Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone‐active hormones*

Abstract

Weight loss therapy to improve health in obese older adults is controversial because it causes further bone loss. Therefore, it is recommended that weight loss therapy should include an intervention such as exercise training (ET) to minimize bone loss. The purpose of this study was to determine the independent and combined effects of weight loss and ET on bone metabolism in relation to bone mineral density (BMD) in obese older adults. One‐hundred‐seven older (age >65 years) obese (body mass index [BMI] ≥30 kg/m²) adults were randomly assigned to a control group, diet group, exercise group, and diet‐exercise group for 1 year. Body weight decreased in the diet (−9.6%) and diet‐exercise (−9.4%) groups, not in the exercise (−1%) and control (−0.2%) groups (between‐group p < 0.001). However, despite comparable weight loss, bone loss at the total hip was relatively less in the diet‐exercise group (−1.1%) than in the diet group (−2.6%), whereas BMD increased in the exercise group (1.5%) (between‐group p < 0.001). Serum C‐terminal telopeptide (CTX) and osteocalcin concentrations increased in the diet group (31% and 24%, respectively), whereas they decreased in the exercise group (−13% and −15%, respectively) (between‐group p < 0.001). In contrast, similar to the control group, serum CTX and osteocalcin concentrations did not change in the diet‐exercise group. Serum procollagen propeptide concentrations decreased in the exercise group (−15%) compared with the diet group (9%) (p = 0.04). Serum leptin and estradiol concentrations decreased in the diet (−25% and −15%, respectively) and diet‐exercise (−38% and −13%, respectively) groups, not in the exercise and control groups (between‐group p = 0.001). Multivariate analyses revealed that changes in lean body mass (β = 0.33), serum osteocalcin (β = −0.24), and one‐repetition maximum (1‐RM) strength (β = 0.23) were independent predictors of changes in hip BMD (all p < 0.05). In conclusion, the addition of ET to weight loss therapy among obese older adults prevents weight loss–induced increase in bone turnover and attenuates weight loss–induced reduction in hip BMD despite weight loss–induced decrease in bone‐active hormones. © 2011 American Society for Bone and Mineral Research

WEIGHT LOSS, EXERCISE, BONE METABOLISM, OBESE OLDER ADULTS

Introduction

In older adults, obesity worsens the age‐related decline in physical function, leading to frailty, loss of independence, and increased nursing home admissions.1, 2 Therefore, the increasing number of obese older adults is a significant public health problem that challenges existing healthcare delivery systems.3 However, the appropriate treatment for obese older adults is controversial. One major concern is that inducing weight loss in obese older adults could lead to further loss of bone mass (on top of age‐related bone loss) and increase the risk for osteoporotic fractures.1 Accordingly, it is recommended that weight loss therapy in older adults includes preventative measures against the loss of bone mass that occurs with weight loss.1 We recently reported that exercise training (ET) added to diet‐induced weight loss not only ameliorates frailty but also attenuates the weight loss–induced reduction in bone mineral density (BMD) and lean body mass, suggesting that a combination of weight loss and ET may be important therapy for obese older adults.4 However, the mechanisms behind this osteoprotective effect of ET during weight loss therapy remain to be elucidated. Moreover, previous studies that examined the effect of weight loss alone or in combination with ET on bone metabolism have been conducted primarily in younger populations and have not directly compared the independent and combined effects of weight loss and ET on biochemical markers of bone turnover, bone‐active hormones, and BMD.5–8

The purpose of this study was to determine the independent and combined effects of weight loss and ET on bone metabolism in relation to changes in BMD in obese older adults. We hypothesized that weight loss would increase while ET would decrease bone turnover; the addition of ET to weight loss would prevent the increase in bone turnover and attenuate the reduction in BMD. We also hypothesized that weight loss–induced reduction in BMD would be associated with decrease in bone‐active hormones; the addition of ET to weight loss would protect against this bone loss despite a decrease in bone‐active hormones. The data reported in this article were obtained using the same subject group that participated in a randomized, controlled trial of the effect of weight loss and exercise on multiple health outcomes including BMD in obese older adults.4

