Wu et al.

BMC Musculoskeletal Disorders (2018) 19:16

DOI 10.1186/s12891-018-1936-7

RESEARCH ARTICLE Open Access

Associations between circulating

adipokines and bone mineral density in
patients with knee osteoarthritis: a cross-
sectional study
Juan Wu1 , Jianhua Xu1, Kang Wang1,2, Qicui Zhu1, Jingyu Cai1, Jiale Ren1, Shuang Zheng2 and
Changhai Ding1,2,3*

Abstract
Background: Associations between adipokines and bone mineral density (BMD) in knee osteoarthritis (OA) remain
indistinct. The aim of this study was to investigate the cross-sectional associations between serum levels of
adipokines and BMD in patients with knee OA.
Methods: This study included 164 patients with symptomatic knee OA from the Anhui Osteoarthritis study. Serum
levels of leptin, adiponectin, and resistin were measured using an enzyme-linked immunosorbent assay (ELISA).
BMD at total body, spine, hip, and femur were measured by dual-energy X-ray absorptiometry (DXA).
Results: In multivariable analyses, serum levels of leptin were significantly associated with reduced BMD at total body,
hip, total femur, femoral neck, and femoral shaft (β = − 0.019, 95% CI -0.034 to − 0.005; β = − 0.018, 95% CI -0.034 to − 0.
003; β = − 0.018, 95% CI -0.034 to − 0.002; β = − 0.016, 95% CI -0.032 to 0.000; β = − 0.026, 95% CI -0.046 to − 0.006;
respectively). Serum levels of adiponectin were significantly and negatively associated with BMD at total femur and
femoral shaft (β = − 0.007, 95% CI -0.013 to 0.000; β = − 0.011, 95% CI -0.018 to − 0.003; respectively). However, no
significant associations were found between serum levels of resistin and BMD at any site measured.
Conclusions: Serum levels of leptin and adiponectin were significantly and negatively associated with BMD,
suggesting potentially detrimental effects of leptin and adiponectin on BMD in knee OA patients.
Keywords: Adiponectin, Bone mineral density, Leptin, Osteoarthritis, Resistin

Background obesity-increased joint loading could not account for the

Osteoarthritis (OA) is the most prevalent joint disease associations between OA and non-weight-bearing joints
worldwide, characterized by gradual loss of articular such as hand and shoulder joints. Recent studies consid-
cartilage, synovial inflammation, osteophyte formation, ered that obesity-related metabolic inflammation might
and other structural changes. OA affected approximately contribute to OA [2, 3].
18% of women and 10% of men aged over 60 years Adipokines, including leptin, adiponectin, and resistin
according to the WHO’s report [1]. which are mostly studied, are secreted by white adipose
Obesity is a well-recognized risk factor for OA, tissue, and have been found in synovial fluid and cartil-
particularly in the weight-bearing joints. However, age tissues obtained from OA patients [4, 5]. Leptin had
been shown to be positively associated with the severity
* Correspondence: [email protected] of OA [6, 7]; however, leptin was significantly associated
1
Department of Rheumatology and Immunology, Arthritis Research Institute, with increased knee cartilage volume in patients with
the First Affiliated Hospital of Anhui Medical University, 218 Jixi Street, Hefei,
China radiographic OA [8]. Another study [9] reported that
2
Menzies Institute for Medical Research, University of Tasmania, Private Bag leptin was not significantly associated with cartilage
23, Hobart, TAS 7000, Australia damage in OA patients. The role of adiponectin in OA
Full list of author information is available at the end of the article

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Wu et al. BMC Musculoskeletal Disorders (2018) 19:16 Page 2 of 7

