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The Effects of Three Weekly Intra-articular Injections of a Bacterial-- Sourced Hyaluronate on Pain and Function in Patients with Knee Osteoarthritis

Shu-Fen Sun*,***, Chien-Wei Hsu*,***,Liang-Ting Lin**, Mei-Chia Chou**,Hung-Ju Li****, Kam-Fai Wong****, Hsien-Pin Sun*****.

*National Yang-Ming University School of Medicine, Taiwan
**Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Taiwan
*** Department of Internal Medicine, Kaohsiung Veterans General Hospital, Taiwan
****Institute of Statistics, National University of Kaohsiung, Taiwan
*****Department of General Surgery, Cheng Ching Hospital, Taiwan.


Address for Correspondence:

Dr. Shu-Fen Sun 
Address: Department of Physical Medicine and Rehabilitation
Veterans General Hospital, Kaohsiung,
No 386, Ta-Chung 1st Road, Kaohsiung 813, Taiwan
Phone : 886-73422121-4210


Background: To evaluate the effects of three weekly injections of a bacterial-sourced hyaluronate (Hya-Joint) in patients with knee osteoarthritis and compare the effects with avian-derived hyaluronate (Hyalgan)

Methods: As a prospective study done in a university-affiliated tertiary care medical center, patients with knee osteoarthritis for at least 6 months were enrolled. Eligible patients were randomized to receive three weekly intra-articular injections of either bacterial-sourced hyaluronate (Hya-Joint) or avian-derived hyaluronate (Hyalgan) into the target knee. The primary outcome was the visual analog scale (VAS) change from baseline for knee pain at 6-month follow-up. Secondary outcome measures included Lequesne index, timed up and go test (TUG), patients’ global satisfaction and analgesics consumption.

Results: Eighty-nine participants completed the study. Both groups had significant improvements in pain as early as 1 and 2 weeks after the first injection. The pain-reduction effects could last for 6 months, with no between–group differences. The Lequesne index scores and results of TUG tests improved significantly from baseline in both group (p<0.001 for each test compared with baseline), with no significant between-group differences at 1-month and 6-month follow-up. Significantly greater improvements favoring the Hya-Joint group were noted at 3-month follow-up (p<0.05). No between-group differences were seen regarding the use of analgesics. Both groups reported high satisfaction at 6-month follow-up. No serious adverse events occurred.

Conclusions: Three weekly injections of bacterial-sourced hyaluronate provide pain relief and improve function in patients with knee osteoarthritis. The treatment effects are comparable to avian-derived hyaluronate and can last for 6 months.

J.Orthopaedics 2011;8(4)e10


Knee joint; Hyaluronic acid; Osteoarthritis; Viscosupplementation


Osteoarthritis (OA) of the knee is a progressive joint disease, causing pain, disability and significant indirect cost to society. Current treatment options for knee OA include the use of simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroid injections, physical therapy, weight reduction, orthotics and surgical treatment ranging from arthroscopy to total knee replacement. Since there is no curative therapy for OA, the most pressing need for the majority of patients with OA is nonoperative treatment that helps relieve symptoms and improve function1. One such option for these patients may be the intra-articular injection of hyaluronic acid (HA).

HA is a major component of synovial fluid and cartilage. Viscosupplementation consists of injecting exogenous HA into the synovial joints to restore the normal rheological environment which deteriorates severely in OA joints and is cited for the treatment of knee OA in the guidelines of several professional societies2-6. There are several different HA products available world-wide from different manufacturers. The products differ in their origin, method of production, average molecular weight, protein content, dosing instructions, cost, biologic characteristics, and possibly clinical outcomes2. Most current HA products are avian in origin, and only few are bioengineered via bacterial fermentation. Extraction and purification of HA from rooster combs is a relatively complex process which results in a very expensive product. Besides, the rooster comb-based extraction process is faced by a growing concern due to the use of animal-derived raw materials for pharmaceutical applications, thereby exposes patients to proteins from an animal source. There are also between-product differences in crosslinking and intracapsular longevity. Although there have been numerous studies concerning intra-articular HA in the treatment of knee OA, conflicting conclusions regarding efficacy among studies have been observed7-13.

The purpose of this study was to determine the effects of 3 weekly intra-articular injections of a bacterial-sourced hyaluronate (Hya-Joint) in participants with knee OA. Visual analog scale (VAS) change for knee pain, Lequesne index14, and clinical tests of walking by using timed up and go test (TUG)15 , patients’ global satisfaction and analgesic consumption were assessed.

