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The Journal of Clinical Endocrinology & Metabolism 90(1):52–59
Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2004-0275
Protection of Bone Mass by Estrogens and Raloxifene
during Exercise-Induced Weight Loss
W. S. Gozansky, R. E. Van Pelt, C. M. Jankowski, R. S. Schwartz, and W. M. Kohrt
Division of Geriatric Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
80262
3.0 ⴞ 0.7% (n ⴝ 10) in the placebo, raloxifene, and HT groups,
respectively; comparable BMD changes in the weight loss
groups were ⴚ1.5 ⴞ 0.5% (n ⴝ 22), ⴚ0.5 ⴞ 0.5% (n ⴝ 23), and 1.1 ⴞ
0.4% (n ⴝ 23). There were no significant interactions between
weight loss and drug treatment on changes in BMD, but there
were significant main effects of weight loss on lumbar spine
(P ⴝ 0.022), total hip (P ⴝ 0.010), and trochanter BMD (P <
0.001). These findings suggest that weight loss, even when
modest in magnitude and induced by exercise training, causes
a reduction in BMD, particularly in women not taking raloxifene or HT. It is not known whether reductions in BMD of this
magnitude increase the risk for osteoporotic fracture. (J Clin
Endocrinol Metab 90: 52–59, 2005)
The aim of this study was to determine whether estrogen
and/or raloxifene help to conserve bone mineral density
(BMD) during moderate weight loss. Postmenopausal women
(n ⴝ 68) participated in a 6-month weight loss program that
consisted primarily of supervised exercise training. Another
26 women were studied over 6 months of weight stability. All
participants were randomized to three treatment arms: placebo, raloxifene (60 mg/d), or hormone therapy (HT; conjugated estrogens, 0.625 mg/d; trimonthly medroxyprogesterone
acetate, 5 mg/d for 13 d, for women with a uterus). Changes in
body weight (mean ⴞ SE) averaged 0.8 ⴞ 0.5 kg in the weightstable group and ⴚ4.1 ⴞ 0.4 kg in the weight loss group. Across
all measured skeletal sites, average changes in BMD in weight
stable women were ⴚ0.6 ⴞ 1.1% (n ⴝ 7), 0.9 ⴞ 0.6% (n ⴝ 9), and
B
ONE MINERAL DENSITY (BMD), measured by dual
energy x-ray absorptiometry (DXA), is a strong determinant of the risk for osteoporotic fracture. According to a
recent meta-analysis, a reduction in hip BMD T-score of 1 (i.e.
equivalent to 1 sd of BMD in young Caucasian women) is
associated with a 140% increase in relative risk for hip fracture in Caucasian women (1).
There is a positive association between body weight and
BMD, and increased body weight is thought to confer protection against osteoporotic fractures (2). However, prospective data indicate that bone loss occurs in women even when
body weight is increasing (3, 4), and weight loss accelerates
the decline in BMD of older women and men (5). In a Finnish
population study of randomly selected peri- and postmenopausal women, the most significant determinants of changes
in BMD of the lumbar spine and femoral neck over a 5-yr
follow-up period were menopausal transition, use of hormone therapy (HT), and change in body weight (6, 7). It was
also noted that the weight loss-related decline in BMD was
significantly attenuated in women who reported any use of
HT (7). Observational studies have also suggested that HT at
least partially counteracts the loss of bone mineral associated
with weight loss (3, 5).
To our knowledge, the protection of bone mass by HT
during weight loss has not been investigated in a randomized, controlled fashion. In light of recent evidence that the
risks of HT are greater than once thought (8 –11), current
recommendations are that HT be used primarily for the management of menopausal symptoms (12–14). Therefore, when
evaluating potential beneficial effects of HT on bone, there is
now greater need to determine whether such effects also
occur in response to selective estrogen receptor modulators.
In this context, the purpose of this study was to determine
whether the reduction in BMD in response to moderate
weight loss is attenuated by HT and/or raloxifene in postmenopausal women. All participants were randomized to
receive placebo, raloxifene, or HT, and those in the weight
loss arm participated in a 6-month, supervised, exercise
training program. Weight loss was induced primarily via
exercise training, because this was part of a larger study
examining certain metabolic responses to exercise training
and drug intervention.
Subjects and Methods
Subjects
The study participants were sedentary, healthy, postmenopausal
women, aged 50 –70 yr, who were nonsmokers and overweight or moderately obese. Postmenopausal status was defined as the absence of
menses for at least 1 yr or, in women who had undergone hysterectomy,
a serum FSH level greater than 30 IU/liter. All participants had a normal
mammogram and Pap test within 1 yr of enrolling in the study.
Screening tests included medical history, physical examination, blood
chemistries, 12-lead electrocardiogram (ECG), and an exercise stress test.
All subjects were confirmed to be euthyroid or receiving adequate replacement therapy based on a normal ultrasensitive TSH level. Volunteers were excluded from the study if they had contraindications to
estrogen or raloxifene treatment, including history of breast cancer or
other estrogen-dependent neoplasm, liver disease, undiagnosed vaginal
bleeding, and history of venous thromboembolism. Other exclusion
criteria included coronary artery disease, clinically significant abnormal
resting ECG, angina and/or ECG evidence of myocardial ischemia dur-
First Published Online October 19, 2004
Abbreviations: BMC, Bone mineral content; BMD, bone mineral density; DXA, dual energy x-ray absorptiometry; ECG, electrocardiogram;
HT, hormone therapy; RMR, resting metabolic rate.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
52
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
ing the maximal exercise stress test, resting blood pressure above 150
mm Hg systolic or 90 mm Hg diastolic, clinically significant arrhythmias,
congestive heart failure, aortic stenosis, or unstable health status. Volunteers were also excluded if they had orthopedic or other problems that
would interfere with exercise testing or training. Women who had been
receiving HT or raloxifene within 6 months of screening were not
enrolled.