remains inconclusive. Some studies suggested a protect- cross-sectional associations between serum adipokines
ive effect of adiponectin in OA [8, 10, 11], while others levels and BMD in patients with knee OA.
found no association [12, 13] or even a positive association
between serum adiponectin and disease severity in knee Methods
OA [14]. Studies regarding correlations between resistin Subjects
and OA are sparse and have been controversial [15, 16]. This study was part of the Anhui Osteoarthritis (AHOA)
The relationship between OA and bone mineral dens- Study, a clinical study of 205 patients aged 34-74 years,
ity (BMD) has been reported in various cross-sectional aimed to identify the environmental and biochemical fac-
and longitudinal studies, but remains controversial. Pre- tors associated with the progression of knee OA. Patients
vious studies revealed that higher BMD was associated with clinical knee OA, diagnosed using American College
with an increased risk of incident OA defined by osteo- of Rheumatology criteria [23], were consecutively re-
phyte or Kellgren-Lawrence (KL) grade, suggesting that cruited from the Department of Rheumatology and
increased BMD was a risk factor for OA [17–19], but a Immunology in the First Affiliated Hospital of Anhui
recent study using MRI reported a positive association Medical University, from January 2012 to November 2013.
between systemic and subchondral BMD and cartilage We excluded institutionalized patients, patients with
thickness in patients with radiographic OA, indicating rheumatoid arthritis or other inflammatory diseases, pa-
that BMD may play a protective role in OA [20]. tients with severe OA planning to have knee arthroplasty
Given that both adipokines and BMD might be in- in 2 years, patients who did not have blood samples so the
volved in the etiology of OA, they would have a close re- adipokines were not able to be measured, and patients
lationship; however, associations between adipokines and who didn’t have BMD measured due to personal reasons.
BMD in OA are rarely reported though numerous stud- Forty-one patients fulfilled the exclusion criteria and
ies reported the associations between adipokines and therefore were excluded from this study, leaving 164 pa-
BMD in healthy human which remains controversial. tients. The study was approved by the First Affiliated Hos-
One study was conducted in 60 postmenopausal women pital Anhui Medical University ethics committee (the
with hip or knee OA and reported no correlation ethics approval number: H1000589), and written informed
between leptin and BMD [21]. Another study found that consent was obtained from all participants according to
whole body BMD was positively correlated with the the Declaration of Helsinki.
serum leptin level in 50 postmenopausal women with
knee OA, but the correlation disappeared after adjust- Anthropometrics
ment for covariates [22]. To the best of our knowledge, Weight was measured to the nearest 0.1 kg (with shoes,
there were no studies reporting the associations between socks and bulky clothing removed) by using a single pair
adiponectin, resistin and BMD in OA patients so far. of electronic scales that were calibrated using a known
The aim of this study, therefore, was to investigate the weight at the beginning. Height was measured to the
Table 1 Characteristics of participants (split by median level of leptin)
Total (n = 164) Leptin ≤ median (n = 82) Leptin > median (n = 82) p value
a
Age, yrs 55.42(8.57) 54.57(8.94) 56.27(8.14) 0.206
Females, %b 88.4 81.7 95.1 0.015
a
Height, cm 158.64(6.83) 158.62(7.70) 158.66(5.90) 0.971
Weight, kga 65.07(10.29) 63.00(9.57) 67.08(10.61) 0.012
2a
BMI, kg/m 25.84(3.75) 24.98(2.83) 26.68(4.32) 0.004
BMD, kg/m2
Total bodya 10,55(1.22) 10.64(1.41) 10.46(1.02) 0.361
Spinea 10.03(1.34) 10.09(1.66) 9.99(1.08) 0.709
a
Hip 8.65(1.23) 8.90(1.42) 8.47(1.06) 0.060
Total femura 9.31(1.30) 9.43(1.37) 9.21(1.24) 0.283
b
Knee ROA, % 71.95 78.05 65.85 0.082
Adiponectin, ug/mlc 27.09(6.80,60.88) 11.73(3.56,35.25) 49.70(20.62,74.10) < 0.001
c
Resistin, ng/ml 2.22(1.40,4.55) 2.06(1.17,4.39) 2.27(1.48,4.63) 0.327
Leptin median level: 5.92 ng/ml
Data in bold denote statistically significant results
BMI body mass index, BMD bone mineral density, BMC bone mineral content, ROA radiographic osteoarthritis
a
t tests were used for mean (standard deviation), bx2 tests for the proportions, cMann-Whitney U tests for median (interquartile range)
Wu et al. BMC Musculoskeletal Disorders (2018) 19:16 Page 3 of 7

