How GLP-1 Therapies Could Impact Bone Density, Muscle Loss

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, including semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), have become central to obesity and type 2 diabetes management. As their use has expanded, so has clinical scrutiny of their effects on bone and muscle.

Several studies—spanning a retrospective cohort analysis, a randomized pilot trial, a case series, and an international consensus commentary—offer converging and sometimes contrasting evidence on how these therapies affect skeletal and lean tissue, along with practical strategies pharmacists and prescribers can discuss with patients.

Bone Density Declines Linked to Weight Loss Magnitude

A retrospective review presented at the 2025 Endocrine Society meeting examined 255 patients (92% female, 63% white, average age 68±9 years) who had at least 6 months of semaglutide or tirzepatide use and 2 bone mineral density (BMD) scans on the same machine. At baseline, 75% of patients had osteopenia or osteoporosis, and 27% had a prior fragility fracture. Over an average follow-up of 34 months, weight decreased by 7.0%, and BMD significantly declined at the lumbar spine (-1.6%±7.3%), femoral neck (-1.8%±6.6%), and total hip (-2.8%±4.9%; P<.001 for all).¹

The decline in total hip BMD was significantly correlated with the amount of weight lost (Pearson r=0.35; P<.001). A total of 33 patients (13%) developed a new fracture after starting treatment, and fracture incidence was significantly higher among patients with diabetes than those without (20.5% vs 7.0%; P=.0014). The authors concluded that greater weight loss was associated with greater total hip BMD decline, underscoring a potential skeletal risk that warrants further prospective study.¹

A contrasting picture emerged from a 20-week pilot randomized controlled trial (RCT) in 20 older adults (72.7±4.8 years) with prediabetes or type 2 diabetes and overweight or obesity, who were randomized to 1.0 mg weekly semaglutide plus lifestyle counseling or lifestyle counseling alone. The semaglutide group lost significantly more weight than the lifestyle-alone group (-5.3% vs -0.89%; P<.01), but no significant between-group differences were observed in whole-body BMD (P=.77) or bone turnover markers, including C-terminal telopeptide of type 1 collagen and procollagen type I N-propeptide. However, a partial Pearson correlation analysis found a strong, significant direct correlation between weight change and pelvis BMD change (r=0.62; P=.01).²

The study authors noted that the weight loss achieved in their pilot trial was modest compared with larger trials and that expected bone loss from a 5% weight reduction would likely fall within the margin of error of a DXA machine. They pointed to other data referenced in their discussion suggesting that more substantial weight loss is associated with greater bone loss. In one 52-week trial, semaglutide produced an 8.8% weight loss along with significantly lower total hip and lumbar spine BMD and higher bone resorption markers compared with placebo, and a large cardiovascular outcomes trial with more than 17,000 participants reported nearly a 5-fold higher incidence of hip and pelvic fractures in adults 75 years and older using semaglutide versus placebo.²

Taken together, the authors suggested that the degree of weight loss—rather than GLP-1 therapy alone—may be the key driver of skeletal risk, a hypothesis consistent with the correlation seen in the larger retrospective cohort.^1,2

Lean Mass Loss Is Common but Variable Across Agents

Bone is not the only concern. An international consensus commentary developed by a panel of clinicians and nutritionists, drawing on presentations from the 42nd International Symposium on Diabetes and Nutrition, cited a systematic review and network meta-analysis of 22 RCTs involving 2258 participants showing that approximately 25% of total weight lost with GLP-1 receptor agonists and dual GIP/GLP-1 agonists consisted of lean mass. Notably, the analysis found heterogeneity across agents. Liraglutide achieved weight loss without significant lean mass reduction, and tirzepatide and semaglutide were the least effective at preserving lean mass. The commentary noted that the magnitude of lean mass loss with these therapies has been likened to that typically accrued over a decade or more of aging, a particular concern for older adults or those with sarcopenic obesity.³

