Bone Health After Exercise Alone, GLP-1 Receptor Agonist Treatment, or Combination Treatment: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.

Objective: To investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined.

Design, setting, and participants: This study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision.

Interventions: After an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo.

Main outcomes and measures: The primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population.

Results: In total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, -0.006 g/cm2; 95% CI, -0.017 to 0.004 g/cm2; P = .24) and lumbar spine (-0.010 g/cm2; 95% CI, -0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, -0.013 g/cm2; 95% CI, -0.024 to -0.001 g/cm2; P = .03) and spine (mean change, -0.016 g/cm2; 95% CI, -0.032 to -0.001 g/cm2; P = .04).

Conclusions and relevance: In this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss.

Trial registration: EudraCT: 2015-005585-32.

Figure 1.. Changes in Body Weight and Body Composition During the Study

Changes are shown for body weight (A), body fat percentage (B), fat mass (C), and lean mass (D). Values are estimated mean changes in kilograms after a low-calorie diet (weeks −8 to 0) and 52 weeks after randomization to treatment with placebo, exercise, liraglutide, or the combination of exercise and liraglutide. The shaded area indicates the period of the low-calorie diet. Results are from the intention-to-treat population (all randomized participants). Randomization was done at week 0, immediately after the low-calorie diet. Error bars are standard errors of the mean.

Figure 2.. Changes in Bone Mineral Density (BMD) During the Study

Changes are shown for BMD at the total hip (A), lumbar spine (B), and distal forearm (C). Values are estimated mean changes in BMD after a low-calorie diet (weeks −8 to 0) and 52 weeks after randomization to treatment with placebo, exercise, liraglutide, or the combination of exercise and liraglutide. The shaded area indicates the period of the low-calorie diet. Results are from the intention-to-treat population (all randomized participants). Randomization was done at week 0, immediately after the low-calorie diet. Error bars are standard errors of the mean.

Figure 3.. Changes in Markers of Bone Turnover During the Study

Changes are shown for plasma type 1 collagen cross-linked C-telopeptide (CTX; A) and plasma propeptide of type 1 procollagen (P1NP; B) during the study. These outcomes were initially analyzed on a log scale. For presentation, these outcomes were back-transformed and expressed as percentage change from week −8 (calculated as estimated ratio − 1 × 100) with 95% CIs. Results are for participants in the intention-to-treat population (all participants who were randomized at week 0). The shaded areas indicate the low-calorie diet period.