Alternatives to Intra Articular Corticosteroid Injections for Osteoarthritis of the Foot, Ankle and Knee
Background
Osteoarthritis (OA) can be a debilitating condition and is one of the principal causes of pain throughout the world (Osteoarthritis: National Clinical Guideline for Care and Management in Adults 2008). OA is characterized by cartilage degradation, which is reflected clinically by a gradual development of pain, stiffness, and loss of motion of the joint [1]. It is a degenerative joint disease which has the potential to bring about joint failure with associated pain and disability [2]. The potential OA joint destruction is due to an imbalance between the repair and breakdown of joint structures and the amalgamation of cellular and biomechanical stresses to the joint [3].
It has been reported that symptomatic radiographic foot OA affects one in six older adults [4] with the estimated lifetime incidence of symptomatic knee OA at 44.7% [5].
In the United Kingdom (UK) it was estimated that between 1999-2000 36 million working days were affected due to symptomatic OA which has led to an approximate loss to the UK economy of £3.2bn (Osteoarthritis: National Clinical Guideline for Care and Management in Adults 2008).
It is clear that OA can potentially severely affect the quality of life of our patients and can subsequently affect not only the physical wellbeing of our patients but also have a negative impact on their psychosocial health [2].
The primary objective for the treatment of OA is to reduce symptoms which there by increases physical function and wellbeing [6]. It is vital that we as clinicians take a holistic approach to the treatment of the OA in our patients. International guidelines have promoted the use of exercise treatment for the management of symptomatic OA [7], [8]. As such providing a tailored exercise treatment protocol to our patients with consideration of age, mobility, joints affected, and co-morbidities should be considered alongside further invasive interventions. My OA patients can testify to the mantra that I repeat which is “motion is lotion!” at each and every consultation.
It has been reported that weight loss for patients with a body mass index >25 can have beneficial impact on symptomatic knee pain OA based on evidence-based guidelines established by the American Academy of Orthopaedic Surgeons in 2013 [9].
Supplementation including the use of Glucosamine and Chondroitin have been shown to relieve pain and improve physical function in patients with symptomatic OA [10].
Footwear advice for patients with symptomatic OA of the foot, ankle and knee can have a beneficial effect on symptoms by helping to reduce load to the affected joint [11]. Combining footwear advice with orthotics can also be valuable with the management of foot and ankle OA [12] however evidence for functional orthotics as an adjunct treatment for knee OA is unclear [13].
Clinicians who are considering injection treatment options for patients with symptomatic OA should consider a holistic treatment plan which is centred around evidence-based adjuncts. In my opinion this paradigm of holistic clinical management should be considered as an axiom for all interventions we offer patients.
Corticosteroid Injections
Intra-articular (IA) corticosteroid injections is a common treatment option offered to patients with symptomatic OA [14]. It has been reported that more than one-third of patients with newly diagnosed knee OA were treated with at least one intra-articular corticosteroid injection [15].
IA corticosteroid injection is thought to provide pain relief in patients with symptomatic OA by decreasing joint inflammation [16]. Short-term complications, including a steroid flare up, injection site pain, skin pigmentation, atrophy, with systemic effects being exceptionally rare [17].
IA corticosteroid injections for symptomatic OA are commonplace both in the NHS and in private practice however the long-term benefits of this modality has little to no evidence supporting its use.
A 2015 Cochrane Review of 27 clinical trials which examined the efficacy of intra-articular corticosteroid injections to treat knee OA established that the clinical benefits of this intervention were from 1-6 weeks with no enduring symptomatic beneficial effect 6 months after the injection [17].
Although the short-term complications of IA corticosteroid injections for OA can usually be managed effectively, in my experience very little thought is given by many clinicians about long-term safety concerns which can ultimately lead to more harm than benefit.
Corticosteroids have been linked to cytotoxicity of articular cartilage [18]. There is however confounding evidence concerning the link with IA corticosteroid injections and loss of cartilage volume. Raynauld, Buckland-Wright [1] in a randomized, double-blind, placebo-controlled trial with 68 participants reported no loss of joint space over time when compared to participants that received saline injections. This is a stark contrast to McAlindon, LaValley [19] in a randomized clinical trial with the use of IA triamcinolone versus saline on knee cartilage reported significantly greater cartilage volume loss and no significant difference in OA when comparing IA triamcinolone, compared with IA saline. The authors stated that “these findings do not support this treatment (corticosteroid) for patients with symptomatic knee osteoarthritis.” Further retrospective studies reported an increased risk of cartilage degeneration in patients with knee OA [20] and hip OA [21] who received IA corticosteroid injections based on radiographic evidence.