Subjects and Methods

Subjects

We conducted this study at the Washington University School of Medicine; it was approved by the Institutional Review Board. We recruited volunteers from the community through advertisements. All subjects gave informed consent before their participation. All potential subjects underwent a comprehensive medical examination, routine chemistries, and an exercise treadmill stress test. Eligibility criteria included older age (≥65 years), obese (body mass index ≥ 30 kg/m²), sedentary lifestyle (did not participate in regular exercise more than twice a week), stable body weight (±2 kg) over the past year, and no changes in medications for at least 6 months before enrolling in the study. Subjects who were treated with bone‐acting drugs (eg, bisphosphonates, glucocorticoids, sex‐steroid compounds) during the previous year were excluded from participation. Additional inclusion and exclusion criteria have been described in detail.4 The effects of weight loss and/or ET on measures of frailty, body composition, BMD, specific physical functions, and quality of life on these subjects have been reported.4

Design

We randomized eligible subjects, with stratification for sex, for a 52‐week period, to one of the following four groups: (1) control group, (2) diet‐induced weight loss (diet group), (3) exercise training (exercise group), and (4) diet‐induced weight loss and exercise training (diet‐exercise group).

Participants randomized to the control group were instructed to maintain their usual diet and activities during the study period. Participants randomized to the diet group were prescribed a balanced diet to provide an energy deficit of 500 to 750 kcal/d.1 Total calorie intake was adjusted to prevent >1.5% loss of body weight per week. The goal was to achieve a 10% weight‐loss at 6 months, followed by weight maintenance for an additional 6 months. Subjects met weekly as a group with a study dietitian. Standard behavioral strategies were used to modify eating habits.9 Participants randomized to the exercise group were counseled on maintaining a weight‐stable diet and participated in a multicomponent ET program supervised by a physical therapist. The ET sessions were conducted as a group on three nonconsecutive days each week at our exercise facility. Each session lasted ∼90 minutes: 15 minutes of flexibility exercises, 30 minutes of aerobic exercise, 30 minutes of progressive resistance training, and 15 minutes of balance exercises. Additional details about the interventions, including exercise intensity, have been described.4 Participants randomized to the diet‐exercise group participated in both weight management and ET programs described above, which were conducted separately from the other groups. All subjects were provided supplements to ensure an intake of ∼1500 mg/d of calcium and ∼1000 IU/d of vitamin D.1 Additional details about the interventions including compliance data have been reported.4

Outcome assessments

Body weight and bone mineral density

At baseline, 6 months, and 12 months, we measured body weight in the morning after subjects had fasted for 12 hours. We measured BMD of the lumbar spine, proximal femur, and whole body by dual‐energy‐X‐ray absorptiometry (DXA) (Delphi 4500‐W; Hologic, Inc., Waltham, MA, USA) at baseline, 6 months, and 12 months. The coefficient of variation (CV) for this technique at our center is 1.1% for the lumbar spine and 1.2% for the proximal femur.10

Serum markers of bone metabolism

At baseline, 6 months, and 12 months, we obtained venous blood samples in the morning after subjects had fasted for at least 12 hours. We used enzyme‐linked immunosorbent assay kits to measure C‐terminal telopeptide of type I collagen (CTX) (Crosslaps; Nordic Bioscience Diagnostics, Herlev, Denmark; CV, 2.1%) as a marker of bone resorption, and osteocalcin (Metra OC; Quidel, San Diego, CA, USA; CV, 4.4%) as a marker of bone formation. We used a radioimmunoassay kit to measure serum intact N‐terminal propeptide of type I procollagen (PINP) (Orion Diagnostica, Espoo, Finland) as an additional marker of bone formation. We also used radioimmunoassay kits to measure serum estradiol (Ultra‐sensitive estradiol DSL‐4800; Diagnostic Systems Laboratories, Inc., Webster, TX, USA), leptin (Leptin HL‐81K; Linco Research, Inc., St. Charles, MO, USA), insulin‐like growth factor 1 (IGF‐1) (Diagnostic Products Group), and 25‐hydroxyvitamin D (25(OH)D) (DiaSorin, Stilwater MN, USA). We used the Milliplex assay kit to measure serum parathyroid hormone (PTH) concentration (Millipore, St. Charles, MO, USA). The CV for these hormone measurements was <10%. Blood samples at 6 and 12 months were obtained ∼40 hours after the last bout of exercise.