Women were recruited separately for the weight loss and weightstable arms of the study, but all met the inclusion and exclusion criteria.
The Colorado Multiple Institutional Review Board approved the study.
All volunteers who underwent screening for the study provided written
informed consent to participate. In addition, active participants reconsented to continued participation in the study on two occasions as a
result of new information regarding risks of continuous, combined hormone therapy (8 –11).
Weight loss arm
For the weight loss arm of the study, 138 volunteers underwent an
orientation session to learn about the study; 20 elected not to participate,
36 were found to be ineligible, and the remaining 82 were randomized
to drug treatment. During the intervention period, 14 participants (five
placebo, seven raloxifene, and two HT) were lost to follow-up evaluation
for personal (n ⫽ 10), medical (n ⫽ 1; worsening of multiple sclerosis),
or unknown (n ⫽ 2) reasons or because of new information regarding
the risks of HT (n ⫽ 1). Data are reported for the 68 women who
completed follow-up evaluations. The racial composition of this cohort
was predominantly Caucasian (Caucasian, n ⫽ 57; black/African-American, n ⫽ 9; Native American/Alaska Native, n ⫽ 2); five women reported being of Spanish/Latino/Hispanic ethnicity.
Weight-stable arm
For the weight-stable arm of the study, 61 volunteers underwent an
orientation session to learn about the study; 16 elected not to participate,
14 were found to be ineligible, and the remaining 31 were randomized
to drug treatment. Three participants (two raloxifene and one HT) were
lost to follow-up evaluation during the intervention period (two did not
tolerate drug treatment; one because of new information regarding risks
of HT), and two finishers were excluded from the final data analysis (one
started bisphosphonate therapy; one had a 20-kg increase in body
weight). Data are reported for the 26 participants included in the final
analyses. The racial composition of this cohort was predominantly Caucasian (Caucasian, n ⫽ 23; Asian/Native Hawaiian/other Pacific Islander, n ⫽ 2; Native American/Alaska Native, n ⫽ 1); one woman
reported being of Spanish/Latino/Hispanic ethnicity.
Drug interventions
Eligible volunteers were randomized to three treatment arms: placebo, raloxifene, and HT. The randomizations were performed separately for the weight loss and weight-stable arms. The intervention was
administered in a double-blinded fashion, to the extent possible given
that side-effects often reveal treatment status to the participant. HT was
daily conjugated estrogens (0.625 mg); women with an intact uterus also
received trimonthly medroxyprogesterone acetate (5 mg/d for 13 consecutive days). Because the HT regimen minimized exposure to progestins while still protecting the endometrium (15), metabolic responses
to HT are thought to reflect the actions of estrogens. The raloxifene
treatment dose was 60 mg daily, and placebo treatment was a daily
placebo tablet; women in these groups with an intact uterus also received
trimonthly placebo medroxyprogesterone acetate treatment.
Weight loss intervention
Weight loss was induced primarily through a 6-month, supervised,
endurance exercise training program. However, because weight loss
with exercise occurs slowly, the program included 1-wk periods of a
reduced calorie diet in the first, third, and fifth months. It has been
reported that 1 wk of a reduced calorie diet serves as a jump start to
losing weight and provides motivation for participants to continue to
lose weight (16).
Participants were expected to attend three supervised exercise ses-
J Clin Endocrinol Metab, January 2005, 90(1):52–59
53
sions per week, but were encouraged to attend more frequently and to
exercise at home. During the first few weeks of the program, the goal
was to exercise at a moderate intensity (i.e. 60 –70% of maximal heart
rate) and gradually increase duration to approximately 50 min/d. Thereafter, the goal for an exercise session was to generate an increase in
energy expenditure of approximately 400 kcal. To enhance compliance
with the exercise program, participants were allowed to select the
mode(s) of exercise (i.e. treadmill walking/running, rowing, cycling,
and/or elliptical exercise).
The General Clinical Research Center provided take-out meals for the
1-wk periods of reduced food intake in months 1, 3, and 5. Energy intake
was reduced to 25 kcal/kg fat-free mass/d, but not less than 1200 kcal/d,
with 60% of the energy as carbohydrate, 25% as protein, and 15% as fat.
Subjects in the weight-stable group did not receive either the exercise
or dietary interventions. These women were contacted only during the
first, third, and fifth months of the study to assess how they were doing
with their study medication and to provide medication refills.
DXA
All participants in the weight-stable arm and all but eight participants
in the weight loss arm had baseline and follow-up DXA scans performed
on a DPX-IQ instrument (Lunar Corp., Madison, WI). Because of a
programatic plan at the institution to phase out the Lunar instrument,
eight participants in the weight loss arm (four placebo, one raloxifene,
and three HT) had both baseline and follow-up scans performed on a
Delphi-W instrument (Hologic, Waltham, MA). Total body, lumbar
spine (L2–L4), and proximal femur (total hip, femoral neck, trochanter,
and femoral shaft) were the three regions scanned at baseline and after
the intervention to determine bone mineral content (BMC) and BMD.
Total mass, fat mass, and fat-free mass were measured during the total
body scans (Lunar extended research analysis software version 4.7c;
Hologic software version 11.2).
Diet evaluation
Participants completed 3-d food records (2 week days and 1 weekend
day) at baseline (n ⫽ 81; 86%) and at the completion of the study (n ⫽
59; 63%). Subjects received detailed instructions about the procedures for
recording foods and portion sizes. Records were analyzed for macronutrient composition and calcium content (Nutritionist IV, version 2.2,
First DataBank, Inc., San Bruno, CA). Subjects self-reported the presence
or absence of calcium supplement use, but the precise mineral content
of the supplements was not obtained.
