Hyaluronic Acid for Arthritis: Effects and Evidence

hyaluronic acid

To start with, let’s see the current situation around arthritis and osteoarthritis. This will help us to get to know more about the use of hyaluronic acid for arthritis.

In developed countries, the number of patients with osteoarthritis (OA) is growing. In the United States, 43 million patients had OA in 1997, and this figure is projected to rise to over 60 million by 2020 [1].

Severe OA is treated with osteotomy or artificial arthroplasty, while conservative treatment includes intra-articular injection of hyaluronan-hyaluronic acid (HA) [2].

The injections improve symptoms, although they create increased mental stress and risk of infection for patients who need to visit the hospital regularly to receive these painful injections.

In the meantime, there are supplements containing HA for oral use. Of course, swallowing a pill or capsule is much easier than injecting it into a joint, but will oral administration be effective? Consider what the research has to say about it.

What is Hyaluronic Acid?

HA is a high molecular weight polysaccharide composed of repeating polymeric disaccharides such as d-glucuronic acid and N-acetyl-d-glucosamine.

All vertebrates and some microorganisms synthesize HA independently in their cells. In humans, HA is present in every connective tissue and organ such as skin, synovial fluid, blood vessels, serum, brain, cartilage, heart valves, and umbilical cord [3]. In particular, the synovial fluid has the highest HA concentration anywhere in the body – 3-4 mg/ml [4].

HA, as already mentioned, is a polysaccharide whose average molecular weight (MW) ranges from several hundred to several million, and therefore has a high viscosity in water.

The viscosity of the synovial fluid is related to the presence of HA in it, and it serves as a lubricant for joint movements, as a result of which the coefficient of friction in the articular cartilage is almost zero. It is known that in patients with osteoarthritis, the concentration of HA in the synovial fluid decreases [5].

Intra-articular HA injections are widely used to restore low blood glucose levels and treat OA. HA’s functions include preventing cartilage denaturation by protecting the outer layer of cartilage by blocking synovial inflammation, increasing the density of chondrocytes, promoting the metabolism of the synovium, normalizing synovial fluid. Also, HA treats acute pain. The mechanism by which HA reduces pain has been reported.

Intra-articular HA injections reduce the level of inflammatory substances such as prostaglandin E2, which leads to pain relief. Therefore, we use hyaluronic acid for arthritis. It has a strong relationship with knee health.

Hyaluronic Acid as an Oral Supplement

hyaluronic acid for arthritis

But as for the oral form, it was previously believed that the body is difficult to assimilate a polysaccharide, like that which is HA. They say HA is not absorbed in the body in the form of a high molecular weight polymer after ingestion.

However, Kurihara et al., in their study, reported that HA is degraded into 2-6-membered polysaccharides by intestinal bacteria, and these polysaccharides are partially absorbed into the body by the small intestine [6].

After the decomposition of HA by intestinal bacteria to a low molecular weight form, free polysaccharides migrate to joints and other tissues. In particular, the intestinal bacteria Lactobacillus and Bifidobacterium are commonly cited among those that play a crucial role in the absorption of HA [7].

Balogh et al. reported that labeled HA accumulates in tissues such as joints after oral ingestion in rats and dogs [8].

In 2010 another mechanism was clarified by Asari et al. [9]. This report identified a signaling cascade where receptors on intestinal epithelial cells (Toll-like receptors-4; TLR-4) are activated by oral HA resulting in pain relief.

Analysis of an array of cytokines showed that HA enhances the production of interleukin-10 (IL-10), an anti-inflammatory cytokine.

At the same time, analysis of the DNA array of colon tissue showed that HA upregulates the expression of cytokine signaling suppressor 3 (SOCS3) and downregulates the expression of pleiotropic. These results indicate that the binding of HA to TLR-4 promotes the expression of IL-10 and SOCS3 and suppresses the expression of pleiotropy, which leads to anti-inflammatory effects.

Since then, the attention of researchers to the oral form of HA has increased. Since 2008 in the EU, the US, and Asia, there have been many randomized, double-blind, placebo-controlled studies that have demonstrated the effectiveness of dietary hyaluronic acid for arthritis and in relieving knee pain.

Research Overview

hyaluronic acid in osteoarthritis

In 2008, after two clinical trials, the first food supplement was registered to contain HA as the main ingredient. Because this supplement contains multiple ingredients, the potential effects of ingredients other than HA on knee pain cannot be denied, but the beneficial effects of hyaluronic acid for arthritis and knee pain have been confirmed.