Muscle strength testing

We determined one‐repetition maximums (1‐RMs) for upper (biceps curl, bench press, and seated row) and lower body exercises (knee extension, knee flexion, and leg press), and used the sum to calculate the total 1‐RM.11

Statistical analysis

The primary outcome in this study was changes in total hip BMD. We estimated that with 26 to 28 participants in each group, the study would have more than 80% power to detect a clinically meaningful 2.5% ± 2.4% difference in the change in total hip BMD (on the basis of preliminary data) among the groups, at an alpha level of 5%. Secondary outcomes included biochemical markers of bone turnover and bone‐active hormones.

We performed intention‐to‐treat analyses using SAS software, version 9.2 (SAS Institute, Inc., Cary, NC, USA), with inclusion of all participants who provided follow‐up data at any time point. We compared baseline characteristics between groups using analyses of variance or Fisher's exact tests. We tested longitudinal changes between groups with mixed‐model repeated‐measures ANOVAs, adjusting for baseline values and sex. The primary focus of these analyses was on the significance of the interaction between group and time point. Within the framework of the mixed model, when the p value for an interaction was significant, we used the specific contrasts to test the null hypothesis that changes between two specific time points in one group were equal to corresponding changes in another group. We also performed analyses testing for within‐group changes using mixed‐model repeated‐measures ANOVA. We first used Pearson's correlation to examine relationships among changes in selected variables and changes in BMD. We then used stepwise multiple linear regression analysis (forward elimination method) to identify which among the selected variables were the important independent contributors to the changes in BMD. Data are presented in tables and text as mean ± SD, except in the figures where data are mean ± SE. All statistical tests were two‐tailed, and p < 0.05 was considered statistically significant.

Results

The results of screening, randomization, and follow‐up have been reported.4 Briefly, 93 (87%) of the 107 volunteers who were randomized completed the study. Fourteen participants discontinued the intervention (eg, owing to personal or medical reasons) but were included in the intention‐to‐treat analyses.

The four groups did not significantly differ in baseline characteristics, including age, sex, weight, BMI, bone mineral content (BMC), BMD, T‐score, Z‐score, and serum concentration of bone turnover markers and bone‐active hormones (Tables 1 and 2). The four groups had normal average T‐scores and Z‐scores.

1

Baseline Characteristics of Study Participants

	Control (n = 27)	Diet (n = 26)	Exercise (n = 26)	Diet‐Exercise (n = 28)	p Value
Age (years)	69 ± 4	70 ± 4	70 ± 4	70 ± 4	0.85
Female [n (%)]	18 (67)	17 (65)	16 (61)	16 (57)	0.89
Weight (kg)	101 ± 16	104 ± 15	99 ± 17	99 ± 17	0.66
BMI (kg/m2)	37.3 ± 4.7	37.2 ± 4.5	36.9 ± 5.4	37.2 ± 5.4	0.93
Whole body BMC (g)	2624 ± 660	2783 ± 652	2536 ± 542	2692 ± 532	0.50
BMD (g/cm2)
Whole body	1.207 ± 0.177	1.252 ± 0.178	1.163 ± 0.119	1.259 ± 0.173	0.29
Lumbar spine	1.096 ± 0.152	1.123 ± 0.160	1.075 ± 0.157	1.174 ± 0.271	0.40
Total hip	0.962 ± 0.132	1.021 ± 0.139	0.958 ± 0.151	1.014 ± 0.151	0.25
Femoral neck	0.816 ± 0.106	0.852 ± 0.118	0.799 ± 0.120	0.865 ± 0.137	0.17
Trochanter	0.711 ± 0.141	0.766 ± 0.118	0.791 ± 0.116	0.865 ± 0.137	0.32
T‐score
Lumbar spine	0.2 ± 1.4	0.5 ± 1.4	−0.2 ± 1.3	0.9 ± 2.4	0.21
Total hip	−0.2 ± 0.9	0.3 ± 1.0	−0.3 ± 1.0	0.2 ± 1.1	0.07
Femoral neck	−0.6 ± 0.8	−0.3 ± 0.9	−0.8 ± 0.9	−0.5 ± 1.0	0.08
Z‐score
Lumbar spine	1.8 ± 1.3	2.2 ± 1.5	1.5 ± 1.4	2.5 ± 2.3	0.20
Total hip	0.7 ± 1.1	1.2 ± 1.1	0.5 ± 1.1	1.0 ± 1.4	0.16
Femoral neck	−0.6 ± 0.9	−0.3 ± 1.2	−0.9 ± 1.1	−0.4 ± 1.4	0.14
Bone turnover markers
CTX (ng/mL)	0.407 ± 0.197	0.309 ± 0.123	0.350 ± 0.143	0.320 ± 0.116	0.09
OC (ng/L)	12.4 ± 4.4	11.6 ± 36	13.2 ± 4.4	12.2 ± 4.4	0.64
PINP (µg/L)	52.2 ± 26.3	41.5 ± 12.2	45.2 ± 14.1	43.1 ± 13.1	0.13