Resting metabolic rate (RMR)
The RMR was measured in the morning after an overnight fast by
indirect calorimetry with a ventilated hood (Vmax system, SensorMedics, Yorba Linda, CA). After 15 min of rest and a 5-min habituation
period under the hood, oxygen uptake and carbon dioxide production
were measured for 25–30 min and used to calculate the RMR (17).
Calculations and statistical analyses
The energy expenditure during walking, running, and cycling was
estimated from the metabolic equations recommended by the American
College of Sports Medicine that predict the oxygen cost of these activities
and from measurements of the energy cost of fast walking (18, 19). It was
assumed that energy expenditure averaged 5 kcal/liter oxygen consumed. Because standardized equations are not available for rowing and
elliptical exercise, estimates of energy expenditure for these activities
were taken directly from the ergometers. For all activities, the values
reflected total energy expenditure. The exercise-induced increase in
energy expenditure was estimated as the increase above the RMR.
Differences among the groups in baseline characteristics were evaluated by analyses of variance and Tukey post hoc tests when indicated.
Changes in outcomes of interest in response to the interventions were
analyzed by two-way (weight group and drug group) ANOVA. The
sample size provided 80% power to detect group differences of a 0.030
g/cm2 change in BMD. A composite BMD score was generated to evaluate the overall effects of weight loss and drug treatment. The composite
score, calculated for each individual, was the average of the relative
54
J Clin Endocrinol Metab, January 2005, 90(1):52–59
changes in BMD at the skeletal sites measured (i.e. lumbar spine, total
hip, femoral neck, trochanter, and femoral shaft). Analysis of covariance
was used to determine whether the magnitude of change in body weight
over the 6-month treatment period was a determinant of the changes in
BMD after adjustment for drug treatment status. For all analyses, statistical significance was defined as ␣ ⱕ 0.05. All data are reported as the
mean ⫾ sd unless otherwise stated.
Results
Baseline characteristics
Weight loss vs. weight-stable groups. The weight loss and
weight-stable groups were similar with respect to age, age of
menopause, previous HT use, dietary calcium intake, and
calcium supplement use. Applying the World Health Organization criteria (20), 22 women in the weight loss group
were osteopenic, and six were osteoporotic; 12 women in the
weight-stable group were osteopenic, and five were osteoporotic. On entry into the study, women who were recruited
for the weight loss arm weighed more (79.2 ⫾ 12.0 vs. 71.1 ⫾
13.1 kg; P ⫽ 0.005) and had more fat mass (35.3 ⫾ 8.7 vs.
29.4 ⫾ 10.7 kg; P ⫽ 0.008) and fat-free mass (43.9 ⫾ 4.7 vs.
41.7 ⫾ 5.3 kg; P ⫽ 0.047) than those in the weight-stable arm.
At study entry, BMD also tended to be higher in the weight
loss group compared with the weight-stable group, with a
significantly greater femoral shaft BMD (1.140 ⫾ 0.157 vs.
1.064 ⫾ 0.183 g/cm2; P ⫽ 0.047) and strong trends for greater
lumbar spine BMD (1.143 ⫾ 0.178 vs. 1.062 ⫾ 0.193 g/cm2;
P ⫽ 0.055), total hip BMD (0.975 ⫾ 0.127 vs. 0.907 ⫾ 0.151
g/cm2; P ⫽ 0.060), and whole body BMC (2436 ⫾ 42 vs.
2300 ⫾ 73 g; P ⫽ 0.095).
Drug treatment groups. There were no significant differences
among the drug treatment groups at baseline in age, age at
menopause, body composition, previous HT use, or BMD in
either the weight loss (Table 1) or the weight-stable (Table 2)
group. Dietary calcium intake was lower (P ⫽ 0.039) in the
HT group than in the placebo group in both the weight loss
and weight-stable groups.
Exercise training and changes in body composition
The volume of exercise performed during the intervention
period by women in the weight loss group did not differ
significantly among the drug treatment groups. Women in
the placebo, raloxifene, and HT groups exercised an average
of 3.3 ⫾ 1.1, 3.6 ⫾ 1.1, and 3.4 ⫾ 0.9 d/wk for 49 ⫾ 22, 50 ⫾
19, and 49 ⫾ 16 min/d at an average heart rate of 133 ⫾ 14,
132 ⫾ 15, and 133 ⫾ 11 beats/min, respectively. The increase
in energy expenditure attributable to exercise was estimated
to be 1189 ⫾ 637, 1272 ⫾ 565, and 1327 ⫾ 507 kcal/wk in the
placebo, raloxifene, and HT groups, respectively. This resulted in an average weight loss of ⫺4.1 ⫾ 3.4 kg and a fat
loss of ⫺4.1 ⫾ 3.4 kg with a preservation of fat-free mass;
changes were not different among the drug treatment
groups, but were significantly different (P ⬍ 0.001) from the
changes in the weight-stable group (Table 3). The increase in
energy expenditure attributable to exercise accounted for a
reduction in fat mass of ⫺3.7 kg when based on the conventional estimate of 7718 kcal/kg fat (i.e. 3500 kcal per
pound), or a reduction of ⫺3.2 kg when based on an estimate
of 9000 kcal/kg fat (i.e. average caloric density for fat of 9
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
TABLE 1. Descriptive baseline characteristics of postmenopausal
women in the weight loss arm randomized to placebo, raloxifene,
or HT
Treatment group
Placebo
(n ⫽ 22)
Age (yr)
Age at menopause (yr)
Hysterectomy
(no.)
