Obesity and osteoarthritis of the knee joint: Is leptin the missing link?

Introduction

Osteoarthritis (OA), a clinical classification for a combination of pathological conditions involving progressive degeneration of articular cartilage, remodeling of subchondral bone, and synovitis (usually limited to the affected joint), commonly affects the knee joint.[1] OA of the knee has been demonstrated to be a complex process that includes multiple changes in the joint components such as cells, matrix, and molecular production. However, despite its prevalence throughout history, the etiology is yet to be fully understood. OA is a multifactorial disease with both genetic and environmental determinants.[2,3] Obesity has been linked to OA, but is most strongly linked to the knee joint.[3] Although some studies have found a cross-sectional association between obesity and OA of the knee joint (including a four-fold increase in radiographic OA of the knee joint in obese women),[3,4] how obesity causes OA of the knee joint has been of considerable debate.

Two major theories have been proposed to explain the association: biomechanical and metabolic theories. The biomechanical theory infers that obesity leads to repetitive application of increased axial loading of the knee with consequent degeneration of the articular cartilage and sclerosis of the subchondral bone.[5] However, the association between obesity and OA in nonweight-bearing joints such as those of the hands/or wrist suggests that other factors may yet play a role. The metabolic theory infers that there is a role for adipokines, especially leptin which has received major attention because of its correlation to body size. Leptin is a glycosylated peptide hormone encoded by the obese gene (ob), and is mainly produced by the adipocytes.[6] Leptin may produce pro-inflammatory and catabolic effects on the cartilage through induction of matrix metalloproteinases and nitric oxide and production of pro-inflammatory cytokines.[7] These factors can lead to articular cartilage damage.

The most common method of radiographic classification of knee OA is the Kellgren–Lawrence (K–L) radiographic grading scheme and Atlas which has been used for more than four decades.[8] It grades OA into the following five levels (from 0 to 4):

• Grade 0 – No abnormality

• Grade 1 – Incipient OA, beginning of osteophyte formation on eminences

• Grade 2 – Moderate joint space narrowing, moderate subchondral bone sclerosis

• Grade 3 – >50% joint space narrowing, rounded femoral condyle, extensive subchondral sclerosis, and extensive osteophyte formation

• Grade 4 – Joint destruction, obliterated joint space, subchondral cysts, and subluxation of the joint.

The objective of this study was to determine if there is a correlation between serum leptin levels and radiological severity of OA of the knee joint in obese patients.

Materials and Methods

This was a prospective study involving 100 patients with OA of the knee joint attending the outpatient department of Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria, between July 2016 and June 2017. Fifty of these patients were obese (body mass index [BMI] ≥30) and the other fifty were nonobese (BMI ≤30).

Approval was sought and obtained from the Nnamdi Azikiwe University Teaching Hospital (on the December 03, 2015, with protocol number: NAUTH/CS/66/VOL. 8/34).

Inclusion criteria were patients diagnosed with OA of the knee joint who voluntarily gave their consent for the study. Patients who had prior surgery, or who had grade 0/1 radiologic knee OA (—K–L), or who refused to give consent were excluded from the study. Grades 2, 3, and 4 were classified as mild, moderate, and severe knee OA, respectively.

The sample size was calculated based on the statistical formula (Daniel, 1999)[9] as shown below:

n = Z² P (1 −P)/d²

where n = sample size,

Z = Statistic for level of confidence; at 95% level of confidence which is conventional, Z value is 1.96,

P = Expected prevalence or proportion. Value of 7% was chosen for this study,[10]

d = Absolute precision, i.e., the value required (in percentage points) which in actual term describes the maximum difference between the population rate and the sample rate that can be tolerated. 5% (0.05) was taken for this study.

Therefore,

n = (1.96)² 0.07 (1 − 0.07)/(0.05)²

=100.03, which is approximately 100.

Therefore, 100 patients were recruited for this study.

Results

A total of 100 patients (fifty each in the obese and nonobese groups) were recruited into this study and analyzed. The age range was from 45 to 79 years, with a mean age of 59 ± 7.2 years.

Table 1 shows that the most commonly affected age group was 51–60 years.

Table 1 Age distribution of the patients

Figure 1 shows a female preponderance with a female-to-male ratio of 2.4:1.

