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The relationship of resistin, leptin, adiponectin, and ghrelin with bone mineral density in healthy postmenopausal women: longitudinal analysis
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The relationship of resistin, leptin, adiponectin, and ghrelin with bone mineral density in healthy postmenopausal women: longitudinal analysis
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Content
THE RELATIONSHIP OF RESISTIN, LEPTIN,
ADIPONECTIN, AND GHRELIN WITH BONE MINERAL
DENSITY IN HEALTHY POSTMENOPAUSAL WOMEN:
LONGITUDINAL ANALYSIS
by
Song Wang
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)
August 2012
Copyright 2012 Song Wang
ii
Table of Contents
List of Tables iii
Abstract iv
1.0 Introduction 1
2.0 Methods 3
2.1 Study Design 3
2.3 Randomization and Data Collection 4
2.4 Bone Mineral Density (BMD) Measurements 4
2.5 Blood Adipocytokines and Ghrelin Measurements 5
2.6 Statistical Analysis 5
3.0 Results 7
3.1 Baseline Characteristics 7
3.2 BMD change over time 7
3.3 Adipocytokines and ghrelin change over time 8
3.4 Annualized change rates in BMD by baseline characteristics 8
3.5 Annualized change rates in adipocytokines and ghrelin by baseline
characteristics 9
3.7 Association between baseline BMD levels and adipocytokines and
ghrelin in multivariate mixed linear models 10
4.0 Discussion 25
5.0 References 29
iii
List of Tables
Table 1. Baseline characteristics of WISH participants (n=350) 11
Table 2. Bone mineral density (in g/cm
2
) for 0, 12, 30 visit in different
treatment groups. 14
Table 3. Adipocytokines and ghrelin for 0, 6, 12, 18, 24, 30 visits by
treatment group. 15
Table 4. Associations of annualized change rates in bone mineral density
with baseline characteristics 17
Table 5. Associations of annualized change rates in adipocytokines and
ghrelin with baseline characteristics 20
Table 6. Associations of annualized change rates in bone mineral density
with adipocytokines and ghrelin 23
Table 7. Associations between baseline bone mineral density levels and
adipocytokines and ghrelin in multivariate analysis 24
iv
Abstract:
Purpose: We investigated the relationship between annualized rates of change in
bone mineral density (BMD) and serum resistin, leptin, adiponectin, and ghrelin
in healthy postmenopausal women.
Methods: Adipocytokines (resistin, leptin, adiponectin), ghrelin, and BMD (lumbar
spine, femoral neck, and total hip) were collected from 350 healthy
postmenopausal women in the Women’s Isoflavone Soy Health (WISH) trial at 0,
6, 12, 18, 24 and 30 months (adipocytokines and ghrelin) and at 0, 12 and 30
months (BMD). For the statistical analysis, we used mixed multiple linear
regression models to investigate the impact of serum levels of adipocytokines
and ghrelin on annualized rates of change in BMD.
Results: Resistin, adiponectin, leptin and ghrelin were not significantly related to
annualized rates of change in BMD (all p-values > 0.05). Leptin had a positive
impact on annualized change rates in femoral neck BMD. Resistin, ghrelin, and
adiponectin were inversely but not significantly associated with rates of change in
BMD of the femoral neck in the multivariable analysis (all p-values > 0.1). After
adjusting for treatment group, race, BMI, DBP, weekly hours in vigorous activity
and weekly hours in vigorous activity interaction with time, leptin and ghrelin were
marginally associated with rates of change in total hip BMD (p=0.06 and p=0.09
separately); resistin and adiponectin were not significantly associated with
change in total hip BMD. Leptin, resistin, ghrelin and adiponectin were not
v
significantly associated with annualized change rates in lumbar spine BMD after
controlling for treatment group, age, race, BMI and age interaction with time (all
p-values > 0.10).
Conclusion: Resistin, leptin, adiponectin, and ghrelin do not significantly relate to
annualized rates of change in BMD in healthy postmenopausal women.
Key words: adipocytokines, resistin, adiponectin, leptin, ghrelin, bone mineral
density, postmenopausal women.
1
1.0 Introduction
More than 10 million Americans have osteoporosis and postmenopausal women
are a high risk population for this disease because of the dramatic reduction in
estrogen levels (14, 4). Osteoporosis directly leads to loss of height, low back
and neck pain, bone pain or tenderness, and fractures (1). Fifty-percent of
women will have an osteoporosis-related fracture in their life-time (14). Higher
body mass index (BMI) is known to have a protective effect on bone mineral
density (BMD) (5). Moreover, increasing BMI relates to increasing amounts of
adipose tissue that secrete hormones that are considered to relate to bone mass
(19). Ghrelin also has inference on weight and BMD in women (3, 10).
Adipose tissue is a major endocrine organ that secretes a number of
adipocytokines, including resistin, adiponectin and leptin. In human biology,
resistin levels may relate to obesity or diabetes since this adipocytokine regulates
insulin resistance (2, 21). Adiponectin has complex metabolic functions on fat
mass and BMD and is inversely associated with body mass from previous
researches (eg. 9). High levels of leptin inhibit appetite and regulating human
weight (10, 19). Ghrelin is not an adipocytokine but a hunger-stimulating peptide
and hormone secreted predominantly from the stomach and pancreas that is
associated with increases in body mass by stimulating appetite (17, 9, and 15). It
is proposed that ghrelin and leptin counter each other’s actions resulting in
satiation and hunger signaling. Both body composition and hormonal levels are
2
important predictors of bone mineral density (BMD) in postmenopausal women (6,
9). However, few studies have evaluated the effects of serum adipocytokines and
ghrelin levels on BMD changes (9, 16, 3, and 13). Therefore, we hypothesized
that high serum adipocytokines and ghrelin level would have influence on rates of
change in BMD in healthy postmenopausal women.
