Body Mass Index- and Waist Circumference-Defined Obesity with the risk of Total Knee Arthroplasty for Osteoarthritis: A prospective cohort study CURRENT STATUS: UNDER REVIEW

Background There is a discordance in classification of obesity when defined by body mass index (BMI) or waist circumference (WC). We aimed to examine whether categories of BMI- and WC-defined obesity are differentially associated with the risk of total knee arthroplasty for osteoarthritis. Methods 38,924 participants from the Melbourne Collaborative Cohort Study with BMI and WC measured at baseline (1990-1994) were included. Obesity status was defined as: not obese (non-obese BMI and non-obese WC); WC-defined obesity only (non-obese BMI and obese WC); BMI-defined obesity only (non-obese WC and obese BMI); and BMI- and WC-defined obesity. The incidence of total knee arthroplasty for osteoarthritis between January 2001 and December 2013 was determined by linking participant records to the National Joint Replacement Registry.


Background
There is a discordance in classification of obesity when defined by body mass index (BMI) or waist circumference (WC). We aimed to examine whether categories of BMI-and WC-defined obesity are differentially associated with the risk of total knee arthroplasty for osteoarthritis.
Methods 38,924 participants from the Melbourne Collaborative Cohort Study with BMI and WC measured at baseline (1990)(1991)(1992)(1993)(1994) were included. Obesity status was defined as: not obese (non-obese BMI and non-obese WC); WC-defined obesity only (non-obese BMI and obese WC); BMI-defined obesity only (non-obese WC and obese BMI); and BMI-and WC-defined obesity. The incidence of total knee arthroplasty for osteoarthritis between January 2001 and December 2013 was determined by linking participant records to the National Joint Replacement Registry.

Conclusions
Individuals with either BMI-or WC-defined obesity should be targeted for prevention of knee osteoarthritis as both are significant predictors for severe osteoarthritis requiring a total knee arthroplasty.

Background
Obesity is an important modifiable risk factor for knee osteoarthritis (OA) [1]. Although body mass index (BMI) is primarily used as a simple screening tool for obesity at the population level [2], it does not take into account the body fat distribution [3]. Waist circumference (WC) estimates central obesity and has been shown to be a better predictor for cardio-metabolic morbidity and premature mortality than BMI [3], particularly for people with low BMI [4] and for women [5]. Discordance between BMI and an Australian study reported that approximately 40% of individuals with WC-defined obesity (WC ≥ 102 cm for men and ≥ 88 cm for women) were not obese with respect to BMI (BMI ≥ 30 kg/m 2 ) [6].
This discordance was greater for Chinese adults with 75.7% who were obese with respect to WC not defined as obese based on BMI [7].
Previous studies have examined obesity as a risk factor for knee OA based on BMI or WC [1,3,8] but it is unknown whether the risk of knee OA differs in relation to different categories of BMI-and WCdefined obesity. Understanding this has implications for the prevention and treatment of knee OA.
Thus we aimed to examine whether the risk of total knee arthroplasty due to OA differed by categories of BMI-and WC-defined obesity.

Participants And Methods Study participants
The Melbourne Collaborative Cohort Study (MCCS) is a well-established cohort study that recruited 41,514 participants (17,045 men, 99.3% aged 40-69 years) during 1990-1994 [9]. The study protocol was approved by the Cancer Council Victoria's Human Research Ethics Committee [9]. For the current study, 2,590 (6.2%) were excluded because they had either: died or left Australia or reported having an arthroplasty prior to 1 January 2001; or their first recorded procedure was a revision arthroplasty [9], leaving 38,924 participants available for analysis.
Demographic data, anthropometric measurements and classification of obesity categories At baseline, demographic and lifestyle data, including date of birth, sex, country of birth, education, smoking and physical activity, were collected using standard questionnaires [9]. WC, height and weight were measured using standard procedures [9]. Obesity was defined by BMI ≥ 30 kg/m 2 or WC ≥ 102 cm for men and ≥ 88 cm for women [10]. Obesity status was classified based on combination of Incidence of total knee arthroplasty for OA The Australian Orthopaedic Association National Joint Replacement Registry (AOA NJRR) collects information on prostheses, patient demographics, type and reason for arthroplasty, with an almost complete data relating to arthroplasty (> 99%) in Australia [11]. Linking the MCCS records to the AOA NJRR identified those who had a primary total knee arthroplasty performed between 1 January 2001 and 31 December 2013. Knee OA was defined as the first primary total knee arthroplasty with a contemporaneous diagnosis of OA, as recorded in the AOA NJRR. If one person had multiple arthroplasties, the first recorded procedure was considered the event. The linkage study was approved by the Human Research Ethics Committee of Cancer Council Victoria and Monash University.

