# Viscosupplementation in the Therapy for Osteoarthritic Knee
## 2 Hyaluronic Acid  
In the 1980s, a substance called polyvinylpyrrolidone (PVP) hyaluronate was developed in Russia that could replace synovial fluid. This was administered to OA patients. It was reported in 1984 that PVP hyaluronate injected into the joint space had anti-inflammatory, prolonging, and anti-commissural effects as well as lubricating effects without major side effects. In 1997, the US Food and Drug Administration (FDA) approved viscosupplementation as a conservative technique for the management of OA [6]. The structure of HA is shown in Figure 1[7]. Since then, until the early 2000s, articles have been published, showing that hyaluronic acid (HA) is more effective in OA compared to the control group (saline group) or that it is non-inferior to previously used corticosteroid (CS) intra-articular (IA) injection. After 2010, papers comparing new HA with existing drugs have been published. Since late 2010, articles have been published, claiming that new substances such as PRP are non-inferior to HA. Most articles have proved that HA is effective for OA, although some papers have reported that there is no difference in efficacy between HA and the control group. Research papers comparing the efficacy of HA with other drugs or treatments from 1984 until recently are summarized in Table 1. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \begin{tabular}{c} **Publication** \\ **Year [Ref.]** \\ \end{tabular} & \begin{tabular}{c} **Study** \\ **Design** \\ \end{tabular} & \begin{tabular}{c} **Comparison** \\ **Agent** \\ \end{tabular} & \begin{tabular}{c} **Patients Number** \\ **(Treat/Control)** \\ \end{tabular} & \
\begin{tabular}{c} **Injection** \\ **Times** \\ \end{tabular} &
\begin{tabular}{c} **Result** \\ \end{tabular} \\ \hline
1987 [8] & RCT & saline & 34(17/17) & 3 &
\begin{tabular}{c} Significant difference compared to control group in all variables of \\ spontaneous pain intensity, tactile sensation, load, and pain when \\ walking at 60 days first post-injection \\ \end{tabular} \\ \hline
1991 [9] & RCT & MPA & 40(20/20) & 3 &
\begin{tabular}{c} When comparing the HA group and the MPA group, the analgesic effect was the same during the treatment period, but the analgesic effect at 45 days after the end of treatment all the pain monitoring parameters \\ presented significant differences in favor of the HA-treated group \\ \end{tabular} \\ \hline
1993 [10] & RCT & \
\begin{tabular}{c} 0.25 mg \\ HA/2.5 mL \\ \end{tabular} & 209(102/107) & 5 &
\begin{tabular}{c} LI showed a significant superiority of the Vermont-treated patients after the \\ third injection until 9 weeks. \\ The consumption of paracetamol did not reveal significant differences \\ between the treatment groups \\ \end{tabular} \\ \hline
1994 [11] & RCT & saline & 91(45/46) & 5 & No significant benefit compared to placebo group \\ \hline
1995 [12] & RCT & TA & 63(32/31) & 5 & Significantly less pain was experienced by the HA group during the 6 months follow-up period \\ \hline
1996 [13] & RCT & saline & 189(96/93) & 5 &
\begin{tabular}{c} Patients with knee OA over 60 years of age and high degree of knee OA \\ have a greater therapeutic effect of IA HA injection \\ \end{tabular} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Clinical studies evaluating the efficacy of intra-articular hyaluronic acid (IA HA) in OA (except cross-linked HA). Figure 1: Structural formula of hyaluronic acid (HA) [7]. Table 1 summarizes 25 RCTs and 1 clinical study that showed meaningful results among a total of 250 IA HA papers searched. In 3 studies, it was revealed that there was no difference in efficacy compared with the saline control group, and 23 papers reported that it was superior to the saline control group or there was no difference in efficacy compared to the IA steroid group or the NSAID oral administration group. Since the 1990s, many review articles on effects of HA have been published. Some review articles have reported that HA is ineffective in improving knee pain and function in patients with OA of the knee.