Height (cm)
Weight (kg)
BMI (kg/m2)
Fat mass (kg)
Fat-free mass
(kg)
Time since last
HT use
[yr (no.)]
Duration of previous HT
use (yr)
Dietary calcium
(mg/d)
Total BMC (g)
BMD (g/cm2)
Lumbar spine
Total hip
Femoral neck
Trochanter
Femoral shaft
Raloxifene
(n ⫽ 23)
HT
(n ⫽ 23)
57 ⫾ 5
47 ⫾ 5
57 ⫾ 5
48 ⫾ 4
57 ⫾ 4
49 ⫾ 5
8
6
8
163 ⫾ 6
76.3 ⫾ 10.1
28.7 ⫾ 3.9
34.0 ⫾ 7.8
42.3 ⫾ 3.9
165 ⫾ 6
82.2 ⫾ 12.9
30.2 ⫾ 4.4
37.4 ⫾ 9.6
44.8 ⫾ 5.0
165 ⫾ 5
78.9 ⫾ 12.4
28.9 ⫾ 4.9
34.5 ⫾ 8.6
44.5 ⫾ 4.7
5.1 ⫾ 9.0 (17)
3.4 ⫾ 4.0 (16)
3.0 ⫾ 5.9 (18)
3.4 ⫾ 6.9
3.6 ⫾ 4.9
4.3 ⫾ 4.8
788 ⫾ 76
842 ⫾ 74
639 ⫾ 61
2336 ⫾ 325
2536 ⫾ 344
2433 ⫾ 347
1.100 ⫾ 0.170
0.939 ⫾ 0.114
0.881 ⫾ 0.117
0.751 ⫾ 0.115
1.101 ⫾ 0.142
1.181 ⫾ 0.165
1.014 ⫾ 0.137
0.952 ⫾ 0.129
0.837 ⫾ 0.130
1.178 ⫾ 0.169
1.147 ⫾ 0.195
0.972 ⫾ 0.122
0.927 ⫾ 0.142
0.784 ⫾ 0.110
1.140 ⫾ 0.156
BMI, Body mass index.
kcal/g). Although paired diet records were available for only
56 subjects (60%), these limited data revealed no significant
change in dietary calcium intake from baseline to 6 months.
After the weight loss intervention, there were no significant
differences (P ⬎ 0.05) between the weight loss and weightstable groups in dietary calcium intake, use of calcium supplements, body weight, body composition, or BMD.
Changes in BMD
Effects of drug treatment. There were no significant interactions between drug treatment and weight group for any of
the skeletal measurements (P ⫽ 0.156 to 0.899). As would be
expected, there were significant main effects (P ⬍ 0.001) of
drug treatment on BMD, such that the largest increases in
BMD occurred in the HT group, and the effects of raloxifene
were intermediate to those of HT and placebo treatment
(Figs. 1 and 2). Specifically, HT was significantly (P ⬍ 0.05)
more effective than placebo treatment in increasing BMD at
all sites measured with the exception of the femoral neck; HT
was also significantly (P ⬍ 0.05) more effective than raloxifene in increasing BMD of the total hip and the trochanter
and shaft regions of the proximal femur. Raloxifene was
significantly (P ⬍ 0.05) more effective than placebo in increasing BMD of the lumbar spine.
Effects of weight loss. In Figs. 1 and 2, the effects of weight loss
on BMD within each drug treatment group are depicted by
the differences in height of the solid (weight-stable) and
striped (weight loss) bars of similar color. Overall, weight loss
superimposed a negative effect on the changes in BMD that
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
J Clin Endocrinol Metab, January 2005, 90(1):52–59
TABLE 2. Descriptive baseline characteristics of postmenopausal
women in the weight-stable arm randomized to placebo, raloxifene,
or HT
Treatment group
Placebo (n ⫽ 7)
Age (yr)
Age at menopause (yr)
Hysterectomy
(no.)
Height (cm)
Weight (kg)
BMI (kg/m2)
Fat mass (kg)
Fat-free mass
(kg)
Time since last
HT use
[yr (no.)]
Duration of previous HT
use (yr)
Dietary calcium
(mg/d)
Total BMC (g)
BMD (g/cm2)
Lumbar spine
Total hip
Femoral neck
Trochanter
Femoral shaft
Raloxifene (n ⫽ 9)
57 ⫾ 4
48 ⫾ 4
relations approached significance for total hip (P ⫽ 0.06) and
trochanter (P ⫽ 0.07) BMD. The strength of these associations
was not improved by using change in fat mass in place of
change in body weight.
HT (n ⫽ 10)
59 ⫾ 6
47 ⫾ 7
56 ⫾ 4
50 ⫾ 4
2
3
3
162 ⫾ 4
72.8 ⫾ 17.1
27.8 ⫾ 6.3
31.8 ⫾ 13.3
41.1 ⫾ 5.3
165 ⫾ 9
71.7 ⫾ 10.9
26.6 ⫾ 4.3
28.3 ⫾ 10.6
43.5 ⫾ 6.5
163 ⫾ 6
69.4 ⫾ 13.2
26.2 ⫾ 4.6
28.7 ⫾ 9.6
40.7 ⫾ 4.3
2.1 ⫾ 0.9 (5)
7.7 ⫾ 7.3 (7)
2.7 ⫾ 2.4 (6)
2.2 ⫾ 2.2
2.3 ⫾ 2.1
4.5 ⫾ 1.9
785 ⫾ 122
637 ⫾ 80
496 ⫾ 42
2300 ⫾ 381
2452 ⫾ 386
2162 ⫾ 328
1.115 ⫾ 0.217
0.963 ⫾ 0.199
0.894 ⫾ 0.127
0.784 ⫾ 0.206
1.133 ⫾ 0.237
1.114 ⫾ 0.227
0.955 ⫾ 0.148
0.923 ⫾ 0.134
0.793 ⫾ 0.143
1.106 ⫾ 0.172
0.979 ⫾ 0.118
0.851 ⫾ 0.099
0.847 ⫾ 0.095
0.699 ⫾ 0.097
0.977 ⫾ 0.126
BMI, Body mass index.
occurred in all drug treatment groups. The only cases in
which this general pattern was not apparent were the
changes in femoral neck and shaft BMD in placebo-treated
groups (Fig. 2). For specific skeletal regions, the main effects
of weight loss (i.e. across all drug treatment groups) were
significant (P ⬍ 0.05) for changes in BMD at all sites of
measurement except the neck and shaft regions of the proximal femur (Figs. 1 and 2).