It would be fair to state that there is an ever-growing tide of evidence to suggest that IA corticosteroid injection can potentially increase the rate of progression of joint degeneration.
Given the unclear efficacy and long-term prognosis with the use of this modality coupled with advice from the Faculty of Podiatric Medicine of the Royal College of Physicians and Surgeons of Glasgow during the pandemic which stated:
“Clearly, corticosteroid injections should not be undertaken in individuals with active COVID-19 infections. However, there is still potential for harm to individuals who may be incubating or later develop COVID-19”, it is incumbent for clinicians to investigate alternative injection options to IA corticosteroid injections which can provide a safe, efficacious and positive long-term impact for patients suffering from foot, ankle and knee OA.
Prolotherapy
Prolotherapy (prolo, an abbreviation of proliferation) also known as regenerative injection therapy is an alternative treatment modality for OA. Prolotherapy is characterised by injecting an irritant substance such as dextrose in an affected area. The irritant solution momentarily increases inflammation in the affected joint however as a result the inflammatory response enhances blood flow and promotes new growth and healing in the damaged structures [22]
The percentage of dextrose injected to treat OA is commonly 25% [23]. Dextrose injectate acts to hyperpolarize nerves by opening their potassium channels, therefore decreasing transmission in nociceptive pain fibres [24]. Recruitment of chemical mediators and growth factors stimulate healing of injured extra and IA structures [25].
Dextrose prolotherapy can be injected in several different ways, IA or with prolotherapy specific techniques such as Lyftogt's technique and Hackett's (Hackett-Hemwall) technique Both techniques involve multiple injections into either subcutaneous tissues to fibro-osseous junctions of tendons and ligaments [26].
A study which recruited 90 participants with knee OA that received monthly dextrose prolotherapy injections for 3 months reported significant improvement in pain function and stiffness scores with 60 subjects reporting continual improvement after 2 years with no adverse effects [22].
Two systematic reviews are of interest, Hauser, Lackner [27] which included 14 RCTs, 1 case-control study, and 18 case series studies in the qualitative synthesis determined that the use of dextrose prolotherapy was supported in the use of knee OA. A further systematic reviews in 2017 which included 10 studies for a qualitative synthesis suggested that moderate evidence suggests that prolotherapy is safe and can help achieve significant symptomatic control in individuals with OA [28].
Clinical Experience & Commentary
For some reason which has escaped me for the last 27 years of my podiatry career, dextrose has not been added to the podiatrist Prescription Only Medicines (POM) – administration list. Access to dextrose is therefore restricted to podiatrists who are independent prescribers or as in my case if you have access to an independent prescriber and obtain a patient specific directive. Dextrose prolotherapy is an inexpensive treatment option with a relatively low risk profile which has proved to be effective in the treatment of OA and should be considered as an alternative to corticosteroids, however some fellow podiatry colleagues may find access to injectable dextrose difficult.
Viscosupplementation
Viscosupplementation involves injecting hyaluronic acid which is characterised by both viscous and elastic properties. These characteristics allow the synovial fluid within the joint to function when shearing forces are applied [29]. This therapeutic modality is designed to restore viscoelasticity of synovial hyaluronan, decrease pain, improve mobility and restore the natural protective functions of hyaluronan in the joint [30].
Viscosupplementation for OA was developed in the 1960s by Balazs and Denlinger [31] and is safe and efficacious [32].
Viscosupplementation as a treatment for knee OA has been studied on many occasions which has subsequently led to a Cochrane review in 2016 which stated “viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period” [30].
A systematic review in 2016 which evaluated the efficacy of viscosupplementation in patients with OA of the ankle found IA hyaluronic acid is a safe treatment modality that significantly improves functional scores of patients, there was however only 5 articles which were included in this review [29].
An interesting study by Hashemi, Madadi [23] which compared intra-articular hyaluronic acid injections Vs. dextrose prolotherapy in the treatment of osteoarthritic knee pain found that intra-articular injections of 25% dextrose prolotherapy could be as effective as hyaluronic acid injections for the treatment of knee pain due to OA.
Clinical Experience & Commentary
Viscosupplementation injectates are classed as a medical device and are therefore accessible to all podiatrists. The costs for these products can potentially be a hindrance for some patients and colleagues alike. Although there are many viscosupplementation injectates on the market I must confess to only using the Ostenil® range of products. I also no longer inject viscosupplementation as a one-off injection, it is always following a PRP or biotherapeutic injections. I find that viscosupplementation when combined with another treatment modality can enhance patient outcomes.
