Obesity and the Incidence and Prevalence of Knee OA

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).

Table 1 - Studies examining the relationship between obesity and the prevalence of knee osteoarthritis.

Full table (57K)

Table 2 - Studies examining the relationship between obesity and the incidence of knee osteoarthritis.

Full table (45K)

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).

Figure 1.

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-, tumor necrosis factor-.

Full figure and legend (18K)

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 and the Symptoms 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).

Table 3 - Studies examining the role of weight and weight loss on symptoms and function in knee osteoarthritis.

Full table (88K)

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.

The Relationship Between Body Composition and Knee OA

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.

Table 4 - Studies examining the relationship between body composition and knee joint structure.

Full table (48K)

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.

Potential Mechanisms for Obesity in the Pathogenesis 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 energy but is now considered an endocrine organ, releasing a multitude of factors, including cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL-1), as well as adipokines, such as leptin, adiponectin, and resistin (51). Dysregulation of lipid homeostasis may therefore be crucial in mediating the obesity–OA relationship.

For instance, there is speculation that leptin is but one example of several adipokines that may influence the pathogenesis of OA (52). This is primarily attributed to the findings of cross-sectional in vitro and in vivo and studies. First, it has been demonstrated that osteoblasts and chondrocytes are capable of leptin synthesis and secretion (53,54). Second, leptin receptors have been found at articular cartilage (55). Indeed, significant levels of leptin were observed in the cartilage and osteophytes of people with OA, yet few chondrocytes produced leptin the cartilage of healthy people (53). Given the evidence that increased fat mass is associated with poor cartilage health (A.J. Teichtahl et al., unpublished data) (35), adipokines such as leptin may be important in helping to understand the obesity–OA relationship.

It may also be that obesity has an indirect effect via elevations in the cytokines IL-1, interleukin 6 (IL-6), TNF-, and C-reactive protein (CRP). Although OA is not considered a classical inflammatory arthropathy, it is characterized by intraarticular inflammation which manifests as synovitis. CRP is an acute-phase protein that is produced in large amounts by hepatocytes, upon stimulation by the cytokines IL-6, TNF-, and IL-1, during an acute-phase response and has been found to be elevated in some individuals with established OA (56,57,58). Recent studies have also demonstrated that both TNF- and IL-1 play a key role in cartilage destruction in OA (59,60). The potential contribution to joint destruction in OA from obesity-related increases in these cytokines is however, unclear.

Finally, there is increasing evidence that OA is not a single disorder but a heterogenous group of disorders, with a complex interplay of several factors that may result in a common pathway of joint damage. Whereas obesity may have a mechanical effect on some joints, it is possible that obesity may have a metabolic effect on other joints. It may be that obesity predominantly manifests increased mechanical stress across weight bearing joints such as the knee, but the effect of obesity on the small non-weight bearing joints of the hand may be predominantly through metabolic mechanisms. It has previously been suggested that OA at non-weight bearing sites such as the carpometacarpal joints and the proximal interphalangeal joints of the hands may be due to metabolic factors related to adiposity (21).

Conclusion

Obesity, defined by either elevated weight or BMI, is an unequivocal risk factor for the onset, progression, and symptoms of knee OA. The maintenance 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 cannot discriminate adipose from non-adipose mass.

Recent studies that have examined measures of body composition and their relationship with joint structure have yielded important information. First, increased non-adipose mass appears to benefit joint health. In particular, increased non-adipose mass appears protective against the onset of radiographic tibiofemoral OA, as well as a reduced rate of tibial cartilage volume loss. Second, increased adipose mass is associated with an increased risk for the presence of cartilage defects at both the tibiofemoral and patellofemoral compartments in healthy subjects. However, because many of these findings are derived from studies examining healthy subjects, further 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.

Executive Summary

    Obesity, measured by either increased weight (kg) or BMI (kg/m²), is an established risk factor for the onset, progression, and symptoms of knee OA.

    Maintenance of an ideal body weight or BMI reduces the risk for the onset and progression of knee OA.

    Reducing weight or BMI helps alleviate pain and disability in people with established disease.

    The BMI and weight are both limited by their inability to discriminate adipose from non-adipose mass.

    Recent studies that have examined measures of body composition and their relationship with joint structure have yielded important information.