Material and Methods :

This clinical trial was conducted in a rehabilitation department at a university affiliated tertiary care medical center from February 2009 to December 2009. The study protocol was approved by the institutional review board and each participant signed a written informed consent prior to their participation. Patients were recruited mainly by responding to advertisements and posted information about a research project ongoing in a rehabilitation center. A research team member screened volunteers using the following inclusion criteria: (1) age 40 years or older, presence of a primary knee OA with knee pain for at least 6 months despite conservative treatment (rest, physical therapy, orthoses or pain medications etc.); (2) had average pain on knee movement of at least 3 cm on a 10-cm VAS; (3) had a current Lequesne index score (described below) >7 (possible range, 0-24); (4) were willing to discontinue all nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesic medication (except for rescue medication) for the duration of the study; and (5) were willing to not receive physical therapy or trial of shoe modifications or orthoses during the study period.

Exclusion criteria included previous orthopedic surgery on the spine or lower limbs, knee instability or marked deformity on examination, clinically apparent tense effusion of the knee, intra-articular steroid or HA injection in any joint within the past 6 months, and concomitant inflammatory arthropathy or other rheumatologic, neurological, cardiovascular or psychiatric disorders that would interfere with the clinical assessment during the study period.

Table 1. Demographic Data and Baseline Characteristics of the Patients


Hya-Joint Group

Control Group


Age (years)




Female, n (%)




Body weight (kg)




Height (cm)




OA of right side, n (%)




Disease duration (year)






5.1± 2.3


Lequesne index








Kellgren-Lawrence grade,
n (%)




Grade 1




Grade 2




Grade 3




Grade 4




Values are mean ± standard deviation or number (%) of patients.
OA= Osteoarthritis; VAS= visual analog scale (score range:0-10);
TUG= Timed “ Up-and-Go” test; higher scores representing worse function

Table 2. Summary of Outcome Measurements Between the Two Groups


Hya-Joint Group (N=59)

Control Group (N=30)


VAS (baseline)


5.1± 2.3


1 week




2 week

3.5±2.4 *



1 month




3 months


2.5± 1.9*


6 months

3.0± 2.1*

2.6± 0.5*


Lequesne index (baseline)




1 month

8.5± 3.6*



3 months


8.1± 3.5*


6 months

8.2± 3.9*

7.2± 3.4*


TUG (baseline)




1 month

13.4± 6.4*

9.8± 2.5*


3 months


8.9± 2.0*


6 months

12.2± 6.1*

9.1± 1.8*






Within group: *P<0.001 when compared with baseline values.
Between groups: †P<0.05 when compared with the control group
Values are mean ± standard deviation
VAS= visual analog scale (score range:0-10);
TUG= Timed “ Up-and-Go” test; higher scores representing worse function

Table 3. Mean Change from Baseline in VAS, Lequesne index and TUG Between the Two Groups










 1 week






 2 weeks






 1 month






 3 months






 6 months






1 week






2 weeks






 1 month






 3 months






 6 months












 1 month





 3 months





 6 months





 1 month





 3 months





 6 months






 1 month





 3 months





6 months





 1 month





 3 months





 6 months




Values are mean ± standard deviation
P-value is derived by comparing difference between the 2 groups by Mann-Whitney U test
VAS= visual analog scale (score range:0-10); Leq= the Lequesne index
TUG= Timed “ Up-and-Go” test; higher scores representing worse function

Study design

This was a prospective, assessor-blinded trial with a 6-month follow-up designed to examine the effects of 3 weekly injections of a bacterial-sourced hyaluronate (Hya-Joint) on reported pain and functional ability in individuals with knee OA.

