Corticosteroids

Corticosteroid intra-articular injections have a potent anti-inflammatory and immunosuppressive effect, with a complex mechanism of action. They bind to intra-cellular steroid receptors and have a multifocal influence on inflammatory and immune cascades. On a cellular level, they reduce vascular permeability and therefore inhibit the accumulation of inflammatory cells, preventing the secretion of inflammatory mediators such as prostaglandins and leukotrienes. For this reason, the rationale for this treatment option is for a resultant reduction in swelling and tenderness of the knee joint.

There are numerous preparations of corticosteroid injections available for use, with methylprednisolone acetate (DepoMedrol) and triamcinolone acetonide (Kenalog) being the most frequently used. The preparation is administered alongside a short-acting local anaesthetic agent, which aims to increase the injected volume and to administer some immediate analgesia. The duration of action is relatively short, reported to be between 1 and 8 weeks, and there is a suggested interval of 3–6 months between injections.

The evidence supports the use of corticosteroid injections to reduce pain and improve function in the short term (up to 6 weeks). A systematic review and meta-analysis of 2314 patients in 15 studies showed that there was a reduction in pain scores and function at 6 weeks compared with placebo. However, this effect was no longer seen at medium-term follow-up, defined as 24 weeks, with diminishing benefits with repeated injections. In a Cochrane review of 27 randomized control trials (RCTs), it was concluded that there was an improvement of pain and function compared with placebo over a 1–6-week period, deemed low quality evidence by the authors. The mean pain improvement was 1 point on a 10-point scale, with the number of patients needed to treat to gain additional benefit being 8. There is also evidence, from a meta-analysis with 620 patients, that those with more severe pain may experience greater improvement in symptoms of pain for up to 4 weeks with intra-articular corticosteroid injection compared with placebo.

Whilst reducing inflammation and providing short-term symptomatic relief, there is growing concerns of the chondrotoxicity of intra-articular corticosteroid injections, with evidence of its potential cumulative destructive effect on cartilage. A systematic review including 40 articles (1 clinical and 39 basic science studies) reported both a dose-dependent and duration-dependent increase in deleterious effect on articular cartilage. In addition, research into the local anaesthetic chosen as a vehicle in administration of intra-articular corticosteroids also exhibited the same dose-dependent and duration-dependent chondrotoxic effect. Interestingly, it was found that the analgesic potency and chondrotoxicity was not correlated. In vitro, ropivacaine has been found to be less chondrotoxic, compared with lidocaine and bupivacaine, with vitamin C found to be chondroprotective when added to the preparation. There is also a potential flare-up of symptoms within the first 24 hours after treatment, which generally improves within the first couple of days. Other documented adverse effects include rapid OA progression, subchondral insufficiency fracture and osteonecrosis. In an important study of nearly 4000 patients with knee OA, with a nearly 10-year follow-up, it was shown that those patients that had received intra-articular steroid injections had a hazard ratio of 1.57 (CI 1.37 to 1.81; p < 0.001) for ending up with knee arthroplasty (compared to the patients who had not had any steroid injections), and was shown that each injection of intra-articular steroid increased the absolute risk of knee arthroplasty by nearly 10% per injection.

There is conflict regarding the current guidelines for the use of intra-articular corticosteroid injections for knee OA. The American Academy of Orthopaedic Surgeons (AAOS) does not currently recommend for or against the use of corticosteroid injections, but advises clinicians to be alert to research providing conclusive evidence to determine the balance between benefits and potential risks. In contrast, the American College of Rheumatology (ACR) strongly recommends corticosteroid injections for hip and knee OA. The Osteoarthritis Research Society International (OARSI) guidelines conditionally recommended corticosteroid injections, echoed by the UK National Institute for Health and Care Excellence (NICE) advice to ‘consider intra-articular corticosteroid injections when other pharmacological treatments are ineffective or unsuitable, or to support therapeutic exercise’.

