Abstract
Summary
Background & aims
The Mediterranean diet appears to be beneficial for several medical conditions, but data regarding osteoarthritis (OA) are not available. The aim of this study was to investigate if adherence to the Mediterranean diet is associated with a lower prevalence of OA of the knee in a large cohort from North America.
Methods
4358 community-dwelling participants (2527 females; mean age: 61.2 years) from the Osteoarthritis Initiative were included. Adherence to the Mediterranean diet was evaluated through a validated Mediterranean diet score (aMED) categorized into quartiles (Q). Knee OA was diagnosed both clinically and radiologically. The strength of the association between aMED (divided in quartiles) and knee OA was investigated through a logistic regression analysis and reported as odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for potential confounders.
Results
Participants with a higher adherence to Mediterranean diet had a significantly lower prevalence of knee OA compared to those with lower adherence (Q4: 25.2% vs. Q1: 33.8%; p < 0.0001). Using a logistic regression analysis, adjusting for 10 potential confounders with those in the lowest quartile of aMED as reference, participants with the highest aMED had a significant reduction in presence of knee OA (OR, 0.83; 95% CIs: 0.69–0.99, p = 0.04). Among the individual components of Mediterranean diet, only higher use of cereals was associated with lower odds of having knee OA (OR: 0.76; 95%CI: 0.60–0.98; p = 0.03).
Conclusions
Higher adherence to a Mediterranean diet is associated with lower prevalence of knee OA. This remained when adjusting for potential confounders.
Keywords: Osteoarthritis, Mediterranean diet, Aged, Healthy ageing, Lifestyle
1. Introduction
The term ‘Mediterranean diet’ encompasses the traditional dietary habits of people from across the Mediterranean region and is usually depicted as a food pyramid [1]. The Mediterranean-style diet is an established healthy-eating diet pattern that has consistently demonstrated to have beneficial effects on musculoskeletal [2], cardiovascular [3], metabolic [4], and cognitive [5] diseases.
Recent global surveys of disease surveys have demonstrated that whilst average life expectancy is increasing [6,7], the number of years people that live with chronic conditions is also rising. One of the most common causes of years lived with disability are chronic musculoskeletal disorders [8,9]. Osteoarthritis (OA) of the knee is the 11th highest contributor to global disability [10]. The worldwide prevalence of OA has been estimated as 10% in men and 20% in women over the age of 60 years [11].
To the best of the author's knowledge, no analyses have investigated the relationship between Mediterranean diet and OA [12]. The Framingham Osteoarthritis Cohort study previously reported that participants with higher vitamin C and E and β-carotene intake may be less likely to have progressive knee OA [13]. However this is only one of the few studies investigating the effect of diet on OA in humans. In mice, the use of olive oil, an essential component of Mediterranean diet, appears to be associated with a lower articular cartilage degradation [14] suggesting a potential role of diets rich in this component for OA.
Given the potential benefits of the Mediterranean diet on several diseases and the absence of data on OA, this study aimed to investigate whether adherence to a Mediterranean diet is associated with lower prevalence of knee OA in a large cohort of North American people from the Osteoarthritis Initiative dataset. We hypothesized that higher adherence to Mediterranean diet was associated with lower prevalence of knee OA.
2. Materials and methods
2.1. Data source and subjects
Data were gathered from the Osteoarthritis Initiative (OAI) database. The OAI is a publically available database open at http://www.oai.ucsf.edu/. Within the OAI, potential participants were recruited across four clinical sites in the United States of America (Baltimore, MD; Pittsburgh, PA; Pawtucket, RI; and Columbus, OH) between February 2004 and May 2006. People eligible in the OAI either: (1) had knee OA with knee pain for a 30-day period in the past 12 months or (2) were at high risk of developing knee OA [15]. For the current paper, we used the data recorded during baseline and screening evaluations (November 2008).
All participants provided informed written consent. The OAI study was given full ethical approval by the institutional review board of the OAI Coordinating Center, at University of California in San Francisco.
2.2. Adherence to the Mediterranean diet (exposure)
Dietary pattern was analysed using a validated tool, the Block Brief 2000 food frequency (FFQ) questionnaire during the baseline visit [16]. Seventy items were assessed for checking the usual food and beverage consumption over the past year. The frequency of consumption was reported at nine levels of intake from “never” to “every day”. In addition, seven dietary behavior questions were available regarding food preparation methods and fat intake, one question on fiber intake, and 13 questions on vitamin and mineral intakes.
