Efficacy and Safety of Intra-articular Sodium Hyaluronate for Ankle-involved Kashin-Beck Disease: A 12-month Prospective Self-controlled Study

Summary

This article presents a 12-month prospective study evaluating the efficacy and safety of intra-articular sodium hyaluronate injections for ankle-involved Kashin-Beck disease (KBD). Results indicate that this treatment significantly reduces pain and improves joint function and quality of life.

Abstract

This study aimed to evaluate the efficacy and safety of intra-articular sodium hyaluronate injection over a 12-month follow-up period in patients with ankle-involved Kashin-Beck Disease (KBD).

A 12-month, prospective, self-controlled study was carried out among 79 adult patients with ankle-involved KBD. Each patient was given three consecutive weekly intra-articular injections of sodium hyaluronate (2 mL, 20 mg) in the affected ankle joint. The Graded Chronic Pain Scale (GCPS) was used to evaluate pain intensity, the KBD Joint Dysfunction Index (JDI) was used to assess joint function, and the EQ-5D-3L was used to assess quality of life (QoL). These three outcome measures were assessed at baseline (prior to the first injection), Week 4 (one week after the third injection), and Month 12 (12 months after the first injection). Longitudinal changes were analyzed using Generalized Estimating Equations (GEE).

Over the 12 months, all the ankle outcomes significantly improved compared with baseline (all p < 0.001). The estimated marginal means (EMM) of GCPS pain score decreased from 67.24 to 30.56. The JDI scores decreased from 7.31 to 3.64, and the EQ-5D-3L utility index increased from 0.707 to 0.869. Significant time × KBD stage interactions were found in ankle pain (Wald χ²= 15.82, p = 0.003) and EQ-5D-3L utility index (Wald χ²= 37.25^, p < 0.001). While patients with Stage III appeared to have the most significant improvements, these subgroup findings should be considered exploratory due to the limited sample size. Only 3.46% of patients reported adverse events, which were mild and transient.

In conclusion, intra-articular sodium hyaluronate injection provides significant and sustained pain relief, functional recovery, and QoL improvement for patients with ankle-involved KBD. It is a safe and effective conservative treatment strategy.

Introduction

Kashin-Beck disease (KBD) is an endemic, disabling osteoarthropathy of unknown etiology, mainly occurring in children during growth and development. Its geographic distribution takes a belt-like pattern from northeast to southwest China^1,2,3. The main pathological change of KBD is multifocal symmetric degeneration and necrosis of articular and epiphyseal plate cartilage, followed by severe sequelae, such as joint pain, joint deformity, functional impairment, and short stature^4,5. After the comprehensive preventive and control measures, including selenium supplementation and grain substitution, the incidence of new cases of KBD has been nearly eliminated in China⁵. However, adult KBD patients with the disease in childhood present with chronic pain and disability, imposing a heavy economic and care burden on families and society⁶.

Due to the high weight-bearing nature, the ankle is one of KBD's most frequently and seriously involved joints. Lesions have been identified in about 92% of patients⁷. The typical clinical presentation includes joint pain, remarkably limited range of motion (ROM), periarticular muscle atrophy, and structural changes, such as talus necrosis and joint space narrowing^8,9. These impair walking and balance, ultimately resulting in a loss of working capacity and decreased quality of life (QoL)¹⁰. However, compared to the knee, another frequently involved joint in KBD, clinical features of ankle KBD have received less attention, and treatment strategies in clinical practice remain unclear¹¹.

Currently, treatment options for ankle KBD are limited. Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics provide only short-term symptomatic relief, do not alter the natural course of the disease, and may cause serious adverse effects on the gastrointestinal and cardiovascular systems when used for prolonged periods¹². Surgical interventions, including ankle arthrodesis or total ankle arthroplasty, are effective for pain relief in end-stage disease but are characterized by significant surgical trauma, high costs, and stringent bone condition requirements; they may also accelerate adjacent joint degeneration^6,13. Therefore, surgery is not indicated in most KBD patients, especially those from economically deprived rural areas⁶. Thus, identifying a minimally invasive and low-cost treatment to relieve symptoms is a pressing unmet need.