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Figure 1

Sex distribution of the patients

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Table 2 shows no statistically significant difference among the age groups of the obese and nonobese groups.

Table 2 Mean age across the obese and nonobese groups

Table 3 shows that the serum leptin levels were significantly higher in the obese patients, and thus there is a positive correlation between serum leptin and BMI (U = 142.00, P < 0.001).

Table 3 Correlation between serum leptin level and body mass index

Table 4 shows the difference in mean leptin levels across the radiological severity groups in nonobese patients. This difference is weakly statistically significant.

Table 4 Correlation between serum leptin levels and radiological severity in nonobese patients

Table 5 shows the difference in mean leptin levels across the radiological severity groups in obese patients. This difference is statistically significant. Post hoc analysis was done to determine which subgroup had more correlation with serum leptin levels.

Table 5 Correlation between serum leptin level and radiological severity in obese (body mass index >30) patients

Table 6 shows that patients with severe radiological features had statistically significant higher leptin levels when compared to those with mild and moderate radiological features.

Table 6 Post hoc test of the correlation between serum leptin and radiological severity

Discussion

This was a prospective study conducted to establish the role of serum leptin in obese patients with OA of the knee joint. It highlighted the correlation between serum leptin levels and obesity and also the correlation between serum leptin level and the radiological severity of OA of the knee joint.

OA of the knee joint was found to occur most commonly within the age range of 51–70 years, with a peak age of occurrence within the 50–60 years' age group. This is similar to the findings of Adebusoye et al.[11] and Ebong,[12] where the most commonly involved age bracket was also between 51 and 65 years. It also agrees with documentation in other literature that OA of the knee joint occurs commonly in females.[13] Similarly, the average age of patients with OA of the knee joint in this study was 59 ± 7.2 years; this agrees with the mean age of 52 years reported by Ebong [12] and also by Kaur et al.[13] in their series.

The current study found a female preponderance, with a female-to-male ratio of 2.4:1, which is within the ratio found by Ebong.[12] However, this was slightly different from the ratio of 3.5:1 found by Akinpelu et al.[13] and 4.95:1 reported by Ojoawo et al.[14] These differences are probably due to the influence of the population being studied on the distribution of OA of the knee joint.

The mean serum leptin level in nonobese patients in this study was 4.88 ± 5.09 ng/ml, whereas that in obese patients was 20.11 ± 15.04 ng/ml; this difference was statistically significant. This difference between the obese and nonobese groups agrees with the study done by Chow and Phoon [15] where overweight/obese individuals generally demonstrate higher circulating leptin concentration than healthy weight/nonobese individuals. This difference was also statistically significant. Similarly, it also agrees with the findings reported by Usman et al.[16] where the mean leptin level was 16.59 ± 13.56 ng/ml compared to that in the nonobese group of 5.58 ± 6.30 ng/ml. A statistically significant positive correlation between obesity and serum leptin level was also found in this study.

In this study, there was a positive correlation between serum leptin level and radiological severity as graded by the K–L classification system.[8] This is in agreement with a study done by Ellaban et al.[17] who found a highly significant correlation between serum leptin and the K–L score of the knee joint. It is also in agreement with the study done by Misra et al.[18] where a positive correlation was found between serum leptin and the severity of knee OA.

In contrast to these findings, in a study by Iwamoto et al.[19] done on postmenopausal Japanese women with OA of the knee joints, it was found that there is no significant correlation between the serum leptin concentration and the radiographic grade of knee OA. This may be due to the different management protocols and inclusion criteria, as most of their patients were receiving weekly to monthly intra-articular injections of hyaluronate.

Conclusion

OA of the knee joint is a common disorder, often characterized by pain, cartilage damage, and joint dysfunction. Although the mechanism of action of leptin in OA in obese patients is still unclear, its role cannot be ignored. This study showed a positive correlation between serum leptin and BMI and also between serum leptin and radiological severity of knee OA. A study by Jiang et al.[20] suggests that resveratrol may relieve OA pathology in obese patients by reducing systemic inflammation and/or inhibiting toll-like receptor 4 signaling in cartilage. It would be pertinent to note in further studies if drugs reducing serum leptin would lead to an alleviation of pathology in obese patients.