In Japan, Hatayama et al. [10] treated 24 patients with chronic knee pain (HA group = 13; placebo group = 11, mean age 47.5) with a mixture containing HA 60 mg/day or placebo for 2 weeks. The HA group showed significant improvement in knee pain and discomfort compared to the placebo group.

In the United States, Kalman et al. [11] treated 20 patients aged ≥40 years with knee OA (HA group = 11; placebo group = 9, mean age 56.3) with a mixture containing HA 48 mg/day or placebo for 2 months, and their results were assessed using the Knee Pain Index, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and the Short Form-36 Index (SF-36v2) as the Quality of Life (QOL) Index.

The WOMAC score in both groups showed significant improvement in knee pain from baseline, but physical function and overall symptom improvement scores in the HA group showed a sharper increase than in the placebo group. On the SF-36 v2, group HA scores were significantly improved from baseline.

In 2009, two clinical trials were conducted using high-purity HA (over 98%). These studies showed that the effect of HA supplementation on knee pain was associated exactly with HA.

Iwaso et al. [12] reported that in Japan, 33 patients with knee pain (HA group = 16; placebo group = 17, mean age 58.3) received HA 240 mg/day or placebo for 8 weeks. Outcomes were assessed using the Japanese Knee Osteoarthritis Measurement Method (JKOM).

The JKOM score was improved from baseline in both groups, especially among 26 patients aged 50-65 years (HA group = 13; placebo group = 13).

Moreover, significant improvements in knee pain and stiffness were reported only in the HA group compared to the placebo group.

Hyaluronic Acid for Arthritis: Research in the Elderly

hyaluronic acid injections hip arthritis

Sato et al. [13] reported a study of 37 Americans with knee OA (HA group = 20; placebo group = 17, mean age 70.8). They orally consumed 200 mg/day of HA or placebo for 8 weeks. The results illustrated that the WOMAC score was significantly improved in both groups from baseline.

In addition, the overall WOMAC score and the activity of daily life were significantly improved in the HA group compared to the placebo one.

In the same year, Möller et al. [14] conducted a retrospective cohort study in Spain comparing hyaluronic acid for arthritis with the pain reliever paracetamol. 69 patients with knee OA and synovitis received a mixture containing HA 48 mg/day or paracetamol for 6 months.

Ultrasound showed that the course of synovitis in the suprapatellar notch was significantly reduced in the HA group compared with the paracetamol group, the number of severe cases of synovial fluid effusion was significantly reduced in the HA group compared with the paracetamol group.

Between 2010 and 2015, 8 clinical trials were registered, indicating that interest in the consumption of HA in developed countries is becoming more intense.

In 2010 in Japan, Nagaoka et al. [15] reported that 40 patients with knee OA (HA group = 19; placebo group = 21, mean age 62.9) received an oral mixture containing HA 60 mg/day or placebo for 4 months, and the result showed that pain/increase and decrease in function and cumulative overall symptoms of the Japanese Orthopedic Association clinical trial response criteria were significantly improved in the HA group compared to the placebo group. Consequently, this indicates relief of knee pain.

Research Among Athletes

hyaluronic acid amploule

In 2012 in Japan, Yoshimura et al. [16] reported that 29 athletes (HA group = 14; placebo group = 15, mean age 20.0) received formula, 72 mg HA/day, or placebo for 12 weeks. The levels of bone metabolic markers of N-terminal telopeptides of bone-specific type I collagen in urine were significantly lower in the HA group. This result indicates that oral HA affects knee health.

Tashiro et al. [17], also in Japan, reported a study in 38 patients with knee OA (HA group = 18; placebo group = 20, mean age 69.9). They received high-purity HA (more than 97%) at a dose of 200 mg/day or placebo for 12 months.

During the study, patients were asked to do quadriceps strengthening exercises daily as part of their treatment.

The result shows that the JKOM quality of life was significantly improved in the HA group compared with the placebo one.

This trend was more evident among patients under 70 years of age. For these patients, the total JKOM score was significantly better in the HA group than in the placebo one.

Thus, HA supplementation and quadriceps strengthening exercises are effective in relieving knee pain, especially in patients <70 years of age.


In 2013 Martinez-Puig et al. [18] reported that 50 healthy subjects with joint discomfort (VAS 10 to 40 mm; HA group = 20; placebo group = 20, mean age 59.6 years) received a mixture containing HA 48 mg/day or placebo in within 90 days, and outcomes were assessed using an isokinetic dynamometer.