In all participants, with adjustment for drug treatment
status, the magnitude of change in body weight was not a
significant determinant of changes in BMD, although the
TABLE 3. Changes in body composition in response to 6 months
of exercise training (weight loss group) or observation (weightstable group) in women randomized to placebo, raloxifene, or HT
Treatment group
Weight loss group
Weight (kg)a
Fat mass (kg)a
Fat-free mass (kg)b
Total BMC (g)c
Weight-stable group
Weight (kg)a
Fat mass (kg)a
Fat-free mass (kg)b
Total BMC (g)c
55
Placebo
Raloxifene
HT
⫺4.0 ⫾ 3.2
⫺4.0 ⫾ 2.7
0.0 ⫾ 1.4
⫺30 ⫾ 58
⫺4.4 ⫾ 3.8
⫺4.2 ⫾ 4.3
⫺0.2 ⫾ 1.5
⫺21 ⫾ 108
⫺4.0 ⫾ 3.2
⫺4.0 ⫾ 3.2
0.0 ⫾ 1.1
54 ⫾ 75
1.6 ⫾ 1.9
1.2 ⫾ 1.4
0.4 ⫾ 0.8
79 ⫾ 134
0.0 ⫾ 2.4
⫺0.1 ⫾ 1.5
0.1 ⫾ 1.3
37 ⫾ 170
0.9 ⫾ 2.8
⫺0.1 ⫾ 2.8
1.0 ⫾ 1.4
50 ⫾ 123
There were no significant main effects of drug treatment for any of
the variables.
a
Weight loss vs. weight stable: main effect, P ⬍ 0.001.
b
Weight loss vs. weight stable: main effect, P ⫽ 0.055.
c
Weight loss vs. weight stable: main effect, P ⫽ 0.025.
Discussion
To our knowledge, this was the first study to determine the
effects of raloxifene and HT on weight loss-related changes
in BMD in a randomized, controlled trial. The relative
changes in composite BMD scores in response to moderate
weight loss in the placebo, raloxifene, and HT groups were
⫺1.5 ⫾ 0.5%, ⫺0.5 ⫾ 0.5%, and 1.1 ⫾ 0.4%, respectively;
comparable changes in the weight-stable group were ⫺0.6 ⫾
1.1%, 0.9 ⫾ 0.6%, and 3.0 ⫾ 0.7%. Despite the fact that the
magnitude of weight loss was modest and was induced
primarily through exercise training, only the HT group maintained a positive BMD balance at the most clinically relevant
skeletal sites (i.e. lumbar spine, total hip, femoral neck, and
trochanter) during weight loss.
It seems plausible that bone mass might be better preserved when weight loss is induced primarily by increasing
energy expenditure through exercise, as in the current study,
than by restricting energy intake, because of both the mechanical loading forces on the skeleton during exercise and
the potential for better preservation of lean body mass during
weight loss. We are aware of only one study, of overweight
men, that evaluated this in a randomized controlled design
(21). The results indicated that when adjusted for fat loss,
which was more than 2-fold greater in dieters, there were
similar reductions in total body BMC of 11.7 and 11.4 g/kg
fat loss in dieters and exercisers, respectively. In the current
study only the placebo-treated group had a decline in total
body BMC, which averaged 6.2 g/kg fat loss. There were
differences between these studies in exercise intensity that
could contribute to the apparent discordance in the extent of
bone loss. Exercise intensity averaged 80 – 85% of maximal
heart rate in the current study compared with a prescribed
intensity of 65–75% of maximal heart rate in the study by
Pritchard and colleagues (21); whether that level of intensity
was achieved and maintained in that study was not reported.
Although the relative heart rate achieved during exercise is
not a direct determinant of the mechanical stimulus to bone,
it is probably a good surrogate measure of mechanical stress
during weight-bearing exercise. The ground reaction forces
that are generated during walking and running increase as
speed increases (22), as does heart rate, and the magnitude
of loading forces is an important determinant of the osteogenic response (23). It should be noted that because the
current study was part of a parent study of the effects of
exercise-induced weight loss on metabolic factors other than
bone, the exercise program was not specifically designed to
mechanically stress bone.
Decreases in BMD in response to weight loss, typically
induced by energy restriction alone or in combination with
exercise, are commonly observed (21, 24 –30). It has been
suggested that the loss of bone is due in part to an artifact of
the measurement, because changes in the thickness and composition of tissue that surrounds bone as a result of weight
loss can influence the measurement of bone mass by DXA
56
J Clin Endocrinol Metab, January 2005, 90(1):52–59
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
FIG. 1. Changes over 6 months in the
composite measure, lumbar spine, and
total hip BMD in women randomized to
placebo (plac), raloxifene (ralox), or HT
who were either weight stable or lost
weight as a result of exercise training.
When the main effects of drug treatment were significant (P ⱕ 0.05), drug
group comparisons that were significant at the P ⱕ 0.05 level by Tukey post
hoc analyses are listed.