Values are means ± SD. Normal values: CTX (0.110–0.690 ng/mL), OC (3.7–10.0 ng/mL), and PINP (19–96 µg/L).

BMI = body mass index; BMC = bone mineral content; BMD = bone mineral density; CTX = C‐terminal telopeptide of type I collagen; OC = osteocalcin; PINP = intact N‐terminal propeptide of type I procollagen.

2

Serum Concentrations of Bone‐Active Hormones

	Control	Diet	Exercise	Diet‐Exercise
25(OH)D (ng/mL)
Baseline	19.2 ± 8.2	22.0 ± 5.7	21.4 ± 8.4	20.9 ± 6.7
6 months	21.8 ± 9.1*	24.7 ± 7.9*	25.1 ± 8.4*	26.0 ± 7.4*
1 year	22.4 ± 8.3*	24.5 ± 7.1*	26.3 ± 7.0*	25.6 ± 7.0*
PTH (pg/mL)
Baseline	32.0 ± 5.0	31.8 ± 4.4	31.0 ± 6.4	31.1 ± 5.0
6 months	31.5 ± 3.5	31.8 ± 4.9	29.1 ± 6.8	31.2 ± 6.9
1 year	31.3 ± 3.0	30.3 ± 4.6	28.9 ± 6.7	29.6 ± 5.3
Leptin (µg/L)
Baseline	33.2 ± 17.7	36.6 ± 17.8	34.4 ± 21.9	31.3 ± 22.5
6 months	30.1 ± 18.4	24.9 ± 15.0*,**	31.7 ± 22.6***	23.6 ± 23.0*,**,****
1 year	33.9 ± 20.5	23.5 ± 11.4*,**	33.9 ± 24.1***	20.3 ± 19.0*,**,****
Estradiol (pg/mL)
All
Baseline	12.2 ± 5.2	14.2 ± 5.1	14.9 ± 8.0	15.9 ± 5.5
6 months	12.1 ± 13.9	11.7 ± 5.5*,**	14.9 ± 10.5***	11.9 ± 4.5*,**,****
1 year	13.9 ± 5.3	12.0 ± 4.5*,**	13.3 ± 6.5	13.0 ± 6.0*,**
Women
Baseline	9.7 ± 2.7	13.3 ± 5.7	14.0‐ ± 9.5	14.7 ± 6.9
6 months	9.5 ± 3.7	11.0 ± 4.0*	14.4 ± 13.6	10.7 ± 4.8*,**,****
1 year	11.7 ± 3.6	11.3 ± 5.1*,**	12.5 ± 7.4**	10.9 ± 5.6*,**
Men
Baseline	17.8 ± 5.5	15.6 ± 3.6	16.3 ± 4.8	17.5 ± 2.8
6 months	17.3 ± 5.3	13.7 ± 2.8*	16.1 ± 5.1	13.5 ± 3.7*,**,****
1 year	17.2 ± 5.9	13.1 ± 3.2*	14.9 ± 5.0	14.8 ± 3.7*
IGF‐1 (ng/mL)
Baseline	102.8 ± 31.9	102.9 ± 31.2	88.0 ± 26.9	91.2 ± 24.5
6 months	105.8 ± 29.8	105.6 ± 36.1	86.5 ± 28.8	97.5 ± 31.1
1 year	104.6 ± 31.8	109.4 ± 36.8	88.8 ± 28.9	99.3 ± 31.9