At screening visit, a complete medical history and physical examination on the knee were performed to determine the eligibility of participants for this study. If both knees were symptomatic, only the more painful knee was treated. Each participant completed a questionnaire, providing details regarding demographics and medical history. All participants also completed baseline measures including VAS, Lequesne index and TUG. A radiographic assessment was performed if no valid x-ray of knees had been taken within 3 months before screening was available. Severity of OA was assessed using the Kellgren-Lawrence grading system16. Eligible participants were randomized to either the Hya-Joint group or the control group by using a computer-generated sequence of randomization. An unequal randomization (2 test:1 control) was used to reduce the cost of the trial. The allocation sequence was held by an external person not directly involved in the trial. The Hya-Joint group received 3 weekly intra-articular injections of 2 ml sodium hyaluronate (Hya-Joint, derived from Streptococcus zooepidemicus and produced by a highly purified biologic fermentation process, molecular weight 650-1200 kDa); while the control group received 3 weekly intra-articular injections of 2 ml sodium hyaluronate (Hyalgan, extracted from rooster combs, molecular weight 500-730kDa) into the knee joints. All injections were done by the same experienced physician in an anterolateral approach into the tibiofemoral joints with the knee in 90-degree flexion using aseptic procedures. If an effusion was present, it was aspirated before injecting. During the study period, no regular analgesics, NSAIDs or physical therapy for knee joint conditions were permitted. Acetaminophen (500mg), up to 4 g/day was allowed as rescue medication. If the treatment dose was above the stipulated limit (acetaminophen 4 g /day), the patient was regarded as a clinical failure. Patients were instructed not to take any pain medicine at least 3 days prior to the baseline assessment and before each study visit. The administration of all analgesic medication during the study period was recorded on a diary card by the patient.

Outcome Measures

Outcome measurements were assessed by the same investigator unaware of each participant’s group at baseline and at 1, 3 and 6 months after the third injection. Knee pain as documented via VAS was also evaluated before the second and the third injections (which was 1 week and 2 weeks after the first injection) to determine the short-term efficacy of HA.

The primary outcome measure was the VAS change from baseline to 6-month follow-up. The patient rated the intensity of pain with regard to average pain on knee movement over the previous week using a 10-cm horizontal VAS (10-cm line; 0= no pain to 10= worst imaginable pain).

Second outcome measures included the following:

(1) Lequesne index was used to assess severity of knee symptoms during the last week14. It is validated and includes the measurement of pain (5 items), walking distance (2 items), and activities of daily living (4 items). Maximal score is 24 and higher scores represent worse function.

 (2) Timed “ Up-and-Go” test (TUG) is a simple test that a patient is asked to rise from an armchair, walk 3 meters at a safe and comfortable pace, turn around, walk back to the chair, and sit down again15. The whole procedure is demonstrated first before the actual test. The score is the time in seconds it takes to complete these tasks.

(3) Patients were asked to rate the level of global satisfaction compared to their preinjection condition at each follow-up visit. The rating was based on a 7-point categorical scale weighted from completely satisfied, satisfied, somewhat satisfied, no change, somewhat dissatisfied, dissatisfied to completely dissatisfied. The data of the patient’ global satisfaction is expressed as the number and percentage of the patients in each of the seven categories.

To monitor the safety of each injection, the occurrence of systemic and local adverse events, defined as any unwanted events whether it was thought to be related to the study drugs or not, were recorded by spontaneous report of the patient throughout the study and by oral questioning by the investigator at each study visit.

Statistical analysis

The primary outcome measure in this trial was VAS change from baseline to 6-month follow-up. The sample size was calculated based on the previous report by Sun et. al. (2006) using five weekly intra-articular HA injection for knee OA, the mean VAS reduction was 2.9 with the standard deviation of 2.2 in 56 patients17. Therefore, to test whether the VAS reduction would be more than 1.5 using pair t-test after 6 months, we need at least 57 patients in the Hya-Joint group to provide more than 85% power to reject the null hypothesis that the mean VAS reduction is not more than 1.5 from baseline to 6-month follow-up, given that the mean and standard deviation of the VAS score reduction are equal to 2.5. Considering possible drop out of participants, we decide to include 63 patients in the Hya-Joint group.

All statistical procedures were conducted with the Statistical Package for the Social Sciences (version 12.0; SPSS Inc., Chicago, Illinois). The data were presented as mean + standard deviation or percentage in the text and tables. Baseline characteristics of the two groups were compared using the independent t tests, Mann-Whitney U tests, or Fisher exact tests. Comparisons in VAS, Lequesne index scores, TUG tests and rescue analgesics consumption were analyzed using paired t-test comparing baseline value with each follow-up score. P values less than 0.05 were regarded as statistically significant.

Subgroup Analysis

After data collection was complete, we stratified patients by age and radiographic severity and compared the outcome scores between the 2 groups by Mann-Whitney U tests to determine whether age or radiographic severity would influence the treatment response.

