Physical inactivity and sedentary behaviour
Sedentary behaviour and the rapid growth of legions of video game, social media and movie-streaming addicted couch potatoes is a consequence of sustained and systemic urbanisation in developed countries, including the United States, where nearly 50% of the population do not undertake even the bare minimum levels of aerobic activity recommended by Physical Activity Guidelines [
13]. This rise in sedentary behaviour is seen as a major risk factor for a number of chronic diseases recognised by the National Health Service (NHS), costing around £1billion a year in the UK, and is recognised as a substantial global economic burden [
14]. Statistics recently provided by the Centre for Economics and Business Research show the cost of “doing nothing”: half a million Europeans die every year as a result of being physically inactive and this costs the economy over €80bn annually [
15]. This global challenge requires urgent and feasible solutions. Increasing physical activity and optimising exercise (as recommended by Arthritis Research UK/Versus Arthritis and World Health Organisation (WHO)) is seen as an optimal way to improve musculoskeletal health. Only 36% of the adult population in the UK take part in moderate intensity physical activity of about 30 min at least once a week [
16]. An increasing body of evidence is showing that even the effects of a sedentary lifestyle (for example, of those with a desk job) can be mitigated by a small amount of activity every day. A recent meta-analysis of the data from studies involving over 1 million individuals concluded that an hour of moderate level activity per day eliminated the increased risk of death associated with 8 h of sitting [
17]. Interestingly, the study also found that these levels of activity did not have an effect on the increased risk of death associated with high levels of leisure-time sedentary behaviour such as watching television. Whilst this level of activity is far more than those recommended by WHO, it is clear that keeping a moderate level of physical activity is a key requirement for healthy ageing and maintaining musculoskeletal health [
17]. WHO recommendations suggest that healthy individuals should take around two hours a week of moderate physical activity or approximately 20 min a day of doing any kind of physical activity like brisk walking. This level of exercise, which involves elevation of heart-rate, has been associated with lower lifetime risk of cardiovascular disease in a 25 year longitudinal study of approximately 13,000 adults [
18]. In addition to benefits for musculoskeletal health, improvements in cardiorespiratory fitness can be achieved by changing sedentary behaviour to achieve a low-intensity physical activity such as walking [
19]. Furthermore, in patients with knee OA, improvement of locomotor function, including balance and strength, and a reduction in pain was seen following supplementation of home exercise with an eight-week class-based programme [
20]. Patients suffering with chronic LBP who were given an exercise programme combining muscle strength, flexibility and aerobic fitness also reported a reduction in stiffness, which can result in back pain [
21]. The idea of exercise for rehabilitation of musculoskeletal injuries has been widely accepted for many years now, and the idea of prescribing exercise as a preventative health measure is also more widely investigated, with guidelines around the type, frequency and duration of activity being considered [
22].
Sedentary behaviour is also contributing to the rise in obesity and type-2 diabetes. Obesity is a major contributor to the development and progression of OA [
23] and numerous epidemiological studies have confirmed the link between adiposity and joint degeneration. The prevalence of diabetes mellitus is between 7 and 14% globally [
24]. Diabetes is an important predictor for severe forms of arthritis [
25] and has recently been shown to be an independent risk factor for the progression of OA in men [
26]. This shows that measures to increase levels of physical activity will not only increase musculoskeletal (MSK) health but also decrease the risk of suffering from obesity-related diseases such as diabetes. This will reduce the numbers in the population susceptible to MSK disorders and ill health.
Healthy ageing and physical exercise
Whilst ageing is inevitable, the benefits of exercise on the ageing body are numerous and, in some circumstances, can reduce the manifestations of ageing, particularly the "ageing phenotype" of the elderly. A recent systematic review looked at evidence supporting nutrition and physical activity in the prevention and treatment of sarcopenia [
27]. Sarcopenia results in loss of muscle strength and mass and this can lead to weakening of musculoskeletal structures and impair tendon, ligament, bone and cartilage function, which will destabilise the joint and increase the risk of arthritis and other musculoskeletal disorders. The authors identified a total of 37 randomised control trials to explore the effect of combined exercise and nutritional intervention for overcoming muscle sarcopenia. They concluded that physical exercise has a positive impact on muscle mass and function in healthy subjects aged 60 and above, however, there were huge variations in outcomes connected with dietary supplementation, highlighting the difficulties associated with cohort studies of well-nourished human beings, where the interactive effects of dietary supplementation may be masked or completely limited [
27]. Physical exercise improves muscle performance by increasing the ratio of type I to type II muscle fibres and increasing the cross-sectional area of type II muscle fibres [
28].
A European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) taskforce looked at dietary protein and vitamin D and calcium supplementation and recommended higher protein intake in combination with physical exercise particularly in post-menopausal women at risk of developing menopause-associated musculoskeletal disease, such as OP [
29]. Physical exercise programmes improve strength and balance in ageing women with OP [
30]. Fragility fracture risk, associated with OP, can be decreased by following an exercise programme, as exercise increases bone density and reduces inflammatory markers [
31]. However, the incidence of OP is usually highest in elderly females who are most unlikely to perform the dynamic exercises needed for bone modelling/remodelling [
32]. This highlights the challenge of preventing OP and OP-related fractures in elderly females that cannot perform ballistic exercise. Some medications are available for these frail patients but having an active lifestyle from an early age and following recommendations for exercise could be more beneficial. The same principle applies to frailty in ageing companion animals, where life-long spontaneous exercise significantly slows down the progression of frailty [
33].