Adherence to the Mediterranean diet was evaluated using the Mediterranean diet score (aMED) as proposed by Panagiotakos et al. [17]. This score is based on a food frequency questionnaire which was recorded during the baseline OAI visit. The aMED takes into consideration several foods commonly consumed within the Mediterranean diet. Each food has a score from 0 (less adherent) to 5 (better adherence); the total score ranges from 0 to 55, with higher values indicating higher adherence to a Mediterranean diet. Cereals (e.g. bread, pasta, rice), potatoes, fruits, vegetables, legumes (e.g. peas, beans), fish were categorized according to servings/month: 0 = never; 1 = 1–4 servings for month; 2 = 5–8; 3 = 9–12; 4 = 13–18; 5 = more than 18 servings/month. Since there was no information regarding the consumption of whole cereals vs. refined cereals, all types of grains were considered in the present analyses under the same heading. The consumption of red meat, poultry and full fat dairy products (e.g. milk cheese, yogurt) was categorized as: 0 = more than 18 servings/month; 1 = 13–17 servings for month; 2 = 9–12; 3 = 5–8; 4 = 1–4; 5 = never. The use of olive oil was categorised as the times used in a week: 0 = never; 1 = rare; 2 ≤1/weekly; 3 = 2 times/weekly; 4 = 3–6; 5 = daily. Finally, the consumption of alcoholic beverages was categorised as: 0 ≤ 700 ml/day or0; 1 600–699 ml/day; 2 = 500–599 ml/day; 3 = 400–499 ml/day; 4 = 300–399 ml/day; 5 ≤300 ml/day.
Since there are no agreed cut-off scores for higher aMED adherence, we divided the population in to quartiles using 25, 28 and 32 points: aMED <25, 26–28, 29–32, and ≥33.
2.3. Outcome
The primary analysis was to determine the presence of knee OA, defined as the combination in the clinical reporting and assessment of pain and stiffness (i.e. pain, aching or stiffness in or around the knee on most days during the last year), and radiographical OA on the baseline fixed flexion radiograph based on the presence of tibiofemoral osteophytes (corresponding to Osteoarthritis Research Society International atlas grades 1–3, clinical center reading). In the OAI, the presence of pain, stiffness, and physical functioning (or disability) due to OA was assessed through the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index). Briefly, the responses for each subscale (pain, stiffness, disability) are categorized on a five-point Likert scale ranging from none (0 points) to extreme (4 points) [18]. The maximum possible score is 68, and the final score was normalized to 100 (range 0–100), with higher scores reflecting greater activity limitations [18].
2.4. Covariates
We identified 10 potential self-reported confounders that we considered when assessing the relationship between aMED and knee OA. These included body mass index (BMI), physical activity evaluated using the Physical Activity Scale for the Elderly scale (PASE) [19], race, smoking habit, educational attainment level and yearly income (<or ≥$50,000 and missing data).
Validated general health measures of self-reported comorbidities were assessed through the modified Charlson comorbidity score [20]. Among the medical morbidities assessed through the Charlson co-morbidity score, we reported descriptively the prevalence of some common diseases in North American people, namely fractures, heart attack and failure, stroke, chronic obstructive pulmonary disease, diabetes and cancer [21].
2.5. Statistical analyses
For continuous variables, normal distributed data assumptions were tested using the Kolmogorov–Smirnov test. The data were shown as means ± standard deviations (SDs) for quantitative measures, and frequency and percentages for all discrete variables. For continuous variables, differences between the means of the covariates by aMED quartiles were calculated using an Analysis of Variance (ANOVA); chi-square test was applied for discrete variables. Levene's test was used to test the homoscedasticity of variances and, if its assumption was violated, then Welch's ANOVA was used. Post-hoc analyses and Bonferroni adjustment were applied to compare data.
