In a study recently published in JAMA Network Open , a group of researchers evaluated the effects of exercise, the glucagon-like peptide-1 receptor agonist (GLP-1 RA) liraglutide, and their combination on hip, spine, and forearm bone health in obese adults after diet-induced weight loss.
Study: Bone health after exercise alone, GLP-1 receptor agonist treatment, or combination treatment. Image credit: siamionau pavel / Shutterstock
background
Weight loss reduces obesity-related complications but often leads to reduced bone mineral density (BMD) and increased bone turnover, increasing fracture risk and mortality. This bone loss is a lifelong concern, especially in older adults after gastric bypass surgery or caloric restriction. Finding treatments that promote weight loss while minimizing bone loss is important. GLP-1RAs promote weight loss by suppressing appetite. Exercise preserves lean body mass and is therefore recommended for healthy weight loss. Current evidence is limited and inconsistent, so further studies are needed to establish the long-term effects of GLP-1RAs and exercise on bone health after significant weight loss.
About the Research
The study was conducted at Hvidovre Hospital and the University of Copenhagen from August 2016 to November 2019. It was approved by the Danish Regional Ethics Committee and the Danish Medicines Agency and conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Participants aged 18-65 years and with a BMI of 32-43 gave informed consent. People with severe chronic diseases such as diabetes were excluded. After 8 weeks of a low-calorie diet (800 kcal per day), participants who had lost 5% or more of their initial body weight were randomly assigned to one of four groups: exercise plus placebo, liraglutide, exercise plus liraglutide, or placebo.
Exercise intervention included 6 weeks of graded exercise followed by high-intensity group and individual sessions. Liraglutide or placebo was administered daily, starting at 0.6 mg and increasing to 3.0 mg or the maximum tolerated dose. Monthly weight consultations were provided with dietary support.
Outcomes included weight, body composition, and bone mineral density at the hip, lumbar spine, and forearm, measured by dual-energy x-ray absorptiometry (DXA). Bone turnover markers, plasma type 1 collagen cross-linked C-telopeptide (P-CTX), and plasma type 1 procollagen propeptide (P-P1NP), were assessed from fasting blood samples. Statistical analyses used restricted linear mixed models adjusting for baseline measurements, with a two-sided P < .05 as significant. Data analyses were performed in March-April 2023, with an additional analysis in February 2024.
research result
A total of 195 participants (mean age 42.84 years, 64% women, mean BMI 37.00) completed a reduced-calorie diet and were randomized into four groups: exercise (48), liraglutide (49), combination (49), or placebo (49). BMD measurements were available for 158 to 161 participants at week 52. No participants were taking osteoporosis medications and no fragility fractures occurred. Safety results have been reported previously.
The average amount of exercise was 118 minutes per week at 78% of maximum heart rate in the exercise group and 111 minutes per week at 79% in the combination group. Eight participants reduced their medication and completed the study, and 11 discontinued the study medication but continued to participate in the study.
Estimated mean weight loss was 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. After an initial weight loss of 13.1 kg, the placebo group regained weight, while the exercise and liraglutide groups maintained their weight loss, and the combination group lost more weight. Both the exercise and liraglutide groups lost percentage fat and fat mass, with the greatest reductions seen in the combination group. The exercise group increased lean mass, and the combination group maintained lean mass despite the greater fat loss.
Changes in BMD from baseline to week 52 showed no significant changes in hip and lumbar spine BMD in the combination group compared with the placebo group. However, hip and lumbar spine BMD decreased in the liraglutide group compared with the exercise and placebo groups. Distal forearm BMD increased in the exercise and combination groups, but there were no significant differences between the four groups. Subgroup analyses by sex and age showed consistent results. Liraglutide and combination treatment were associated with increases in total body BMD compared with the placebo group.
Bone turnover markers showed that P-CTX increased by 27% after the hypocaloric diet and decreased in all groups by week 26, with the lowest levels in the placebo group. P-P1NP increased by 7% during the hypocaloric diet and returned to initial levels by week 52 in all groups.
Conclusion
In summary, this secondary analysis of a randomized clinical trial examined changes in segmental BMD during 1 year of intervention with liraglutide (3.0 mg/day), exercise, or their combination compared with placebo after diet-induced weight loss. Combined treatment resulted in the greatest weight and fat loss while maintaining hip, spine, and forearm BMD. Liraglutide alone reduced hip and spine BMD despite weight loss. Exercise alone preserved lean body mass and maintained hip and spine BMD. The results suggest that combining exercise and GLP-1RA therapy may be the most effective strategy to lose weight while maintaining bone health.
Journal References:
Jensen SBK, Sørensen V, Sandsdal 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) doi:10.1001/jamanetworkopen.2024.16775, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820308
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