Obesity and Knee Osteoarthritis: New Insights Provided by Body Composition Studies

Obesity, defined by either increased weight (kg) or BMI, is an unequivocal risk factor for the onset, progression, and symptoms of knee osteoarthritis (OA). Moreover, maintaining an ideal body weight or BMI reduces the risk for the onset of knee OA, and a reduction in either weight or BMI helps alleviate pain and disability in people with established disease. Despite most previous OA studies having examined the weight or BMI as a surrogate measure of obesity, neither measure discriminates adipose from non-adipose mass. Therefore, it is only possible to demonstrate that it is added mass relative to height that predates the risk for the onset, progression, and symptoms of knee OA. Recent studies that have examined measures of body composition and their relationship with joint structure offer new insights into the pathogenesis and potential treatment of knee OA. The emerging data suggest that whereas increased adipose mass has a deleterious effect on joint health and increased non-adipose mass benefits tibiofemoral joint health in people without established knee OA. This discussion reviews the available evidence regarding obesity and the development of knee OA. Furthermore, new perspectives into the obesity–OA relationship are discussed in the context of recent findings from body composition studies. Osteoarthritis (OA) is the third leading cause of disease burden, measured as disability-adjusted life years, in the developed world and is predicted to increase over the coming decades ((1)). In addition to being a painful and disabling condition, OA incurs substantial costs to the community in terms of work absences, contacts with health professionals, drug treatment, and surgical procedures ((2)). In the Unites States in 2003, the cost of arthritis and other rheumatic conditions was estimated at 1.2% of gross domestic product ((3)). In similar to that, in Australia in 2004, the cost of arthritis was estimated at 1.4% of gross domestic product ((4)). Of the spectrum of the arthropathies, OA was by far the major contributor to the direct and indirect costs of arthritis and other rheumatic conditions ((3),(4)). Obesity is arguably the most important modifiable risk factor for the onset, progression, and symptoms of knee OA ((5),(6),(7),(8),(9),(10),(11)). Maintaining an ideal body weight has been shown to reduce the risk for the onset of knee OA ((8)), and reducing the BMI helps reduce pain and increase function in people with established disease ((12),(13)). Despite these findings, the association between obesity and joint disease is not mechanistically well understood. Measures of central adiposity, such as waist circumference and waist-to-hip ratio, are better predictors of major public health problems such as diabetes and cardiovascular diseases than the BMI ((14)). In contrast, most available data have suggested that fat distribution does not affect the risk of developing knee OA ((15),(16),(17)). Studies that have examined the obesity–OA relationship have predominantly used either the BMI (kg/m2) or weight (kg) as a surrogate measure of obesity ((8),(9),(10),(11),(18),(19)). However, a limitation of either weight or BMI is that these measures do not discriminate adipose from non-adipose mass ((20)). Therefore, it is only possible to determine whether added mass relative to height effects the risk for the onset, progression, and symptoms of knee OA. It is unclear whether it is weight per se, or the specific components of body composition, such as fat mass or fat-free mass, which are associated with knee OA. Determining which components of body composition are associated with knee OA may provide potential pathways to understanding the pathogenesis of the disease, as well as more focused management strategies for the prevention and treatment of knee OA. Recently, several studies have examined the relationship between knee joint structure and body composition measures in both healthy and arthritic states. This discussion reviews the available evidence regarding obesity and the development of knee OA. Furthermore, new perspectives into the obesity–OA relationship are discussed in the context of recent findings from body composition studies. Cross-sectional and longitudinal studies have consistently demonstrated an association between obesity, measured by weight or the BMI and the prevalence and incidence of knee OA ((7),(8),(9),(10),(11),(15),(18),(19),(21),(22),(23),(24),(25)) (Tables 1 and 2). For instance, the risk for knee OA was increased by ∼15% for each additional kg/m2 unit increase in people whose BMI was >27 ((18)). Moreover, the first National Health and Nutrition Examination Survey demonstrated that the risk for knee OA was increased almost fourfold in obese women and 4.8-fold in obese men ((18)). Cross-sectional twin studies have demonstrated that a twin with tibiofemoral and patellofemoral OA is likely to be 3–5 kg heavier than their co-twin ((21)). Some of the strongest evidence implicating obesity as a risk factor for knee OA is derived from the Framingham Study ((7)) (Figure 1). This cohort study (n = 1,420), which assessed weight at baseline between 1948 and 1951 and the presence of knee arthritis at follow-up between 1983 and 1985, found that for men, the risk of developing knee OA was increased in those in the heaviest quintile of weight in young adulthood, compared with those in the lightest three quintiles (age-adjusted relative risk, 1.51; 95% confidence interval (CI) 1.14–1.98). For women in the most overweight quintile in young adulthood, the relative risk was 2.07 (95% CI, 1.67–2.55) ((7)). Furthermore, the Framingham Study demonstrated that