The maximum peak torque was significantly greater in the HA group than in the placebo group. In the HA group, total knee extension and mean knee extension strength was also significantly higher than those in the placebo group. This study showed that oral HA effectively improved the knee’s ability to flex and stretch.

Moriña et al. [19] reported a meta-analysis of two randomized, controlled, double-blind, placebo-controlled trials involving a total of 148 patients with mild knee pain (VAS 30 to 50 mm, aged 20 to 75).

During the studies, patients were administered an oral mixture containing HA 48 mg/day or placebo for 3 months, and the outcome was assessed using an isokinetic dynamometer. The analysis showed that the affected joint showed greater flexion in the HA group than in the placebo group.

Ultrasound results of synovial effusion showed that synovial effusion was significantly reduced in the HA group. The VAS assessment showed that knee pain was further improved in the HA group compared to the results in the placebo group.

In 2014, Sánchez et al. [20] reported that 68 patients with mild knee pain (VAS between 30 and 50 mm; HA group = 34; placebo group = 34, mean age 69.5 years) received an oral mixture containing HA-48 mg/day or placebo for 90 days.

Significant improvement in knee pain as measured by VAS was recorded in the HA group compared with the placebo group. Ultrasound examination showed that synovial effusion was reduced in the HA group.

The result of using an isokinetic dynamometer showed that muscle strength (peak torque) was significantly higher in the HA group than in the placebo group.

Blood tests for RNA expression were performed in 20 patients (HA group = 10; placebo group = 10). The results obtained showed that the expression of genes associated with the metabolism of glycosaminoglycans and the dynamics of the extracellular matrix differed between the HA and placebo groups.

It was summarized that differences in gene expression explain the improvement in knee pain and muscle strength in the HA group.

Reduced Inflammation Rates

hyaluronic acid for osteoarthritis of the knee

In 2015, Nelson et al. [21] treated 40 patients with knee OA (VAS> 50 mm; HA group = 21; placebo group = 19, mean age 61.0) with an oral mixture containing HA 56 mg / day or placebo for 3 months.

There was a significant improvement in VAS, WOMAC total score, and WOMAC pain score in the HA group compared to the placebo group.

Analysis of blood serum and synovial fluid showed that the level of inflammatory cytokines was significantly increased in the placebo group and significantly decreased in the HA group.

For bradykinin, which is associated with inflammation and pain, and leptin, which is associated with obesity-related OA, levels of both substances were significantly lower in the HA group than in the placebo group.

10 patients in each group drank large amounts of water to study the circulation of HA in the synovial fluid. The turnover rate was significantly reduced in the HA group compared to the placebo group. Hence, this report demonstrated that oral HA supplementation is beneficial for the treatment of obese patients with OA.

In 2015, Jensen et al. [22] conducted a study in which 72 patients with OA of the knee joint took part (HA group = 37; placebo group = 35, mean age – 47.2 years). They consumed a liquid mixture of HA or a placebo for 4 weeks. During the first 2 weeks, the HA mixture was given 45 ml/day (HA content 225 mg/day), and over the next 2 weeks – 30 ml/day (HA content 150 mg/day).

After 2 weeks of dosing, knee pain assessed by the VAS was significantly improved in the HA group compared to baseline. In contrast, no improvement in knee pain was reported in the placebo group. Thus, oral hyaluronic acid was able to relieve knee pain.



The use of oral hyaluronic acid in osteoarthritis patients is more than effective.

Studies using a mixture containing HA and other ingredients could not rule out the possibility that other ingredients had an effect on knee pain.

However, studies that used high-purity HA (over 97%) also reported beneficial effects. Thus, oral hyaluronic acid can effectively improve knee pain. So, you should use hyaluronic acid for arthritis.

In the aforementioned clinical studies, there were slightly more women than men (average ratio: men 43%, women 57%). However, each study took into account the same sex ratio in the HA and placebo groups.

In general, the number of patients with OA among women was higher than among men. This is probably due to the fact that women have smaller muscles than men, and therefore the load on the knee increases.

HA intake differs among the relevant studies by dose and timing, in particular, 48-240 mg/day for 2 weeks to 12 months. Thus, further research is needed to clarify the minimum effective dose and the minimum period for taking hyaluronic acid for arthritis patients.


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