In order to consider the relationship between knee OA and aMED scores, a logistic regression was conducted with the presence of knee OA considered as the outcome and the aMED as the exposure taking in Q1 (=lowest aMED) as the reference group. The basic model was not adjusted for any confounders, whilst the fully adjusted model included adjustments for the following confounders: age (as continuous); sex; race (whites vs. others); BMI (as continuous); education (degree vs. others); smoking habits (current and previous vs. others); yearly income (categorized as ≥ or <50,000$ and missing data); Charlson comorbidity index; PASE score (as continuous) and total energy intake (as continuous). Multi-collinearity among covariates was assessed through the variance inflation factor (VIF), taking a cut-off of two as reason of exclusion, but no covariate was excluded for this reason. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were finally calculated to estimate the strength of the associations between aMED (categorised as quartiles) and knee OA. We performed the same analyses taking individual components of Mediterranean diet as exposure and dividing the adherence in low (score 0–1–2 points over 5 available) and high (4–5).
The analyses for the paper were undertaken with the SPSS software version 21.0 for Windows (SPSS Inc., Chicago, Illinois). All of the statistical tests were two-tailed taking a p-value <0.05 as significant.
3. Results
3.1. Sample selection
The OAI dataset includes a total of 4796 North American participants. After excluding 109 participants with hip or knee replacement, 175 participants due to missing aMED data and 62 with unreliable caloric intake (<500 or >5000 kcal/day), 4358 participants were finally included in the current analyses.
3.2. Descriptive characteristics
Among the final sample of 4358 participants, 1831 were males and 2527 females. Mean age was 61.2 years (±9.1 years; range: 45–79). Mean aMED score was 28.1 points (5.1 points; range: 5–44). The prevalence of OA (diagnosed by the presence of pain, stiffness and radiographical tibiofemoral osteophytes) in this cohort was 29.1%.
Table 1 illustrates the baseline characteristics by aMED quartiles. Those in the highest quartile (reflecting higher adherence to Mediterranean diet) were older, more likely to be female, white, with higher educational level and income than those within the other quartiles. Those in the highest quartile of aMED had lower BMI values and had fewer medical morbidities, even if these participants reported a higher prevalence of cancer (Table 1).
Table 1.
Descriptive findings of the participants by adherence to Mediterranean diet.
| Q1 (n = 1328), aMED <25 | Q2 (n = 939), aMED 26–28 | Q3 (n = 1236), aMED 29–32 | Q4 (n = 856), aMED ≥33 | P value* | |
|---|---|---|---|---|---|
| aMED score | 22.1 (2.8) | 27.1 (0.9) | 30.4 (1.1) | 35.0 (2.0) | <0.0001 |
| Energy intake (kcal/day) | 1399.7 (600.7)a,b,c | 1409.9 (566.7)a,d,e | 1436.3 (577.0)b,d,f | 1419.3 (518.7)c,e,f | 0.43 |
| Age (years) | 59.3 (8.9) | 61.3 (9.1)g | 62.0 (9.2)g,h | 62.9 (9.1)h | <0.0001 |
| PASE (points) | 161.1 (89.9)i,l,m | 160.9 (80.3)i,n,o | 160.9 (81.0)l,n,p | 163.7 (82.2)m,o,p | 0.86 |
| Females (n, %) | 714 (53.8) | 552 (58.8) | 731 (59.1) | 325 (62.0) | 0.001 |
| White race (n, %) | 949 (71.5) | 756 (80.5) | 1048 (84.8) | 750 (87.6) | <0.0001 |
| Smoking (previous/current) | 713 (53.7) | 473 (50.4) | 664 (53.7) | 437 (51.1) | 0.27 |
| Graduate degree (n, %) | 323 (24.3) | 284 (30.2) | 391 (31.6) | 327 (38.2) | <0.0001 |
| Yearly income (<50,000 $) | 718 (54.1) | 560 (59.6) | 750 (60.7) | 554 (64.7) | <0.0001 |
| Medical conditions | |||||
| BMI (kg/m2) | 29.6 (4.9) | 28.9 (4.7) | 28.2 (4.7) | 27.4 (4.5) | <0.0001 |
| Fractures (n, %) | 208 (15.7) | 181 (19.3) | 223 (18.2) | 154 (18.0) | 0.14 |
| Heart attack (n, %) | 34 (2.6) | 14 (1.5) | 13 (1.1) | 24 (2.8) | 0.007 |
| Heart failure (n, %) | 37 (2.8) | 14 (1.5) | 16 (1.3) | 17 (2.0) | 0.03 |
| Stroke (n, %) | 44 (3.4) | 30 (3.2) | 28 (2.3) | 26 (3.1) | 0.41 |
| COPD (n, %) | 34 (2.6) | 20 (2.2) | 24 (2.0) | 18 (2.1) | 0.72 |
| Diabetes (n, %) | 128 (9.9) | 87 (9.4) | 72 (5.9) | 41 (4.9) | <0.0001 |
| Cancer (n, %) | 32 (2.5) | 40 (4.4) | 43 (3.5) | 47 (5.5) | 0.002 |
| Presence of one or more disease (n, %) | 347 (26.3) | 247 (26.5) | 259 (21.1) | 211 (24.7) | 0.03 |
Notes: The data are presented as mean (with standard deviations) for continuous variables and number (with percentage) for categorical variables.