Values are means ± SD. Normal values: 25(OH)D (>30 ng/mL), PTH (10–60 pg/mL), leptin (lean men, 3.8 ± 1.8 µg/L; lean women, 7.4 ± 3.7 µg/L), estradiol (untreated postmenopausal women, 5.7–102.8 pg/mL; adult males, 5.6–50.1 pg/mL), and IGF‐1 (25–39 years, 90–360 ng/mL; 65–85 years, 69–166 ng/mL).

25(OH)D = 25‐hydroxyvitamin D; PTH = parathyroid hormone; IGF‐1 = insulin‐like growth factor 1.

*

p < 0.05 for the comparison of the value from baseline, as calculated with the use of mixed‐model repeated measures analyses of variance.

**

p < 0.05 for the comparison of the value from control group, as calculated with the use of mixed‐model repeated measures analyses of variance contrasts.

***

p < 0.05 for the comparison of the value from diet group, as calculated with the use of mixed‐model repeated measures analyses of variance contrasts.

****

p < 0.05 for the comparison of the value from exercise group, as calculated with the use of mixed‐model repeated measures analyses of variance contrasts.

As reported,4 body weight decreased significantly and similarly in the diet group (−9.6% ± 5.5%) and the diet‐exercise group (−9.4% ± 4.6%) but not in the exercise group (−0.6% ± 3.6%) and control group (−0.2% ± 3.3%) (p < 0.001 for the between‐group differences). However, despite comparable weight loss, bone loss at the total hip was relatively less in the diet‐exercise group (−1.1% ± 2.7%) than in the diet‐group (−2.6% ± 2.1%), whereas BMD increased in the exercise group (1.5% ± 1.6%) (p < 0.001 for the between‐group differences) (Fig. 1). Similar trends were observed in BMD at the femoral neck and trochanter (Fig. 1). There were no significant changes in BMD of the whole body: control (0.1% ± 3.1%), diet (0.6% ± 2.7%), exercise (0.5% ± 2.0%), and diet‐exercise (0.8% ± 2.8%); or at the lumbar spine: control (0.4% ± 2.8%), diet (1.1% ± 3.0%), exercise (0.8% ± 2.6%), and diet‐exercise (0.8% ± 2.8%), as reported.4 Likewise, there were no significant changes in BMC of the whole body: control (−0.3% ± 4.4%), diet (−0.1% ± 3.1%), exercise (0.5% ± 2.6%), and diet‐exercise (1.6% ± 6.4%) (p = 0.59 for the between‐group differences). Lean body mass decreased less in the diet‐exercise group (3.2% ± 3.1%) than in the diet group (−5.3% ± 3.4%) while it increased in the exercise group (2.4% ± 2.5%).4 Moreover, in response to the exercise training, total 1‐RM strength increased in the diet‐exercise (34% ± 30%) and exercise (35% ± 36%) group but not in the control (−3% ± 26%) or diet (3% ± 17%) group (p < 0.001 for the between‐group differences).

1

Changes from baseline in (A) body weight and bone mineral density at the (B) total hip, (C) femoral neck, and (D) trochanter in obese older adults during the 1‐year interventions. Values are mean ± SE. *p < 0.05 for the comparison of the value from baseline, calculated using mixed‐model repeated‐measures analyses of variance. ^†p < 0.05 for the comparison of the value from the control group, ^‡p < 0.05 for the comparison of the value from the diet group, and ^§p < 0.05 for the comparison of the value from the exercise group, all calculated using mixed‐model repeated‐measures analyses of variance contrasts.

Serum CTX and osteocalcin concentrations increased in the diet group (31% ± 53% and 24% ± 32%, respectively), whereas they decreased in the exercise group (−13% ± 31% and −15% ± 28%, respectively) (p < 0.001 for the between‐group differences) (Fig. 2). In contrast, similar to the control group, serum CTX and osteocalcin concentrations did not significantly change in the diet‐exercise group. Moreover, serum PINP concentrations decreased in the exercise group (−15% ± 25%) compared with the diet group (9% ± 29%) (p = 0.04 for the between‐group differences).