Physical activity is also known to increase insulin mediated glucose uptake and, in individuals without type-2 diabetes, exercise positively impacts on systemic glucose homeostasis. However, in patients with type-2 diabetes where beta-cell impairment is significant, physical training does not decrease insulin secretion [
34]. A recent study found that a 30 min daily increment in moderate to vigorous intensity physical activity also significantly reduced glycated haemoglobin, a measure of type-2 diabetes risk [
19]. Physical exercise reduces the risk of cardiovascular and metabolic comorbidities associated with joint diseases.
In addition to the positive effects of exercise on physical and mental well-being, there is also ample evidence to suggest that exercise and mechanical loading have a positive impact at the molecular, cellular and tissue levels. For example, in tendons, where ageing decreases the potential for cell proliferation and number of stem/progenitor-like cells, it has been shown that exercise/loading can induce an increase in tendon collagen synthesis [
35], increasing tendon strength. In an animal model of ageing, it was found that moderate exercise could also enhance the quality of tissue produced during healing of injured tendons [
36]. There is plenty of published evidence to support a positive role for physical exercise and mechanical loading for cartilage [
37] and bone health [
38].
Dietary factors
It is generally accepted that maintaining a healthy weight can help to improve musculoskeletal health and prevent degenerative diseases, but research also focuses on whether dietary factors can influence disease progression. Eating a varied diet high in fresh fruit and vegetables is recommended by many health organisations. A combined regime of exercise and increased intake of fruit and vegetables increased life expectancy in women; those in their 70s with the highest level of activity and vegetable consumption were eight-times more likely to survive a five-year follow up period [
45]. However, few direct links between fruit and vegetable intake and improved musculoskeletal health have been shown but one three year follow-up study of nearly 400 adults showed that diets high in potassium (from fruit and vegetable intake) reduced the amount of muscle loss in adults > 65 years [
46]. Dietary flavonoid intake, the compound found in many fruit and vegetables, was positively correlated with good bone health (measured by bone mineral density and bone resorption) in a population of peri-menopausal women [
47].
As current treatment options in OA are very limited, OA patients may benefit from the ability to self-manage their condition through improving their diet [
48]. Vitamin D, calcium and protein (particularly protein) optimise muscle, bone and functional outcomes in older people reducing falls and fractures [
49]. Calcium and protein intake work together to optimise bone health [
50]. Previously, it was thought that, in older patients, diets too high in protein should be avoided due to the detrimental effect on the kidneys. However, increasing evidence now shows that protein levels should not be decreased, as the effects of metabolic acidosis on the kidneys can be offset by increased fruit and vegetable intake (as these foods decrease renal acid load) [
51,
52].
Several studies recommend the benefits of supplementing the diet with “nutraceuticals”. A recent systematic review found promising but nevertheless limited research evidence to support the oral use of several herbal supplements including
Boswellia serrata extract and pycnogenol, curcumin and methylsulfonylmethane in people with OA despite the poor quality of the published studies [
53]. Dietary strategies for improving musculoskeletal health can include consumption of long-chain fatty acids and vitamins D and K [
54,
55] as well as decreasing blood cholesterol [
56]. OA patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K, which has a role in bone and cartilage mineralization. However, the currently available evidence for a role of vitamin D supplementation in OA is unconvincing [
48]. Research has focussed on a number of dietary supplements to modulate progression of the disease or ease joint stiffness (and therefore pain). A diet rich in antioxidants may provide a useful therapeutic tool for athletes, improving tissue repair, although the optimum dosage is unknown [
57]. Combining exercise with a dietary supplement of whey protein fortified with vitamin D is effective at increasing muscle mass and strength in elderly people affected with sarcopenia [
58].
Both human and veterinary research has shown promise for a number of other natural products or compounds derived from natural sources for alleviation of arthritic symptoms. Green-lipped mussel extract has been shown to be an effective chondroprotective agent [
59], reducing OA symptoms in dogs with OA [
60]. More recently, fish oil and krill oil have been found to have even greater protective effects against proteoglycan and collagen degradation in an in vitro model of canine arthritis [
61]. These substances are all known to be rich in long-chain omega-3 polyunsaturated fatty acids. A separate study found that supplementing the diet of dogs with eicosapentaenoic acid and docosahexaenoic acid (both long-chain omega-3 polyunsaturated fatty acids) significantly reduced the clinical signs of OA [
62]. In humans, these substances have also been demonstrated to provide an alternative to anti-inflammatory pain medications for the relief of chronic neck and back pain as well as joint pain in rheumatoid arthritis [
63,
64]. Whilst the molecular mechanism of action of these fatty acids is not entirely understood, it has been shown that these compounds reduce the expression of cartilage-degrading proteases and inflammatory cytokines [
65].