Sodium hyaluronate is an essential constituent of synovial fluid and performs several biological functions, including joint lubrication, mechanical shock absorption, and anti-inflammatory effects¹⁴. The rationale for using intra-articular sodium hyaluronate injection in ankle-involved KBD lies in the pathological similarities between KBD and osteoarthritis (OA); both show articular cartilage degeneration, decreased viscoelasticity of synovial fluid, and inflammatory reactions^8,15,16. Intra-articular sodium hyaluronate injections have been effective and safe in treating primary knee and hip osteoarthritis¹⁵. Other studies have also shown that intra-articular sodium hyaluronate injection can relieve symptoms and improve the function of KBD-affected knees^3,17,18. Early evidence has also supported the effect of sodium hyaluronate on primary ankle OA¹⁹. Compared with NSAIDs and surgery, intra-articular sodium hyaluronate injection is a minimally invasive, safe, and cost-effective alternative that avoids surgical trauma and the long-term adverse effects of systemic medication^6,12,13. However, despite this theoretical basis and indirect evidence, the efficacy and safety of sodium hyaluronate specifically for ankle-involved KBD have not yet been systematically evaluated.

This study aimed to evaluate the efficacy and safety of one treatment course of intra-articular sodium hyaluronate injection in patients with ankle KBD systematically. Thus, we conducted a 12-month prospective self-controlled study to test the hypothesis that this treatment is safe and effective in improving pain, joint function, and QoL in patients with ankle KBD.

Protocol

This study was performed according to the Declaration of Helsinki and approved by the Ethics Committee of Xi'an Jiaotong University (Approval No: 2016106). All participants signed informed consent before enrollment in the study procedures. According to the protocol approved by the ethics committee, a 2-week washout period was provided to minimize the confounding effect of previous medication use.

Study design and setting

This was a prospective, self-controlled study conducted in Yongshou and Linyou Counties, Shaanxi Province, where the reported prevalence rate of KBD is among the highest in China²⁰, to evaluate the efficacy and safety of intra-articular sodium hyaluronate injection in KBD ankle involvement from October 2019 to October 2020. Figure 1 shows the schematic diagram of the study design.

Sample size calculation

The sample size was determined by an a priori power analysis with G*Power (version 3.1.9.7). This calculation was based on the established minimum clinically important difference (MCID) of 1.0 point for the pain Numeric Rating Scale (NRS) in musculoskeletal conditions²¹. Given our pre-test and post-test study design, a two-tailed paired-samples t-test was selected as the primary statistical model. For the power analysis, we set the alpha level (α) to 0.05, signifying a 5% risk of a Type I error (false positive). To ensure a high probability of detecting a true effect if one exists, the statistical power was set to 90% (1-β = 0.90), implying a 10% risk of a Type II error (false negative). The medium effect size (Cohen's d = 0.5) was used for the calculation, an estimate consistent with conventional benchmarks for clinical research and the anticipated magnitude of change in pain intensity. Based on these parameters, the analysis yielded a required minimum sample size of 45 participants.

To address potential screening failures and participant attrition, an initial cohort was determined. Based on similar research on KBD patients, an approximate 25% screening failure rate was anticipated (i.e., individuals not meeting the eligibility criteria during the initial assessment)³. Furthermore, considering the inconvenient transportation in the region where this study was conducted, which could lead to additional participant attrition during the procedure and follow-up phases, we aimed to screen a larger number of individuals. To ensure sufficient final sample size despite these factors, an initial cohort of 131 individuals was screened in this study. This effectively accounted for both the anticipated screening failures and subsequent attrition, ensuring that the final number of participants would meet the statistical power requirements. After all screening, intervention, and follow-up procedures were completed, a final cohort of 79 participants was successfully included in the analysis. This final sample size far exceeded the minimum requirement for 90% power.

Participant screening and diagnostic procedures

Comprehensive screening included a detailed medical history, physical examination, and radiographs of the hands and ankles. The diagnosis of KBD was confirmed by two senior orthopedic surgeons from the local hospital based on clinical and radiological features according to the national diagnostic criteria standard WS/T 207-2010, issued by the National Health Commission of the People's Republic of China²² (http://www.nhc.gov.cn/wjw/s9500/201006/47920.shtml).