2

Changes from baseline in markers of bone turnover in obese older adults during the 1‐year interventions. Values are given as mean ± SE. (A) CTX; (B) OC; (C) PINP. *p < 0.05 for the comparison of the value from baseline, as calculated using mixed‐model repeated‐measures analyses of variance. ^†p < 0.05 for the comparison of the value from the control group, ^‡p < 0.05 for the comparison of the value from the diet group, ^§p < 0.05 for the comparison of the value from the exercise group, all calculated using mixed‐model repeated‐measures analyses of variance contrasts. CTX = C‐terminal telopeptide of type I collagen; OC = osteocalcin; PINP = intact N‐terminal propeptide of type I collagen.

Serum 25(OH)D concentrations increased in all groups (control 20% ± 33%; diet 16% ± 29%; exercise 30% ± 40%; and diet‐exercise 25% ± 38%) (Table 2). Serum leptin concentrations decreased in the diet (−25% ± 31%) and diet‐exercise groups (−38% ± 26%) but not in the exercise group or control group (p = 0.001 for the between‐group differences). Likewise, serum estradiol concentrations decreased in the diet (−15% ± 18%) and diet‐exercise groups (−13% ± 30%) but not in the exercise group or control group (p = 0.001 for the between‐group differences). The decrease in both serum leptin and estradiol concentrations occurred at 6 months with no further decrease at 12 months. Stratification for gender showed a similar decrease in serum estradiol between women and men. There were no significant changes in serum PTH and IGF‐1 concentrations.

Changes in hip BMD correlated positively with changes in body weight (r = 0.46; p < 0.001), lean body mass (r = 0.49; p < 0.001), serum leptin concentrations (r = 0.29; p = 0.004), and strength (r = 0.23; p = 0.04), whereas it correlated negatively with changes in serum CTX (r = −0.32; p = 0.004), osteocalcin (r = −0.37; p = 0.001), and PINP (r = −0.30; p = 0.005) concentrations. There was a trend for changes in hip BMD to correlate with changes in serum estradiol (r = 0.19; p = 0.06). In the stepwise multiple regression analyses of the variables affecting the changes in hip BMD, changes in lean body mass (β = 0.33), serum osteocalcin (β = −0.24), and total 1‐RM strength (β = 0.23) remained significant in the final model, explaining 29% of the variance in changes in hip BMD (multiple r = 0.56; p < 0.001) (Table 3).

3

Stepwise Multiple Regression Analysis of the Variables Affecting Changes in Hip Bone Mineral Density: Final Model

Variable	Standardized Beta coefficient	T Value	p Value
Change in lean body mass	0.329	2.791	.01
Change in serum osteocalcin	−0.241	−2.076	.04
Change in total one‐repetition strength	0.230	2.076	.04

Multiple r = 0.56; multiple r² = 0.31. Candidate variables not included in the final model: change in body weight, change in serum estradiol, change in serum leptin, change in serum intact N‐terminal propeptide of type I procollagen, and change in serum C‐terminal telopeptide of type I collagen.

Discussion

Obesity in older adults is a major public health problem.3 However, weight loss therapy to improve health in obese older adults is limited by concomitant bone loss, which could worsen age‐related osteopenia.12 The current study demonstrates that: (1) weight loss increases bone turnover and decreases BMD; (2) ET decreases bone turnover and increases BMD; and most importantly, (3) ET added to weight loss prevents the weight loss–induced increase in bone turnover and attenuates the weight loss–induced decrease in BMD. In addition, the ability of ET to offset the adverse effects of weight loss on bone turnover and BMD occurs despite weight loss–induced decline in bone‐active hormones (eg, estradiol, leptin). This is the first study to directly compare the independent and combined effects of weight loss and ET on bone metabolism and BMD in obese older adults within a randomized‐controlled trial (RCT). By demonstrating the importance of incorporating ET in a weight‐loss program in order to minimize bone loss among obese older adults engaged in dietary caloric restriction, these findings have major clinical implications.