(31, 32). The magnitude of this effect has been evaluated by
acutely manipulating thickness and composition, using materials that have similar x-ray attenuation characteristics as
fat and lean tissue (e.g. lard and water). The results of such
experiments have been equivocal (24, 32–34), but suggest that
the effects on the measurement of BMD are very small when
weight change is moderate, as in the current study.
There is additional evidence that weight loss-induced
bone loss is not simply an artifact of measurement. Reductions in body weight of 5–10% have been found to result in
increases in serum and urinary markers of bone turnover and
in urinary calcium excretion, with accompanying declines in
BMC and/or BMD (28, 35). It has been suggested that these
responses occur as a result of reduced calcium intake during
diet-induced weight loss, and in fact, calcium supplementation has been found to have an ameliorating effect (27, 28,
36). However, in men who lost weight via either diet or
exercise, the decrease in BMC per kilogram of fat loss was
similar in the two groups despite an increase in self-reported
dietary calcium intake in the exercise group and no change
in the diet group; information regarding supplemental calcium intake was not provided (21). In the current study
dietary calcium intake and the prevalence of calcium supplement use were similar in the weight-stable and weight
loss groups at baseline and 6 months. However, only 60% of
our subjects completed 6-month dietary assessments, and
detailed information on the mineral content of calcium supplements was not obtained, thus limiting the reliability of our
data for total daily calcium intake.
Estrogen status has been suggested to be an important
determinant of bone loss in response to weight loss. In adult
female rats, reducing energy intake while maintaining calcium intake had deleterious effects on bone mass and
strength, and it was suggested that this was related to the
concomitant decrease in serum estradiol levels that occurred
(37). In an observational study of older women and men,
weight loss was a major determinant of bone loss, but the
magnitude of the effect was dampened in women receiving
estrogen therapy (5). Another observational study of postmenopausal women suggested that HT protected against
weight loss-related bone loss (7). Ricci and colleagues found
that the negative effects of weight loss on bone mass in
postmenopausal women (27, 35) did not occur in premenopausal women (36). They suggested that the increased susceptibility of postmenopausal women not receiving HT to
weight loss-induced bone loss could be estrogen mediated,
because adipose tissue is an important site of estrogen production via the aromatization of androgens (38). This was
based on the observation that changes in fat mass were significantly related to changes in serum estrone levels in postmenopausal women (35).
In one respect the results of the current randomized, controlled trial may appear to support the concept that estrogens
provide osteoprotection during weight loss in postmenopausal women. Among women in the weight loss arm, those
receiving placebo treatment had significantly larger reductions in BMD of the total body, lumbar spine, total hip, and
trochanter and less increase in femoral shaft BMD than those
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
J Clin Endocrinol Metab, January 2005, 90(1):52–59
57
FIG. 2. Changes over 6 months in femoral neck, trochanter, and femoral shaft
BMD in women randomized to placebo
(plac), raloxifene (ralox), or HT who
were either weight stable or lost weight
as a result of exercise training. When
main effects of drug treatment were significant (P ⱕ 0.05), drug group comparisons that were significant at the P ⱕ
0.05 level by Tukey post hoc analyses
are listed.
receiving HT. Indeed, only the HT group maintained a positive BMD balance at all sites of measurement in response to
moderate weight loss. However, compared with women in
the weight-stable arm, the effects of weight loss were apparent in all drug treatment groups. An osteoprotective effect
of HT during weight loss would have been supported by
interactions between drug treatment and weight group,
which were not significant. However, it should be noted that
the parent study from which these data were generated was
not designed to detect such interactions. The power to detect
a significant interaction effect at any of the sites of BMD
measurement was less than 40%; the results must therefore
be interpreted cautiously. It is possible that the baseline differences between the weight-stable and weight loss groups
in body composition and BMD, which were probably related
to recruiting women separately for these two intervention
arms, may have further limited our ability to detect an interaction between drug treatment and weight group. The
mechanisms by which weight loss alters skeletal metabolism
and results in a loss of bone mineral remain to be determined.
Because body weight influences the magnitude of skeletal
loading forces during all ambulatory activities, it is possible
that a decrease in BMD represents an appropriately coupled
response. This did not appear to be the case in the current
study, because a change in body weight was not a significant
determinant of a change in BMD. However, it cannot be ruled
out that such an association was masked by the superimposed effects of the exercise per se and drug treatment on
BMD. Alternatively, it is possible that weight loss is accom-
panied by changes in metabolic or hormonal factors that
independently influence bone metabolism.
Regardless of the mechanisms, the fact that weight reduction causes bone loss in postmenopausal women suggests
that weight loss could increase bone fragility in a population
already at risk for osteoporosis. Women in the weight loss
arm were overweight to mildly obese at the time of study
enrollment, yet 46% of them were osteopenic or osteoporotic.
Furthermore, the observations in premenopausal women
that BMD levels are lower in those with a history of weight
cycling than in nonweight cyclers (39) and that preweight
loss BMD levels may not be restored with weight regain (26)
suggest that weight cycling may be harmful for postmenopausal women at risk for osteoporosis. In the current study
the effects of weight loss were most detrimental at skeletal
sites that have high trabecular bone content (i.e. lumbar spine
and trochanter) and are susceptible to osteoporotic fractures.
In this context, repeated attempts at weight loss could be
particularly devastating for postmenopausal women if irreversible changes in the microarchitecture and strength of
certain skeletal regions occur with each attempt.