P values were calculated using the Analysis of Variance for continuous and chi-square test for categorical ones, respectively.
Means not sharing a superscript letter are significantly different at a Bonferroni corrected P value of 0.05/6 (=0.0083).
Abbreviations: aMED: adherence to Mediterranean diet score; PASE: Physical Activity Scale for the Elderly; BMI: body mass index; OA: osteoarthritis; COPD: chronic obstructive pulmonary disease.
3.3. Adherence to Mediterranean diet and osteoarthritis
As shown in Table 2, there was a significant lower presence of knee OA in those with higher aMED scores (Q4) compared to those with lower aMED (Q1) (Q4: 25.2% vs. Q1: 33.8%; p < 0.0001). Using a logistic regression analysis adjusting for 10 potential confounders, and taking those with the lowest adherence to Mediterranean diet as reference (=Q1), participants with the highest adherence to Mediterranean diet had a significantly reduced probability of knee OA (OR = 0.83; 95%CI: 0.69–0.99, p = 0.04; Table 2). Other factors significantly associated with knee OA in the multivariate analysis were: BMI (for each increase in 1 kg/m2: OR = 1.08; 95%CI: 1.06–1.10, p < 0.0001), non-white ethnicity (OR = 1.60; 95%CI: 1.35–1.90, p < 0.0001) and below college level education (OR = 1.23; 95%CI: 1.04–1.44; p = 0.03), while age was marginally significant (for each year: OR = 1.008; 95%CI: 1.00–1.02, p = 0.05).
Table 2.
Association between adherence to Mediterranean diet and presence of knee osteoarthritis.
| Number of events/number of participants | Prevalence (%) | Unadjusted OR (95%CI) | P value | Fully-adjusteda OR (95%CI) | P value | |
|---|---|---|---|---|---|---|
| Q1 (aMED <25) | 448/1328 | 33.8 | 1 [reference] | 1 [reference] | ||
| Q2 (aMED 26–28) | 276/939 | 29.4 | 0.82 (0.68–0.98) | 0.03 | 0.90 (0.75–1.09) | 0.28 |
| Q3 (aMED 29–32) | 330/1236 | 26.7 | 0.70 (0.59–0.83) | <0.0001 | 0.85 (0.70–1.05) | 0.13 |
| Q4 (aMED ≥33) | 216/856 | 25.2 | 0.66 (0.55–0.80) | <0.0001 | 0.83 (0.69–0.99) | 0.04 |
All the data are presented as odds ratios (ORs) with their 95% confidence intervals.
Bold values are significant results after fully-adjustment, as p-value < 0.05.
Abbreviations: CI: confidence intervals; OR: odds ratio.
Fully-adjusted model included as covariates: age (as continuous); sex; race (whites vs. others); body mass index (as continuous); education (degree vs. others); smoking habits (current and previous vs. others); yearly income (categorized as ≥ or <50,000$ and missing data); Physical Activity Scale for Elderly score (as continuous); Charlson comorbidity index; daily energy intake.
Table 3 illustrates the effect of individual components of Mediterranean diet and their association with the presence of knee OA. After adjusting for potential confounders, only higher use of cereals was associated with a significantly reduced probability of knee OA (OR = 0.76; 95%CI: 0.60–0.98; p = 0.03).
Table 3.
