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LEAN & STRONG: PREVENTING MUSCLE AND BONE LOSS ON GLP-1RA THERAPY

Prajesh Man Joshi, MD

Mercy Endocrinology

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Learning Objectives

By the end of this presentation, the audience will be able to:

  • Define body composition
  • Describe the scope of lean mass and bone mineral density (BMD) loss associated with GLP-1 receptor agonist (GLP-1RA) therapy
  • Differentiate between lean mass loss and true skeletal muscle loss
  • Identify patients at highest risk for clinically significant musculoskeletal consequences
  • Apply evidence-based nutritional, exercise, and monitoring strategies to mitigate muscle and bone loss
  • Discuss emerging pharmacologic therapies targeting muscle preservation during GLP-1RA treatment

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The GLP-1RA Revolution

  • FDA-approved GLP-1RAs and dual/triple agonists: semaglutide (Ozempic, Wegovy, Rybelsus), tirzepatide (Mounjaro, Zepbound), dulaglutide (Trulicity), liraglutide (Saxenda)
  • Expanding indications: T2DM, obesity, MASH, cardiovascular risk reduction, CKD, OSA
  • Weight loss efficacy: semaglutide 2.4 mg → ~15–16% weight loss; tirzepatide 15 mg → ~20–21% weight loss
  • Key question: What is the quality of the weight being lost?

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Body Composition

Carter et al. Surgery for Obesity and Related Diseases 21 (2025) 354-361

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Body Composition

Dubin et al. Diabetes Obes Metab 2024;26:5503-5518

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Healthy adult reference for body composition

Body Compartment

Men

Women

Fat mass

15% ( fit) to 28% ( population average)

25% ( fit) to 40% ( population average)

Fat- free mass (FFM)

72 to 85 %

60-75%

Lean Body mass

Similar to FFM

Similar to FFM

Skeletal muscle mass

35-40 % of weight (50-55% of FFM)

28 % to 33 %

Bone Mineral

4-5%

5%

Total body Water

60% of weight( 73 % of FFM)

50% of weight (70% of FFM)

Organs/ viscera

10-15% of weight

10-15 % of weight

Dubin et al. Diabetes Obes Metab 2024;26:5503-5518

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The Body Composition Problem: Not All Weight Loss Is Equal

  • Weight loss = fat mass loss + lean mass loss
  • Lean mass ≠ skeletal muscle mass (lean mass includes organs, bone, fluids, hydration in fat tissue)
  • Key trial data:
    • STEP 1 (semaglutide): 15.3 kg weight loss → 10.4 kg fat mass + 6.92 kg lean mass (~40% lean mass)
    • SURMOUNT-1 (tirzepatide 15 mg): 22.1 kg weight loss → lean mass ~25.7% of total weight lost
    • Meta-analysis: ~30% of body weight lost with GLP-1RA-based therapy is lean mass

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Jastreboff et al. NEJM 2022;387:205-16

Wilding et al. NEJM 2021;384 (11):989-1002

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Semaglutide and change in body composition

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Wilding et al. NEJM 2021;384 (11):989-1002

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Tirzepatide and change in body composition

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Jastreboff et al. NEJM 2022;387:205-16

Look et al. Diabetes Obes Met. 2025;27:2720-2729

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Muscle Quality vs. Muscle Quantity�

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  • SURPASS-3 MRI substudy (tirzepatide): modest reductions in muscle volume, but significant improvements in muscle quality
    • Marked reductions in muscle fat infiltration (myosteatosis) across all doses
    • Reduction in myosteatosis was 2–4× greater than the mean increase seen with 1 year of aging
  • Functional capacity generally improves despite lean mass loss
  • Overall body composition (fat-to-lean ratio) improves with treatment
  • Absolute lean mass decreases, but relative lean mass proportion is generally preserved

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Sattar et al. Lancet Diabetes Endocrinol 2025;13:482-93

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Mechanisms of GLP-1RA Effects on Skeletal Muscle�

  • Indirect effects (via weight loss/caloric restriction):
    • Reduced mechanical loading on muscle
    • Decreased protein intake due to appetite suppression
    • Caloric deficit → proteolysis
  • Direct effects (preclinical evidence):
    • GLP-1 receptors present on human skeletal muscle
    • Anti-inflammatory: suppression of NF-κB, reduction of IL-1β, IL-6, TNF-α
    • Antioxidant and mitochondrial-supportive: AMPK/SIRT1/PGC-1α pathway activation
    • Upregulation of myogenic factors (MyoD, MyoG)
    • Suppression of proteolytic markers (MuRF1, MAFbx/Atrogin-1)
    • Suppression of myostatin

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GLP-1RA Effects on Bone: Preclinical vs. Clinical Evidence�

  • Preclinical (in vitro/animal):
    • Promotes osteoblastogenesis, inhibits osteoclast activity
    • Enhances bone formation markers
  • Clinical (human): Variable
    • Primarily stimulates bone resorption (↑ CTX levels)
    • BMD reduction correlates with degree of weight loss
    • More pronounced at weight-bearing sites (femur, tibia)
    • Data variable in Type 2 diabetes vs Obesity
    • Fragility fracture incidence does NOT appear to increase

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GLP-1RA Effects on Bone in Type 2 diabetes mellitus

Tan et al. Acta Diabetological 2025;62:589-606

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GLP-1RA Effects on Bone in Obesity

