Hand osteoarthritis (OA) is a common joint disease worldwide, resulting in weakened grip strength and significant functional disability 1. As nonweight-bearing joints, the hand is a useful target for the study of nonmechanical risk factors for OA pathogenesis 2345678910.

Obesity has been observed to have associations with OA development in nonweight-bearing joints as well as in weight-bearing joints 11121314. Adipokine hormones such as leptin have long been thought to contribute to OA pathogenesis directly, independent of the mechanical effect of obesity 341115. Leptin, a small polypeptide, is predominantly produced in white adipose tissue and regulates food intake and energy expenditure. Leptin has also been increasingly recognized to play a role in inflammation, angiogenesis, as well as cartilage and bone metabolism, and thus has been implicated in the development of osteoarthritis 315161718.

Studies have suggested a possible relationship between leptin and OA of weight-bearing joints 1516. However, there have been few studies of nonweight-bearing joints - such as the hand joints - to examine nonmechanical risk factors for OA. Leptin was not associated with hand OA progression in a recent study of fewer than 300 subjects 19. To date, no study has examined the cross-sectional association between leptin and hand OA in a population-based sample. The objective of our study was to determine whether a cross-sectional relationship exists between leptin and OA in a US population-based sample of adults at least 60 years of age.

Of the 2,589 subjects who had interviews and hand examinations, examination data were complete in 2,498. Nineteen patients with rheumatoid arthritis were excluded. Of 2,477 subjects that were eligible for the analysis, 1,056 (42.6%) had a serum leptin measurement and comprised our sample. Subjects with leptin measurements and those who did not have leptin measurements were similar with respect to demographic factors (age, sex, race, BMI) (see Additional file 1). Among those in our final sample, hand OA was symptomatic in 90 patients (8.5%), asymptomatic in 376 patients (35.6%), and not present in 590 patients (55.9%).

The mean age of the final sample was 70.3 ± 8.2 years and the mean BMI of the final sample was 26.4 ± 4.9 kg/m². Subjects with hand OA (both symptomatic and asymptomatic) were more likely to be female than those without hand OA. Subjects with symptomatic hand OA were more likely to be overweight (45%) and obese (25%) than those with asymptomatic hand OA (39% overweight and 16% obese). Detailed data on the demographic and clinical characteristics of our sample stratified by hand OA status are shown in Table 2.

Unadjusted mean leptin levels stratified by sex and all potential confounders are shown in Table 3. Among males, the unadjusted mean leptin level did not vary substantially by hand OA status. Those with no hand OA had a mean leptin of 8.22 (95% confidence interval (CI) = 7.47, 8.97) compared with 7.38 (95% CI = 5.31, 9.46) for those with symptomatic hand OA and 6.69 (95% CI = 5.19, 8.18) for those with asymptomatic hand OA. Among females, the unadjusted mean leptin did vary slightly by hand OA status, with those with asymptomatic hand OA having the lowest mean leptin at 17.09 (95% CI = 15.00, 19.18). However, all of the 95% CIs overlapped. The mean leptin for females with symptomatic hand OA was 21.55 (95% CI = 17.08, 26.02) and for no hand OA was 20.77 (95% CI = 18.01, 23.53). Mean leptin levels increased as BMI increased for both males and females.

Results of the linear regression showed similar findings to the unadjusted analysis. The final model included hand OA status, age, and obesity status. Race/ethnicity, diabetes, polyarticular OA, and total cholesterol were not included in the final model. Among males, the adjusted mean leptin for those with symptomatic hand OA was 8.88 (95% CI = 7.08, 10.67) compared with 8.21 (95% CI = 6.62, 9.80) for those with asymptomatic hand OA and 9.40 (95% CI = 8.59, 10.21) for those with no hand OA. Similarly, among females, the adjusted mean leptin for those with symptomatic hand OA was 21.89 (95% CI = 18.70, 25.07) compared with 20.13 (95% CI = 18.32, 21.95) for those with asymptomatic hand OA and 23.09 (95% CI = 21.83, 24.34) for those with no hand OA (Table 4). None of these differences in adjusted mean leptin levels was statistically significant (all P > 0.05).

The present study used data from NHANES III to describe the cross-sectional relationship between leptin and hand OA. The study did not provide evidence to support the hypothesis that hand OA is associated with increased serum leptin level. Stratified and multivariable analyses did not show evidence of a difference in leptin levels in the symptomatic hand OA, asymptomatic hand OA, and no hand OA groups. The multivariable analyses adjusted for age, race/ethnicity, BMI status, and the presence of polyarticular OA as indicated by radiographic knee OA, diabetes status, and serum cholesterol.

Our analyses have several important strengths. NHANES III has a large sample size, making it unlikely that we simply missed an effect due to chance. Also, selection bias is unlikely because the NHANES III sample was representative of the US population. Lastly, since we accounted for the complex sample design and used the sampling weights, the estimates are representative of the US population 22.

The study also has limitations. A possible explanation for our null result is that the association between hand OA and leptin is complex and cannot be assessed using a cross-sectional sample. Leptin may be associated with hand OA at one time point of its development only. However, in the longitudinal study carried out by Yusuf and colleagues, serum leptin was not found to be associated with hand OA progression in 6-year follow-up of 248 participants 19. The paper by Yusuf and colleagues used a longitudinal design with a radiographic case definition 19. In the present cross-sectional study, we measured hand OA by an algorithm that incorporates symptoms and physical examination. These two approaches are complementary, and neither supports an association between serum leptin and hand OA.

Another explanation for the null result is the possible misclassification of hand OA in NHANES III. There is no gold standard for the diagnosis of hand OA. Our use of the classification criteria suggested by Dillon and colleagues could have resulted in misclassification. Many patients with early or developing OA start with pain, followed by delayed onset of bony enlargement for months or years. Using our criteria, these subjects would be categorized as having no OA. Misclassification of this sort would tend to bias associations toward the null and could indeed play a role in our negative findings.

As expected, our results confirmed that leptin is associated with gender and BMI status, consistent with prior animal and human studies 30313233. These findings provide face validity for the leptin measurements. Our study is the largest population-based confirmation of such a relationship in humans, with prior studies in the literature having sample sizes ranging from 87 to 426 subjects 30313233.

We did not find a cross-sectional association between hand OA and serum leptin in our sample. Prospective studies are needed to further evaluate the possibility that elevated leptin levels predate the onset or progression of clinically apparent hand OA.

BMI: body mass index; CI: confidence interval; NHANES III: Third National Health and Nutrition Examination Survey; OA: osteoarthritis.

The authors declare that they have no competing interests.

All authors read and approved the manuscript for publication. MM was involved in the conception and design of the study, analysis and interpretation of the data, drafting the article, and critical revision of the article for important intellectual content. WMR was involved in the analysis and interpretation of data, drafting the article, critical revision of the article for important intellectual content, statistical expertise, and collection and assembly of data. EL was involved in conception and design of the study, analysis and interpretation of the data, critical revision of the article for important intellectual content, and statistical expertise. DHS was involved in the analysis and interpretation of the data and critical revision of the article for important intellectual content. JNK was involved in conception and design of the study, analysis and interpretation of the data, critical revision of the article for important intellectual content, final approval of the article, and takes responsibility for the integrity of the work as a whole, from inception to finished article.