Osteoarthritis involves abnormal remodelling of joint tissues driven by inflammatory mediators. Articular cartilage damage is thought to be the earliest process occurring in osteoarthritis, with secondary changes including subchondral bone sclerosis, the formation of osteophytes, bone cyst formation and changes in synovium, joint capsule and ligaments (Goldring and Goldring, 2010). In osteoarthritis, there is upregulation of cartilage degrading proteases (eg matrix metalloproteinases), inflammatory cytokines (including interleukin-1 and tumour necrosis factor-alpha) and prostaglandin E2, resulting in loss of articular cartilage caused by extracellular matrix breakdown. There is also inflammation of synovial fluid with reduced hyaluronic acid and altered viscosity (Kusayama et al, 2014).
Exercise modification
Exercise modification is a key component of managing any horse with pain and lameness caused by osteoarthritis. Older horses benefit from regular, low-intensity exercise rather than box confinement or infrequent intense exercise. Horses should not be overweight, as increased bodyweight has negative effects on osteoarthritis. Exercise should aim to maintain joint range of motion in the affected joints with passive or active range of motion exercises. Passive range of motion can be achieved by manually moving the joint through its full range. Active range of motion can be achieved by using poles, pastern weights and stimulators, or underwater treadmills (Clayton et al, 2010; Mendez-Angulo et al, 2013; Brown et al, 2015). These exercises also improve proprioception, core stability and balance, which are important to reduce the risk of further injury through more coordinated and symmetrical movement.
Benefits of underwater exercise include:
It is important to understand the effect of different water depths on weight bearing. Water at the olecranon level will reduce weight bearing by 10%, while water at the level of the tuber coxae will reduce weight bearing by 75–80% (King, 2016). The effect of water height on joint range of motion should also be considered. Maximal joint flexion and longest stride length are achieved with water at the level of the carpus/tarsus, but there is no effect of buoyancy, viscosity or hydrostatic pressure at this level (Mendez-Angulo et al, 2013). The greatest carpal range of motion is achieved when water is at tarsal depth, and greatest tarsal flexion is achieved when water is at stifle depth (Mendez-Angulo et al, 2013). For conditioning and reduced weight-bearing, water should be at the level of tuber coxae. It is important to decide whether the priority is to reduce load on the limbs or to target joint range of motion when selecting water depth. Horses should begin underwater treadmill exercise using low water depths, and treadmill speed should be decreased as water depth is increased (because of increased drag). It is important to tailor underwater treadmill exercise to each individual horse and ensure the gait quality is closely monitored during each exercise session. The water depth or treadmill speed should be modified as necessary to avoid detrimental changes in gait and posture that may occur with fatigue (Nankervis et al, 2021).
Deeper water increases core muscle activation compared to shallower water. Water at the stifle level will generally cause extension in the cranial thoracic spine and flexion in the caudal thoracic and lumbar spine (this is useful if the horse has impinging dorsal spinous processes from T18–L3, but not if the pathology is more cranial) (Nankervis et al, 2016). Higher water depths can increase pain if the horse has caudal cervical or cranial thoracic issues, so lower water depths should be used in these cases to avoid excessive head elevation. This reinforces the importance of evaluating the whole horse. If the horse has concurrent pathology in the cranial thoracic spine, then work at deep water levels to reduce load on osteoarthritic joints in the distal limb may exacerbate back pain.
King et al (2017) showed significantly reduced synovial membrane inflammation, improved carpal range of motion and more symmetrical thoracic limb loading in horses with mid-carpal joint osteoarthritis exercised on an underwater treadmill compared to control horses exercised on an underwater treadmill with no water. In another study using the same model, underwater treadmill exercise was also shown to significantly improve postural stability (King et al, 2013).