Platelet-rich plasma (PRP)
Biological treatments such as platelet-rich plasma (PRP) have been studied and advocated for OA [33]. PRP is an autologous blood product that comprises an elevated concentration of human platelets. Once injected theoretically PRP stimulates the distribution of growth factors such as platelet-derived growth factor, growth factor-β, type I insulin-like growth factor and vascular endothelial growth factor [34].
Numerous studies have shown that PRP could potentially be efficacious for knee OA [35], [36]. Ankle OA is more common than hip or knee OA in a younger demographic; with a prevalence of 3.4% [37]. PRP for ankle OA has been shown to be safe and can improve quality of life of recipients [38].
However the recent RESTORE Randomized Clinical Trial findings did not support use of PRP for the management of knee OA [39]. This is a really interesting study which is well designed with blinding and MRI pre and post assessment. The primary outcome found that PRP did not modify cartilage however secondary outcomes suggested that there was an improvement in pain results. Although this study has not recommended PRP for OA disease modification (i.e. cartilage regeneration) several systematic meta-analysis reviews have shown benefit for this modality for OA [40]. If one was critical of the studies involving PRP for OA it would be fair to state that differing methods in both preparation and methodological protocols may affect the risk of bias within these studies [41]. There also remains a high degree of inconsistency between PRP preparation systems with a systematic review reporting that only 11.5% of studies reported the variables to repeat study protocols [42].
The safety profile for PRP is advantageous. Studies have indicated that PRP is safe and efficacious for OA with common adverse effects including moderate pain, swelling and mild effusion that can potentially last a few days [43].
PRP is prepared by withdrawing peripheral blood from your patient and subjecting the sample to centrifugation to acquire a highly concentrated sample of platelets. There are differing methods of preparing a PRP sample with either one-step or two-step-centrifugation protocol.
Clinical Experience & Commentary
Podiatrists that wish to offer this treatment modality to patients need to be proficient in phlebotomy to acquire a blood sample from patients. Continual professional development courses are readily available however in my opinion it is a demonstrable failure of our profession that podiatry undergraduates are not taught phlebotomy. Beauticians with little to no medical knowledge have acquired this skill for so called “vampire facials” yet the podiatry profession has somewhat lagged behind with what is a basic procedure once taught correctly.
Various PRP kits are available on the market which can be confusing for colleagues when deciding which is the most suitable. A centrifuge is also needed for the treatment protocol, these have recently reduced in cost and are affordable for most podiatrists.
I regularly provide PRP to patients in clinic for knee and ankle OA utilising the Raeissadat protocol of two IA injections 3 weeks apart. Outcomes have been beneficial however some patients are reluctant in having blood taken which should be taken into consideration as patients having vasovagals in clinic can be rather inconvenient and troublesome.
Biotherapeutic and Homeopathic preparations
Although there are many biotherapeutic and homeopathic injectable preparations available on the market for OA, the combination of two particular products will be the focus of this section. Traumeel® and Zeel® have been available worldwide for over 20 years and have been shown to be effective for musculoskeletal injuries [44] and OA [45] [46].
Each of these products are a composite of 14 ingredients of plant and mineral origin [47]. Studies have reported that both products can potentially have an anti-inflammatory [48] [49] and antioxidative [50] effect.
It has been reported that Zeel® mediated inhibition of the pathways involving the enzymes cyclooxygenase-1 and -2, and also the 5-lipoxygenase pathways which consequently reduced levels of both eicosanoids and leukotrienes which are the two classes of molecules partly responsible for arthritic pain and inflammation [49].
In a double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered IA injections of Traumeel® and Zeel® for treatment of painful osteoarthritis of the knee reported significant pain relief compared to saline-control throughout the observation period. Treatment effect sizes were clinically relevant and the safety profile was benign [46]. Subjects in this study received one injection per week for three consecutive weeks. The homeopathic injection group with Traumeel® and Zeel® had statically significant improvements in all parameters with no serious adverse events being reported.
Clinical Experience & Commentary
Both Traumeel® and Zeel® are readily available without a prescription and are relatively cost effective with little to no reported adverse effects. The study by Lozada, del Rio [46] provided an evidence based rationale for this modality. A cursory audit of my 2021 procedures indicates that I have used this modality a total of 94 occasions for patients with OA with favourable patient outcomes.