Hyaluronic acid

Hyaluronic acid (HA), also known as ‘viscosupplementation’, is a naturally occurring glycosaminoglycan. It is a key component of synovial fluid, and is multifunctional in maintaining knee homeostasis. It consists of repeating units of N-acetyl- d -glucosamine and d -glucoronic acid. In a healthy knee, endogenous HA is a high-molecular-weight biopolymer produced by type B synoviocytes and synovial fibroblasts. Its main functions include lubrication, structural support, anti-inflammation and the maintenance of the integrity of the extracellular matrix. As part of the pathogenesis of OA, there is a progressive reduction in the molecular weight and concentration of HA. Therefore, the rationale for intra-articular injections of HA is to provide a mechanical solution for the synovial fluid that has lost its viscoelastic properties.

When administered as an intra-articular injection, HA has a relatively short half-life, reported to be between 1 and 9 days, due to its rapid clearance by the synovial membrane. Therefore, techniques have been used to increase the molecular weight and size through cross-linking, as well as the specific formulation and stabilizing agents. With regards to the molecule size, HA preparations range from a molecular weight of 500 kDa to over 10,000 kDa, and can be grouped into low-molecular-weight (LMW), moderate-molecular-weight (MMW), high-molecular-weight (HMW) and ultra-high-molecular-weight (UHMW) preparations. Due to these variations, there are numerous available products. There is no universally agreed timing and dosage protocol for the administration of intra-articular HA; however, treatment generally involves a series of 1–3-weekly injections. Single preparations contain 2–4 ml of HA, and are product-dependent. Series of injections can be performed every 6–12 months, depending on the patient’s response and on symptom recurrence.

Early clinical trials showed that intra-articular HA injections are effective in treating the pain associated with OA, which was further supported by a 2006 Cochrane Review of 76 randomized control trials comparing HA and placebo. More recently, in 2022, a systematic review and meta-analysis involving 9423 patients reported a small, but not significant, improvement in both pain and functional outcomes compared with controls. This paper also found a statistically significant increase in serious adverse events in patients receiving HA injections compared with placebo (3.7% vs 2.5% respectively).

It has been observed that HA with an increased molecular weight (>6000 kDa) had the greatest effect on pain at 13 weeks, raising the suggestion that all HA treatments should not be considered as a single entity, but specifically based on their molecular weight.

There is inconsistency amongst different guidelines, reflecting the conflicting nature of the evidence surrounding the use of intra-articular HA injections in knee OA. NICE guidelines advise ‘do not offer hyaluronan injections to manage osteoarthritis’, citing minimal evidence of efficacy and safety concerns. The AAOS aligns with these NICE guidelines, whereas the ACR and European Alliance of Associations for Rheumatology (EULAR) still recommend its use in this same setting.

Biologics

Orthobiologic therapies for knee osteoarthritis are a relatively new and evolving area of research. ‘Orthobiologics’ is a definition encompassing naturally occurring substances that can positively influence cellular and molecular events, leading to healing in musculoskeletal tissue. The therapies include, but are not limited to, autologous blood products, cell-based therapies and growth factors ( Figure 1 ). In recent years, there has been a rapid increase in the number of available therapies, but for the purpose of this review, the most common agents, platelet-rich plasma (PRP), mesenchymal stromal cells (MSCs) and bone marrow aspirate concentrate (BMAC) will be discussed in more detail.

Autologous blood products refers to any preparation derived directly from a patient’s whole blood. They include a spectrum of products that can arranged into the following categories: PRP, platelet-poor plasma (PPP) and autologous anti-inflammatory preparations (AAIs). As they can be obtained through peripheral venepuncture (a low morbidity procedure), and contain factors and cells with pro-regenerative properties, autologous blood products are attractive.

Platelet-rich plasma is the most commonly used orthobiologic administered for the treatment of knee OA. The rationale for the use of PRP to treat knee OA is to deliver a high quantity of cells (platelets) that are responsible for releasing pro-regenerative or immunomodulatory cytokines into the knee joint. The mechanism of action is complex and poorly understood, but pre-clinical studies performed in animal models have shown a reduction of synovial inflammation, a reduction in biomarker levels and a reduction in the progression of articular cartilage damage.

The term PRP is used to describe any autologous preparation with a platelet concentration higher than baseline. This is achieved usually through differential centrifugation, allowing for a range of preparations of PRP, with approximately 20 different commercially available systems. The heterogeneity amongst preparations is under-appreciated. There is a multitude of different preparations of PRP, and the effect of treatment is further influenced by varying injection and application protocols, including the number and timing of each injection.