higher baseline BMI increased the risk of incident radiographic knee OA (odds ratio (OR) = 1.6 per 5-unit increase, 95% CI 1.2–2.2) at a 7–10 year follow-up assessment in the elderly, and that weight change was directly correlated with the risk of radiographic knee OA (OR = 1.4 per 10-lb change in weight, 95% CI 1.1–1.8) ((9)). Likewise, data from the Chingford study demonstrated that middle-aged women in the top tertile of obesity (BMI > 26.4 kg/m2) had significantly increased risk of incident knee osteophytes (OR 2.38, 95% CI 1.29–4.39) ((19)). : A potential disease paradigm for factors mediating the role of obesity in the development of knee osteoarthritis. CRP, C-reactive protein; IL-1, interleukin 1; IL-6, interleukin 6; TNF-α, tumor necrosis factor-α. Given the unequivocal relationship between obesity and the risk of radiographic knee OA, it is not surprising that a reduction in BMI has been shown to reduce the risk for the development of radiographic knee OA ((8)). When 64 women with confirmed radiographic knee OA were compared with women without the disease, a reduction in the BMI of two or more units over the 10 years before follow-up decreased the odds for developing knee OA by >50% (OR 0.46; 95% CI 0.24–0.86) ((8)). Women with a high risk for OA, defined by elevated baseline BMI (>25 kg/m2), also decreased their risk for the onset of OA by weight-loss of two or more BMI units (OR 0.41) ((8)). Despite evidence demonstrating that weight loss helps reduce the risk for the onset of radiographic knee OA ((8)), no randomized controlled trial has examined the effects of weight loss programs in people with established radiographic knee OA. Therefore, despite international bodies, including the American College of Rheumatology, recommending weight loss for the management of OA ((26),(27)), it is unclear whether weight loss helps prevent or delay the progression of knee OA. Obesity has been shown to compound knee pain and lead to activity limitations and the risk for knee joint replacement ((5),(6),(28),(29)) (Table 3). In people without established knee OA, it was demonstrated that knee pain was significantly greater among individuals with increased body weight compared to those with lower body weight, in both affluent and poor socioeconomic classes ((6)). In the context of knee OA, a 10-year longitudinal study demonstrated that the relationship between BMI and the incidence of developing disabling knee OA is linear ((5)). One potential mechanism thought to contribute toward the association between disability-derived knee pain and obesity, is the finding that obese individuals demonstrate attenuated dynamic balance performance, and that poorer balance is associated with higher pain scores in the presence of weaker knees ((28)). It is important to note that one of the most clinically significant associations between obesity and disabling knee OA is the final risk for knee joint replacement ((29)). A recent study demonstrated that there was a strong dose–response relationship between increasing BMI and knee replacement procedures. In males, the highest OR for knee replacement was for men with a BMI of 37.50–39.99 kg/m2 (OR = 16.40; 95% CI 5, 19–51.86), compared with men with a BMI of 20–22.49 ((29)). In females, the highest OR for knee replacement was for women with a BMI of 40 kg/m2 or more (OR = 19.05; 95% CI, 9.79–37.08), compared with women with a BMI of 20–22.49 ((29)). Given the convincing data indicating that obesity compounds knee pain and disability, it is not surprising that weight loss is consistently associated with a reduction in the symptoms of knee OA ((8),(12),(13),(30)–(33)) (Table 3). For instance, 89% of morbidly obese people with musculoskeletal pain who lost, on average 44 kg, reported a reduction or resolution of pain in one or more joints, including the knee ((12)). Moreover, weight reduction of 10% improved function (as measured by the Western Ontario and McMaster Universities (WOMAC)) by 28% in people with OA ((13)). In Christensen et al. study, this improvement in WOMAC score was noted to be best predicted by a reduction in percentage body fat ((13)), providing evidence that adiposity is an important parameter in the genesis of symptoms. In similar to that, in a weight control program, where 22 subjects with BMI > 26.4 kg/m2 were treated with body weight reducing interventions, such as a low-calorie diet and a walking program, decreasing percentage of body fat was more important than reductions in other indices of obesity, such as body weight, in producing symptomatic relief from knee OA (r = 0.62, P = 0.00013) ((30)). However, moderate physical activity is known to produce symptom relief and benefit knee joint structure ((34)), and it is likely that any reduction in knee pain is due to both a reduction in body fat, as well as the physical activity. Nevertheless, the reduction in body fat does substantiate recent work demonstrating that increased adipose mass rather than non-adipose mass is more detrimental for the health of articular knee cartilage (A.J. Teichtahl et al., unpublished data) ((35)), as highlighted in the preceding discussion. Recently, several studies have examined the association between body composition measures and healthy and arthritic joint structure ((35),(36),(37),(38)) (Table 4). One cross-sectional study that examined 235 Japanese women with knee OA for less than five years demonstrated that lower but not upper limb or total lean body mass was significantly smaller in people with tibiofemoral OA when compared with normal controls (19.2 ± 2.7% vs. 21.0 ± 2.9%; P < 0.0001) ((36)). This may suggest that reduced limb muscle mass is a risk for the onset and/or progression of tibiofemoral