Systemic medications
Anti-inflammatory drugs
Phenylbutazone (4.4 mg/kg) can be used as required in horses with osteoarthritis to reduce pain and inflammation and is especially useful in joints with acute inflammation. Care should be taken in horses with concurrent gastric ulceration. Firocoxib (0.3 mg/kg on day one, then 0.1 mg/kg daily) offers a good alternative in horses with possible gastric disease or when longer term anti-inflammatory drugs are required; there are fewer adverse effects because of the selective inhibition of cyclo-oxygenase-2. While meloxicam (0.6 mg/kg) preferentially inhibits cyclo-oxygenase-2, it usually offers less potent anti-inflammatory action for musculoskeletal conditions (Knottenbelt and Malalana, 2005).
Hyaluronic acid
There are many studies supporting the use of hyaluronic acid, mostly for intra-articular administration. However, it can also be used systemically with an intravenous dose of 40–60 mg. In the carpal chip model of osteoarthritis, administration of intravenous hyaluronic acid (40 mg once weekly for 3 weeks) resulted in improved lameness scores, improved synovial histology and lower concentrations of total protein and prostaglandin E2 in synovial fluid (Kawcak et al, 1997). High molecular weight hyaluronic acid has been shown to provide greater cellular protective effects in synovial cells challenged with lipopolysaccharide when compared to low molecular weight hyaluronic acid, although both molecular weights had similar anti-inflammatory and anticatabolic effects (Santangelo et al, 2007). A study in human osteoarthritis showed that intra-articular hyaluronic acid resulted in reduced pain and improved joint function with no significant difference between low and high molecular-weight products (Gupta et al, 2019).
Benefits
Pentosan polysulphate
Pentosan polysulphate has been shown to reduce articular cartilage fibrillation and increase synovial concentrations of chondroitin sulphate in the carpal chip model of osteoarthritis (McIlwraith et al, 2012). Pentosan polysulphate should be given at 3 mg/kg intramuscularly weekly for 4 weeks – there is no evidence for monthly treatments.
Benefits
Caution
Polysulphated glycosaminoglycan
Polysulphated glycosaminoglycans are registered in the UK for intramuscular use, although the licensed product (Adequan) is not readily available and requires a special import certificate to obtain. A very similar product (Zycan) is more easily available but is not licensed in the UK and therefore also requires a special import certificate. Polysulphated glycosaminoglycans should be administered at a dose of 500 mg intramuscularly every 4 days for 7 treatments. As with pentosan, there is no evidence for monthly maintenance treatments. Intramuscular administration shows some benefit in osteoarthritis in horses. A study using a chemical arthritis model in horses demonstrated mildly increased matrix staining intensity for glycosaminoglycans following administration of 500 mg polysulphated glycosaminoglycan intramuscularly every 4 days for seven treatments compared to controls (Trotter et al, 1989). Another study in 12 horses with chemically-induced osteoarthritis of the mid-carpal joint showed reduced lameness and greater carpal flexion when administered intramuscular polysulphated glycosaminoglycan every 4 days for seven treatments compared to a control group (Verde et al, 2010). Administration of intramuscular polysulphated glycosaminoglycan every 4 days for 28 days had no effect on subchondral bone, serum biomarkers or synovial fluid biomarkers in horses with mid-carpal joint osteoarthritis (carpal chip model) (Kawcak et al, 2011). There is more convincing evidence for intra-articular use, but the drug is not registered for this in the UK.
Benefits
Caution
Bisphosphonates
There is little evidence of a beneficial effect of bisphosphonates in human osteoarthritis progression, but they have been shown to reduce pain (Villatoro-Villar and Kwoh, 2021). There is strong evidence of symptom-modifying effects but weak evidence of disease-modifying effects. Tildren (tiludronate, single intravenous infusion at 1 mg/kg or 0.1 mg/kg daily for 10 days) reduces back pain in horses with osteoarthritis of the thoracolumbar spine (Coudry et al, 2007). It also reduces lameness in navicular disease and distal hock joint osteoarthritis (Denoix et al, 2003; Gough et al, 2010). Osphos (1.8 mg/kg intramuscularly divided between three sites) results in a mild, short-lived improvement in lameness caused by navicular syndrome (Mitchell et al, 2019).