Curcumin is a well-known plant-derived compound with anti-oxidant and anti-inflammatory properties. Its effects have been described in numerous chronic illnesses in humans, including diabetes, allergies and arthritis. It modulates growth factors, transcription factors and inflammatory cytokines [
66]. Interestingly, a recent systematic review, has investigated the efficacy and safety of dietary supplements for OA human patients and found that lesser known supplements such as curcumin from
Curcuma longa and Boswellic acid from
Boswellia serrata were more effective than well-known nutraceuticals, such as glucosamine and chondroitin [
67]. Glucosamine and chondroitin are popular supplements that have been suggested to promote healthy joint function. However, there is little evidence of their benefit [
67]. Glucosamine was recommended in early guidelines issued by the European League Against Rheumatism (EULAR) and the Osteoarthritis Research Society International (OARSI) for the management of knee OA [
68,
69] but it was not recommended in the National Institute for Health and Care Excellence (NICE) guidelines and in the most recent set of OARSI recommendations it was identified as being “uncertain” [
70]. More recent guidelines published by EULAR, OARSI and ACR do not recommend glucosamine.
In vitro evidence for glucosamine is generally good. At relatively high concentrations, glucosamine has been shown to have a protective effect on cartilage and synovial fluid; however many clinical trials have shown that this substance is unable to reach the tissue that it is meant to affect in appropriate and sufficient doses [
68]. Structural heterogeneity of chondroitin sulphate, another supplement commonly taken alongside glucosamine, means that it is difficult to see consistent effects of this supplement, and the supplements available on the market are unlikely to be pure due to contamination with other glycosaminoglycans during the manufacturing process [
71]. There is some evidence that glucosamine and chondroitin sulphate together provide superior effects on the inhibition of nitric oxide and prostaglandin synthesis and on protection of cartilage structure, than when applied alone [
72,
73]. This combination may also be effective with the addition of manganese ascorbate, as shown in patients with knee OA [
74]. However, this is again in an in vitro model, so it is doubtful that these substances would reach the required tissues at an appropriate dose. A small number of studies have found side effects of glucosamine and chondroitin sulphate treatment, which include inducing insulin resistance and glucose metabolism disorders [
75]. There is also concern over the formulation of glucosamine, as it is commonly given as a salt (glucosamine sulphate potassium/sodium chloride) which could affect renal function, particularly in elderly patients, who are arguably more likely to be taking the supplement [
68].
The gut microbiome is also an area of increasing focus for health research. There is an association between The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores of hip and knee OA and the gut microbiome of individuals [
76], so possible future dietary interventions for OA could include maintaining a healthy gut flora. Since dysbiosis of the intestinal microbiota is strongly associated with the pathogenesis of several metabolic and inflammatory diseases, it is conceivable that also the pathogenesis of OA might be related to it. However, the mechanisms and the contribution of intestinal microbiota metabolites to OA pathogenesis are still not clear [
77]. Other foods and food supplements, such as blueberry leaves and milk thistle, have been found to have an anti-inflammatory or anti-oxidant effect in other body systems, however the effect of their function on the musculoskeletal system is yet to be realised [
78,
79].
Other co-morbidities and musculoskeletal disorders
There is increasing awareness of the effects of the pain from musculoskeletal disorders on mental health. A study on the effects of musculoskeletal chronic pain of 5900 individuals (including fibromyalgia or chronic back or neck pain) indicated that they are at increased risk of poor mental health and diminished quality of life compared to those who did not report suffering from these conditions [
80]. Whilst the links between mental health and musculoskeletal disorders are complex, it is thought that living with the pain of OA can lead to depression and anxiety; conversely, psychological distress and depression worsen pain [
81‐
83]. This can develop into a vicious cycle with worsening pain and low mood. An Australian study has found a strong association between musculoskeletal health and mental health; 470,000 more Australians had both a musculoskeletal condition and a mental disorder than would be expected if occurrences of the two conditions were independent of each other [
84]. Chronic insomnia can also indicate musculoskeletal pain, as the two commonly co-occur, and doctors should enquire about sleep patterns in patients consulting with pain conditions [
85].
A significant number of people suffering from OA also have OP, which affects approximately 3 million people in the UK. However, it was found that unless bone mineral density measurements were taken from sites other than the OA affected joints, there was a high likelihood of an osteoporosis diagnosis being missed [
86]. Another musculoskeletal disorder, fibromyalgia, is often associated with chronic fatigue, sleep disorders, irritable bowel syndrome and other psychological disorders, as well as cardiovascular dysregulation [
87].
Chronic musculoskeletal disorders can also aggravate other disease conditions, due to their activity-limiting effects. Where patients are diagnosed with a musculoskeletal condition, it often means that they will have limited mobility or that activity is painful to them. This restriction of movement can then cause other ill health, such as obesity or diabetes, or contribute to the effects of respiratory disease [
88]. For example, in a population of war veterans, arthritis was shown to be associated with diabetes, obesity and cardiovascular comorbidities [
89]. Obesity has also been shown to reduce the efficacy of anti-TNF treatment in rheumatoid arthritis [
90].