A meta-analysis of Level 1 evidence examining the effect of PRP in the treatment of knee OA, with 27 randomized control trials (RCTs), showed that PRP significantly outperformed HA and placebo, with respect to pain and patient-reported outcomes measures. A similar result was found in another meta-analysis, but fell beneath the minimal clinically important difference for all outcomes, and the quality of evidence was deemed low. A recent review of guidelines had a similar finding, with 38 out of 48 RCTs showing that PRP was superior to other injections, including corticosteroids, HA and saline. The remaining 10 RCTs reported no significant difference amongst treatments, a finding authors attributed to the heterogenous nature of PRP preparations, and diverse methodology.

PRP treatment in patients with knee OA is strongly recommended against in the OARSI international guidelines, citing the concern ‘regarding the heterogeneity and lack of standardization in available preparations of platelet-rich plasma, as well as techniques used, making it difficult to identify exactly what is being injected’. For the same reason, the AAOS guidelines, EULAR recommendations and ACR guidelines are all consistent in recommending against the use of PRP intra-articular injection therapy for knee OA. NICE guidelines state that PRP injections for knee OA “raises no major safety concerns. However, the evidence on efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research”.

Other autologous blood products – there are numerous other forms of autologous blood products available for use. These include autologous conditioned serum (ACS, Orthokine), autologous protein solution (APS) and PPP. ACS is a type of AAI that is a cell-free preparation, containing anti-inflammatory factors released from activated leukocytes. It is obtained by venepuncture followed by incubation with chromium sulphate to stimulate the interleukin-1 (IL-1) receptor antagonist as well as other anti-inflammatory cytokines. This then is subject to centrifugation and filtration, prior to intra-articular injection. The rationale for their use is to target the inflammatory cascade responsible for the symptoms of OA, through inhibition of pro-inflammatory cytokines. There is evidence from an RCT (n = 376) comparing ACS with HA and placebo, which reported significantly reduced symptoms and quality of life compared with baseline, with ACS significantly superior to the other interventions at all time points (104 week follow-up). While preliminary evidence supports the use of ACS for the treatment of OA, clinical outcomes vary across the literature, with clinical studies failing to replicate the cytokine changes seen in vitro .

APS is similar to PRP, but contains a larger cell fraction, retaining white cells and plasma usually discarded during the PRP preparation process. It is derived from a patient’s blood to produce a concentrate of inflammatory cells and cytokines. nSTRIDE is a specific preparation of APS, which has been shown in a placebo-controlled randomized control trial involving 40 patients to have no significant benefit on patient reported outcome measures. In fact, the study found patient’s reported pain to be worse in the nSTRIDE group, compared to placebo saline injections.

Cell-based therapies: the most frequently researched cell-based orthobiologic for treatment of knee OA are so-called mesenchymal stromal cells (MSCs). In vitro, these multipotent cells, derived from bone marrow, can differentiate into different musculoskeletal cell types, such as osteocytes and chondrocytes. The nomenclature of these cells is surrounded with ambiguity and controversy, often misleadingly called ‘stem cells’, suggesting that they are able to regenerate cells at the site of injury. Evidence shows that their effect is seen because of the release of mediators to positively influence the biological environment, rather than engraftment. MSCs are also present outside of the bone marrow in other readily accessible tissues for harvest, most notably in adipose tissue, skin and blood. ‘Culture-derived’ therapies are those where the harvested sample is delivered to the patient after a delay. The laboratory culture process can produce a preparation consisting of exclusively MSCs. ‘Point of care’ cell therapies refer to the immediate delivery of harvested cells back into the patient.

Bone marrow aspirate concentrate (BMAC) is an example of a ‘point of care’ therapy, typically acquired through needle aspiration of bone marrow, followed by concentration to increase the relative proportion of MSCs. Whilst this process is advantageous, in that it can be carried out in one sitting, the concentration of MSCs is only approximately 0.0001–0.005% of the total number of cells present. The exact mechanism of action of BMAC is not yet fully understood, though it contains factors that are thought to promote tissue healing through activation of cell proliferation and differentiation. However, it should be noted that the harvesting process is invasive, with associated risk of donor site morbidity.