In summary, our study documents that moderate weight
loss in women nearly a decade beyond the menopause transition results in a significant BMD decline in skeletal regions
susceptible to osteoporotic fracture. Because weight loss was
induced through exercise training, which presumably has
osteoprotective effects via mechanical loading and the maintenance of fat-free mass, randomized trials are needed to
determine whether weight loss mediated by energy restric-
58
J Clin Endocrinol Metab, January 2005, 90(1):52–59
tion is even more detrimental to BMD than weight loss mediated by exercise. Although intervention with raloxifene did
not prevent a decrease in BMD with exercise-induced weight
loss, the expected skeletal benefits of raloxifene and HT were
superimposed on the negative effects of weight loss. Thus,
raloxifene was effective in attenuating the decrease in BMD
during moderate weight loss, whereas the more potent HT
was effective in preventing a decrease in BMD. Examining
whether other agents (e.g. bisphosphonates) known to prevent osteoporotic fracture (40) may also shield women from
bone loss during weight reduction is an important area for
future inquiry. Clinicians should remain cognizant of the fact
that being overweight does not necessarily confer protection
against low BMD in postmenopausal women. It will be important to determine how overweight and obese postmenopausal women can gain the cardiovascular benefits of moderate weight loss without simultaneously increasing risk for
osteoporotic fracture.
Acknowledgments
We express our gratitude to the nursing, bionutrition, core laboratory,
information systems, and administrative staffs of the General Clinical Research Center and the energy balance core and administrative staffs of the
Clinical Nutrition Research Unit for their assistance in conducting this
study. We also acknowledge the members of our research group who
carried out the day to day activities for the project, including D. Dahl, D.
Day, S. Howar, G. Keisling, J. Lynn, A. Moquin, J. Murray, J. Quick, N.
Scherer, E. Sdrulla, J. Smoldt, and K. Sutika. Finally, we thank the women
who volunteered to participate in the study for their time and efforts.
Received April 16, 2004. Accepted September 28, 2004.
Address all correspondence and requests for reprints to: Dr. Wendolyn S. Gozansky, 4200 East Ninth Avenue, Campus Box B179, Denver,
Colorado 80262. E-mail: [email protected].
This work was supported by awards from the NIH, including R01-AG18198 and F32-AG-05899 (to W.S.G.), K01-AG-19630 (to R.E.V.P.), M01RR-00051 (to the General Clinical Research Center), and P30-DK-48520 (to
the Clinical Nutrition Research Unit). W.S.G. was supported in part by a
North American Menopause Society/Wyeth-Ayerst Clinical Research Fellowship and a Hartford/Jahnigen Center of Excellence career award.
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
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References
1. Cummings SR, Bates D, Black DM 2002 Clinical use of bone densitometry:
scientific review. JAMA 288:1889 –1897
2. Lane JM, Russell L, Khan SN 2000 Osteoporosis. Clin Orthop 372:139 –150
3. Wu F, Ames R, Clearwater J, Evans MC, Gamble G, Reid IR 2002 Prospective
10-year study of the determinants of bone density and bone loss in normal
postmenopausal women, including the effect of hormone replacement therapy. Clin Endocrinol (Oxf) 56:703–711
4. Hui SL, Perkins AJ, Zhou L, Longcope C, Econs MJ, Peacock M, McClintock
C, Johnston Jr CC 2002 Bone loss at the femoral neck in premenopausal white
women: effects of weight change and sex-hormone levels. J Clin Endocrinol
Metab 87:1539 –1543
5. Hannan MT, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson
PW, Kiel DP 2000 Risk factors for longitudinal bone loss in elderly men and
women: the Framingham Osteoporosis Study. J Bone Miner Res 15:710 –720
6. Sirola J, Kroger H, Honkanen R, Jurvelin JS, Sandini L, Tuppurainen MT,
Saarikoski S 2003 Factors affecting bone loss around menopause in women
without HRT: a prospective study. Maturitas 45:159 –167
7. Sirola J, Kroger H, Honkanen R, Sandini L, Tuppurainen M, Jurvelin JS,
Saarikoski S 2003 Risk factors associated with peri- and postmenopausal bone
loss: does HRT prevent weight loss-related bone loss? Osteoporos Int 14:27–33
8. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen
JM, Ockene J 2002 Risks and benefits of estrogen plus progestin in healthy
postmenopausal women: principal results from the Women’s Health Initiative
randomized controlled trial. JAMA 288:321–333
9. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D,
Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A 2003 Influence of estrogen plus progestin on breast
25.
26.
27.
28.
29.
30.
31.
32.
33.
cancer and mammography in healthy postmenopausal women: the Women’s
Health Initiative Randomized Trial. JAMA 289:3243–3253
Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH,
Dailey M, Bowen D 2003 Effect of estrogen plus progestin on global cognitive
function in postmenopausal women: the Women’s Health Initiative Memory
Study: a randomized controlled trial. JAMA 289:2663–2672
Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones
III BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J 2003 Estrogen plus progestin and the incidence of dementia
and mild cognitive impairment in postmenopausal women: the Women’s
Health Initiative Memory Study: a randomized controlled trial. JAMA 289:
2651–2662
American College of Obstetricians and Gynecologists 2002 ACOG committee
opinion. Risk of breast cancer with estrogen-progestin replacement therapy.