OA. Alternatively, a reduction in lower-limb body mass may have been a consequence of muscle atrophy that may have occurred as a consequence of disuse in a painful chronic diseased state. Another study suggested that increased muscle mass and quadriceps strength may protect against the onset of radiographic medial tibiofemoral OA ((37)). We also demonstrated that when healthy adults without established knee OA were examined using magnetic resonance imaging (MRI), total body muscle mass was positively associated with tibial cartilage volume, and increased muscle mass was also associated with a reduction in the rate of loss of tibial cartilage ((35),(38)). The only previous study to have examined the patellofemoral joint demonstrated no significant association between fat-free mass and patella cartilage volume in healthy adults (A.J. Teichtahl et al., unpublished data). Such findings infer that the relationship between muscle mass and cartilage volume may differ between the tibiofemoral and patellofemoral compartments of the knee. In general, increased muscle mass appears to benefit the amount of cartilage at the knee, particularly at the tibiofemoral compartment. Although fat distribution does not affect the risk of developing knee OA ((15),(17),(39)), total fat mass appears to be detrimental to articular cartilage. In healthy adults, greater fat mass increased the risk for the presence of articular cartilage defects at the tibia ((35)) and the patella (A.J. Teichtahl et al., unpublished data). Cartilage defects have been associated with a longitudinal loss in cartilage volume, inferring that the defects represent early cartilage abnormalities that may predate clinical OA ((39)). However, because these studies have examined people without clinical or radiographic knee OA, it is unclear whether fat mass is associated with a reduction in articular cartilage volume in the presence of disease. In people with established OA, decreasing body fat was more important than reductions in other indices of obesity, such as body weight, in producing symptomatic relief from knee OA ((30)). Further longitudinal work is required to help better understand the relationship between body composition and the onset and progression of knee OA. The limited data derived from people without established knee OA indicate that whereas fat-free mass benefits cartilage health, fat mass appears to affect articular knee cartilage adversely, and may be more of a determinant of deleterious change in woman than in men (A.J. Teichtahl et al., unpublished data) ((35),(38)). Therefore, the limited data have indicated that it is adiposity, rather than simply “added body mass” that is detrimental to the knee joint. Weight loss programs that aim to reduce fat mass preferentially while maintaining muscle mass may provide the best approach for reducing the risk of knee OA. Although the mechanism by which obesity influences the pathogenesis of OA is unknown, metabolic and biomechanical hypotheses have been proposed. biomechanical Mechanism For Knee Oa. Biomechanical Factors May Mediate The Association Between Obesity And Knee Oa. Nevertheless, The Mechanical Hypothesis Has Received Little Attention In Epidemiological Studies. Although the knee adduction moment, which predisposes increased medial tibiofemoral joint load during dynamic tasks such as walking, is one of the most important biomechanical variables associated with knee OA ((41)), no study has examined its relationship with obesity. Nevertheless, it is plausible that added weight increases joint reaction forces, which may adversely affect joint structure. For example, the knee adduction moment has been associated with the size of the medial tibial plateau ((42)), although it is unclear whether obesity may have mediated this relationship. At the patellofemoral joint, increasing degrees of knee flexion increase retropatellar load, and it has been estimated that at 60 degrees knee flexion, retropatellar load may exceed 3.3 times total body weight ((43)). In obese individuals, the effect of added mass may stress articular cartilage beyond biological capabilities, causing degenerative changes. The implications of the recent discovery of mechanoreceptors at the surface of chondrocytes, whose activation may result in the expression of cytokines, growth factors, and metalloproteinases, with mediators such as prostaglandins and nitrous oxide being produced, are not yet fully understood, but may ultimately result in oxidative stress and initiate inflammation at the joint and induce tissue breakdown ((44),(45)). Obesity may be an important biomechanical mediator of detrimental mechanocellular transduction mechanisms that contribute to the onset and progression of OA. Whether it is by this mechanism that obesity contributes to the risk of knee OA is at this stage, purely speculative. Although dynamic measures, such as the knee adduction moment, have received little attention in the context of obesity, the relationship between obesity and knee malalignment in the pathogenesis of OA is of growing interest. In a study examining adults with knee OA, 154 patients demonstrated genu varum alignment, while 115 had genu valgum alignment. Among these individuals, the severity of radiological OA, as measured by the amount of joint space narrowing, was related to the BMI in those people with varus (r = −0.29, P = 0.0009), but not valgus alignment (r = −0.13, P = 0.17) ((46)). Moreover, the partial correlation between BMI and OA severity, controlling for sex, was reduced from 0.24 (P = 0.002) to 0.04 (P = 0.42) when varus malalignment was added to the model, demonstrating that almost all of the effect of the BMI on medial tibiofemoral disease severity was