At the time of writing, there is a paucity of robust data evaluating the efficacy of BMAC for the treatment of knee OA, with conflicting evidence. Several papers report a reduction in pain and improved patient reported outcome measures compared with saline, but these studies are susceptible to significant bias. A systematic review of 8 studies, with a mean follow-up of 13 months, reported that BMAC did not demonstrate clinical superiority in relation to PRP or placebo.

Stromal vascular fraction (SVF) is another ‘point of care’ therapy. It is a cell-based product, derived from adipose tissue, where the adipose cells are separated either mechanically or chemically, and the resulting preparation is delivered as an orthobiologic. SVF contains heterogenous cell populations, including type 2 macrophages, T cells, pericytes, mesenchymal stromal cells and progenitor cells. The rationale for using SVF in knee OA is to deliver the aforementioned cells to enhance angiogenesis, immunomodulation, proliferation and cell differentiation. A systematic review, including 239 patients (274 knees) in 9 clinical studies has shown that SVF is safe, but with varied improvements in pain and patient-reported outcome measures. It was noted that only 1 study had a placebo-controlled group. The authors noted the heterogeneity of the methodologies, as well as the included patient demographics and stages of knee OA, raising concerns about the applicability of the results to the general population. Level 1 evidence is required to better inform clinical decision making.

Microfragmented autologous fat tissue (MFAT) is a ‘point of care’ cell-based therapy where the lipoaspirate is harvested from the subcutaneous adipose tissue of a patient and prepared through the non-enzymatic mechanical disruption and rinsing with saline into small particles (using a Lipogems system). It contains adipose-derived mesenchymal stromal cells (AD-MSCs). The rationale for the use of MFAT in the context of knee OA is to provide cushioning and support, as well as the capacity for the cells present to release a range of trophic and immunomodulatory factors. There is evidence, from a recent randomized control trial, that MFAT (n = 26) and PRP (n = 23) both provide a significant improvement in pain and function at 12 months, compared with baseline, with no significance between the treatment groups. This supports findings from another RTC (MFAT vs PRP) with 24 months of follow-up.

Criticism has been made over the absence of placebo-controlled trials, with further Level 1 evidence required before appropriate information is available to include MFAT in routine evidence-based treatment protocols. At present, the ACR strongly recommend against the use of ‘stem cell therapies’, with the AAOS not giving an evaluation on their use.

Considerations with orthobiologic therapies – there is ongoing ambiguity in the nomenclature surrounding orthobiologics, especially with regards to cell-based therapies. To combat the limitations of the term ‘stem cells’, as well as their misinterpretation in the literature, a system has been designed to increase transparency and communication around these therapies. Orthobiologic therapies are also prone to direct-to-consumer marketing and misinformation, an increasing occurrence with healthcare products. Patients can be poorly informed regarding the benefits and risks of available treatment options, and are potentially vulnerable to information presented though marketing, including online advertisement and social media. There is evidence that 96% of 896 clinics in USA had at least one piece of misinformation on their website. In the UK, there has been a ruling by the Advertising Standards Agency against the actions of The Regenerative Clinic in London. In order to avoid this misinformation, there are professional recommendations and minimum standards to guide physicians offering novel therapies, in both clinical practice and research. These standards prioritize informed consent, transparency and shared decision-making.

Injectable polyacrylamide hydrogel

Arthrosamid® is an injectable polyacrylamide hydrogel, containing polyacrylamide and non-pyrogenic water. It is a synthetic biocompatible hydrogel, which is non-toxic and non-degradable. It acts as a viscoelastic substance, and has been said to provide mechanical support to the joint through lubrication and cushioning between the articulating surfaces. This molecular structure permits usual water exchange and integration with the surrounding soft tissue, without the loss of volume. It is structurally stable, and integrates with the synovial tissue of the inner capsule after intra-articular injection. This aims to reduce the friction between the bones, alleviating pain and improving mobility. At present, there is no available, placebo-controlled Level 1 evidence to support its use. However, an RCT (n = 239) published in 2024 has shown that injectable polyacrylamide hydrogel was as effective and as safe as HA for the treatment of knee OA over 1 year. Whilst short-term studies are available, to fully appreciate the efficacy and safety of injectable polyacrylamide hydrogels, long-term follow-up data is required.