Comparative efficacy of treatments for patients with knee osteoarthritis: a network meta-analysis

Knee osteoarthritis (OA) is a degenerative disease with clinical manifestations, including joint pain, tenderness, joint swelling restricted movement as well as joint deformities and a leading cause of disability and healthcare economic burden [1, 2]. More than 50% aged 60–75 years old people owned radiological evidence of knee OA and 80% of population over 75 years old suffered from knee OA [3, 4]. In recent years, the incidence of OA has increased and presents as a serious threat to human health and quality of life [5]. The current optional treatments for knee OA include oral anti-inflammatory drugs, physical therapy, topical anti-inflammatory gels and intra-articular injections [6]. The intra-articular injection consists of various drugs such as corticosteroid, hyaluronic acid (HA) and platelet-rich plasma (PRP).

Corticosteroids are commonly utilized as intra-articular injection agents [7]. Significant effects of corticosteroids have been reported by several studies for treating the knee OA [8‐10]. The short-term benefits of intra-articular corticosteroid injection are well recognized, while the long-term benefits and the value of repetitive injections are still debatable [11, 12].

OA is characterized by degenerative of articular cartilage, osteophyte formation, changes in the synovial membrane, subchondral bone sclerosis, and reduced viscosity of synovial fluid [13]. HA is a widely distributed, liner glycosaminoglycan constituent of cartilage, synovial fluid, skin and aqueous humor [14]. It has been proved that synovial fluid from arthritic joints contains lower concentrations of HA than that from normal joint [15]. Since the elasticity and viscosity of synovial fluid are directly proportional to HA content and integrity, intra-articular injection of HA is a rational approach to the treatment of OA [14]. Although beneficial effects on pain, function and patient global assessment have been documented, the real entity of improvement and which of the many available HA products can offer the best results is not clear [16].

Platelet-rich plasma (PRP) has also been introduced as an alternative treatment for patients with knee OA [17]. PRP comprised a potent cellular milieu containing platelet concentrations above baseline, as well as an undifferentiated mixture of anti-inflammatory, pro-inflammatory, anabolic and catabolic mediators in an attempt to stimulate a supra-physiologic response and elicit the body’s natural healing potential [17‐19]. The analysis of Zhang’s et al. review demonstrated that published literatures supported the efficacy of PRP in the treatment of tendinous, cartilaginous, ligamentous, and muscular injuries [12]. In a systematic review and meta-analysis, Laudy et al. found that patients treated with PRP injections reduced more pain than those receiving placebo injections [20]. Nevertheless, the level of evidence was limited since the risk of bias was high. Although intra-articular saline injections are used commonly as placebos in many trails, there has been increasing recognition that the application of intra-articular saline may have some effect [21, 22]. However, this result was drawn from clinically heterogeneous samples [22].

Controversies remain regarding in the treatment of knee OA. Many articles compared HA and PRP to determine which therapy was better in terms of pain reduction. In 2016, a meta-analysis reported that PRP was more effective when compared with HA [23]. Cole et al. observed that there was no difference between HA and PRP in the primary outcome in terms of the patient-reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score [6]. Similarly, studies of HA and corticosteroid injection in patients with knee OA have displayed various results [24, 25].

Therefore, a network meta-analysis (NMA) is required due to contradictions and to give more scientific evidence for the choice of treatments. We performed the first NMA to evaluate the efficacy and safety of five different treatments for patients with OA, including corticosteroid, HA, PRP, placebo and HA + PRP, in regard to their performance on pain, stiffness, physical function or total assessed with quantitative scores by WOMAC, in order to provide optimal treatments for knee OA patients.

Knee OA is a chronic progressive joint disease and the second main cause of disability, followed by a heavy social and economic burden [30]. Since the optimal treatment for knee OA patients remains inconclusive, the present NMA is performed to determine the best regime for patients with knee OA and provide a medical guideline. In the present study, the most important finding in this study is that HA + PRP showed the best efficacy in relieving stiffness, improving physical function and total scores, while PRP took the first place in terms of pain reduction.

As for stiffness, physical function and total scores, HA combined with PRP had the highest SUCRA value of 0.743, 0.772 and 0.765, respectively, which means that according to these three appraisal tools, HA combined with PRP is the first choice. This result was in accordance with the conclusions of some previous studies. The results of Yu et al. indicated that patients with knee OA who were treated with the combination of HA and PRP had more positive effects on body pain, and reduced arthralgia, bone damage and cartilage destruction, when compared with HA or PRP treatment alone [31]. Lana’s et al. study showed that HA and PRP combination treatment enjoyed better outcomes than HA alone up to 1 year and PRP alone up to 3 months [17]. Therefore, HA + PRP is the preferred therapy for knee OA patients.

Meanwhile, based on the SUCRA results of this NMA, PRP was another effective regime, as it ranked the first in pain reduction (0.691) and the second in stiffness (0.603), physical function (0.608), and total scores (0.624). A RCT study found that compared with therapeutic exercise alone, PRP injections and therapeutic exercise combination treatment could be more effective in reducing pain and improving stiffness as well as quality of life [32]. Another prospective, double-blind RCT supported that PRP injections had a better short-term effectiveness than placebos in the reduction of pain and stiffness and the improvement of knee function in early knee OA [33].

In the current study, we can see that irrespective of whether the HA was combined with PRP injection or the PRP injection alone, the key factor of these two treatments is PRP. Researches have indicated that inflammatory cytokines serve a critical function in the induction and development of OA [34, 35]. PRP is an autologous and multifunctional platelet concentrate of the blood that contains highly concentrated platelets and highly levels of cell growth factors. PRP promotes synovial cell proliferation and differentiation, as well as recovery of cartilage morphology [31]. That may be the key reason why the injection containing PRP shows an ideal outcome. Although plenty of studies have proven the efficacy of PRP in treatment of OA clinically, more mechanism research about OA and interaction research about the relationship between OA and PRP is required.

Although this NMA addressed many controversies on the clinical efficacy and safety of different treatments, there were still some limitations of the present study that require to be acknowledged. The limitations of our study include the following: (i) English studies were included, while non-English language articles without English abstract were omitted, which may lead to language bias; (ii) the study used self-reported questionnaire named WOMAC to evaluate outcomes, including pain, stiffness, physical function and total scores, which might limit the objectivity of results; (iii) due to insufficient data, the subgroup analysis in terms of severity of the disease, the frequency and dosage of the medication and the degree of activity has not been performed in this NMA. The fact of paucity of homogeneous studies also indicated to us that more high-quality and homogeneous studies should be carried out to provide us more strong evidence of this topic; (iv) the study sample size was relatively small, ranging from 10 to 174, which might have a negative effect on the conclusions. Hence, further high-quality RCTS are needed to address uncertainties regarding various treatments as well as qualify clinical efficacy.

In conclusion, this NMA revealed that HA + PRP demonstrated the best efficacy in the improvement of stiffness, physical function, and total scores, while PRP had the best performance in terms of pain reduction. Ultimately, we hope that more and more researchers to compare the efficacy and safety of different regimes for patients with knee OA, and thus there will be more data and literatures to be referenced, which will provide more theoretical basis for clinical therapy of knee OA.