Statistical analysis
Cox proportional hazard regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the incidence of total knee arthroplasty due to OA associated with obesity categories, with age as the time scale. Follow-up for arthroplasty (calculation of person-time) began 1 January 2001 and ended at the date of first knee arthroplasty for OA or date of censoring. Participants were censored at either the date of first knee arthroplasty for indications other than OA, the date of death, or end of follow-up, whichever came first. All analyses were adjusted for sex, education, smoking status, physical activity and country of birth. As men and women demonstrate different obesity category distributions and have different risks of knee arthroplasty, stratified analyses by gender were performed. Tests based on Cox regression methods showed no evidence that proportional hazard assumptions were violated for any analysis. All statistical analyses were performed using Stata 15.0 (StataCorp LP., College Station, TX, USA).

Results
In the analytic sample, 26.5% (n = 10,311) of participants had either BMI-or WC-defined obesity; 20.4% based on BMI definition and 20.9% based on WC definition. Of the 10,311 obese participants, 55.9% (n = 5762) had obesity defined by both BMI and WC, 22.9% (n = 2,363) had obesity defined by WC only and 21.2% (n = 2,186) had obesity defined by BMI only (Fig. 1).
A total of 1,875 participants underwent a total knee arthroplasty for OA over an average of 11.5 ± 3.1 years follow-up. The characteristics of study participants according to knee arthroplasty are presented in Table 1. Those who had a total knee arthroplasty were older and more likely to be born in Australia/UK and had a higher BMI and WC than those without knee arthroplasty.

Discussion
We found when obesity was defined by either BMI or WC alone, almost 40% of obese persons were missed. However, any participant defined as obese (BMI only, WC only, or both BMI and WC) had an increased risk of total knee arthroplasty for OA compared with those defined as not obese. Those who had both BMI-and WC-defined obesity were at the greatest risk of total knee arthroplasty for OA.
In our study, over 40% of participants were classified as obese based on either BMI or WC, but not both. Using BMI alone to define obesity resulted in 7,948 participants, or 21.2% being defined as obese. Another 2,363 participants (6.1%) had WC-defined obesity associated with adverse outcomes, but were not defined as obese based on their BMI. We found that all categories of obesity (WC-defined obesity only, BMI-defined obesity only, or BMI-and WC-defined obesity) were associated with increased risk of total knee arthroplasty for OA. This is consistent with observations regarding other obesity-related chronic diseases such as cardiovascular disease [12] and type 2 diabetes [13].
Additionally, our study showed that, those with BMI-and WC-defined obesity had the greatest risk, particularly for women. BMI mainly captures body weight related obesity whereas WC mostly reflects central obesity [12]. Having both BMI-and WC-defined obesity further increases the risk of total knee arthroplasty compared with having either BMI-or WC-defined obesity alone. This might be due to the interaction of biomechanical factors with metabolic and inflammatory factors to promote OA initiation and progression.
Those with elevated BMI or WC alone do not identify the same individuals as obese, and do not capture the whole obesity-related risk of knee OA. This is of particular importance for the aging population given the discrepancy between BMI and WC appears particularly in older age, when people tend to lose lean mass but continue to gain fat mass that is reflected by WC [6]. Recently, for the identification of individuals at risk of knee OA, BMI has been suggested as a sufficient measure of obesity [14] but our data show that individuals without BMI-defined obesity but with WC-defined obesity are also at increased risk of knee OA compared with those who are not obese. Our study supports the inclusion of both BMI and WC to identify and target those at risk of knee OA for the prevention and management of the disease.
The strengths of our study include its prospective design, large sample size, participants of varying age and countries of birth, and the validation and completeness of arthroplasty data from the AOA NJRR [11]. Our results need to be considered within the study's limitations. Arthroplasty is used as a proxy for severe symptomatic OA, however, there are other factors such as access to health care, patient and clinician factors that may influence the decision for arthroplasty [15]. However, the publicly-funded universal health system (Medicare) in Australia ensures that everyone has equal access to arthroplasty facilities. Additionally, our analyses have adjusted for age, sex, education, smoking status, physical activity and country of birth to attempt to control for these factors.
Arthroplasty data were not available prior to 2001 and as a result, some misclassification of arthroplasty may have occurred. This is most likely to have been non-differential which might have attenuated the strength of our observed associations.

Conclusion
Obesity should be assessed by both BMI and WC in order to identify those at risk of knee OA, as both 8 measures are associated with an increased risk of severe knee OA and there is discordance between these measures at the individual level in defining obesity. Individuals with either BMI-or WC-defined obesity should be targeted for prevention and management of obesity in order to reduce the burden of severe knee OA.

Availability of data and materials
All data generated or analysed during this study are included in this published article [and its supplementary information files].