    Increased non-adipose mass appears to reduce the rate of tibial cartilage volume loss, and is positively associated with cartilage volume at the tibia.

    Increased adipose mass is associated with an increased risk for the presence of cartilage defects at both the tibiofemoral and patellofemoral compartments in healthy subjects, and may be related to a reduction in cartilage volume, particularly in women.

    Further work examining the relationship between body composition is required, both in the presence and absence of joint disease.

Disclosure

The authors declared no conflict of interest.

References

REFERENCES

1. Acheson RM, Collart AB. New Haven survey of joint diseases. XVII. Relationship between some systemic characteristics and osteoarthrosis in a general population. Ann Rheum Dis 1975;34:379–387. | PubMed | ChemPort |
2. Rabenda V, Manette C, Lemmens R et al. Direct and indirect costs attributable to osteoarthritis in active subjects. J Rheumatol 2006;33:1152–1158. | PubMed |
3. Centers for Disease Control and Prevention (CDC). National and state medical expenditure and lost earnings attributable to arthritis and other rheumatic conditions—United States, 2003. MMWR Morb Mortal Wkly Rep 2007;56:4–7.
4. Arthritis—The bottom line. The economic impact of arthritis in Australia—Arthritis Australia 2005. Access Economics: Canberra, Australia, 2005.
5. Manninen P, Riihimaki H, Heliovaara M, Makela P. Overweight, gender and knee osteoarthritis. Int J Obes Relat Metab Disord 1996;20:595–597. | PubMed | ChemPort |
6. Gibson T, Hameed K, Kadir M et al. Knee pain amongst the poor and affluent in Pakistan. Br J Rheumatol 1996;35:146–149. | Article | PubMed | ChemPort |
7. Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988;109:18–24. | PubMed | ISI | ChemPort |
8. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study. Ann Intern Med 1992;116:535–539. | PubMed | ISI | ChemPort |
9. Felson DT, Zhang Y, Hannan MT et al. Risk factors for incident radiographic knee osteoarthritis in the elderly: the Framingham Study. Arthritis Rheum 1997;40:728–733. | Article | PubMed | ISI | ChemPort |
10. Gelber AC, Hochberg MC, Mead LA et al. Body mass index in young men and the risk of subsequent knee and hip osteoarthritis. Am J Med 1999;107:542–548. | Article | PubMed | ISI | ChemPort |
11. Schouten JS, van den Ouweland FA, Valkenburg HA. A 12 year follow up study in the general population on prognostic factors of cartilage loss in osteoarthritis of the knee. Ann Rheum Dis 1992;51:932–937. | PubMed | ISI | ChemPort |
12. McGoey BV, Deitel M, Saplys RJ, Kliman ME. Effect of weight loss on musculoskeletal pain in the morbidly obese. J Bone Joint Surg Br 1990;72:323–324. | PubMed |
13. Christensen R, Astrup A, Bliddal H. Weight loss: the treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthritis Cartilage 2005;13:20–27. | Article | PubMed | ISI | ChemPort |
14. Grinker JA, Tucker KL, Vokonas PS, Rush D. Changes in patterns of fatness in adult men in relation to serum indices of cardiovascular risk: the Normative Aging Study. Int J Obes Relat Metab Disord 2000;24:1369–1378. | Article | PubMed | ChemPort |
15. Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol 1993;20:331–335. | PubMed | ISI | ChemPort |
16. Davis MA, Neuhaus JM, Ettinger WH, Mueller WH. Body fat distribution and osteoarthritis. Am J Epidemiol 1990;132:701–707. | PubMed | ISI | ChemPort |
17. Hochberg MC, Lethbridge-Cejku M, Scott WW Jr et al. The association of body weight, body fatness and body fat distribution with osteoarthritis of the knee: data from the Baltimore Longitudinal Study of Aging. J Rheumatol 1995;22:488–493. | PubMed | ISI | ChemPort |
18. Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am J Epidemiol 1988;128:179–189. | PubMed | ISI | ChemPort |
19. Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study. Arthritis Rheum 1999;42:17–24. | Article | PubMed | ISI | ChemPort |
