Knee osteoarthritis and obesity

There is a large body of evidence demonstrating a substantial increased risk in development and progression of knee OA with obesity, and the risk increases as the level of obesity increases. There is increasing evidence that this is not just related to increased load on the knee, but there are metabolic factors. Adipose tissue contains immunologically active cells (adipocytes) which secrete cytokines (adipokines) leading to a general state of inflammation.  The knee appears particularly vulnerable to this inflammatory process. Obese military personnel are at substantially increased risk of developing knee OA, and if they have early signs, weight loss will substantially reduce the risk of disease progression. 

Some genotypes appear to be at specifically increased risk of knee OA when overweight. A large case-control study of 2018 cases of severe symptomatic and radiographic knee and hip OA and 967 controls were studied.  The odds ratio of developing knee OA with homozygous genotype 11 of SNP rs2278422 in overweight individuals was 6.95 (p<0.001). Significant interactions with variant alleles was noted (Muthuri et al., 2013).

Waist circumference is a risk factor for knee OA independent of obesity. A cross-sectional study of 2323 participants in the American NHANES study from 1988-94 classified participants by body mass index and waist circumference into sex-specific tertiles and looked at radiographic knee arthritis. Independent of sex, the likelihood of knee OA increased in a graded fashion when moving from the lowest to highest BMI tertile and when moving from the lowest to highest waist circumference tertile (Ptrend<0.01, OR 3.79, 95%CI 2.44-5.89). Within the lowest BMI tertile,  waist circumference had no significant effect (P>0.1).  Within the middle BMI tertile, the middle and high waist circumference tertiles were more likely to have knee OA (P<0.05). Within the highest BMI tertile, the highest waist circumference tertile was more likely to have knee OA than the lowest (P<0.05) (Janssen and Mark, 2006).

Greater body mass index in young men aged 20-29 years is associated with increased risk of subsequent knee but not hip OA. One thousand one hundred and eighty male medical students at mean age 23 were followed up for a mean of 36 years. Those in the BMI range 24.7-37.6 had a three-fold greater risk of developing radiographic and symptomatic knee OA than those in the BMI range 15.6-22.8 (P=0.0001), RR 1.7 (95% CI 1.3-2.1). BMI at age 20-29 was more predictive of future osteoarthritis than BMI at ages 30-39 or 40-49 (Gelber et al., 1999).

The risk of knee OA post-meniscectomy is significantly increased in obese individuals. Obesity is associated with post-meniscectomy OA (OR 2.5, 95% CI 1.1-5.7) (Englund and Lohmander, 2004).

A meta-analysis of 47 observational studies totalling nearly half a million subjects concluded that the overall pooled ORs for overweight and obese individuals developing knee OA were 2.02 (95% CI 1.84-2.22) (Muthuri et al., 2011).

Adipokine levels are distinctly higher in knee OA patients compared to controls.  A study of 172 severe knee OA patients found higher levels of adipokine (particularly adiponectin and leptin)  associated with BMI (P<0.001).  No association between serum levels of adipokines with cartilage damage was found, whereas weak but positive associations were found with synovial inflammation (de Boer et al., 2012).

Half the total effect of BMI on knee OA may be mediated by the serum adipokine leptin. A study of 653 participants found  that a 5kg/m2 increase in BMI was associated with 32% increased odds of knee OA (OR 1.32, 95% CI 1.10-1.58) and a 200pM increase in serum leptin levels was associated with 11% increased odds of knee OA (OR 1.11, 95% CI 1.05-1.17) (Fowler-Brown et al., 2015).

DE BOER, T. N., VAN SPIL, W. E., HUISMAN, A. M., POLAK, A. A., BIJLSMA, J. W., LAFEBER, F. P. & MASTBERGEN, S. C. 2012. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage, 20, 846-53.

ENGLUND, M. & LOHMANDER, L. S. 2004. Risk factors for symptomatic knee osteoarthritis fifteen to twenty-two years after meniscectomy. Arthritis Rheum, 50, 2811-9.

FOWLER-BROWN, A., KIM, D. H., SHI, L., MARCANTONIO, E., WEE, C. C., SHMERLING, R. H. & LEVEILLE, S. 2015. The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults. Arthritis Rheumatol, 67, 169-75.

GELBER, A. C., HOCHBERG, M. C., MEAD, L. A., WANG, N. Y., WIGLEY, F. M. & KLAG, M. J. 1999. Body mass index in young men and the risk of subsequent knee and hip osteoarthritis. Am J Med, 107, 542-8.

JANSSEN, I. & MARK, A. E. 2006. Separate and combined influence of body mass index and waist circumference on arthritis and knee osteoarthritis. Int J Obes (Lond), 30, 1223-8.

MUTHURI, S. G., DOHERTY, S., ZHANG, W., MACIEWICZ, R. A., MUIR, K. R. & DOHERTY, M. 2013. Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFbeta1) gene in knee and hip osteoarthritis. Arthritis Res Ther, 15, R52.

MUTHURI, S. G., HUI, M., DOHERTY, M. & ZHANG, W. 2011. What if we prevent obesity? Risk reduction in knee osteoarthritis estimated through a meta-analysis of observational studies. Arthritis Care Res (Hoboken), 63, 982-90.