nearest 0.1 cm (with shoes, socks and headgear regression analyses were used to examine the associations
removed) by using a stadiometer. Body mass index between adipokines and BMD before and after adjustment
(BMI) was calculated [weight (kg)/height (m)2]. for age, sex, BMI and ROA. Scatter plots were also used
to depict the associations between adipokines and BMD
Serum adipokines measurements after adjustment for the above-mentioned covariates.
Fasting blood was obtained from all patients in the morn- Standard diagnostic checks of model fit and residuals were
ing. Serum was separated and aliquotted into plastic stor- routinely made, and data points with large residuals and/
age tubes. Aliquots were stored at − 80 °C till analysis. or high influence were investigated for data errors. A p
Serum levels of leptin, adiponectin, and resistin were mea- value < 0.05 (two-tailed) or a 95% confidence interval (CI)
sured by using enzyme-linked immunosorbent assay not including the null point was regarded as statistically
(ELISA; eBioscience, USA) kits, according to the manufac- significant. All statistical analyses were performed using
turer’s instructions. The intra- and inter-assay coefficient SPSS 13.0 for Windows (SPSS, Chicago, IL, USA).
of variations for leptin, adiponectin, and resistin were 5.7
and 6.9%, 4.2 and 3.1%, 5.1 and 8.1%, respectively. Results
A total of 164 subjects between 34 and 74 years of age
BMD measurement (mean, 55.4 yrs) participated in our study. Of these, all
BMD of the total body, spine, hip and total femur, including subjects measured the BMD of total body and total femur,
femoral neck, Wards triangle, greater trochanter, and however, only 133 subjects measured the BMD of spine
femoral shaft were measured using dual-energy x-ray and hip. There were no significant differences in demo-
absorptiometry (DXA) (Lunar Prodigy DF + 310,504, GE graphic factors (age, sex, and BMI) between these partici-
Healthcare, USA). BMD was calculated from the bone area pants and those excluded (n = 41; data not shown).
(cm2) and bone mineral content (g) and expressed in g/cm2 Characteristics of the participants are presented in Table 1.
[24]. The unit of BMD was converted to kg/m2 to keep the The mean BMI was 25.84 kg/m2. The median levels of
levels of adipokines and BMD at the similar magnitudes. leptin, adiponectin, and resistin were 5.92 ng/ml, 27.09μg/
ml, and 2.22 ng/ml, respectively. Subjects with higher and
Knee radiographic assessment lower levels of leptin (split at the median level) were simi-
A standing anteroposterior semiflexed view of the dis- lar in age, height, BMD at all sites measured, prevalence
eased knee (the severer one if both were affected) with of ROA and levels of resistin; however, subjects with
15° of fixed knee flexion, was performed in all partici- higher leptin levels had greater proportion of females,
pants. KL grading system (grades 0-4) was used to assess higher weight, higher BMI and higher adiponectin levels.
the radiographic severity of OA [25]. Radiographic OA There were no interactions between serum levels of adi-
(ROA) was defined as KL grade of ≥2. pokines and sex on the BMD (data not shown). Therefore,
males and females were combined for analyses in our study.
Statistical analysis Associations between leptin and BMD were shown in
Student’s t tests, Mann-Whitney U tests or chi-squared Table 2. In univariable analyses, we did not find any
tests were used to compare means, median or propor- significant associations between serum levels of leptin
tions, respectively. Univariable and multivariable linear and BMD at any site measured. However, after
Table 2 Associations between leptin and BMD in various regions
Univariable Multivariablea
β(95% CI) p value β(95% CI) p value
Total body BMD −0.011(− 0.026,0.004) 0.155 − 0.019(− 0.034,-0.005) 0.009
Spine BMD 0.004(− 0.013,0.021) 0.653 − 0.010(− 0.028,0.007) 0.248
Hip BMD − 0.010(− 0.025,0.006) 0.213 − 0.018(− 0.034,-0.003) 0.018
Total femur BMD − 0.007(− 0.023,0.008) 0.352 − 0.018(− 0.034,-0.002) 0.024
Femoral neck −0.010(− 0.025,0.006) 0.218 −0.016(− 0.032,0.000) 0.048
Wards triangle −0.007(− 0.025,0.011) 0.462 −0.012(− 0.029,0.006) 0.194
Greater trochanter −0.004(− 0.018,0.009) 0.538 −0.013(− 0.026,0.001) 0.074
Femoral shaft −0.008(− 0.028,0.011) 0.386 −0.026(− 0.046,-0.006) 0.012
Dependent variable: BMD in respective compartment
Independent variable: leptin
Data in bold denote statistically significant results
BMD bone mineral density, BMI body mass index, ROA radiographic osteoarthritis
a
Adjusted for age, sex, BMI and ROA
Wu et al. BMC Musculoskeletal Disorders (2018) 19:16 Page 4 of 7

