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

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• Exercise with GLP-1 (liraglutide) treatment may help reduce the risk of associated bone mineral density loss in obese patients under 65.

Introduction

• Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.

• The aim of this study was 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.

Methods

• Predefined secondary analysis of a blinded randomised clinical trial conducted between August 2016 and November 2019 in Denmark.

• Participants included adults aged 18 to 65 years with obesity (BMI of 32-43) and without diabetes.

• After an 8-week low-calorie diet (800 kcal/day), participants were randomised 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.

• The primary outcome measured 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.

• Participants, personnel, and investigators were blinded regarding study medication until the primary outcomes were analysed.

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 randomised, 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).

Conclusion

• 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.

• More awareness of the affects of GLP-1 treatments such as liraglutide on bone-mineral-density and the need for lifestyle changes such as increased exercise in parallel, is needed to reduce bone loss risk in patients.

• The substantial weight loss of 16.9kg for the combination group vs 7.0kg for the placebo group in this RCT and the combination treatment of exercise with GLP-1 preserving site - specific BMD compared with placebo, suggests recommendation of combination of GLP-1 (liraglutide) treatment with exercise may benefit maintenance of bone density of patients during this specific weight loss treatment.

• This study has limitations as cohort limited to adults aged 18 to 65 years without other chronic diseases, therefore the results may not be generalisable to patients with diabetes or older individuals.

• A strength of the reviewed secondary RCT was that the primary RCT sample had a large sample size (195 participants) and was heterogeneous, including males and premenopausal and post-menopausal females. However, this study has limitations as the cohort was limited to adults in Denmark aged 18 to 65 years without other chronic diseases, therefore the results may not be generalisable to patients with diabetes or older individuals or in other (non Danish) populations. More studies are needed in wider populations.