20. Roubenoff R. Applications of bioelectrical impedance analysis for body composition to epidemiologic studies. Am J Clin Nutr 1996;64(Suppl 3):S459–S462.
21. Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol 1996;23:1221–1226. | PubMed | ISI | ChemPort |
22. Spector TD, Hart DJ, Doyle DV. Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: the effect of obesity. Ann Rheum Dis 1994;53:565–568. | PubMed | ISI | ChemPort |
23. Cooper C, Snow S, McAlindon TE et al. Risk factors for the incidence and progression of radiographic knee osteoarthritis. Arthritis Rheum 2000;43:995–1000. | Article | PubMed | ChemPort |
24. Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker AM. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiology 1999;10:161–166. | Article | PubMed | ChemPort |
25. Felson DT, Chaisson CE. Understanding the relationship between body weight and osteoarthritis. Baillieres Clin Rheumatol 1997;11:671–681. | Article | PubMed | ChemPort |
26. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905–1915. | ISI |
27. Pendleton A, Arden N, Dougados M et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2000;59:936–944. | Article | PubMed | ISI | ChemPort |
28. Jadelis K, Miller ME, Ettinger WH Jr, Messier SP. Strength, balance, and the modifying effects of obesity and knee pain: results from the Observational Arthritis Study in Seniors (oasis). J Am Geriatr Soc 2001;49:884–891. | Article | PubMed | ISI | ChemPort |
29. Wendelboe AM, Hegmann KT, Biggs JJ et al. Relationships between body mass indices and surgical replacements of knee and hip joints. Am J Prev Med 2003;25:290–295. | Article | PubMed | ISI |
30. Toda Y, Toda T, Takemura S et al. Change in body fat, but not body weight or metabolic correlates of obesity, is related to symptomatic relief of obese patients with knee osteoarthritis after a weight control program. J Rheumatol 1998;25:2181–2186. | PubMed | ISI | ChemPort |
31. Miller GD, Nicklas BJ, Davis C et al. Intensive weight loss program improves physical function in older obese adults with knee osteoarthritis. Obesity (Silver Spring) 2006;14:1219–1230. | PubMed |
32. Messier SP, Loeser RF, Miller GD et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the arthritis, diet, and activity promotion trial. Arthritis Rheum 2004;50:1501–1510. | Article | PubMed | ISI |
33. Messier SP, Loeser RF, Mitchell MN et al. Exercise and weight loss in obese older adults with knee osteoarthritis: a preliminary study. J Am Geriatr Soc 2000;48:1062–1072. | PubMed | ISI | ChemPort |
34. Roos EM, Dahlberg L. Positive effects of moderate exercise on glycosaminoglycan content in knee cartilage: a four-month, randomized, controlled trial in patients at risk of osteoarthritis. Arthritis Rheum 2005;52:3507–3514. | Article | PubMed | ChemPort |
35. Wang Y, Wluka AE, English DR et al. Body composition and knee cartilage properties in healthy, community-based adults. Ann Rheum Dis 2007;66:1244–1248. | Article | PubMed |
36. Toda Y, Segal N, Toda T, Kato A, Toda F. A decline in lower extremity lean body mass per body weight is characteristic of women with early phase osteoarthritis of the knee. J Rheumatol 2000;27:23449–23454.
37. Slemenda C, Heilman DK, Brandt KD et al. Reduced quadriceps strength relative to body weight: a risk factor for knee osteoarthritis in women? Arthritis Rheum 1998;41:1951–1959. | Article | PubMed | ChemPort |
38. Cicuttini F, Teichtahl A, Wluka A et al. The relationship between body composition and knee cartilage volume in healthy, middle-aged subjects. Arthritis Rheum 2005;52:461–467. | Article | PubMed | ISI |
39. Davis MA, Ettinger WH, Neuhaus JM. Obesity and osteoarthritis of the knee: evidence from the National Health and Nutrition Examination Survey (NHANES I). Semin Arthritis Rheum 1990;20(3 Suppl 1):34–41.