Additionally, a case series of 3 patients (2 female, 1 male; baseline body mass index 32.9-51.9 kg/m²) treated with semaglutide or tirzepatide offers proof of concept for mitigation. All 3 patients engaged in intentional exercise or structured physical activity 4 to 7 days per week, including resistance training 3 to 5 days per week, and reported protein intakes of 1.6 to 2.3 g/kg/day relative to fat-free mass. Changes in weight, fat mass, and lean soft tissue were -33.0%, -53.4%, and -6.9% for case 1; -26.8%, -61.6%, and +2.5% for case 2; and -13.2%, -46.9%, and +5.8% for case 3.⁴

In other words, only 1 of the 3 patients lost lean soft tissue—amounting to 8.7% of total weight lost—and the other 2 patients actually increased their lean soft tissue despite substantial fat loss. By comparison, the authors noted that landmark trials of semaglutide and tirzepatide reported lean soft tissue losses corresponding to approximately 26% to 40% of total weight lost, a range the case series patients notably outperformed.⁴

Practical Strategies for Pharmacists to Discuss With Patients

The consensus commentary translated this evidence into actionable guidance. Recommended strategies to preserve lean mass during GLP-1 therapy include protein intake greater than 1.2 g/kg/day, evenly distributed across meals, combined with aerobic activity and structured resistance training. The commentary cited supporting evidence from a 3-year study of adults aged 70 to 79 years, in which those in the highest quintile of protein intake lost nearly 40% less lean mass than those in the lowest quintile, and from a trial showing that distributing protein evenly across meals increased muscle protein synthesis by 25% compared with a skewed intake pattern. A separate trial combining exercise with liraglutide produced the greatest total weight loss among treatment arms while preserving lean mass, whereas liraglutide alone was associated with loss of both fat and lean tissue.³

The commentary also addressed the gastrointestinal (GI) tolerability challenges that can undermine adherence to these mitigation strategies. GI symptoms—nausea, constipation, diarrhea, and vomiting—occur in around 40% of patients and remain the leading cause of treatment discontinuation. Practical counseling points include smaller, more frequent meals and avoidance of high-fat or spicy foods for nausea; adequate fiber (approximately 14 g/1000 kcal/day) and fluid intake (more than 2 to 3 L/day) for constipation; and gradual dose titration to improve overall tolerability.³

Collectively, these 4 studies suggest that although bone and muscle loss are real risks associated with GLP-1 and GLP-1/GIP receptor agonist therapy—particularly with greater weight loss and in older or diabetic populations—they are not inevitable. Pharmacists counseling patients on these therapies can reinforce the value of resistance training, adequate and evenly distributed protein intake, and proactive GI symptom management as tools to support both adherence and favorable body composition outcomes.

REFERENCES

1. Liu Y, Walzer D, Schmitz S, Shukla A, Kashyap SR, D’Angelo D. MON-817 Association of Semaglutide and Tirzepatide Use on Bone Density and Fracture Risk in Obese Patients with and without Diabetes. J Endocr Soc. 2025;9(Suppl 1):bvaf149.558. Published 2025 Oct 22. doi:10.1210/jendso/bvaf149.558

2. Dinkla L, Beavers KM, Robbins R, et al. Bone mineral density and turnover response to GLP-1 receptor agonists in older adults with overweight/obesity and prediabetes/type 2 diabetes: a 20-week pilot trial post hoc analysis. Front Aging. 2025;6:1691007. Published 2025 Nov 27. doi:10.3389/fragi.2025.1691007

3. Noronha JC, Van Gaal LF, Neeland IJ, et al. Optimizing GLP-1 therapies for obesity and diabetes management. Obes Pillars. 2025;16:100222. Published 2025 Oct 24. doi:10.1016/j.obpill.2025.100222

4. Tinsley GM, Nadolsky S. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series. SAGE Open Med Case Rep. 2025;13:2050313X251388724. Published 2025 Oct 16. doi:10.1177/2050313X251388724