According to these diagnostic criteria, KBD is classified into three stages (I, II, and III), with an increasing degree of severity. In Stage I, there was an enlargement of finger joints, arthralgia in knee and ankle joints, and abnormal X-ray manifestation, i.e., a metaphyseal lesion in the phalanx. In Stage II, shortening of fingers, clinical symptoms similar to Stage I, and a more severe X-ray sign than Stage I were present. In Stage III, retardation of growth or dwarfism, clinical symptoms similar to Stages I and II, and an X-ray sign more severe than Stage II were present. Therefore, this categorization helps define the level of disease severity for treatment purposes.

Inclusion and exclusion criteria

Inclusion Criteria: Subjects were enrolled if they met all of the following criteria: (1) clinical and radiological diagnosis of KBD based on the national diagnostic standard (WS/T 207-2010)²²; (2) age ≥ 18 years; (3) presenting with chronic ankle pain for > 3 months with radiological evidence of ankle involvement; and (4) baseline pain score of ≥ 4 on the NRS (0-10 points).

Exclusion criteria were as follows: (1) inflammatory arthropathies such as rheumatoid arthritis (RA) and gout; (2) any history of intra-articular injection of corticosteroids or sodium hyaluronate in the target ankle within 6 months; (3) known allergy to hyaluronate preparations; (4) skin infection or skin diseases at the injection site; (5) bleeding disorders or severe systemic comorbidities that could interfere with the outcomes or pose a risk to the patient.

Intervention protocol

Prior to the first procedure, a two-week washout period was mandated for all eligible patients with ankle KBD to eliminate potential confounding effects from previous medications. All procedures were performed by an experienced orthopedic surgeon under strict aseptic conditions. Patients were placed in a supine position with the lower limb extended. The ankle was positioned at the edge of the examination bed to allow the foot to hang naturally in slight plantar flexion (approximately 30°), thereby distracting the joint space to facilitate needle insertion.

Routine disinfection was performed by a surgeon wearing a mask, cap, and sterile gloves. A surgical drape was applied to establish a sterile field, and the skin on the anteromedial aspect of the ankle (disinfected area ≥ 10 cm) was prepared with iodophor or 75% alcohol. The injection target was identified by palpating the "soft spot" between the tibialis anterior tendon and the medial malleolus. Specifically, the needle insertion point was located medial to the tibialis anterior tendon, approximately 1.5 cm from the medial malleolar tip, avoiding the great saphenous vein and nerve. Local anesthesia was achieved by infiltrating the site with approximately 1 mL of 1% lidocaine to create a subcutaneous wheal.

A 22-gauge needle was inserted at a 30° angle relative to the sagittal plane, directed posterolaterally, and advanced to a depth of 1.5-2.0 cm until a loss of resistance indicated capsular entry. Intra-articular placement was confirmed by the aspiration of synovial fluid or the absence of resistance during saline injection. Any existing effusion was aspirated completely. Sodium hyaluronate (2 mL; 20 mg) was then injected slowly; if resistance was encountered, the needle depth or angle was adjusted without forcing the fluid. Following the injection, pressure was applied to the site for 3 min, and a sterile dressing was applied.

The treatment course consisted of one injection per week for three consecutive weeks. Patients were instructed to rest the affected ankle for 24-48 h post-injection, avoid heavy weight-bearing or strenuous activity for 3 days, and monitor for signs of local infection. During the 3-month follow-up period, the use of anti-inflammatory analgesics or other treatments was prohibited. Clinical outcomes were assessed using the Grading Chronic Pain Scale (GCPS)²³, the Joint Dysfunction Index (JDI)²⁴, and the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L)²⁵ at baseline (prior to the first injection), Week 4 (one week after the third injection), and Month 12 (12 months after the first injection).

Outcome measures

Pain intensity assessment

The GCPS is widely applied to measure both pain intensity and associated disability in chronic musculoskeletal conditions^23,26. It includes 7 items: 3 for pain intensity (current, worst, average pain in the past month) and 3 for functional interference (with daily, social activities and work ability), all scored on a 0-10 NRS (0 = no pain/interference; 10 = worst pain/ inability to perform activities). In this study, only the 3 pain intensity items were used. Their average score was multiplied by 10 to get a 0-100 Characteristic Pain Intensity Score (higher scores = more severe pain)²⁷. The Chinese version of GCPS has good psychometric properties: Cronbach's α is 0.68 for the Characteristic Pain Intensity Scale and 0.87 for the Disability Scale²⁸.