3
2.0 Methods
2.1 Study Design: This is an ancillary analysis from the Women’s Isoflavone
Soy Health (WISH) trial, a randomized, double-blind, placebo-controlled trial
testing whether high-dose isflavone-rich soy protein (ISP) supplementation
positively effects health outcomes, including, atherosclerosis, osteoporosis,
cognition, and breast density, in healthy postmenopausal women without pre-
existing cardiovascular disease (8). The WISH trial recruited over a 2-year period
and women were followed on randomized treatment for 2.5 to 3 years.
2.2 Subjects: 350 postmenopausal women without vaginal bleeding for at
least 1 year and serum estradiol level <20 pg/ml were recruited for the WISH trial.
All subjects signed an informed consent that was approved by the University of
Southern California Institutional Review Board. Eligible participants were: free of
medical signs, symptoms or personal history of cardiovascular disease; without
diabetes mellitus (fasting serum blood glucose<140 mg/dL); had serum
triglyceride levels<500 mg/dL and serum creatinine<2.0 mg/dL; free of
hypertension (systolic blood pressure<160 mmHg and/or diastolic blood
pressure<110 mmHg); had no thyroid disease or any endangering life diseases
with a prognosis diagnosed < 5 years; no alcohol abuse (usage <5 drinks per
day); no allergy with certain trial-related food (soy, nut, etc.); and, not taking any
hormone replacement therapy or related medications to reduce menopause
symptoms.
4
2.3 Randomization and Data Collection: 350 women were randomly
assigned into two groups (175 each group), within strata defined by baseline
CIMT (< 0.75 mm, > 0.75 mm). For the active treatment group, subjects received
25 g soy protein daily that contained 85 mg aglycone weight isoflavones (150 mg
total isoflavones) of genistein 45 mg aglycone weight (80 mg total weight),
daidzein 35 mg aglycone weight (60 mg total weight) and glycitein 5 mg aglycone
weight (10 mg total weight).The placebo group took the same amount of milk
protein substitute with 0 isoflavones.
All participants were scheduled for clinic visits every month for the first 6 months.
For the remaining follow-up, participants visited the clinic every other month. At
baseline and every 6 month visit, plasma isoflavone and lipid levels were
measured. Adipocytokines and ghrelin were obtained from blood and urine
samples at baseline, 6, 12, 18, 24 and 30 months.
2.4 Bone Mineral Density (BMD) Measurements: Subjects completed dual-
energy x-ray absorptiometry (DXA) bone scans at baseline, 12 and 30 months.
BMD was measured by DXA using a Hologic Bone Densitometer (Waltham, MA)
over multiple sites. Since the lumbar spine, femoral neck and total hip are most
likely affected areas from osteoporosis, they are measured most commonly for
diagnosis of osteoporosis and monitoring bone loss over time (12, 18). Therefore,
these sites were used in these analyses.
5
2.5 Blood Adipocytokines and Ghrelin Measurements: At 0, 6, 12, 18, 24
and 30 months, blood samples were drawn from all subjects after a 10 hour fast.
Serum leptin was measured using a highly specific radioimmunoassay using
reagents obtained from Linco Research (St. Charles, MO). The assay sensitivity
is 0.5 ng/ml, and the interassay coefficients of variation (CVs) are 6.2%, 4.7%
and 3.6% at 4.9 ng/ml, 10.4 ng/ml and 25.6 ng/ml, respectively. Adiponectin was
measured by a competitive direct RIA. The assay sensitivity is 1 ng/ml, and the
interassay CVs are 9.2%, 6.9% and 9.2% at 1.5 ng/ml, 3.0 ng/ml and 7.5 ng/ml,
respectively. Total ghrelin was also quantified by a competitive RIA. The assay
sensitivity is 93 pg/ml, and the interassay CVs are 14.7%, 16.0% and 16.7% at 1
ng/ml, 2 ng/ml and 3 ng/ml, respectively.
2.6 Statistical Analysis: All statistical analyses used SAS version 9.2. Mixed
multiple linear regression models were used to determine the relationship
between serum adipocytokines or ghrelin levels and rates of change in BMD. The
primary independent variables included the baseline levels of resistin,
adiponectin, leptin and ghrelin and dependent variables were lumbar spine,
femoral neck and total hip BMD measured at 0, 12 and 30 months. Random
effects were specified for individual subject variation for the levels of bone
density (intercept) and rates of change of bone density (slop). To model
associations with BMD rate of change, an additional independent variable was
time (in months after randomization) at which the BMD measurements were
obtained. The main effects of adipocytokines and ghrelin levels estimated their
6
association with baseline BMD; the interaction of adipocytokines and ghrelin with
follow-up time estimated their association with BMD rate of change. For analysis,
we focus on the associations of adipocytokines with the rates of change of BMD
rather than comparing the two treatment groups on BMD. However, since this
was a clinical trial, we included the treatment group and its interaction with follow-
up time to control for treatment effects on BMD change. Other variables
considered as possible confounders included age, race, baseline diastolic blood
pressure (DBP), baseline systolic blood pressure (SBP), baseline body mass
index (BMI), physical activity, years since menopause, type of menopause,
marital status, employment status, and annual income. These variables were
included as independent variables in the multivariate random effects models if
they were associated with BMD change rates in univariate models (p<0.1). In the
multivariate models, nonsignificant associations between independent variables
and BMD were eliminated using backward procedures selection with significance
set at p<0.1.
7
3.0 Results
3.1 Baseline Characteristics: A total of 350 postmenopausal women were
randomized to either active soy (n=175) or placebo groups (n=175).Baseline
demographic and clinical characteristics including age, race, marital status,
income, employment status, BMI, exercise, blood pressure, and menopause
were well balanced between soy and placebo groups (Table 1). The average age
at randomization was 60.6 years, and ranged from 44 to 91 years. The majority
of the subjects (56%) were older than 60 years and were non-Hispanic white
63.7%, and overweight or obese (BMI≥25 kg/m
2
, 57%). The average years since
women experienced menopause was 11.2 years (range 1 to 50). The vast
majority of the women (89.97%) experienced natural menopause. Most of the
participants exercised moderately (average 5 hours per week of moderate
physical activity) and a few reported vigorous activity (Table 1).