I often hear incomprehensible sounds with the mere mention of homeopathy to my colleagues; the word almost feels like heresy to some! Podiatrists risk being called every pejorative under the sun if you support homeopathic preparations which by the way have been established as early as 400 B.C (not really a new kid on the block!). Homeopathic treatment grew acceptance in Europe and The United States with the Royal London Hospital for Integrated Medicine being founded as the London Homoeopathic Hospital by Dr Frederick Foster Hervey Quin in 1849. However, the popularity of homeopathy faded around the world with the NHS no longer offering homeopathic medical treatments which seems on the surface ill-considered as a blanket ban on “all homeopathic” treatments is rather perplexing. In my opinion targeted restrictions on homeopathic treatments that have a poor evidence base may have been prudent and conversely homeopathic treatment options such as Traumeel® and Zeel® with a growing body of evidence should be promoted as an alternative to corticosteroid injections with patients who are either not suitable candidates or to offer patient choice.
Riley, Fischer [51] is a study I often find myself quoting to colleagues which is not directly related to OA but does highlight the potential role of homeopathy in the primary care setting. An international multicentre, prospective, observational study with a sample size of 500 patients found that homeopathy appeared to be at least as effective as conventional medical care. One could make the case that potential positive outcomes for our OA patients combined with the do no harm Hippocratic oath makes homeopathic interventions a viable alternative in some cases.
Mesenchymal stem cell (MSC) Injections
The new kid on the block is mesenchymal stem cell (MSC) therapy which is a treatment option for OA and has high expectations.
Proponents of this modality have hypothesised that stem cells have immunomodulatory and anti-inflammatory properties [52] and it is claimed that they can stimulate the process of cartilage regeneration to affect the long affects for patients with OA [53]. It has been reported that activated MSCs are adept at modifying the immune response locally by selectively inhibiting the proliferation of immune cells.
Lamo-Espinosa, Mora [55] compared a single MSC IA injection combined with hyaluronic acid to hyaluronic acid alone in the treatment of knee osteoarthritis found that the combination of MSC and hyaluronic acid was more effective at the 12 month follow up.
An interesting study which has made bold claims is Lu, Dai [56] which was prospective, randomized, double-blind, phase IIb clinical trial which involved 53 patients that were either randomised to receive either human adipose-derived mesenchymal progenitor cells (haMPCs) or hyaluronic acid knee injection. MRI evaluations were completed at screening and week 48. Knee cartilage volume (including the femur, tibia, and patella) was graded by two blinded, independent radiologists. This study reported that significant improvements in joint function, pain, quality of life as well as cartilage regeneration.
A systematic review of autologous stem cell therapy in knee osteoarthritis which examined 14 RCT’s found a positive effect of autologous MSC therapy compared with control treatments on patients-reported outcome measures, and disease severity however the certainty of this evidence was low to very low [57].
Clinical Experience & Commentary
Access to MSC therapy is limited and costs are excessive with some suppliers retailing MSC at over £1000 per vial. In my opinion this makes this treatment option not viable for the vast majority of patients. However, I am hopeful that MSC therapy will be more accessible with time and further research.
Summary
Patient preferences should be considered before any intervention we provide our patients. This is particularly evident as studies have reported that patient preferences can correlate to the success of the outcome of any intervention through psychological factors concerning the effectiveness of the intervention [58]. The psychological factors that affect patient preference for a particular intervention can be complex and could potentially include on several factors, including speed and degree of pain relief, symptom recurrence, functional disability, consistency of effect, ease of administration, and adverse events [59]. A study to investigate patient preferences for osteoarthritis treatment found the attributes significantly influencing treatment preference included the risk of experiencing serious treatment-related adverse events [60]. It therefore seems prudent to consider patient preferences to encourage adherence [61].
In theory a podiatrist should serve as a conduit to disseminate impartial evidence-based information to the patient in a framework that can be easily understood. In reality often the personal preferences of the podiatrist when speaking to patients concerning possible interventions can inadvertently play a role in informed patient consent and preference. This paradoxical situation, many find themselves in during patient consultations is difficult to reconcile but I feel as clinicians we should provide our patients with the advantages and disadvantages of each injection intervention for OA and allow the patient to make a decision based on informed consent without letting the clinician’s personal preferences interfere in this process.
Finally, I feel I need to enter a virtual podiatry confessional box and state dear podiatry world forgive me for I have sinned. I have a natural proclivity towards regenerative and homeopathic injectables. Of course, this is rather tongue and cheek of me however the growing body of evidence, individual clinician experiences coupled with positive patient outcomes indicates that podiatrists should at least consider alternatives to corticosteroids for OA of the foot, ankle and knee.
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