Assessment for therapeutic efficacy on KBD

The JDI, a tool for measuring therapeutic efficacy in KBD patients, was documented in 2011 in the publication "Assessment for Therapeutic Efficacy on Kashin-Beck Disease (WS/T 79-2011)", issued by the National Health Commission of the People's Republic of China (https://www.nhc.gov.cn/wjw/s9500/201112/53525.shtml)²⁴. The JDI comprises five items: Q1 (nocturnal rest arthralgia), Q2 (walking arthralgia), Q3 (morning stiffness), Q4 (maximum walking distance), and Q5 (lower limb activities). Each item is scored on a scale from 0 to 2, resulting in a total score ranging from 0 to 10. The JDI is calculated as the sum of the individual item scores, referred to as the Sum of the Joint Dysfunction Index (SJDI): SJDI = Q1 + Q2 + Q3 + Q4 + Q5. The index demonstrates good psychometric properties in KBD patients, with a Cronbach's alpha coefficient of 0.689²⁹, indicating acceptable internal consistency and reliability for clinical and research applications.

QoL assessment

QoL was assessed via the EQ-5D-3L^25,30. It evaluates five health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each scored on a 3-level scale (no/some/extreme problems), plus a 0-100 visual analogue scale (VAS: 0 = worst, 100 = best health)³¹. Utility values were calculated using Zhuo et al.'s (2018) Chinese EQ-5D-3L value set (nationally representative sample), with index values 0.170-1.000 (higher = better health; 1.000 = full health)³². The simplified Chinese EQ-5D-3L in this study was sourced from our research group's previous work. Importantly, the psychometric properties of this specific version have been rigorously validated in KBD patients, demonstrating satisfactory reliability and validity. Specifically, it showed moderate correlations with the physical domain of the WHOQOL-BREF (r = 0.339-0.475) and effectively discriminated between patients with varying disease severities³³. In agreement with the EuroQol Research Foundation, it was used as the 'suboptimal version' (Registration ID: 168217), which was not supplied by the Foundation.

Adverse events (AEs)

Between 24 and 48 h after each injection, research nurses conducted telephone follow-ups to document injection site reactions (pain, swelling, ecchymosis, pruritus) and systemic reactions (rash, fever). The severity of AEs was assessed using the Adverse Event Severity Grading Criteria: mild (no impact on daily activities), moderate (partial impact on activities), and severe (inability to perform activities)³⁴. For mild AEs (e.g., mild swelling), patients were instructed to apply local cold compresses (15 min per session, 3 times daily). For moderate or severe AEs (e.g., persistent swelling for > 3 days, fever > 38.5 °C), patients were immediately scheduled for an outpatient visit. Anti-infective or anti-allergic treatment was administered if necessary. All AEs were recorded in the adverse event record form and promptly reported to the Ethics Committee.

Patient overall treatment effects and satisfaction

During the final follow-up, two questions were posed to the study participants to assess treatment efficacy and treatment satisfaction, respectively. For the assessment of treatment efficacy, the question was "How effective do you perceive the treatment for your disease to be?" with response options categorized as: effective, partially effective, and ineffective. For the assessment of treatment satisfaction, the question was "How satisfied do you feel about the treatment received for your disease?" Patients responded by indicating one of the following: "Very Satisfied," "Satisfied," "Neutral," "Dissatisfied," and "Very Dissatisfied."

Statistical analysis

Analyses were performed with SPSS software (Version 26.0). Descriptive statistics (mean ± standard deviation for continuous variables, frequency and percentage for categorical variables) were used to summarize baseline characteristics. The effect size (Cohen's d) is classified as small (d = 0.2), medium (d = 0.5), and large (d ≥ 0.8)³⁵. A two-sided p-value < 0.05 was considered statistically significant for all analyses.