3.2 BMD change over time: Table 2 summarizes the mean (SD) BMD at 0,
12, and 30 month visits and the annualized change rates at the lumbar spine,
femoral neck and total hip by treatment group and in the combined sample.
Lumbar spine BMD did not significantly change over time in either treatment
group (p>0.05). Both femoral neck BMD and total hip BMD significantly
decreased during the trial period in both the soy and placebo groups as well as in
the total sample (all p<0.05, Table 2).
8
3.3 Adipocytokines and ghrelin change over time: The mean (SD) of
adipocytokines and ghrelin levels are summarized at 0, 6, 12, 18, 24 and 30-
month visits and the annualized change rates were estimated (Table 3). Resistin,
leptin and ghrelin significantly increased over the 6 visits (all p<0.05).
Adiponectin did not significantly change over the trial with a mean (SE) change
rate of 0.048 (0.115) ug/ml/year (p>0.05) (Table 3).
3.4 Annualized change rates in BMD by baseline characteristics: Table 4
shows that the annualized rates of change in lumbar spine BMD significantly
differed across 3 age groups using the mixed linear model (p=0.03).
Postmenopausal women above 60 years old had a positive change in lumbar
spine BMD, women aged 55 or younger had decreasing rate of change of lumbar
spine BMD, and rate of change of lumbar spine BMD in women aged 56-60
years old remained stable over the study period. Femoral neck and total hip BMD
annualized change rates significant differed by weekly hours in vigorous activity
(p=0.05 and p=0.03 separately). Women who participated in vigorous activity ≥15
minutes a week had smaller reductions in femoral neck and total hip BMD over
the study period than those who participated in vigorous exercise activity for <15
minutes a week. Comparisons by race, income, employment status, BMI, years
since menopause, type of menopause, and blood pressure demonstrated no
significant difference in BMD annualized change rates (all p>0.1).
9
3.5 Annualized change rates in adipocytokines and ghrelin by baseline
characteristics: In the mixed linear models (Table 5), age, family income, and
employment status had significant impact on annualized rates of change in
adiponectin (p=0.03, p=0.006, and p=0.03, respectively). Menopausal women
aged over 60 years old had increased rates of change of adiponectin compared
to women younger than 55 years old. Menopausal women with family income
$40,000 or more had an increased annualized change in adiponectin compared
to those with lower income. Unemployed postmenopausal women had increased
adiponectin change rates compared to employed postmenopausal women. There
were no significant associations between other baseline demographic and clinical
characteristics and annualized rates of change in other adipocytokines or ghrelin
(all p>0.1).
3.6 Annualized change rates in BMD in multivariate mixed linear models
(Table 6): Adjusted for treatment group, age, race, BMI, weekly hours in vigorous
activity and weekly hours in vigorous activity interaction with time, the baseline
level of leptin was positively associated with an average annualized change rate
in femoral neck (Estimate: 0.05 (SE: 0.05)) in 1000 g/cm
2
/year/unit of leptin
(p=0.09). Leptin and ghrelin were positively associated with annualized rates of
change in total hip BMD (β=0.042 × 10
-3
, p=0.06 and β=0.001 × 10
-3
, p=0.09,
respectively) after adjusting for treatment group, race, BMI, diastolic blood
pressure, weekly hours in vigorous activity and weekly hours in vigorous activity
interaction with time. Resistin, leptin, adiponectin and ghrelin did not statistical
10
significantly modify on annualized rates of change in lumbar spine BMD (p>0.1)
after adjusting for treatment group, age and age interaction with time, race, and
BMI.
3.7 Association between baseline BMD levels and adipocytokines and
ghrelin in multivariate mixed linear models: Table 7 presents the
associations between baseline BMD levels and adipocytokines and ghrelin.
Adipocytokines and ghrelin were not significantly associated with lumbar spine,
femoral neck and total hip BMD (all p>0.1)
11
Table 1. Baseline characteristics of WISH participants (n=350)
Placebo
n=175
Mean ± SD
n (%)
Soy
n=175
Mean ± SD
n (%)
Total
n=350
Mean ± SD
n (%)
Age (Years) 60.6 ± 6.9 60.7± 7.4 60.6 ± 7.1
≤ 55 years 46 (26%) 42 (24%) 88 (25%)
56-60 years 33 (19%) 34 (19%) 67 (19%)
> 60 years 96 (55%) 99 (57%) 195 (56%)
Race
White Non-Hispanic 118 (67%) 105 (60%) 223 (64%)
Black Non-Hispanic 9 (5%) 12 (7%) 21 (6%)
Hispanic 24 (14%) 31 (18%) 55 (16%)
Asian or Pacific Islander 19 (11%) 19 (11%) 38 (11%)
Other 5 (3%) 8 (5%) 13 (4%)
Marital Status
Married 103 (59%) 94 (59%) 197 (56%)
Divorced/widowed 56 (32%) 63 (36%) 119 (34%)
Never Married 16 (9%) 18 (10%) 34 (10%)
Annual Income (n=320)
Under $ 40,000 45 (26%) 44 (26%) 89 (26%)
$ 40,000 to $ 80,000 65 (37%) 69 (41%) 134 (35%)
Above $ 80,000 63 (36%) 55 (32%) 118 (34%)
Employment Status
Employed 89 (51%) 102 (58%) 191 (55%)
Unemployed 86 (41%) 73 (41%) 159 (45%)
12
Table 1. (Continued).