Benefits
Caution
Intra-articular medications
Corticosteroids
Triamcinolone acetonide has been shown to reduce lameness with beneficial effects on synovial fluid, synovial membrane and articular cartilage in the carpal chip model of equine osteoarthritis (Frisbie et al, 1997). There is greater evidence for the use of triamcinolone acetonide because of its disease- and symptom-modifying effects compared to betamethasone or methylprednisolone acetate.
Which corticosteroid should be used?
Benefits
Caution
Hyaluronic acid
The accepted intra-articular dose is 20–40 mg (depending on joint size). Intra-articular hyaluronic acid has been shown to reduce cartilage fibrillation in horses with mid-carpal joint osteoarthritis (carpal chip model), but did not result in any improvement in lameness (Frisbie et al, 2009). Another study comparing two intra-articular injections of hyaluronic acid and polysulphated glycosaminoglycan in lame Standardbreds showed that both products reduced lameness (Gaustad and Larsen, 1995).
There is evidence that hyaluronic acid can mitigate the negative effects of corticosteroids on glycosaminoglycan metabolism by reducing proteoglycan breakdown. However, clinical studies do not reflect this, as triamcinolone acetonide alone has been shown to result in slightly better lameness improvement than when combined with hyaluronic acid (McCluskey, 2007; de Grauw et al, 2016).
Polyacrylamide hydrogel
Polyacrylamide hydrogels (eg Arthramid 2.5%) have been shown to significantly reduce lameness and joint effusion in horses with osteoarthritis, with superior effects to triamcinolone (Tnibar et al, 2015; McClure and Wang, 2017; de Clifford et al, 2019; da Silva Xavier et al, 2021). A blinded study of 49 Thoroughbred racehorses with lameness associated with the mid-carpal or fetlock joints demonstrated a significant improvement in lameness following intra-articular administration of 2 ml of a 2.5% polyacrylamide hydrogel at weeks 1, 12 and 24 compared to baseline at week 0 (de Clifford et al, 2019). A systematic review and meta-analysis summarised that intra-articular polyacrylamide hydrogels result in a greater reduction of lameness for a longer period of time than intra-articular hyaluronic acid in horses with osteoarthritis (da Silva Xavier et al, 2021). Beneficial effects of polyacrylamide hydrogels have also been demonstrated in humans with knee osteoarthritis (Henriksen et al, 2017).
Benefits
Mechanism of action
Water is forced between the polyacrylamide chains, generating a porous biomaterial which maintains its viscoelastic properties. It also integrates into the synovial membrane, producing synovial hyperplasia and creating a matrix for new cells. Following intra-articular injection, the gel is entirely incorporated into the synovium where it lasts for up to 24 months (Tnibar et al, 2017). Arthramid is not an anti-inflammatory, so does not result in the rapid, reduced joint effusion often noted with corticosteroids and may result in increased joint effusion for up to 2 weeks. Time for effect is also longer than corticosteroids, with improvements in lameness usually seen between 3 and 4 weeks after intra-articular injection. Some horses may take up to 6 weeks to respond. In cases of partial improvement, repeat medication is recommended.
Biologics
Platelet-rich plasma
Intra-articular platelet-rich plasma produces similar shortterm results and superior long-term results to corticosteroids or hyaluronic acid in human osteoarthritis (Shen et al, 2017). Combining platelet-rich plasma with low-molecular-weight hyaluronic acid has beneficial synergistic effects (Zhao et al, 2020). Platelet-rich plasma has some beneficial effects (such as modulation of tissue healing and inflammation, potentially leading to reduced lameness) in horses with osteoarthritis (Garbin and Olver, 2020). Leukocyte-rich or leukocyte-poor preparations are available: white blood cells may have both positive and negative effects. Pro-inflammatory cytokines produced by neutrophils are undesirable but monocytes are thought to be beneficial (Everts et al, 2020). Leukocyte-poor preparations are likely a better choice for intra-articular injection into joints with osteoarthritis. Platelet-rich plasma is a good choice earlier in osteoarthritis and is also a good option if soft tissue injuries are present (eg meniscal tears in the stifle or collateral ligament injuries).