Int J Gynaecol Obstet 76:333–335
North American Menopause Society 2003 Amended report from the NAMS
Advisory Panel on Postmenopausal Hormone Therapy. Menopause 10:6 –12
Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith Jr SC, Taubert KA, Wenger NK
2001 Hormone replacement therapy and cardiovascular disease: a statement
for healthcare professionals from the American Heart Association. Circulation
104:499 –503
Williams DB, Voigt BJ, Fu YS, Schoenfeld MJ, Judd HL 1994 Assessment of
less than monthly progestin therapy in postmenopausal women given estrogen replacement. Obstet Gynecol 84:787–793
Racette SB, Weiss EP, Obert KA, Kohrt WM, Holloszy JO 2001 Modest
lifestyle intervention and glucose tolerance in obese African Americans. Obes
Res 9:348 –355
Weir JB 1949 New method for calculating metabolic rate with special reference
to protein metabolism. J Physiol 109:1–9
Kohrt WM, Spina RJ, Holloszy JO, Ehsani AA 1998 Prescribing exercise
intensity for older women. J Am Geriatr Soc 46:1–5
American College of Sports Medicine 2000 Guidelines for exercise testing and
prescription, 6th Ed. Philadelphia: Lippincott Williams & Wilkins.
Genant HK, Cooper C, Poor G, Reid I, Ehrlich G, Kanis J, Nordin BE,
Barrett-Connor E, Black D, Bonjour JP, Dawson-Hughes B, Delmas PD,
Dequeker J, Ragi ES, Gennari C, Johnell O, Johnston Jr CC, Lau EM, Liberman UA, Lindsay R, Martin TJ, Masri B, Mautalen CA, Meunier PJ, Khaltaev
N 1999 Interim report and recommendations of the World Health Organization
Task-Force for Osteoporosis. Osteoporos Int 10:259 –264
Pritchard JE, Nowson CA, Wark JD 1996 Bone loss accompanying dietinduced or exercise-induced weight loss: a randomised controlled study. Int
J Obes Relat Metab Disord 20:513–520
Keller TS, Weisberger AM, Ray JL, Hasan SS, Shiavi RG, Spengler DM 1996
Relationship between vertical ground reaction force and speed during walking, slow jogging, and running. Clin Biomech 11:253–259
Lanyon LE 1996 Using functional loading to influence bone mass and architecture: objectives, mechanisms, and relationship with estrogen of the mechanically adaptive process in bone. Bone 18:37S– 43S
Jensen LB, Quaade F, Sorensen OH 1994 Bone loss accompanying voluntary
weight loss in obese humans. J Bone Miner Res 9:459 – 463
Chao D, Espeland MA, Farmer D, Register TC, Lenchik L, Applegate WB,
Ettinger Jr WH 2000 Effect of voluntary weight loss on bone mineral density
in older overweight women. J Am Geriatr Soc 48:753–759
Fogelholm GM, Sievanen HT, Kukkonen-Harjula TK, Pasanen ME 2001
Bone mineral density during reduction, maintenance and regain of body
weight in premenopausal, obese women. Osteoporos Int 12:199 –206
Ricci TA, Chowdhury HA, Heymsfield SB, Stahl T, Pierson RNJ, Shapses SA
1998 Calcium supplementation suppresses bone turnover during weight reduction in postmenopausal women. J Bone Miner Res 13:1045–1050
Jensen LB, Kollerup G, Quaade F, Sorensen OH 2001 Bone minerals changes
in obese women during a moderate weight loss with and without calcium
supplementation. J Bone Miner Res 16:141–147
Svendsen OL, Hassager C, Christiansen C 1993 Effect of an energy-restrictive
diet, with or without exercise, on lean tissue mass, resting metabolic rate,
cardiovascular risk factors, and bone in overweight postmenopausal women.
Am J Med 95:131–140
Ryan AS, Nicklas BJ, Dennis KE 1998 Aerobic exercise maintains regional
bone mineral density during weight loss in postmenopausal women. J Appl
Physiol 84:1305–1310
Svendsen OL, Hendel HW, Gotfredsen A, Pedersen BH, Andersen T 2002
Are soft tissue composition of bone and non-bone pixels in spinal bone mineral
measurements by DXA similar? Impact of weight loss. Clin Physiol Funct
Imaging 22:72–77
Kohrt WM 1998 Preliminary evidence that DEXA provides an accurate assessment of body composition. J Appl Physiol 84:372–377
Tothill P, Hannan WJ, Wilkinson S 2001 Comparisons between a pencil beam
and two fan beam dual energy X-ray absorptiometers used for measuring total
body bone and soft tissue. Br J Radiol 74:166 –176
Gozansky et al. • Bone, Hormone Therapy, and Weight Loss
34. Tothill P, Hannan WJ 2000 Comparisons between Hologic QDR 1000W, QDR
4500A, and Lunar Expert dual-energy x-ray absorptiometry scanners used for
measuring total body bone and soft tissue. Ann NY Acad Sci 904:63–71
35. Ricci TA, Heymsfield SB, Pierson RNJ, Stahl T, Chowdhury HA, Shapses SA
2001 Moderate energy restriction increases bone resorption in obese postmenopausal women. Am J Clin Nutr 73:347–352
36. Shapses SA, Von Thun NL, Heymsfield SB, Ricci TA, Ospina M, Pierson Jr
RN, Stahl T 2001 Bone turnover and density in obese premenopausal women
during moderate weight loss and calcium supplementation. J Bone Miner Res
16:1329 –1336
37. Talbott SM, Cifuentes M, Dunn MG, Shapses SA 2001 Energy restriction
J Clin Endocrinol Metab, January 2005, 90(1):52–59
59
reduces bone density and biomechanical properties in aged female rats. J Nutr
131:2382–2387
38. Burger HG 2001 Physiological principles of endocrine replacement: estrogen.
Horm Res 56(Suppl 1):82– 85
39. Fogelholm M, Sievanen H, Heinonen A, Virtanen M, Uusi-Rasi K, Pasanen
M, Vuori I 1997 Association between weight cycling history and bone mineral
density in premenopausal women. Osteoporos Int 7:354 –358
40. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C 2002
Meta-analyses of therapies for postmenopausal osteoporosis. IX. Summary
of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev
23:570 –578
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