Placebo
n=175
Mean ± SD
n (%)
Soy
n=175
Mean ± SD
n (%)
Total
n=350
Mean ± SD
n (%)
Weekly Hours in Moderate Activity 5.9 ± 6.5 5.4 ± 5.4 5.7 ± 6.0
Less than 4 hours 87 (50%) 85 (48%) 172 (49%)
4 to 8 hours 40 (23%) 54 (31%) 94 (27%)
More than 8 hours 48 (27%) 36 (21%) 84 (24%)
Weekly Hours in vigorous Activity 0.4 ± 1.4 0.3 ± 1.5 0.4 ± 1.4
0-15 min 145 (83%) 150 (85%) 295 (84%)
>15 min 30 (17%) 25(14%) 55 (16%)
Body Mass Index (BMI) 26.7 ± 5.4) 26.5 ± 5.0 26.6 ± 5.2)
Obese (BMI >= 30 kg/m
2
) 46 (26%) 39 (22%) 85 (24%)
Overweight (BMI 25 – 29 kg/m
2
) 55 (31%) 57 (32%) 112 (32%)
Normal (BMI < 25 kg/m
2
) 74 (42%) 79 (45%) 153 (44%)
Systolic Blood Pressure (mmHg) 118.5± 14.3 117.4 ± 13.6 118.0 ± 13.9
≤ 120 mmHg 108 (62%) 109 (62%) 217 (62%)
>120 mmHg 67 (38%) 66 (38%) 133 (38%)
Diastolic Blood Pressure (mmHg) 75.3 ± 8.6 74.7 ± 8.6 75.0 ± 8.6
≤ 80 mmHg 129 (74%) 138 (78%) 267 (76%)
>80 mmHg 46 (26%) 37 (21%) 83 (24%)
Years Since Menopause (years)
11.5 ± 8.3
(n=154)
11.0 ± 7.8
(n=159)
11.2 ± 8.0
(n=313)
>10 years 81 (46%) 88 (50%) 169 (48%)
≤ 10 years 73 (42%) 71 (41%) 144 (41%)
Unknown (Missing) 21 (12%) 16 (9%) 37 (11%)
13
Table 1. (Continued).
Placebo
n=175
Mean ± SD
n (%)
Soy
n=175
Mean ± SD
n (%)
Total
n=350
Mean ± SD
n (%)
Type of Menopause
Natural 154 (88%) 160 (91%) 314 (90%)
Surgical 20 (11%) 15 (9%) 35 (10%)
Numbers in table are mean ± SD, or n (%)
14
Table 2. Bone mineral density (in g/cm
2
) for 0, 12, 30 visit in different treatment groups.
Visit
Month
Placebo
Mean (SD)
n=174
a
Soy
Mean (SD)
n=175
a
Total Sample
Mean (SD)
n=349
a
Lumbar spine (g/cm
2
) 0 0.935 ± 0.137
b
0.939 ± 0.138 0.937 ± 0.137
12 0.942 ± 0.125 0.945 ± 0.136 0.943 ± 0.131
30 0.945 ± 0.130 0.942 ± 0.141 0.943 ± 0.135
0.915 (1.391)
c
-0.250 (1.250)
c
0.308 (0.934)
c
Femoral Neck (g/cm
2
) 0 0.734 ± 0.114 0.726 ± 0.114 0.730 ± 0.114
12 0.728 ± 0.115 0.727 ± 0.112 0.727 ± 0.114
30 0.722 ± 0.113 0.719 ± 0.111 0.720 ± 0.112
-2.4 (0.952)
c,d
-3.21 (0.971)
c,d
-2.82 (0.680)
c,d
Total hip (g/cm
2
) 0 0.902 ± 0.118 0.895 ± 0.125 0.898 ± 0.122
12 0.899 ± 0.117 0.894 ± 0.120 0.896 ± 0.118
30 0.893 ± 0.116 0.888 ± 0.119 0.890 ± 0.118
-2.41 (0.849)
c,d
-3.0 (0.836)
c,d
-2.71 (0.596)
c,d
a.n for the baseline (0) visit.
b.Numbers in table are mean ± SD.
c. mean (SE) change rate in 1000 g/cm
2
/year from univariate linear mixed model.
d.p-value < 0.05; p-values for the main effect of time using univariate linear mixed model.
15
Table 3. Adipocytokines and ghrelin for 0, 6, 12, 18, 24, 30 visits by treatment group.
Visit
Month
Placebo
Mean (SD)
n=175
a
Soy
Mean (SD)
n=175
a
Total Sample
Mean (SD)
n=350
a
Resistin (pg/ml) 0 1.49 ± 0.81
b
1.52 ± 0.81 1.51 ± 0.80
6 1.46 ± 0.78 1.50 ± 0.75 1.48 ± 0.76
12 1.55 ± 0.83 1.56 ± 0.77 1.55 ± 0.80
18 1.53 ± 0.82 1.56 ± 0.78 1.55 ± 0.80
24 1.64 ± 0.90 1.63 ± 0.82 1.64 ± 0.86
30 1.59 ± 0.85 1.69 ± 1.00 1.6 ± 0.93
0.077 (0.026)
c,d
0.102 (0.027)
c,d
0.097 (0.015)
c,d
Leptin (ng/ml) 0 17.7± 13.5 18.4 ± 12.7 18.1 ± 13.1
6 18.6 ± 12.8 19.2 ± 14.4 18.9 ± 13.6
12 18.3 ± 13.8 18.4 ± 12.8 18.3 ± 13.3
18 17.8 ± 13.9 19.7 ± 13.7 18.8 ± 13.8
24 19.0 ± 14.9 19.6 ± 13.7 19.3 ± 14.3
30 17.7 ± 13.9 18.7 ± 12.6 18.2 ± 13.3
0.547 (0.368)
c
0.410 (0.303)
c
0.476 (0.185)
c,d
Adiponectin ( ug/ml) 0 15.1 ± 7.1 14.9 ± 7.3 15.0 ± 7.2
6 15.5 ± 7.0 15.4 ± 7.7 15.4 ± 7.3
12 15.0 ± 7.0 15.4 ± 7.4 15.2 ± 7.2
18 16.3 ± 7.9 15.3 ± 7.3 15.8 ± 7.6
24 15.8 ± 7.3 14.9 ± 7.0 15.3 ± 7.2
30 15.4 ± 6.9 15.3 ± 7.5 15.4 ± 7.2
0.104 (0.182)
c
-0.069 (0.156)
c
-0.048 (0.115)
c
16
Table 3. (Continued).