Singular components of Mediterranean diet and presence of knee osteoarthritis.
| Number of events/number of participants (=prevalence, %) [higher adherence; 4–5 points] | Number of events/number of participants (=prevalence, %) [lower adherence; 0–3 points] | Unadjusted OR (95%CI) | P value | Fully-adjusteda OR (95%CI) | P value | |
|---|---|---|---|---|---|---|
| Cereals | 1152/4009 (=28.7%) | 118/349 (=33.8%) | 0.82 (0.64–1.03) | 0.09 | 0.76 (0.60–0.98) | 0.03 |
| Potatoes | 127/465 (=27.3%) | 1142/3891 (=29.3%) | 0.90 (0.72–1.12) | 0.34 | 0.82 (0.65–1.04) | 0.10 |
| Fruits | 886/3170 (=27.9%) | 383/1187 (=32.3%) | 0.81 (0.70–0.94) | 0.005 | 0.89 (0.76–1.04) | 0.13 |
| Vegetables | 1208/4172 (=29.0%) | 61/184 (=33.2%) | 0.84 (0.61–1.15) | 0.27 | 0.97 (0.69–1.35) | 0.84 |
| Legumes | 293/871 (=33.6%) | 976/3485 (=28.0%) | 1.33 (1.13–1.56) | 0.001 | 1.17 (0.98–1.38) | 0.08 |
| Fish | 126/371 (=34.0%) | 1137/3962 (=28.7%) | 1.30 (1.04–1.64) | 0.02 | 1.29 (0.99–1.64) | 0.06 |
| Meat | 154/587 (=26.2%) | 1116/3771 (=29.6%) | 0.83 (0.68–1.01) | 0.07 | 0.99 (0.80–1.23) | 0.95 |
| Poultry | 525/1879 (=27.9%) | 738/2454 (=30.1%) | 0.89 (0.78–1.02) | 0.10 | 1.05 (0.90–1.21) | 0.55 |
| Dairy | 71/223 (=31.8%) | 1198/4134 (=29.0%) | 1.13 (0.84–1.52) | 0.42 | 0.97 (0.71–1.33) | 0.86 |
| Alcohol | 508/1988 (=25.6%) | 758/2355 (=32.2%) | 0.72 (0.63–0.82) | <0.0001 | 0.88 (0.77–1.02) | 0.09 |
| Oil | 147/558 (=26.3%) | 1107/3759 (=29.4%) | 0.87 (0.71–1.07) | 0.19 | 0.99 (0.80–1.21) | 0.88 |
All the data are presented as odds ratios (ORs) with their 95% confidence intervals.
Bold values are significant results after fully-adjustment, as p-value < 0.05.
In all the analyses, we considered higher adherence to a component (as 4 or 5 points) vs. lower (0–3; reference).
Abbreviations: CI: confidence intervals; OR: odds ratio.
Fully-adjusted model included as covariates: age (as continuous); sex; race (whites vs. others); body mass index (as continuous); education (degree vs. others); smoking habits (current and previous vs. others); yearly income (categorized as ≥ or <50,000$ and missing data); Physical Activity Scale for Elderly score (as continuous); Charlson comorbidity index; daily energy intake.
4. Discussion
In this large cross-sectional study, we found evidence to suggest that North American people who are more adherent to a Mediterranean diet had a significantly lower presence of knee OA. After adjusting for 10 potential confounders, those with the highest aMED score (i.e. more adherent to the Mediterranean diet) had a significant lower prevalence of knee OA by approximately 17%.
Participants with a higher adherence to a Mediterranean diet had significantly lower BMI values and fewer medical morbidities (particularly diabetes), higher education level and greater income than other participants. This suggests that these factors may also influence the prevalence of knee OA in individuals with higher adherence to Mediterranean diet. At the same time, such participants had a significantly higher presence of two important risk factors for knee OA, namely being female and older in age [22]. The apparent paradox of higher prevalence of cancer among those with higher aMED score could be due to a change toward a healthier diet among those diagnosed with cancer [23]. This discrepancy, however, indirectly confirmed a significant and independent association between higher adherence to this dietary pattern and lower prevalence of knee OA. After adjusting for potential confounders (including severity of comorbidity and social and economic factors), the association between aMED and knee OA remained statistically significant. The multivariate analysis suggests that obesity, education and race are associated with prevalent OA, also taking in account other potential confounders. Thus, since our research suggests that Mediterranean diet is associated with a lower risk of knee OA, obese, less educated and non-white people should be monitored in order to encourage them to follow a healthier diet.