The trial was registered at (Registry number NCT01185444).

Source of Funding: The study was supported by SciVision Biotech Corporation, manufacturers of Hya-Joint. The funding source did not play a role in the investigation and data analyses. 

Results :

One hundred and twelve patients were screened for eligibility in the study, 17 patients were excluded because 8 did not meet inclusion criteria and 9 met exclusion criteria. A total of 95 patients were randomized into 2 groups (63 subjects in the Hya-Joint group and 32 in the control group) (Figure 1). Of these, 6 patients (4 in the Hya-Joint group and 2 in the control group) did not complete the study and were excluded from the data analysis. Among them, 1 patient in the Hya-Joint group withdrew his consent, 1 moved to another city and 2 patients were lost to follow-up because of noncompliance. Two patients in the control group dropped out because of transportation problem and unrelated intercurrent illness. Eight-nine patients completed the trial and were included in the analysis. There were no significant differences between the 2 groups in demographics, disease duration, pain, and radiographic grade of OA, with the exception of mean baseline TUG scores (Table 1). Table 2 summarizes the outcomes between the 2 groups at each following visit.

A significant decrease in VAS scores from baseline was observed in both groups over the 6-month follow-up period (p<0.001 for each test compared with baseline) (Table 2). Mean VAS scores decreased from 5.6±1.7 at baseline to 3.0±2.1 at 6-month follow-up (mean reduction 2.6 cm) in the Hya-Joint group and from 5.1±2.3 at baseline to 2.6±0.5 (mean reduction 2.6 cm) in the control group. Both groups showed a significantly rapid pain reduction at 1 week and 2 weeks after the first injection (p<0.001), and the effects remained significant at 1, 3 and 6-month follow-up (p<0.001). No significant between-group differences were noted at each study visit (Table 2).

The Lequesne index scores and results of TUG tests improved significantly from baseline in both group at all follow-up visits (p<0.001 for each test compared with baseline), with no significant between-group differences at 1-month and 6-month follow-up. There were statistically significant between-group differences in favor of the Hya-Joint group at 3- month follow-up (p<0.05) (Table 2).

Treatment of the knees in this study resulted in high patients’ satisfaction in both groups. Acetaminophen consumption dropped significantly following treatment in both groups (p < 0.001), with no between-group differences.

In general, both groups were well tolerated. A total of 12 of 89 patients reported adverse events. All adverse events were reported as local reactions, including swelling, warmth, and pain at the injection site of mild or moderate intensity. The overall frequency of adverse events was comparable between the 2 groups (n=8, 13.5 % in the Hya-Joint group and n=4, 13.3 % in the control group). These patients had relief within a few days without sequelae. No severe or systemic adverse events were observed during the study.

Results of Subgroup Analysis

In this study, we stratified patients with grade 1 and 2 OA as mild group and patients with grade 3 and 4 OA as severe group. In the Hya-Joint group, there were 40 patients in the mild group, 19 patients in the severe group; whereas in the control group, there were 21 patients in the mild group and 9 patients in the severe group. Subgroup analyses results showed no significant between-group difference in VAS, Lequesne index scores and TUG tests between patients of the mild group and the severe group in each study period, but we found a significantly greater improvement in TUG in the mild group of the Hya-Joint group compared with the control group at 3-month follow-up.

When patients were stratified by age, some interesting findings emerged. Using 65 years of age as the cutting point, patients were classified into the younger age-group (aged < 65 years) and the older age-group (older than 65 years). The improvements in outcomes were compared between the 2 age groups at each follow-up period (Table 3). In the younger-age group, patients in the control group demonstrated significantly greater reduction in VAS at 1-week post the first injection compared with the Hya-Joint group. In the older-age group, patients in the Hya-Joint group demonstrated significantly greater improvements in VAS at 2-week and 3-month follow-up than patients in the control group. Besides, we also found significantly greater improvements in Lequesne index scores in older-age patients in the Hya-Joint group than the control-group at 3-month follow-up.

Discussion :

This study was performed to investigate the effects of three weekly intra-articular injections of a bacterial-sourced hyaluronate (Hya-Joint) in patients with knee OA. The results showed that participants with knee OA who received intra-articular injections of Hya-Joint had significant improvements in pain and function. The patients’ satisfaction rate was high with no serious adverse events.