Visit
Month
Placebo
Mean (SD)
n=175
a
Soy
Mean (SD)
n=175
a
Total Sample
Mean (SD)
n=350
a
Ghrelin ( pg/ml) 0 1336.1 ± 504.2 1289.6 ± 482.0 1312.8 ± 493.1
6 1347.3 ± 507.3 1334.0 ± 451.5 1340.5 ± 478.7
12 1424.6 ± 538.7 1408.2 ± 522.1 1416.1 ± 529.3
18 1428.5 ± 512.0 1384.9 ± 493.0 1405.7 ± 501.7
24 1416.2 ± 540.5 1400.3 ± 531.0 1408.0 ± 534.7
30 1399.0 ± 619.2 1382.5 ± 579.5 1390.5 ± 598.1
28.042 (14.367)
c
13.624 (13.440)
c
34.706 (8.168)
c,d
a.n for the 0 visit
b.numbers in table are mean ± SD.
c. mean (SE) change rate in 1 units per year from univariate mixed model
d.p-value < 0.05; p-values from univariate linear mixed model
17
Table 4. Associations of annualized change rates in bone mineral density with baseline characteristics
Lumbar Spine Femoral Neck Total Hip
Age
≤ 55 years -2.97 (1.74) -4.06 (1.31)
a
-4.08 (1.32)
a
55-60 years -0.82 (1.48) -2.22 (1.49) -2.27 (1.16)
a
>60 years 2.82 (1.48) -2.51 (0.90)
a
-2.20 (0.76)
a
P value 0.03 0.52 0.36
Race
White non-Hispanic 1.19 (1.25) -2.84 (0.85) -2.50 (0.71)
a
Black non-Hispanic 4.89 (3.61) -1.86 (2.51) -1.05 (1.84)
Hispanic -0.27 (2.02) -3.37 (1.54)
a
-2.47 (1.49)
Asian or Pacific Islander -4.96 (2.36)
a
-2.16 (2.18) -4.02 (2.10)
Other -0.13 (5.20) -3.19 (4.17) -7.03 (2.38)
a
P value 0.21 0.88 0.47
Marital Status
Married -0.55 (1.25) -2.92 (0.85)
a
-2.10 (0.81)
a
Divorced/widowed 1.48 (1.61) -2.19 (1.30) -3.05 (0.95)
a
Never Married 1.71 (2.65) -4.37 (2.16) -5.18 (1.95)
a
P value 0.56 0.68 0.29
Annual Income (n=320)
Under $ 40,000 1.15 (1.96) -2.71 (1.49) -0.59 (1.60)
$ 40,000 to $ 80,000 0.66 (1.25) -3.42 (0.99) 0.25 (1.40)
Above $ 80,000 -0.78 (1.86) -2.73 (1.24) -2.83 (1.04)
P value 0.74 0.86 0.86
18
Table 4. (Continued).
Lumbar Spine Femoral Neck Total Hip
Employment Status
Employed -0.37 (1.24) -3.16 (0.97) -3.42 (0.91)
Unemployed 1.06 (1.40) -2.52 (0.94) -2.03 (0.72)
a
P value 0.46 0.63 0.23
Weekly Hours in Moderate
Activity
Less than 4 hours -0.63 (1.27) -2.56 (0.95) -2.18 (7.64)
4 to 8 hours 1.64 (1.63) -0.57 (1.29) -2.54 (1.11)
More than 8 hours -0.57 (2.18) -4.01 (2.02) -4.43 (1.44)
P value 0.38 0.95 0.79
Weekly Hours in vigorous
Activity (n=319)
0-15 min 0.70 (1.01) -3.06 (0.74) -3.10 (0.65)
>15 min -1.58 (2.63) -0.20 (1.73) -1.49 (1.23)
P value 0.43 0.05 0.03
Body Mass Index (BMI)
Obese (BMI >= 30
kg/m
2
)
1.39 (2.12) -3.65 (1.49)
a
-3.08 (1.55)
a
Overweight (BMI 25-29
kg/m
2
)
1.66 (1.82) -3.45 (1.13)
a
-3.16 (0.95)
a
Normal (BMI < 25 kg/m
2
) -1.15 (1.20) -1.94 (1.01) -2.19 (0.82)
a
P value 0.35 0.52 0.73
Systolic Blood Pressure
(mmHg)
≤ 120 mmHg -0.02 (1.14) -2.73 (0.89) -3.01 (0.76)
>120 mmHg 0.87 (1.61) -2.95 (1.06) -2.23 (0.86)
P value 0.63 0.87 0.51
19
Table 4. (Continued).
Lumbar Spine Femoral Neck Total Hip
Diastolic Blood Pressure
(mmHg)
≤ 80 mmHg 0.69 (1.07) -2.91 (0.78) -3.25 (0.68)
>80 mmHg -0.83 (1.72) -2.55 (1.35) -1.10 (1.03)
P value 0.48 0.83 0.11
Years since menopause
≤10 years -2.19 (1.22) -3.65 (1.09) -3.21 (0.90)
a
>10 years 2.38 (1.46) -2.81 (0.93) -2.72 (0.84)
Unknown 1.05 (3.26) 0.59 (1.86) -0.45 (2.20)
P value 0.06 0.18 0.47
Type of menopause
Surgical -1.66 (2.76) -4.12 (2.62) -3.76 (1.69)
Natural 0.53 (0.99) -2.71 (0.70)
a
-2.61 (0.64)
a
P value 0.57 0.55 0.59
a.p-value < 0.05
Numbers are mean (SE) change rate in 1 unit per year; p-values from univariate linear mixed model.