Benefits
Autologous conditioned serum (interleukin-1 receptor antagonist protein)
Autologous conditioned serum treatment has demonstrated significant clinical and histological improvement in horses with mid-carpal joint osteoarthritis (carpal chip model), with horses showing reduced lameness and decreased synovial membrane hyperplasia (Frisbie et al, 2007). It has also been shown to significantly improve clinical signs and symptoms of human knee osteoarthritis (Baltzer et al, 2009). Blood is harvested, then incubated over chromium sulphate-coated glass beads for approximately 24 hours, so patient-side preparation is not possible. A course of 3–5 treatments at 1–2 weekly intervals is recommended.
Benefits
Autologous protein solution (Prostride)
While autologous protein solution has been shown to result in significant improvements in lameness, gait asymmetry and joint range of motion in horses with naturally occurring osteoarthritis after a single injection (using two kits per joint) (Bertone et al, 2014). In this study, autologous protein solution was found to be less effective in the presence of severe lameness, severe periarticular osteophytes, subchondral sclerosis or narrowed joint space. In humans, autologous protein solution has been shown to improve pain for up to 3 years in knee osteoarthritis (Vitale et al, 2019).
Benefits
Autologous modified plasma
Products available (eg Alpha2EQ) mostly isolate alpha-2-macroblobulin, which is a naturally circulating acute phase protein found in plasma. Autologous modified plasma has been anecdotally shown to reduce lameness and joint effusion in chronic and acute inflammatory synovitis in sports horses, but unbiased controlled studies are required.
Benefits
Mesenchymal stem cells
Mesenchymal stem cells act on the local environment to stimulate the influx of stem cells and growth factors, which in turn stimulate and modulate the repair of tissue. They have been shown to reduce lameness and have positive effects on synovial fluid (higher viscosity and lower glycosaminoglycan concentration) in horses with surgically-induced fetlock osteoarthritis (Broeckx et al, 2019). Symptom-modifying and disease-modifying effects of intra-articular mesenchymal stem calls in horses and humans remain inconclusive (Kalamegam et al, 2018).
Benefits
Amnion allograf
Amnion allograf (eg Renovo, Strydaflex) contains amniotic fluid and membranes, and is an acellular preparation harvested from healthy mares. It is cryopreserved and may be used intra-articularly or intralesionally. Controlled equine studies are needed to understand its effects on osteoarthritis.
Benefits
The use of intra-articular antibiotics
The addition of antibiotics for joint injections should be avoided because of the chondrotoxic effects of aminoglycosides. Antibiotics are unnecessary for routine joint injections.
Conclusions
Successful management of osteoarthritis involves a multi-modal approach. Systemic medications can help to manage mild cases of osteoarthritis and may also help reduce the frequency that intra-articular medication is required. When deciding which intra-articular medication to use, an accurate diagnosis is essential. Biologics are likely to be better choices earlier in the disease process with platelet-rich plasma, autologous protein solution and mesenchymal stem cells being the best choices if any soft tissue injuries are present. Biologics and polyacrylamide hydrogels are also good options in metabolic horses (that have a higher risk of laminitis with corticosteroids) and in competition horses as a result of having no detection time. Alpha2EQ and interleukin-1 receptor antagonist protein are sensible choices if multiple joints require treatment as one blood collection typically results in 5–6 intra-articular treatment doses. Finally corticosteroids are most cost effective so will often be chosen in cases with financial constraints. Exercise modification and maintenance of joint range of motion are vital in osteoarthritis. Physical therapies including cold and heat therapy, shockwave, laser and joint mobilisation and manipulation can all have beneficial effects. Finally, arthroscopic surgery may be indicated in some cases of osteoarthritis, with potential for therapeutic and diagnostic benefits.