Bone turnover increases with advancing age, leading to progressive bone loss and osteoporosis.13, 14 Weight loss further increases bone turnover and decreases BMD in older adults15–17; our results are consistent with these findings: the diet group lost ∼10% body weight and had an increase in bone turnover associated with a ∼3% reduction in hip BMD. Epidemiologic studies also suggest that weight loss–induced bone loss increases the risk for osteoporotic fractures in older adults.18, 19 On the other hand, some studies have shown that ET increases BMD and decreases the risk for osteoporotic fractures.20 Therefore, ET is recommended to prevent and treat osteoporosis.21 However, the effect of ET on bone turnover is unclear; previous studies reported that ET increased,22–24 decreased,25 or did not change26, 27 markers of bone resorption and formation. Such conflicting results may be related to differences in subject characteristics, type and quantity of exercises, and timing of the samples relative to the exercise. In the current study involving obese older adults, we used a multicomponent, high‐intensity, progressive ET protocol which included different types of exercise that stimulated major muscles attached to bone.28 To avoid the acute effects of exercise,29 we collected blood samples ∼40 hours after the last bout of exercise. Our results clearly demonstrate for the first time that ET in older adults decreases bone turnover and increases BMD, effects that are the exact opposite of weight loss. Given these divergent effects, our four‐group study design directly assessed whether ET can effectively reverse the negative effects of weight loss on bone turnover and BMD. This issue is clinically relevant given that previous studies have shown inconsistent results regarding the efficacy of ET, likely related to limitations such as lack of a control group, nonrandomization to groups, and/or lack of separate weight loss alone and exercise alone groups to compare with the weight loss plus exercise group.30–32 Accordingly, the most important finding in the current study is that ET added to weight loss was able to offset the weight loss–induced increase in bone turnover and decrease in BMD. In contrast to the diet group, the diet‐exercise group demonstrated no significant changes in biochemical markers of bone resorption (CTX) and formation (osteocalcin and PINP) associated with a ∼60% less reduction in hip BMD (−1.1% in the diet‐exercise versus −2.6% in the diet group).

The exact mechanisms underlying the weight loss–induced bone loss are currently unknown. One hypothesis is that it may be due to a reduced dietary calcium and vitamin D intake and/or efficiency of absorption.33, 34 In the current study, we supplemented all participants with calcium and vitamin D. As a result, serum 25(OH)D levels increased to levels considered optimum for bone health (>20 ng/mL)35 and there were no significant changes in levels of serum PTH. Another hypothesis is that bone loss may be due to alterations in several bone‐active hormones that occur with weight loss.12 Indeed, we found significant declines in serum estradiol and leptin levels in the weight‐loss groups and the changes in both hormones tended to correlate with the changes in hip BMD. Thus, one possibility is that not only the further decline in estrogen levels but also the decline in leptin levels owing to weight loss could stimulate the receptor activator of NF‐κB ligand(RANKL)/receptor activator of NF‐κB (RANK) pathway, leading to enhanced bone resorption and bone loss in our subjects.36, 37 Contrary to previous studies,38 we found no decline in serum IGF‐1 levels in response to weight loss, probably because we used a diet protocol that ensured adequate protein intake to our participants.4, 39

A common explanation given for the bone loss induced by weight loss is reduction in mechanical stress on the weight‐bearing skeleton mediated by changes in local bone factors (eg, prostaglandins) and the mechanostat.6, 40 Indeed, the important role of changes in mechanical stress in mediating the changes in BMD in our subjects is suggested by the positive correlations between the changes in hip BMD and the changes in (1) lean body mass and (2) total 1‐RM strength. Lean body mass, which is predominantly skeletal muscle, is known to induce muscle and gravitational forces influencing bone mass via mechanical loading.41 Further support for this hypothesis is provided by the fact that we found changes in BMD at the hip but not at the lumbar spine or whole body, which may be consistent with a site‐specific skeletal effect of the changes in mechanical stress28 that occurred during the interventions. This might suggest that the hip, an important weight and impact‐bearing skeletal site, is the site that responds most sensitively to changes in bone unloading (eg, weight loss) and loading (eg, ET) in our obese older subjects. Given that hip fractures are an important cause of disability,42 our findings that ET not only increases hip BMD but also attenuates the reduction in hip BMD that occurs with weight loss have important implications for the clinical care of this population.1

