Exercise Plus GLP-1 RA May Preserve BMD During Weight Loss, Study Finds

In adults with obesity, the combination of glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with a moderate-to-vigorous exercise program led to significant weight loss with no change in bone mineral density (BMD) compared with either GLP-1RA therapy or an exercise program alone despite greater weight loss with the combined approach, according to findings of new research published in JAMA Network Open.

The investigators also found that the study drug, the GLP-1RA liraglutide, used alone was associated with weight and fat loss vs placebo but also with reduced hip and spine BMD compared with placebo or exercise alone over the 52-week study period. Exercise alone led to weight loss commensurate with liraglutide as well as increased lean mass and BMD preservation at the hip and spine.

Weight loss helps reduce the risk of obesity-related comorbidities but is also associated with decreased BMD and higher bone turnover, both risk factors for fracture and mortality. A similar effect is seen after gastric bypass surgery for weight loss and calorie-restricted diet regimens in younger adults with and without obesity. Bone loss affects adults across the lifespan and so identifying weight loss strategies that minimize this effect is essential for long-term management of obesity, senior author Signe Sørensen Torekov, PhD, professor in clinical and translational metabolism in the department of biomedical sciences at the University of Copenhagen, and colleagues observed.

Current evidence on the long-term effects of GLP-1RAs and exercise on bone health following significant weight loss, however, is both limited and inconsistent, the team wrote. The current findings come from a secondary analysis of a study that investigated exercise alone, liraglutide, and both treatments combined for maintenance of healthy weight loss. The primary outcome was change in body weight.

In the original randomized clinical trial of 195 adults with obesity, Jensen and colleagues randomly assigned 49 patients to receive GLP-1RA treatment (3 mg daily of liraglutide), 48 patients to receive exercise alone, 49 patients to receive a combination of exercise and liraglutide and 49 patients to receive a placebo. All participants completed an 8-week low-calorie diet before the intervention began and followed the assigned regimen for 52 weeks. Median age of the cohort was approximately 43 years, mean BMI 37 kg/m² and 64% were women.

For this secondary analysis, the primary outcome measure was change in site-specific BMD, at the hip, lumbar spine and distal forearm measured by dual-energy X-ray absorptiometry.

FINDINGS

At week 52, Torekov and colleagues reported total estimated mean weight loss of 7.03 kg in the placebo group, 11.19 kg in the exercise group, 13.74 kg in the liraglutide group and 16.88 kg in the combination group.

When they assessed BMD change across treatment groups, the researchers found participants in the group that combined liraglutide therapy with exercise had no significant changes in BMD at the hip (mean change, -0.006 g/cm²) or spine (mean change, -0.010 g/cm²) compared with the placebo group. Participants who received only liraglutide after weight loss experienced decreased BMD at the hip (mean change, -0.013 g/cm2) and spine (mean change, -0.016 g/cm²) compared with those in the exercise-only group and the placebo group (mean change, -0.019 g/cm²), according to the study results.

Additionally, the team reported an increase in distal forearm BMD in the exercise group and the combination treatment group, with no differences between all 4 groups for this measure. The liraglutide and combination treatments were both associated with an increase in whole-body BMD compared with placebo.

The preserved bone mass in the combination treatment group (16.9 kg) “was observed despite a weight reduction of a magnitude that is clinically relevant in the context of novel incretin-based obesity therapies, such as semaglutide and tirzepatide, which resulted in weight losses of approximately 15% to 19% according to findings of a systematic review,” Torekov et al wrote.

The preserved bone mass in the combination treatment group (16.9 kg) “was observed despite a weight reduction of a magnitude that is clinically relevant in the context of novel incretin-based obesity therapies, such as semaglutide and tirzepatide, which resulted in weight losses of approximately 15% to 19% according to findings of a systematic review.”

The authors also point out in the study’s discussion that just as people who have had gastric bypass surgery are at greater risk for bone fracture, exercise has been shown to preserve BMD in this vulnerable population, “collectively highlighting that exercise should be considered alongside GLP-1-based therapy to minimize bone loss.

Among the study's limitations, the authors noted that the age restriction and absence of other chronic disease among participants may limit generalization of findings to those with diabetes or older adults who could be at greater risk for fracture. Also, because change in bone health was a secondary outcome, the analyses were not adjusted for multiple comparisons "and should be considered exploratory."

Source: Jensen SBK, Sørensen V, Sandsal RM, et al. Bone health after exercise alone, GLP-1 receptor agonist treatment or combination treatment: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024;7(6):e2416775. doi:10.1001/jamanetworkopen.2024.16775