20
Table 5. Associations of annualized change rates in adipocytokines and ghrelin with baseline characteristics
Resistin Leptin Adiponectin Ghrelin
Age
≤ 55 years 0.076 (0.026)
a
0.54 (0.28) -0.38 (0.18)
a
43.72 (12.07)
a
56-60 years 0.089 (0.037)
a
0.31 (0.53) -0.20 (0.23) 8.60 (19.78)
> 60 years 0.082 (0.030)
a
0.72 (0.35)
a
0.33 (0.18) 19.03 (15.62)
P value 0.98 0.52 0.03 0.17
Race
White non-Hispanic 0.061 (0.023) 0.56 (0.27)
a
0.22 (0.15) 24.30 (13.52)
Black non-Hispanic 0.14 (0.19) 2.58 (2.48) -0.52 (0.64) 21.55 (42.05)
Hispanic 0.11 (0.043) 0.49 (0.65) -0.15 (0.20) 15.53 (18.16)
Asian or Pacific
Islander
0.15 (0.051)
a
-0.71 (0.46) -0.46 (0.46) 31.69 (25.21)
Other -0.013 (0.07) -0.41 (1.07) -0.80 (0.36) -0.99 (64.71)
P value 0.56 0.23 0.19 0.85
Marital Status
Married 0.064 (0.023)
a
0.76 (0.31) 0.031 (0.16) 11.72 (12.72)
Divorced/widowed 0.16 (0.036)
a
-0.012 (0.40) 0.097 (0.20) 26.95 (16.44)
Never Married 0.006 (0.046) 0.26 (0.88) -0.48 (0.48) 68.73 (36.34)
P value 0.03 0.37 0.54 0.25
Annual Income
(n=320)
Under $ 40,000 0.053 (0.024)
a
0.72 (0.31)
a
-0.62 (0.17)
a
37.86 (16.70)
a
$ 40,000 to
$ 80,000
0.067 (0.031)
a
0.54 (0.35) 0.21 (0.17) 14.66 (15.27)
Above $ 80,000 0.140 (0.035)
a
0.41 (0.43) 0.24 (0.24) 13.49 (17.67)
P value 0.09 0.60 0.006 0.41
21
Table 5. (Continued).
Resistin Leptin Adiponectin Ghrelin
Employ Status
Employed 0.084 (0.024)
a
0.25 (0.29)
a
-0.24 (0.18) 13.72 (12.29)
Unemployed 0.091 (0.030)
a
0.65 (0.38)
a
0.27 (0.17) 26.56 (15.58)
P value 0.94 0.50 0.03 0.43
Weekly Hours in
Moderate Activity
Less than 4 hours 0.09 (0.02) 0.56 (0.28) 0.07 (0.16) 40.74 (11.43)
4 to 8 hours 0.10 (0.03) -0.18 (0.38) -0.12 (0.21) 29.75 (16.88)
More than 8 hours 0.12 (0.04) 0.30 (0.43) 0.02 (0.28) 56.84 (20.04)
P value 0.46 0.50 0.61 0.25
Weekly Hours in
vigorous Activity
(n=319)
0-15 min -0.10 (0.02) 0.43 (0.21) -0.08 (0.13) 33.67 (9.05)
>15min 0.02 (0.06) 0.96 (0.38)
a
0.27 (0.29) 30.93 (18.85)
P value 0.45 0.61 0.37 0.87
Body Mass Index
(BMI)
Obese (BMI >= 30
kg/m
2
)
0.067 (0.036) 0.36 (0.66) 0.13 (0.26) 7.71 (18.53)
Overweight (BMI
25-29 kg/m
2
)
0.110 (0.036)
a
1.290 (0.47)
a
-0.36 (0.19) 18.81 (16.23)
Normal (BMI < 25
kg/m
2
)
0.074 (0.022)
a
-0.017 (0.18) 0.20 (0.18) 51.08 (12.55)
a
P value 0.08 0.11 0.08 0.27
Years since
menopause
≤10 years 0.10 (0.026)
a
0.58 (0.34) -0.20 (0.19) 19.35 (14.19)
>10 years 0.055 (0.027)
a
0.68 (0.35) 0.25 (0.17) 22.38 (14.66)
Unknown 0.120 (0.048)
a
0.12 (0.56) -0.20 (0.34) 67.56 (18.66)
P value 0.27 0.75 0.14 0.09
22
Table 5. (Continued).
Resistin Leptin Adiponectin Ghrelin
Systolic Blood
Pressure (mmHg)
≤ 120 mmHg 0.11 (0.02) 0.10 (0.02) 0.024 (0.15) 28.52 (10.13)
>120 mmHg -0.05 (0.04)
a
0.06 (0.04) -0.16 (0.17) 23.36 (16.16)
P value 0.12 0.12 0.59 0.99
Diastolic Blood
Pressure (mmHg)
≤ 80 mmHg 0.11 (0.02) 0.37 (0.21) -0.06 (0.13) 32.53 (9.31)
>80 mmHg 0.05 (0.04) 0.39 (0.53) 0.05 (0.22) 28.12 (17.24)
P value 0.13 0.97 0.66 0.72
Type of menopause
Surgical 0.12 (0.047) 0.45 (0.85) -0.54 (0.50) 10.59 (30.81)
Natural 0.086 (0.02) 0.48 (0.25) 0.063 (0.13) 22.45 (10.36)
a
P value 0.65 0.97 0.28 0.72
a.p-value < 0.05
Numbers are mean (SE) change rate in 1 unit per year; p-values from univariate linear mixed model.