explained by varus malalignment ((46)). Similarly, Felson et al. found that the effect of BMI in knee malalignment influenced the progression of radiographic disease, but only when knee malalignment was moderate ((47)). Such data provide clear evidence for the role of biomechanical factors mediating the association between obesity and knee OA. Metabolic mechanism for knee OA. The female disparity and increased incidence of postmenopausal onset of generalized OA, as well as the prevalence of disease in non-weight bearing joints, such as the hand, suggest the likely existence of systemic factors in the pathogenesis of OA. Despite this, the majority of studies have not identified a metabolic link between obesity and OA. The Chingford study showed that metabolic factors such as hypertension, hypercholesterolemia, and blood glucose were associated with both unilateral and bilateral knee OA in women, independent of obesity ((48)). However, adjusting for blood pressure, body fat distribution, serum lipids, serum uric acid, and blood glucose has generally failed to reduce the association between obesity and OA, implying that these metabolic factors are not significant mediators of the association between either BMI or adiposity and OA ((16),(17),(18),(49),(50)). Nevertheless, previous studies have predominantly examined metabolic risk factors in the context of radiographic knee OA and few studies have examined joint properties, such as cartilage volume as measured by MRI, as dependent variables. Despite the generally non-significant associations of metabolic variables with obesity and knee OA, it may be that unexamined or unidentified systemic factors mediate the association between obesity and OA. Adipose tissue was previously thought to be a passive store of but is an a of factors, including such as tumor necrosis factor and interleukin 1 as well as such as and of may be in mediating the obesity–OA relationship. For instance, there is that is but one of several that may the pathogenesis of OA This is to the findings of cross-sectional in and in and studies. it has been demonstrated that and are of and have been found at articular cartilage significant of were in the cartilage and osteophytes of people with OA, yet few the cartilage of healthy people Given the evidence that increased fat mass is associated with poor cartilage health (A.J. Teichtahl et al., unpublished data) ((35)), such as may be important in to understand the obesity–OA relationship. It may also be that obesity has an indirect effect in the IL-1, interleukin TNF-α, and C-reactive Although OA is not a it is by inflammation which as is an that is in by by the IL-6, TNF-α, and IL-1, during an and has been found to be elevated in individuals with established OA Recent studies have also demonstrated that both and a role in cartilage in OA The potential to joint in OA from increases in these is there is increasing evidence that OA is not a but a of with a of several factors that may result in a of joint obesity may have a effect on joints, it is possible that obesity may have a metabolic effect on other It may be that obesity predominantly increased stress weight bearing such as the knee, but the effect of obesity on the non-weight bearing of the may be predominantly metabolic It has previously been suggested that OA at non-weight bearing such as the and the of the may be due to metabolic factors related to adiposity ((21)). Obesity, defined by either elevated weight or BMI, is an unequivocal risk factor for the onset, progression, and symptoms of knee OA. The of an ideal body weight or BMI reduces the risk for the onset of knee OA, while reducing weight or the BMI helps alleviate pain and disability in people with established disease. Nevertheless, weight and BMI discriminate adipose from non-adipose mass. Recent studies that have examined measures of body composition and their relationship with joint structure have important increased non-adipose mass appears to benefit joint In increased non-adipose mass appears against the onset of radiographic tibiofemoral OA, as well as a reduced rate of tibial cartilage volume increased adipose mass is associated with an increased risk for the presence of cartilage defects at both the tibiofemoral and patellofemoral compartments in healthy However, because of these findings are derived from studies examining healthy work is required in the presence of disease. Nevertheless, it appears that whereas increased adipose mass has a deleterious effect on joint health and increased non-adipose mass benefits joint health in people without established knee OA. Obesity, measured by either increased weight (kg) or BMI is an established risk factor for the onset, progression, and symptoms of knee OA. of an ideal body weight or BMI reduces the risk for the onset and progression of knee OA. weight or BMI helps alleviate pain and disability in people with established disease. The BMI and weight are both limited by their to discriminate adipose from non-adipose mass. Recent studies that have examined measures of body composition and their relationship with joint structure have important non-adipose mass appears to reduce the rate of tibial cartilage volume and is positively associated with cartilage volume at the adipose mass is associated with an increased risk for the presence of cartilage defects at both the tibiofemoral and patellofemoral compartments in healthy and may be related to a reduction in cartilage volume, particularly in Further work examining the relationship between body composition is both in the presence and of joint disease. The no of interest. is the of a National Health and is the of an Health

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