Pathophysiology

• Osteoarthritis (OA) is the most common form of arthritis occurring in knees, hips, spine, and hand joints. ^[1] OA is characterised by several compounding processes that facilitate the progressive deterioration of joint structures (Figure 1). ^[2]
• Dysfunctional changes within subchondral bone, articular cartilage, synovial membranes and meniscal cartilage are the principal drivers of OA. ^[3] Central to this is the inability of chondrocytes to maintain homeostasis between the degradation and synthesis of extracellular matrix[*] (ECM), which is required for the maintenance and regeneration of joint tissues. ^{[4] ,[5]}
• When trauma to cartilage produces high levels of damage-associated molecular proteins (DAMPs) as a result of mechanical stress, this overwhelms the ability of local macrophages to eliminate damaged ECM fragments. ^[6],[7] These in turn become mediators of inflammation that stimulate chondrocytes to release degradative protease enzymes and proinflammatory cytokines, including tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-1) and IL-6. ^[8]
• These cytokines bind to chondrocyte receptors, triggering the release of metalloproteinase enzymes (MMPs) that degrade cartilage, as well as inhibiting type II collagen production; accelerating cartilage loss. ^[9]
• This weakens the collagen network due to decreased synthesis of type II collagen, causing additional mechanical damage and further increasing breakdown of pre-existing collagen. ^[10]
• These events perpetuate the inflammation of synovial membranes, triggered by the secretion of local mast cell mediators (e.g. histamine, cytokines, chemokines and prostaglandins). ^[11] These further provoke the release of ECM-degrading enzymes and reactive oxygen species (ROS) that compound cartilage damage and degradation. ^[12]
• Mast cells may also activate angiogenesis and vascular hyperplasia, as well as the production of nerve growth factor (NGF) which amplifies pain, thereby further compounding osteoarthritic progression and symptoms. ^[13],[14]
• Under these conditions, perpetual meniscal degeneration also occurs. This diminishes the ability of meniscal structures to withstand loading and force transmission during local joint movements, leading to further degenerative tears and inflammation. ^[15]
• The restoration of joint cartilage is difficult to achieve due to the perpetual nature of OA, and the amplification of mechanical stress from joint degradation. ^[16] Current treatments can provide effective pain relief, however have limited efficacy on disease progression. ^[17]

Figure 1: Vicious cycle of mechanically induced inflammation in OA. ^[18]

Key: DAMPs – Damage-associated molecular proteins.

Key Drivers:

• Mechanical stress: Mechanical joint injury or overuse, joint malalignment, and dysplasia are the most prominent drivers in OA. ^[21] Chondrocytes have several mechano-sensing mechanisms and can perceive loads above a defined threshold as injurious. Excess joint loading results in chronic cartilage catabolism and degeneration. This can occur when abnormal loads are sustained by a normal joint (e.g. increased mechanical stress due to obesity, repetitive occupational loads, or increased load due to structural joint malalignment). Mechanical stress also occurs when normal loads are experienced by a joint that has lost its mechano-protective mechanisms (i.e. loss of muscle support, joint destabilisation due to ligament damage, cartilage weakened by previous arthritis etc.). ^[22]
• Ageing: As part of the ageing process, the ability to reduce the impact of joint loading during normal activities is reduced by loss of muscle mass (e.g. quadriceps strength across the knee), loss of gait reflexes, and poor response times. ^[23] Joint tissue also becomes less flexible because of increased ECM cross-linking, and this influences how joints respond both to physiologic and injurious mechanical load. Cellular ageing also changes the metabolic phenotype of the cell, making it more susceptible to free radical-induced damage, driving cell death or cellular senescence. These features likely contribute to a reduction in regeneration potential with age. ^[24]
• Obesity/Metabolic dysfunction: Obesity contributes to OA that affects the knee and hip joints through mechanical overload, as well as poor joint muscle support as a result of sedentary behaviour. ^[25],[26] Excess adiposity is also associated with increased systemic inflammation driven in part by inflammatory cytokines that may further compound chronic inflammation within OA. ^[27] In patients who are overweight (i.e. body mass index [BMI] >25 kg/m ²) or obese (BMI>30 kg/m ²), a minimum weight loss target of 5% to 7.5% of body weight is recommended to improve OA outcomes. ^[28]
• Inflammation: Chronic inflammation, characterised by prolonged and maladaptive production of inflammatory mediators, can perpetuate oxidative stress, resulting in a proinflammatory environment that may contribute to progressive tissue damage. ^[29] This may further exacerbate inflammation via production of mast cell mediators and ROS, promoting inflammation and cartilage degeneration.