23
Table 6. Associations of annualized change rates in bone mineral density with adipocytokines and ghrelin
Lumbar Spine
c
Femoral Neck
d
Total Hip
e
Resistin
-0.10 (0.95)
a
-0.95(0.71)
-0.85 (0.60)
Leptin
0.02 (0.06)
0.05 (0.05)
b
0.042 (0.038)
b
Adiponectin
0.08 (0.11)
-0.05(0.08)
0.0070 (0.07)
Ghrelin
2.08 (1.42)
-0.00014 (0.0011)
-0.001 (0.0009)
b
a. numbers are mean (SE) change rate in 1000 g/cm
2
/year
b. p-value < 0.1; p-value from multivariate linear mixed model
c. adjusted for treatment group, age, age interaction with time, race, and bmi
d. adjusted for treatment group, age, race, bmi, weekly hours in vigorous activity, weekly hours in vigorous
activity interaction with time
e. adjusted for treatment group, race, bmi, dbp, weekly hours in vigorous activity, weekly hours in vigorous
activity interaction with time
24
Table 7. Associations between baseline bone mineral density levels and adipocytokines and ghrelin in
multivariate analysis
Lumbar Spine
b
Femoral Neck
c
Total Hip
d
Resistin -0.42 (0.89)
a
-0.37 (0.69) -0.17 (0.56)
Leptin -0.14 (0.079) -0.08 (0.06) -0.08 (0.05)
Adiponectin 0.073 (0.14) -0.06 (0.11) -0.07 (0.09)
Ghrelin 0.0013 (0.0016) 0.0016 (0.0012) 0.0013 (0.00099)
a. numbers are estimate (SE) in 1000 units of cross-section association with BMD
b. adjusted for treatment group, age, age interaction with time, race, and bmi
c. adjusted for treatment group, age, race, bmi, weekly hours in vigorous activity, weekly hours in vigorous
activity interaction with time
d. adjusted for treatment group, race, bmi, dbp, weekly hours in vigorous activity, weekly hours in vigorous
activity interaction with time
25
4.0 Discussion
We expect adipocytokines and ghrelin would have influence on rates of change
in BMD in healthy postmenopausal women. However, we did not find any
relationship between adipocytokines and ghrelin and rates of change in BMD in
healthy postmenopausal women.
Our study showed that BMD at the femoral neck and total hip significantly
decreased over the 30 month trial period (p<0.05) in postmenopausal women,
while BMD at the lumbar spine remained stable (p>0.05). The lack of change in
lumbar spine BMD may have been-due to the length of the observational period.
Moreover, we observed that levels of serum resistin, leptin and ghrelin
significantly increased over the 6 visits measured over the 30 month trials
(p<0.05); adiponectin levels did not change over this period (p>0.05).
While BMD is generally lost with age in women over 50 years old (11), we found
a contrary result in the annualized change of lumbar spine BMD across the 3 age
groups-≤ 55 years old, 56-60 years old and >60 years old. Lumbar spine BMD
decreased in the two younger age groups but increased in the >60 years old
group. Consistent with this observation, BMD reduced at a larger rate in women
who were 10 years or less since menopause than those who were more than 10
years since menopause. These associations may be explained by the rapid
decrement in estrogen levels that occur within the few years after menopause,
but essentially remain stable throughout the later years after menopause. It has
26
been shown that the extent of reduction in the level of estrogen has an important
effect on BMD (4).
BMI did not significantly influence annualized rates of change in BMD over the
three bone sites analyzed in WISH. However, in most cross-sectional studies,
body mass or fat mass is an important positive predictor of BMD (4, 9, 11). In
those cross-sectional studies, adipose tissue increased along with increasing
BMI and this relationship between adipose tissue and BMD was positive in
postmenopausal women (3, 5, 19). Levels of adipocytokines have been positively
related to estrogen level (9, 10). Nevertheless, menopause would be expected to
be associated with decreases in BMD but increases in body mass over time (19).
Since our study population was healthy postmenopausal women, estrogen levels
or physiological change for women at this phase might suppress the effect of BMI
on rates of change in BMD. Another finding from current study is that women
who engage in vigorous exercise (more than 15 minutes weekly) had less
change in femoral neck and total hip BMD than women who did not exercise at a
vigorous level.
There was a trend in our study that leptin was positively associated with average
annualized change rates in the femoral neck and total hip BMD after adjusting for
treatment group, age, diastolic blood pressure, race, BMI, weekly hours in
vigorous activity and weekly hours in vigorous activity interaction with time
(p<0.1). Even though the major functions of leptin are restraining appetite and
27
body mass (9), which means while people increase fat mass, plasma levels
would be increased. BMI is an important predictor of BMD (9). Thus, leptin was
positively related to average annualized change rates in BMD. We also found
that ghrelin had a marginally negative impact on annualized rates of change in
total hip BMD after controlling for treatment group, race, BMI, diastolic blood
pressure, weekly hours in vigorous activity and weekly hours in vigorous activity
interaction with time (p<0.1). Earlier studies have shown that ghrelin levels were
positively correlated with bone mass after adjusting for BMI in bone men and
women (7, 13). However, in WISH, the level of ghrelin was inversely associated
with total hip BMD loss during the study period. It might because estrogen level
would be dramatically reduced in postmenopausal women (4). In addition, there
was no significant correlation between ghrelin and BMD in healthy older women
(9, 10). In the present study, there was no statistically significant association
between adiponectin or resistin and annualized change rates in BMD at any of
the three bone sites after baseline characteristics were controlled.