In both groups, there was a clear improvement from baseline in the primary outcome variable, the VAS scores. Reduction in pain was apparent from as early as 1 week and 2 weeks after the first injection, was maximized at 3 months, and was maintained for up to 6 months. Previous trials of viscosupplementation in the knee joint demonstrated comparable results to those presented here. Pietrogrande showed a pain reduction 60 days after the intraarticular injections of HA from VAS values of 6 cm down to 2 cm10.

Raynauld JP et al reported that intra-articular injection of HA reduced knee pain in patients with OA by 20-40% over 6-12 months and the peak efficacy occurs between 8 and 12 weeks after the first injection11. Di Marco and Letizia analyzed pain on weight bearing following treatment with HA and they found a reduction of the pain level from 6.7 cm to 4.7 cm12. Reviewed studies demonstrated that significant improvements in pain and function with HA products were most effective between 5 and 13 weeks after injection, with improvements also observed at 14-26 weeks or sometimes longer18. The analgesic effect is thought to be achieved by multiple mechanisms including directly inhibiting nociceptors or binding substance P, reducing pain-eliciting nerve activity by providing an elastoviscous protective barrier around the nociceptive afferent fibers in the intercellular metrix19,20. Our study was the first study that demonstrated rapid pain reduction after knee viscosupplementation as early as 1 week and 2 weeks after the first injection. This rapid pain reduction may have been related either to the lubricating effect of HA in dry joints or may be due to a strong placebo effect from joint injections, which may cause a nearly 30% reduction in pain relief during the first 2 weeks21.

Various studies with HA had also used the Lequesne index score to quantify joint function. The functional analysis as defined by Lequesne in past studies with HA documented improved scores by about 4 points with a follow-up of one year8. Lequesne defined effective treatment forms as those leading to a score improvement of 30–40% at the time of follow-up22. In our study, the reduction of the Lequesne index scores from 11.8± 3.3 points at baseline to 8.2±3.9 points at 6 months follow-up in the Hya-Joint group represented an improvement of 30.5%. Therefore, using the Lequesne criteria, the intra-articular injection of Hya-Joint can be defined as an effective therapeutic measure in the treatment of knee OA.
It is not clear what participants or disease characteristics would predict good response to intra-articular HA. In a previous study by Lohmander et al., a subgroup analysis suggested that patients aged 60 years or above with a baseline Lequesne index above 10 and radiographically verified OA of the knee (Ahlbäck grade I or II) showed significant benefit from intra-articular treatment with HA8. The study by Wobig and Colleagues also showed improvement after HA treatment in patients over 60 years old9. In a meta-analysis, patients older than 65 years of age and those with the most advanced radiographic stage of OA (complete loss of the joint space) were less likely to benefit from intraarticular injection of HA23. In our study, we found that patients with younger-age group and older-age group responded differently from intra-articular injections of HA. It should be noted that the magnitude of the clinical effect is different for different products, comparisons, time points, variables, and trial designs. There are only few randomized head-to-head comparisons of different viscosupplements, thus there is no consistent evidence from well-controlled studies that documents the superior efficacy of one product over another24.  

The study had several limitations. The number of participants studied was small and they were not blinded in treatment. Participants were recorded by age, gender and body weight, they were not analyzed on the basis of preinjection or postinjection functional levels. The more precise identification of subgroups of patients who would most benefit from this treatment must be clarified in the future. Future studies should also investigate the effects of different HA on cartilage and help determine whether HA would aid in chondropretection and slowing the progression of disease. The best HA for the treatment of OA need to be clarified in the future also.


On the basis of this prospective study of patients with knee OA, we concluded that three weekly intra-articular injections of bacterial-sourced hyaluronate (Hya-Joint) produced significant improvements in pain and physical function. The effects were comparable to avian-derived hyaluronate (Hyalgan). It was a useful and well-tolerated treatment for knee OA, with rapid pain reduction at 1 and 2 weeks after the first injection and the treatment effects could last for 6 months or longer.

Conflicts of interest

No conflicts of interest were declared in relation to this article.

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This is a peer reviewed paper 

Please cite as : Shu-Fen Sun,The Effects of Three Weekly Intra-articular Injections of a Bacterial-- Sourced Hyaluronate on Pain and Function in Patients with Knee Osteoarthritis.

J.Orthopaedics 2011;8(4)e10




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