Fig. 1 Scatter plot for associations between serum levels of leptin and bone mineral density (BMD). In multivariable analyses, higher serum levels
of leptin were associated with lower BMD at total body (a) and hip (b)

adjustment for age, sex, BMI and ROA, serum levels of Discussion
leptin were significantly associated with reduced BMD at The present study investigated the cross-sectional asso-
total body, hip, femoral neck, femoral shaft, and total ciations between adipokines (including leptin, adiponec-
femur (Table 2, Fig. 1). tin, and resistin) and BMD in patients with knee OA.
Serum adiponectin was significantly and negatively We found that the serum leptin levels were negatively
associated with BMD at femoral shaft and total femur in associated with total body, hip and total femur (includ-
univariable analyses. These negative associations ing femoral neck and femoral shaft) BMD. Serum adipo-
remained unchanged after adjustment for the covariates nectin was also significantly associated with reduced
mentioned above (Table 3, Fig. 2). We did not find any BMD at total femur and femoral shaft. In contrast, no
significant associations between serum adiponectin and association was found between serum resistin and BMD.
BMD at total body, spine, and hip. The association Leptin, a protein encoded by the ob gene, was found
between adiponectin and femoral neck BMD was also to regulate bone metabolism. Various studies have
negative but of borderline statistical significance demonstrated the association between leptin and BMD.
(Table 3). Ducy et al. [26] found that intracerebroventricular infu-
The associations between serum resistin and BMD at sion of leptin induced bone loss in both leptin-deficient
any site did not reach statistical significance before and and wild-type mice, suggesting that leptin could inhibit
after adjustment for age, sex, BMI and ROA (Table 4). bone formation acting through the hypothalamus.

Table 3 Associations between adiponectin and BMD in various regions

Univariable Multivariablea
β(95% CI) p value β(95% CI) p value
Total body BMD −0.005(− 0.010,0.000) 0.072 −0.002(− 0.007,0.003) 0.432
Spine BMD −0.006(− 0.013,0.002) 0.123 −0.002(− 0.010,0.005) 0.518
Hip BMD −0.006(− 0.012,0.001) 0.100 −0.002(− 0.009,0.004) 0.456
Total femur BMD −0.006(− 0.012,0.000) 0.034 −0.007(− 0.013,0.000) 0.030
Femoral neck −0.006(− 0.011,0.000) 0.061 −0.005(− 0.011,0.001) 0.088
Wards triangle −0.005(− 0.012,0.002) 0.137 −0.004(− 0.010,0.003) 0.234
Greater trochanter −0.004(− 0.009,0.001) 0.116 −0.002(− 0.007,0.003) 0.436
Femoral shaft −0.008(− 0.015,-0.001) 0.025 −0.011(− 0.018,-0.003) 0.006
Dependent variable: BMD in respective compartment
Independent variable: adiponectin
Data in bold denote statistically significant results
BMD bone mineral density, BMI body mass index, ROA radiographic osteoarthritis
a
Adjusted for age, sex, BMI and ROA
Wu et al. BMC Musculoskeletal Disorders (2018) 19:16 Page 5 of 7

Fig. 2 Scatter plot for associations between serum levels of adiponectin and bone mineral density (BMD). In multivariable analyses, higher serum
levels of adiponectin were associated with lower BMD at total femur (a) and femoral shaft (b)

Epidemiological studies reported that serum leptin con- change [32, 33]. It was noteworthy that these studies
centrations were inversely associated with calcaneal mentioned above were conducted in healthy persons.
BMD after adjustment for body weight in 221 healthy Only two clinical studies investigated the association
adult men [27], and leptin had a negative correlation between leptin and BMD in OA [21, 22] and reported
with lumbar spine BMD in perimenopausal healthy inconsistent results. Our study found that serum leptin
women [28]. On the contrary, some studies reported a was significantly associated with reduced BMD in
positive association between leptin and BMD. Martin et patients with knee OA, independent of age, sex, BMI,
al. [29] demonstrated that peripheral administration of and ROA. This suggests that leptin may play a
leptin could prevent disuse-induced bone loss through potentially detrimental effect on BMD in knee OA.
inhibiting the increase in bone resorption mediated by Adiponectin was considered to have a negative effect
the RANKL/OPG and preventing the decrease in bone on bone metabolism. Adiponectin levels were negatively
formation in tail-suspended female rats. Blain et al. [30] associated with femoral neck and total body BMD in
found that leptin was positively associated with whole postmenopausal women after adjustment for potential
body and femoral neck BMD in 155 postmenopausal confounders [32], and highest tertile of adiponectin had
women. Weiss et al. [31] reported that leptin predicted significantly greater hip BMD loss than the lowest tertile
an increase in BMD in postmenopausal women but not of adiponectin in women [33]. A meta-analysis indicated
older men after adjustment for age, BMI, and other bone that adiponectin was the mostly relevant adipokine that
related factors. In addition, several clinical studies re- was negatively associated with BMD in healthy subjects,
ported no association between leptin and BMD or BMD regardless of menopausal status and gender [34].