The strengths of our study were that a comprehensive panel of adipocytokines
(resistin, leptin, adiponectin) and ghrelin and BMD at three sites were evaluated
individually. This minimized the possible collinearity among resistin, leptin,
adiponectin, and ghrelin. Moreover, we focused on the change rates in BMD at
different sites (lumbar spine, femoral neck and total hip) rather than change rates
in total BMD. We noted different associations over study sites. For example, the
annualized rates of change in lumbar spine BMD was significantly different
28
across 3 age groups; but the annualized rates of change in femoral neck and
total hip BMD did not differ across 3 age groups. Thirdly, most studies have
investigated the relationship between adipocytokines and BMD using cross-
sectional analysis (7, 13, 19, 20). We used longitudinal analysis for the data
collected over 30 months. WISH was a randomized clinical trial, so all serum
adipocytokines and BMD measurements were obtained from all active subjects.
Finally, in the univariate analysis, we included a number of additional covariates
(age, race, marital status, annual income, employment status, physical activity,
BMI, systolic blood pressure, diastolic blood pressure, type of menopause, years
since menopause) that might confound the association of adipocytokines or
ghrelin with rates of change in BMD. However, there were some weakness in our
study, first of all, relationship between visfatin and BMD were measured in other
studies (3, 20) which we failed to test. Visfatin is secreted by visceral adipose
tissue, and correlated with human fat mass and appetite (21). In addition, as the
subjects were healthy postmenopausal women enrolled in a randomized clinical
trial, our findings may not be representative of the general population of
postmenopausal women.
29
5.0 References
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2. Almehed K, dElia HF, Bokarewa M, Carlsten H. Role of resistin as a
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Cortet B. Influence of adipocytokines and ghrelin on bone mineral density
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LeBoff M, Lewis CE, McGowan J, Neuner J, Pettinger M, Stefanick ML,
Wactawski-Wende J, Watts NB, for the Women’s Health Initiative
Investigators. Effects of estrogen plus progestin on risk of fracture and
bone mineral density: the Women’s Health Initiative Randomized Trial.
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Frammingham study. Journal of Bone and Mineral Research. 1993; 8:567-
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6. Gallagher JC, Rosen CJ, Chen P, Misurski DA & Marcus R. Response
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7. Gollelli S, Caffarelli C, Del Santo K, Cadirni A, Guerriero C, Lucani B,
Franci B, Franci B & Nuti R. The relationship of ghrelin and adiponectin
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8. Hodis N. Howard, Mack J. Wendy, Kono Naoko, Azen P. Stanley, Shoupe
Donna, Hwang-Levine Juliana, Petitti Diana, Whitfield-Maxwell Lora, Yan
Mingzhu, Franke A. Adrian, Selzer H. Robert. Isoflavone Soy Protein
Supplementation and Atherosclerosis Progression in Healthy
Postmenopausal Women: A Randomized Controlled Trail. Stroke. 2011;
42:3168-3175.
9. Jurimae Jaak, Kums Tatjana, Jurimeae Toivo. Adipoctokine and ghrelin
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160:381-385.
10. Jurimae Jaak, Jurimeae Toivo, Leppik Aire, Kums Tatjana. The influence
of ghrelin, adiponectin, and leptin on bone mineral density in healthy
postmenopausal women. J Bone Miner Metab. 2008; 26:618-623.
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11. Looker C. Anne, Borrud G. Lori, Dawson-Hughes Bess, Shepherd A. Jone,
Wright C. Nicole. Osteoporosis or low bone mass at the femur neck or
lumbar spine in older adults: United states, 2005-2008. NCHS Data Brief.
April 2012; (PHS) 2012-1209.
12. Maghraoui El& Abdellah. Bone mineral density measurement with DXA
[Internet]. Version 3. Knol. Jul 28 2008. Available from:
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measurement-with/15wl1e4rlzd1w/2
13. Napoli N, Pedone C, Pozzilli P, Lauretani F, Bandinelli S, Ferrucci L,
Incalzi RA. Effect of ghrelin on bone mass density: the InChianti study.
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Osteoporosis Int 1998; 8:S1-S882
15. Otto B, Spranqer J, Benoit SC, Cleqq DJ, Tschop MH. The many faces of
ghrelin: new perspectives for nutrition research. Br J Nutr. Jun
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17. Tschop M, Smiley DL & Heiman ML. Ghrelin induces adiposity in rodents.
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Robert, Deng Hong-Wen. Relationship of obesity with osteoporosis. J Clin
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between serum adiponectin, apelin, leptin, resistin, visfatin levels and
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Abstract (if available)
Abstract
Purpose: We investigated the relationship between annualized rates of change in bone mineral density (BMD) and serum resistin, leptin, adiponectin, and ghrelin in healthy postmenopausal women. ❧ Methods: Adipocytokines (resistin, leptin, adiponectin), ghrelin, and BMD (lumbar spine, femoral neck, and total hip) were collected from 350 healthy postmenopausal women in the Women’s Isoflavone Soy Health (WISH) trial at 0, 6, 12, 18, 24 and 30 months (adipocytokines and ghrelin) and at 0, 12 and 30 months (BMD). For the statistical analysis, we used mixed multiple linear regression models to investigate the impact of serum levels of adipocytokines and ghrelin on annualized rates of change in BMD. ❧ Results: Resistin, adiponectin, leptin and ghrelin were not significantly related to annualized rates of change in BMD (all p-values > 0.05). Leptin had a positive impact on annualized change rates in femoral neck BMD. Resistin, ghrelin, and adiponectin were inversely but not significantly associated with rates of change in BMD of the femoral neck in the multivariable analysis (all p-values > 0.1). After adjusting for treatment group, race, BMI, DBP, weekly hours in vigorous activity and weekly hours in vigorous activity interaction with time, leptin and ghrelin were marginally associated with rates of change in total hip BMD (p=0.06 and p=0.09 separately)
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Wang, Song
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The relationship of resistin, leptin, adiponectin, and ghrelin with bone mineral density in healthy postmenopausal women: longitudinal analysis
School
Keck School of Medicine
Degree
Master of Science
Degree Program
Biostatistics
Publication Date
07/31/2012
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