Signs and Symptoms: ^[19],[20]

Red Flags:

• Septic arthritis: Abrupt onset of swelling, erythema, and warmth over affected joint (most commonly the knee, hip, or shoulder) with such intense pain that movement is often impossible, indicates infectious complications to OA. Refer patient to General Practitioner for joint fluid analysis, including leucocyte count, gram stain, polarizing microscopy, and culture to confirm diagnosis and to initiate appropriate treatment. ^[30]
• Anxiety and depression: Chronic pain associated with OA negatively influences the stress response, predisposing patients to anxiety and low moods. The amygdala, responsible for the expression of fear, aggression and defensive behaviour, activates the hypothalamic-pituitary-adrenal (HPA) axis. Severe stress with chronic amygdala activation can lead to lasting structural changes including enlargement of the amygdala and shrinkage of the hippocampus, causing dysfunction, a predisposition to anxiety and mood disorders, and a loss of emotional resilience. ^[31] Use the DASS and the Mood and Stress Questionnaire to assess the patient’s mental wellbeing and refer to a General Practitioner or Psychologist experienced in managing chronic pain where indicated.

Additional Considerations

For heightened sensitivity to chronic pain:

Highly Bioavailable Palmitoylethanolamide (PEA) with Endocannabinoid Action

Dosage: Take 1 capsule twice daily.

Highly bioavailable palmitoylethanolamide (PEA), providing endocannabinoid-like actions to support pain relief, including nerve pain, while also providing neuroprotection and anti-inflammatory assistance to OA patients.

Mechanism of Action/Clinical Research:

• PEA is an endocannabinoid-like lipid mediator influencing a variety of receptors and immune cells to provide anti-neuroinflammatory, analgesic and neuroprotective actions. PEA is endogenously produced in the body, with levels declining during chronic disease, tissue damage, inflammation, pain syndromes and ageing. ^[67]
• From indirect actions on cannabinoid 2 receptors (CB2) receptors, PEA regulates mast cell activity and modulates mast cell phenotypes, ^{[68] , [69], [70], [71]} shifting their phenotypic expression from activated to resting. ^[72] PEA further inhibits mast cell migration and degranulation, blocking the release of histamine, prostaglandins and TNFα. ^[73]
• PEA has an association with the endocannabinoid system (ECS) and key bioactive endocannabinoids, anandamide (AEA) and 2- arachidonoylglycerol (2-AG).The ECS regulates an array of physiological functions in the body, ^[74] with imbalances contributing to the development of several psychological and neurodegenerative disorders. ^{[75] , [76], [77]}
• PEA supports the ECS via directly modulating endocannabinoid signalling (via receptor expression of PPARs or orphan G protein-coupled receptor [GPR55] or G protein-coupled receptors [GPCR]) and indirectly activating transient receptor potential vanilloid receptor type 1 (TRPV1) and cannabinoid receptors (i.e. CB1, CB2). ^{[78] , [79], [80]}

Specialised Pro-Resolving Mediators ^[†]

Specialised pro-resolving mediators (SPMs) to resolve systemic inflammation, which is associated with progressive joint disease and immune dysregulation.