Liu et al. JCEM 2026;111:1959-1966

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Who is at the Highest Risk?�

  • Older adults (>=65 years) with preexisting sarcopenia or frailty
  • Postmenopausal women/ men with low testosterone
  • Sarcopenic obesity
  • Sedentary individuals without resistance training
  • Individual with limited habitual physical activity
  • Rapid weight loss ( >5%/ month or >=14% over 3-4 months)
  • Weight regain after discontinuation ( regain of predominantly fat, not muscle)

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Strategies to Prevent Muscle and Bone Loss on GLP-1RA Therapy

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Structured Exercise

  • Resistance/strength training is the single most important intervention
  • Aerobic exercise alone has a smaller effect on preserving lean mass
  • GLP-1 therapy + exercise preserved BMD
  • GLP-1 + exercise also produced greater reductions in abdominal fat and preserve lean mass
  • Exercise programs should be customized to fitness level and physical capacity

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Jensen et. Al. Jama Network Open. 2024;7(6):e2416775

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GLP-1RA + Exercise and Bone�

Jensen et. Al. Jama Network Open. 2024;7(6):e2416775

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GLP-1 + Exercise and Body Composition

Lundgren et al. NEJM 2021;384:1719-1730

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Importance of Resistance Training for preservation of lean body mass

Sardeli et al. Nutrients 2018; 10:423

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Exercise framework

Nadolsky et al. Endocrine Practice 31 (2025) 1351-1394

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Nutritional Optimization

  • Practical tips for patients with reduced appetite:
    • Eat protein-rich foods first in a meal
    • Choose nutrient-dense, low-volume options: eggs, Greek yogurt, cottage cheese, fish, nuts/seeds
    • Supplement with high-protein shakes/bars if needed
  • Protein alone is insufficient without resistance training
  • Ensure adequate calcium and vitamin D for bone health

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Nadolsky et al. Endocrine Practice 31 (2025) 1351-1394

Kokura et al. Clinical Nutrition ESPEN 63 (2024) 417e426

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Protein intake and Preservation of muscle mass

  • Protein targets during active weight loss: 1.2–1.6 g/kg/day (some recommend up to 1.3 g/kg/day for older adults)
  • Higher protein intake prevents muscle mass decline
  • Higher protein intakes (≥2.3 g/kg/day) may be needed to maximize the retention of lean body mass while prioritizing resistance training during hypocaloric periods

Nadolsky et al. Endocrine Practice 31 (2025) 1351-1394

Kokura et al. Clinical Nutrition ESPEN 63 (2024) 417e426

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Emerging pharmacologic therapies targeting muscle preservation during GLP-1RA treatment

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Agents

Mechanism

Key Trial

Key Findings

Bimagrumab

Anti-activin antibody

BELIEVE (Phase 2b)

Semaglutide + bimagrumab: 22.1% weight loss at 72 wks, ~93% of weight lost was fat; monotherapy: 22% fat mass reduction + 3.6% lean mass increase

Apitegromab

Myostatin inhibitor

EMBRAZE (Phase 2)

Tirzepatide + apitegromab: 54.9% vs. 30% lean mass retention (P = .001)

Trevogrumab ± Garetosmab

Anti-myostatin ± anti-activin A

COURAGE (Phase 2)

Semaglutide + trevogrumab: 50–51% lean mass preserved; triplet regimen: up to 80% lean mass preserved

IBIO-600

Dual anti-myostatin/GDF11

Preclinical

Preserves lean mass in obese mice on GLP-1RA; ~52-day half-life in primates

Enobosarm

SARM

Early studies

Improved physical function and lean mass

Heymsfield et al. Nature Medicine 2026;32:869-882

Pratley et al. Nature Medicine 2026;32:2673-2678

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Bimagrumab

    • Investigational monoclonal antibody
    • Blocks type II activin receptor
    • intended to reduce total body and visceral fat mass
    • promote muscle growth

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Heymsfield et al. Nature Medicine 2026;32:869-882

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Bimagrumab

Heymsfield et al. Nature Medicine 2026;32:869-882

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Clinical Framework

  • During therapy
    • Co-prescribe resistance + aerobic exercise
    • Target protein intake 1.2-1.6 g/kg/day
    • Ensure adequate calcium and vitamin D
    • Monitor rate of weight loss
  • Before initiating GLP-1A therapy:
    • Asses baseline body composition
    • Screen for sarcopenia risk
    • Evaluate bone health
    • Assess dietary protein intake
    • Establish a structured exercise plan (resistance + aerobic)

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Clinical Framework

  • Monitor for weight regain ( predominantly fat)
  • Continue resistance training to prevent sarcopenic obesity
  • Reassess body composition and bone health

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Key Takeways�

  • GLP-1RA induced lean mass loss ( 25-40% of total weight lost) is proportional to weight loss and comparable to other weight loss intervention
  • Bone loss correlates with weight loss magnitude and may differ by diabetes status
  • Fracture risk does not appear to be increase based on current evidence
  • Resistance training + adequate protein intake are the cornerstones for mitigating loss
  • Emerging therapies ( bimagrumab, apiteromab, trevogrumab) show promise for preserving lean mass in the future
  • Individualized risk assessment and monitoring are essential, especially in older adjust and those with rapid weight loss

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�Questions?