Whilst our data is cross sectional and causality cannot be determined, there may be a number of mechanisms that might explain the relationship we observed. Firstly, a higher adherence to a Mediterranean diet is linked to a decrease in inflammation [24]. Inflammation is acknowledged as an important pathway in the development of knee OA [25]. Therefore the anti-inflammatory properties derived from the phytochemicals in a Mediterranean diet may modify this pathway [14]. Secondly, a Mediterranean diet may influence a reduction in oxidative stress markers [26]. These factors have been reported to influence the onset of OA though providing increasing levels of collagen type II and aggrecan expression whilst inhibiting apoptosis-related proteins expression, providing a chondroprotective effect [27,28]. Finally, Mediterranean diet could play a role in the remodeling of extracellular matrix (ECM) [29] promoting effective repair of the ECM which is frequently defective in those who develop and present with OA. All factors could play an important role in the development of knee OA, and provide a physiological rationale for these findings [30].
Previous literature on Mediterranean diet and rheumatic diseases has largely focused on population with rheumatoid arthritis. In this case, several observational [31–34] and interventional [35–37] studies suggest a protective role for some components of Mediterranean diet on rheumatoid arthritis indirectly suggesting a potential role also for OA. However the pathogenesis of this condition is very different to OA, thereby making these finding important. Whilst a subset of people with OA may present with an inflammatory phenotype to their disease process, this is not uniform [38]. Accordingly, these results suggest that the protective mechanism which a Mediterranean diet is suggestive to confer may not be solely attributed to the inflammatory pathway [37], but to some other pathophysiological or epigenetic mechanism.
Previously there had been limited investigation into the impact of Mediterranean diet on knee OA. Animal models have shown that the supplementation of olive oil, an essential component of Mediterranean diet, may preserve the articular cartilage, particularly when prescribed in combination with physical activity [14]. From our analyses, there was no independent association between the use of olive oil and knee OA. Conversely, on assessing the individual components of a Mediterranean diet, only higher use of cereals was associated with lower probability of knee OA. There is limited evidence around the consumption of cereals and the relationship to knee OA. However it could hypothesized that a higher intake of cereals could contribute to a lower prevalence of knee OA through anti-inflammatory and anti-oxidative stress action, but also due to these being good sources of vitamins and minerals (such as magnesium [39,40]) which may play a role in lower prevalence of knee OA. However it should be noted that pasta and rice are often consumed in association with olive oil and vegetables and, as supported in previous studies [1,41], not the single components, but the combination of the different ingredients of the Mediterranean diet is responsible for the protective effect and the health benefit observed with this dietary pattern.
The analysis suggests a negative association between Mediterranean diet and knee OA, suggesting a possible a protective effect on knee OA. Clinically, these findings indicate that for those at higher risk of developing knee OA, recommendation and promotion of such a diet may be warranted. Further investigation to identify which types of individuals are most to benefit from this recommendation and what the mechanisms and contexts should be in which to implement such dietary advice, should be undertaken.
The findings of our research should be considered within its limitations. The main is the cross-sectional nature of our research therefore precluding any consideration of a potential causal relationship between Mediterranean diet and knee OA, making residual confounding very likely. Second, we were not able to see the influence of bio-humoral markers (e.g. inflammation) in the association between Mediterranean diet and knee OA, but these markers could be of importance. A third limitation is that the medical conditions are self-reported and this could introduce a bias. Finally, we have used a slight modified version of a previous Mediterranean diet adherence [17] and also this choice could introduce another bias. On the contrary, among the strengths of our work, we could include the large sample size included and the fact this is the first epidemiological study reporting data on the impact of this dietary pattern on a frequent condition, like knee OA.
To conclude, the results from our paper indicate that a higher adherence to a Mediterranean diet is associated with lower prevalence of knee OA, even after adjusting for several important confounders. Further longitudinal research is required to confirm/refute our findings and explore potential pathophysiological mechanisms.
Acknowledgments
Statement of authorship: Analysis and interpretation of data: Veronese, Noale, Luchini. Draft of the article: Stubbs, Veronese, Maggi, Solmi. Critical revision for important intellectual content: Cooper, Smith, Guglielmi, Reginster, Rizzoli. All authors approved the version submitted.
Funding source: The OAI is a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. This manuscript was prepared using an OAI public use dataset and does not necessarily reflect the opinions or views of the OAI investigators, the NIH, or the private funding partners.
Sponsor's role: The sponsors had no role in the design, methods, subject recruitment, data collection, analysis or preparation of this paper.
Footnotes
Conflict of interest: None.
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