To analyze the longitudinal changes in the primary (GCPS) and secondary (JDI, EQ-5D-3L) outcomes, Generalized Estimating Equations (GEE) were employed³⁶. This approach was chosen for its robustness in handling correlated data from repeated measurements. For each outcome measure, a separate GEE model was constructed with the score as the dependent variable, including time (baseline, 4-week, and 12-month) as a within-subject factor and KBD stage (I, II, III) as a between-subject factor. The primary focus was on the time-by-stage interaction effect to assess whether the trajectory of improvement differs across the KBD stages. Sensitivity analyses were conducted to determine the optimal working correlation structure for each outcome by comparing Independent, Exchangeable, AR (1), and Unstructured matrices. Based on the lowest Quasi-likelihood under the Independence Model Criterion (QIC) value, an exchangeable working correlation structure was adopted for all outcome measures (GCPS, JDI, and EQ-5D-3L), as it provided the best model fit and stability. In cases where the overall model or interaction effect was significant, post-hoc pairwise comparisons with Bonferroni correction were performed to identify significant differences between specific time points within each stage. Finally, multivariable GEE models were constructed to adjust for potential confounders. Covariates, including age, sex, body mass index (BMI), education level, and marital status, were incorporated as main effects. The interactions between these covariates and time were tested in preliminary analyses but were excluded from the final models due to a lack of statistical significance, thereby optimizing statistical power.

As detailed in the patient flowchart (Figure 1), a total of 24 patients dropped out or were lost to follow-up after the initial enrollment of 103 eligible participants. Consequently, the statistical analysis was restricted to the 79 patients who completed the full treatment and all follow-up assessments (complete-case analysis). Participants with incomplete primary outcome data were excluded, and no data imputation was performed. To address potential biases arising from this attrition, we utilized GEE with robust standard errors (Huber-White sandwich estimator). This method ensures consistent parameter estimates and valid statistical inferences even if the correlation structure is misspecified due to the exclusion of missing data.

Results

Baseline characteristics of study participants

A total of 79 patients with KBD involving the ankle were enrolled in this prospective study. All of them were farmers. The mean age of participants was 60.07 ± 6.83 years, and 54.43% were male. According to the KBD radiological classification, most patients were in Stage I (n = 47, 59.49 %), followed by Stage II (n = 24, 30.38 %) and Stage III (n = 8, 10.13%). At baseline, no significant differences were found among the stages in ...

Discussion

This prospective self-controlled study provides important preliminary evidence of the efficacy and safety of intra-articular sodium hyaluronate in the ankle involvement of KBD. The experimental protocol was feasible and effective using a standard regimen of three weekly intra-articular injections¹⁴. Over a 12-month follow-up, patients showed statistically significant improvement in pain, joint function, and QoL. The robust GEE analysis revealed that the significant main effect of time was found fo...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
75% Alcohol Disinfectant	Shandong Lierkang Medical Technology Co., Ltd.	20190405A	Used for skin disinfection at the injection site to prevent infection
Disposable Syringe	Shandong Weigao Group Medical Polymer Products Co., Ltd.	20190821	Used to draw sodium hyaluronate injection for injection operations
Iodophor Disinfectant	Shanghai Likang Disinfection Technology Co., Ltd.	20190814J	Used for skin disinfection at the injection site to prevent infection
Lidocaine Hydrochloride Injection	Beijing Jiuneng Tianyuan Technology Co., Ltd.	1H 19031701	used for local anesthesia at the injection site with a specification of 2 mL vial)
Numerical Rating Scale (NRS) for Pain	N/A (a common tool)	N/A	Used to assess the patient's pain level and screen patients with an NRS score of ≥ 4 (on a scale of 0 - 10)
Sofast (Sodium Hyaluronate Injection)	Shandong Bausch & Lomb Freda Pharmaceutical Co., Ltd.	190302113	Used for ankle joint injection in enrolled patients, with a specification of 2 mL(20mg per vial)
The joint dysfunction index (JDI) for Kashin-beck disease (KBD)	N/A (a common tool)	N/A	Used for the measurement of therapeutic efficacy in KBD patients
The three-level EuroQol five-dimensional questionnaire (EQ-5D-3L)	the EuroQol Research Foundation	N/A	Used for assessing the quality of life of Kashin-Beck disease
X - ray Equipment	Toshiba Electron Tubes & Devices Co., Ltd.	E7876X	Used to take X - ray films of patients' hands and ankles to assist in determining whether they meet the inclusion criteria