continue treatment for a broken leg due to a car accident; one patient quit the treatment due to the inconvenience caused by relocation from their original address; three patients gave up on treatment to take care of their grandchildren; two patients could not continue treatment due to the diagnosis of a malignant tumor.
Note ■: One patient gave up on treatment due to the inconvenience caused by a change of original dwelling place.
Note ●: One patient could not be connected on the phone and follow-up could not be completed.
Note ○: One patient could not be connected on the phone and follow-up could not be completed.