40. Ding C, Cicuttini F, Scott F, Boon C, Jones G. Association of prevalent and incident knee cartilage defects with loss of tibial and patellar cartilage: a longitudinal study. Arthritis Rheum 2005;52:3918–3927. | Article | PubMed |
41. Andriacchi TP. Dynamics of knee malalignment. Orthop Clin North Am 1994;25:395–403. | PubMed | ChemPort |
42. Jackson BD, Teichtahl AJ, Morris ME et al. The effect of the knee adduction moment on tibial cartilage volume and bone size in healthy women. Rheumatology 2004;43:311–314. | Article | PubMed | ChemPort |
43. Hungerford DS, Barry M. Biomechanics of the patellofemoral joint. Clin Orthop Relat Res 1979;144:9–15. | PubMed |
44. Millward-Sadler SJ, Salter DM. Integrin-dependent signal cascades in chondrocyte mechanotransduction. Ann Biomed Eng 2004;32:435–446. | Article | PubMed | ChemPort |
45. Guilak F, Fermor B, Keefe FJ et al. The role of biomechanics and inflammation in cartilage injury and repair. Clin Orthop Relat Res 2004;423:17–26. | Article | PubMed |
46. Sharma L, Lou C, Cahue S, Dunlop DD. The mechanism of the effect of obesity in knee osteoarthritis: the mediating role of malalignment. Arthritis Rheum 2000;43:568–575. | Article | PubMed | ISI | ChemPort |
47. Felson DT, Goggins J, Niu J, Zhang Y, Hunter DJ. The effect of body weight on progression of knee osteoarthritis is dependent on alignment. Arthritis Rheum 2004;50:3904–3909. | Article | PubMed | ISI |
48. Hart DJ, Doyle DV, Spector TD. Association between metabolic factors and knee osteoarthritis in women: the Chingford Study. J Rheumatol 1995;22:1118–1123. | PubMed | ChemPort |
49. Davis MA, Ettinger WH, Neuhaus JM. The role of metabolic factors and blood pressure in the association of obesity with osteoarthritis of the knee. J Rheumatol 1988;15:1827–1832. | PubMed | ISI | ChemPort |
50. Carman WJ, Sowers M, Hawthorne VM, Weissfeld LA. Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study. Am J Epidemiol 1994;139:119–129. | PubMed | ISI | ChemPort |
51. Pottie P, Presle N, Terlain B et al. Obesity and osteoarthritis: more complex than predicted! Ann Rheum Dis 2006;65:1403–1405. | Article | PubMed | ChemPort |
52. Teichtahl AJ, Wluka AE, Proietto J, Cicuttini FM. Obesity and the female sex, risk factors for knee osteoarthritis that may be attributable to systemic or local leptin biosynthesis and its cellular effects. Med Hypotheses 2005;65:312–315. | Article | PubMed | ChemPort |
53. Dumond H, Presle N, Terlain B et al. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 2003;48:3118–3129. | Article | PubMed | ISI | ChemPort |
54. Kume K, Satomura K, Nishisho S et al. Potential role of leptin in endochondral ossification. J Histochem Cytochem 2002;50:159–169. | PubMed | ChemPort |
55. Figenschau Y, Knutsen G, Shahazeydi S, Johansen O, Sveinbjornsson B. Human articular chondrocytes express functional leptin receptors. Biochem Biophys Res Commun 2001;287:190–197. | Article | PubMed | ISI | ChemPort |
56. Conrozier T, Carlier MC, Mathieu P et al. Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and healthy subjects: a cross sectional study. Ann Rheum Dis 2000;59:828–831. | Article | PubMed | ChemPort |
57. Sturmer T, Brenner H, Koenig W, Gunther KP. Severity and extent of osteoarthritis and low grade systemic inflammation as assessed by high sensitivity C reactive protein. Ann Rheum Dis 2004;63:200–205. | Article | PubMed | ChemPort |
58. Punzi L, Oliviero F, Ramonda R, Sfriso P, Todesco S. Laboratory findings in osteoarthritis. Semin Arthritis Rheum 2005;34(6 Suppl 2):58–61.
59. Evans CH. Novel biological approaches to the intra-articular treatment of osteoarthritis. BioDrugs 2005;19:355–362. | Article | PubMed | ChemPort |
60. Malemud CJ. Cytokines as therapeutic targets for osteoarthritis. BioDrugs 2004;18:23–35. | Article | PubMed | ChemPort |

Acknowledgments

Y.W. is the recipient of a National Health and Medical Research Council (NHMRC) PhD Scholarship. A.E.W. is the recipient of an NHMRC Public Health Fellowship.