A more important role for changes in mechanical stress than bone‐active hormones in mediating the changes in hip BMD was also suggested by the results from the stepwise multiple regression analyses, as only changes in lean body mass and total 1‐RM strength along with osteocalcin were selected in the final model. Given that changes in estradiol and other hormones were excluded from the final model, our results suggest an indirect (eg, modulatory) rather than a direct role of hormones in the bone's adaptive response to ET.43 Although some studies have shown that hormone‐replacement therapy (HRT) through the estrogen receptor may augment the osteogenic response to ET,27, 44 hormones do not appear to be essential for bone cells to be able to respond to mechanical strain.43 Accordingly, the current study demonstrates that ET attenuates the weight loss–induced decrease in hip BMD despite weight loss–induced decline in bone‐active hormones. In addition, it appears that the relative degree of changes in bone formation rather than bone resorption may be better predictors of the changes in hip BMD, as changes in serum osteocalcin remained in the final model. These data are consistent with the notion that a primary defect in osteoblastic function occurs during weight loss and is reversed by ET. Indeed, caloric restriction has been shown to suppress bone formation,45 whereas exercise exerts anabolic effects on bone.46 Further studies are needed to examine the molecular and signaling pathways by which weight loss and ET interact to induce adaptations of bone to changes in mechanical loading.

The strengths of our study include the RCT design, the 1‐year duration, the good compliance of the participants, and the comprehensive assessments of bone metabolism. A limitation is that we did not measure bone quality (eg, bone architecture), which is another determinant of bone fracture.47 Although ET did not completely prevent the weight loss–induced decrease in hip BMD, it is possible that ET had a beneficial effect on bone quality. The relatively small number of subjects and duration of this study precluded an assessment of the intervention on falls and fractures. Whether the remaining modest loss of hip BMD increases the risk of fractures needs to be determined in future studies. It remains unclear whether the aggregate benefits of weight loss and ET on physical function4, 48 could lower the risk of falls and fractures despite the decline in hip BMD. Strategies to prevent further bone loss in future studies might include resistance training or endurance training alone (rather than combined resistance/endurance exercise49) due to the potential interference between the adaptations to the two types of exercise.50 Our study was not powered to examine potential sex differences in BMD responses. We controlled for the effect of sex by including it as a covariate in the mixed model ANOVA.

In conclusion, the addition of ET to weight‐loss therapy among obese older adults prevents the weight loss–induced increase in bone turnover and attenuates the weight loss–induced reduction in hip BMD despite weight loss–induced decrease in bone‐active hormones. Therefore, ET should be incorporated as part of a comprehensive weight loss program in obese older adults in order to minimize the adverse effects of weight loss on bone health.

Disclosure

All the authors state that they have no conflicts of interest.

Acknowledgements

We thank the participants for their cooperation and the staff of the Intensive Research Unit of the Institute of Clinical and Translational Sciences for their skilled assistance in the performance of this study. This study was supported by grants RO1‐AG025501, P30‐DK56341 (Clinical Nutrition Research Unit), UL1‐RR024992 (Clinical and Translational Science Award), and DK20579 (Diabetes Research and Training Center) from the National Institutes of Health. TH was supported by a New Investigator Fellowship Training Initiative from the Foundation for Physical Therapy and T32 HD007434‐16. Funded by the National Institutes of Aging; Clinical Trials.gov number, NCT00146107.

Authors' roles: Study design: DTV and DRS. Study conduct: DTV, KS, TH, NP, NN, SC. Data analysis: DTV, KS, RA, NN, DS, CQ. Data interpretation: DTV, KS, RA, NN, DS, CQ. Revising manuscript content: DTV, KS, RA, DS, TH, NP, SH, CQ. Approving final version of manuscript: DTV, KS, RA, NP, SC, DRS, NN, CQ. DTV takes responsibility for the integrity of the data analysis.

Author notes

This work was presented in part to the 2010 Annual Meeting of the American Society for Bone and Mineral Research, Toronto, Canada, October 15–19, 2010.