Table 4 Associations between resistin and BMD in various regions

Univariable Multivariablea
β(95% CI) p value β(95% CI) p value
Total body BMD 0.005(−0.042,0.053) 0.825 0.005(−0.037,0.048) 0.801
Spine BMD −0.022(− 0.117,0.072) 0.639 − 0.024(− 0.120,0.071) 0.612
Hip BMD − 0.005(− 0.093,0.083) 0.913 0.012(− 0.072,0.096) 0.777
Total femur BMD − 0.010(− 0.061,0.042) 0.712 −0.007(− 0.056,0.043) 0.792
Femoral neck −0.023(− 0.075,0.029) 0.376 −0.023(− 0.073,0.027) 0.358
Wards triangle −0.030(− 0.090,0.030) 0.327 −0.031(− 0.086,0.023) 0.257
Greater trochanter −0.014(− 0.059,0.031) 0.528 −0.012(− 0.054,0.030) 0.568
Femoral shaft 0.002(−0.062,0.066) 0.951 0.003(−0.061,0.067) 0.918
Dependent variable: BMD in respective compartment
Independent variable: resistin
BMD bone mineral density, BMI body mass index, ROA radiographic osteoarthritis
a
Adjusted for age, sex, BMI and ROA
Wu et al. BMC Musculoskeletal Disorders (2018) 19:16 Page 6 of 7

Oshima et al. [35] reported that adiponectin supplement Acknowledgments

increased bone mass in trabecular bone via inhibiting We would like to thank the participants who made this study possible, and
thank the staff and volunteers who collected the data.
osteoclast and activating osteoblast. In contrast, Konto-
gianni et al. [28] found no associations between adipo- Funding
nectin and lumber spine BMD in perimenopausal This study was supported by the National Natural Science Foundation of
China (81172865).
women, and Barbour et al. [33] found adiponectin levels
were not correlated with whole-body areal BMD or Availability of data and materials
trabecular lumbar spine volumetric BMD loss in older The datasets used and analysed during the current study are available from
the corresponding author on reasonable request.
women and men. Our current study is the first to inves-
tigate the association between adiponectin and BMD in Authors’ contributions
patients with knee OA, indicating a potentially Study conception and design: CD and JX. Acquisition of data: JW, KW, QZ,
JC, JR and SZ. Analysis and interpretation of data: JW and CD. Drafting of the
detrimental effect of adiponectin on BMD in knee OA. article: JW and CD. Revising and final approval of the article: All authors.
Serum leptin levels are positively correlated with BMI,
while serum adiponectin levels are negatively correlated Ethics approval and consent to participate
The study was approved by the First Affiliated Hospital Anhui Medical
with BMI [36]. However, we found that both serum University ethics committee (the ethics approval number: H1000589), and
levels of leptin and adiponectin were negatively associ- written informed consent was obtained from all participants according to
ated with BMD in OA. The potential mechanism is un- the Declaration of Helsinki.

clear, and it needs to be further investigated. Consent for publication

So far, there are a few studies reporting the association Not applicable.
between resistin and BMD. Serum resistin was not asso-
Competing interests
ciated with BMD of total body, lumbar spine, and total The authors declare that they have no competing interests. Changhai Ding is
hip before and after adjustment for age and fat mass in a Deputy Section Editor of BMC Musculoskeletal Disorders.
232 Chinese men [37], and was not an independent pre-
dictor of BMD in 336 healthy postmenopausal Chinese Publisher’s Note
women aged 41-81 years [38]. One study reported that Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
serum resistin levels were significantly and negatively
associated with lumbar spine BMD in 80 middle-aged Author details
1
men [39]. In our current study, we didn’t find any Department of Rheumatology and Immunology, Arthritis Research Institute,
the First Affiliated Hospital of Anhui Medical University, 218 Jixi Street, Hefei,
significant association between serum resistin and BMD China. 2Menzies Institute for Medical Research, University of Tasmania, Private
in patients with knee OA. Bag 23, Hobart, TAS 7000, Australia. 3Institute of Bone & Joint Translational
There are several limitations in our study. First, due to Research, Southern Medical University, Guangzhou, Guangdong, China.
the cross-sectional nature, the causality between adipo- Received: 12 August 2017 Accepted: 11 January 2018
kines and BMD is not able to be determined. Further lon-
gitudinal studies are needed to verify our findings. Second,
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