Investigating the Impact of GLP-1 RA Therapy on Osteosarcopenia in Older Female Adults With Diabetes

Older females with type 2 diabetes experience a disproportionately high burden of osteosarcopenia, a condition defined by the coexistence of low muscle mass, reduced muscle strength, and decreased bone mineral density. Osteosarcopenia is associated with increased risks of falls, fractures, functional decline, hospitalization, and loss of independence. Diabetes contributes to these risks through multiple mechanisms, including impaired bone microarchitecture, reduced muscle quality, neuropathy-related balance disturbances, and chronic inflammation. These effects are amplified in older women, who already experience age-related declines in muscle and bone health following menopause.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide, are widely used for glycemic management and weight reduction in type 2 diabetes. While these medications provide substantial metabolic benefits, clinical studies have reported that weight loss associated with GLP-1 RA therapy may include reductions in lean body mass. The implications of these changes for muscle strength, bone turnover, and bone mineral density remain unclear, particularly in older females with type 2 diabetes who may be more vulnerable to muscle and bone loss. Existing data on GLP-1 RAs and fracture risk are limited and inconsistent, and most prior studies have evaluated older, less potent agents with minimal weight-loss effects.

This prospective observational study is designed to characterize changes in muscle and bone health during 6 months of GLP-1 RA therapy in older females with type 2 diabetes who are receiving treatment as part of routine clinical care. The study will enroll 20 women over the age of 65. Participants will undergo standardized assessments of muscle strength, bone turnover markers, and bone mineral density at baseline and follow-up. Muscle strength will be evaluated using validated functional measures, and bone health will be assessed through laboratory markers of bone remodeling and imaging-based measures of bone density.

The study does not alter clinical treatment decisions; GLP-1 RA therapy is prescribed independently by participants' healthcare providers based on FDA-approved indications. Study procedures focus on evaluating physiological changes associated with treatment in a population at elevated risk for osteosarcopenia. Data collected will help clarify whether GLP-1 RA therapy influences muscle strength, bone turnover, or bone mineral density in older females with type 2 diabetes. Findings may inform future strategies to support musculoskeletal health in this growing and medically vulnerable population.

Inclusion criteria

• Postmenopausal women aged 65 years or older
• Has type 2 diabetes
• Body Mass Index (BMI) ≥27 kg/m² to max 40kg/m2 (inclusive)
• Hemoglobin A1c between 7-10% within 3 months of the first visit.
• Willingness and ability to comply with all study procedures, including fasting requirements for certain visits.
• No osteoporosis confirmed on DEXA scan within 12 months
• Able to provide informed consent and participate in all study assessments

Exclusion criteria

• Patients with type 1 diabetes mellitus or other types of diabetes that are not T2D
• eGFR <30 ml/min in the last 3 months
• Patients with a history of treatment with anti-osteoporosis agents
• Documented primary or secondary osteoporosis on a DEXA scan within the last 12 months, or are on osteoporosis therapies
• Documented presence of prosthesis or devices in the spine or hip
• Previous fragility fracture
• Males
• Moderate to severe gastroesophageal reflux disease based on patient history.
• Inability to comply with the treatment protocol or to understand the consent form.
• Aspartate aminotransferase (AST) > 3 times normal or alanine aminotransferase (ALT) > 3 times the normal
• Subjects with uncontrolled thyroid or parathyroid disease that may influence the study results.
• Personal or family history of medullary thyroid carcinoma.
• Personal or family history of multiple endocrine neoplasia type 2 syndrome.
• Personal history of gastroparesis, celiac disease, hypogonadism, severe COPD, hypopituitarism, or Cushing's disease
• Personal history of severe diabetic retinopathy.
• Known serious hypersensitivity, including anaphylaxis and angioedema, to semaglutide or any of its excipients.
• Any of the following drugs or treatments were used within 6 months before screening: treated with GLP-1RA, GIP analogues, pioglitazones or DPP-4 inhibitors
• Concomitant treatment with GLP-1 receptor agonist therapy
• Long-term intravenous, oral and intra-articular administration of high dose corticosteroids within 2 months before screening (more than 7 days in a row)
• Use of weight control drugs or surgery that can lead to weight changes during the last 6 months before screening, or are currently in the weight loss plan and are not in the maintenance stage
• Incarcerated individuals