Mechanism of Action/Clinical Research:

• SPMs encourage resolution by regulating macrophage polarisation. SPMs trigger the switch from proinflammatory M1 macrophages to anti-inflammatory M2 macrophages, reducing inflammation and tissue damage, and promoting resolution. Additionally, M2 macrophages have been shown to inhibit polymorphonuclear neutrophils (PMNs) and promote efferocytosis and tissue repair. ^[81]

Supportive Programs

The Metagenics Shake It Practitioner Weight Management Program is designed to help patients comfortably transition from a hypercaloric diet to a hypocaloric diet, facilitating sustainable weight loss while also improving insulin sensitivity and optimising metabolic function. This in turn can reduce loading weight on hip and knee joints, and lower systemic inflammation associated with obesity. Weight loss in adulthood reduces risk for radiographic and symptomatic osteoarthritis. ^[82] Full instructions and food lists are available for free download.

The Metagenics Clinical Detoxification Program is designed to reduce toxic burden, increase toxin resilience and improve the efficiency of waste elimination. In particular, the Gut Pathogen Elimination Detoxification stream may be used to address gut dysbiosis and intestinal permeability, whilst the Liver Chemical Clearance Program may support the elimination of toxic metals that may exacerbate chronic inflammation in OA.

Diet and Lifestyle Recommendations

Diet:

• If patient is overweight or obese, successful weight loss may be achieved using either a hypocaloric ketogenic-style diet or a low-fat diet outlined in the Metagenics Shake It Practitioner Weight Management Program:
  • Both dietary options feature adequate protein for satiety, increased thermogenesis (i.e. promoting fat burning) and to help maintain lean muscle mass.
  • Both of these diets emphasise the minimisation of refined starches, sugar, and saturated and trans-fatty acids, which are generally of poor nutritional value. Further, due to their inflammatory nature, these may cause an activation of the innate immune system by excessive production of proinflammatory cytokines. ^[83] This may negatively influence inflammation caused by OA, and potentiate degenerative processes within afflicted joint tissues.
  • If patient is not overweight or obese, a Mediterranean style diet is recommended to minimise intake of inflammatory foods and compounds.
• Current evidence suggests that the Mediterranean diet provides protection against several diseases associated with inflammation and immune activation. ^[84]
• The Mediterranean diet is inclusive of a high intake of fruits and vegetables, lean protein, quality essential fatty acids, and wholegrains (limiting starchy grains and vegetables).
• The Metagenics Wellness Diet reflects the wholefood principles of the Mediterranean diet and provides a simple guide to moderate portion size and the overall balance of macronutrients.

Lifestyle-based therapies:

• Consider manipulation (i.e. self-massage), transcutaneous electrical nerve stimulation (TENS) machines, and stretching as adjuncts to core treatments, particularly for OA of the hip. ^[85]
• Bracing and splinting can help support painful or unstable joints. ^[86]
• Subtalar strapped lateral footwear insoles and medial wedge insoles may be conditionally recommended for valgus and varus knee OA respectively. ^[87]
• Application of local heat and cold may be used as an adjunct to primary treatment modalities. ^[88]
• Acupuncture has been shown to assist with management of symptoms of OA. ^[89]
• Using a cane of other walking devices may be appropriate for some people with knee or hip OA.
• Cognitive behavioural therapy (CBT) may also be supportive in OA patients to address mental or emotional distress caused by OA symptoms. ^[90]

Exercise:

• Physical activity provides pain relief, improves physical function and quality of life without concern of worsening the condition for exercise less than 10,000 steps daily. ^[91]
• Muscle-strengthening exercises such as walking, Tai Chi, stationary bicycle exercise, gentle yoga or aquatic exercise can safely reduce the pain and disability of knee OA, with accompanying improvements in balance and reduced tendency to fall.
• Increasing exercise in a modest way increases the thickness of cartilage, consistent with a hypertrophic tissue response. However, excessive activity (such as prolonged treadmill exercise or other high-impact activities) can accelerate cartilage degradation and disease. ^[92] As such, Practitioners should educate patients on moderating activities such as running and excessive treadmill exercise.

Clinical Assessment

Footnote

For formulations containing Palmitoylethanolamide (PEA) - This medicine is not to be used for more than 21 consecutive days, and may interact with other prescription analgesic medicines.