Evaluation of Denosumab on Insulin Sensitivity and Muscle Strength in Patients with Diabetes Mellitus and Postmenopausal Osteoporosis

The primary objective of this study is to evaluate the effect of **denosumab** on insulin sensitivity and muscle strength in individuals with **Diabetes Mellitus** and **Postmenopausal osteoporosis**. This randomized, placebo-controlled trial aims to provide insights into the potential benefits of denosumab, a human monoclonal antibody, in improving metabolic and musculoskeletal health. Understanding the impact of denosumab on these parameters is clinically relevant as it may offer a therapeutic option for enhancing insulin sensitivity and muscle function, which are critical factors in managing diabetes and osteoporosis.

The clinical trial involves a study population of **postmenopausal women** aged 40 years and older, specifically targeting individuals with **Diabetes Mellitus type 2** and **postmenopausal osteoporosis**. Participants are required to have been postmenopausal for at least two years and must be undergoing treatment with metformin as monotherapy. The trial does not include male subjects or vulnerable populations. The selection criteria emphasize a **Bone Mineral Density (BMD) T-score** of -2.0 or higher at the lumbar spine, total hip, or femoral neck, and the ability to evaluate at least two lumbar vertebrae using dual-energy x-ray absorptiometry (DXA). The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **placebo-controlled**, prospective study to evaluate the effect of **denosumab** on insulin sensitivity and muscle strength in postmenopausal women with type 2 **diabetes mellitus** and postmenopausal **osteoporosis**. The trial will involve the administration of denosumab, a human monoclonal antibody, and a placebo, saline solution, both delivered via subcutaneous injection. The study is expected to span a total duration of 12 months, with participant recruitment anticipated to commence on March 1, 2024, and the trial estimated to conclude by January 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as being postmenopausal for at least two years, aged 40 years or older, and having a BMD T-score of -2.0 or higher. The primary endpoints will assess changes in muscle mass, muscle strength, and insulin sensitivity from baseline to month 12. Secondary endpoints will include changes in DPP-4, GLP-1, CTX, PINP, lumbar spine BMD, AGEs, and additional assessments of muscle strength and insulin sensitivity at months 1 and 3.

Participants are expected to be involved in the trial for the full 12-month period unless conditions arise that necessitate early termination, such as adverse reactions or withdrawal of consent. The trial will include follow-up visits at months 1, 3, and 12 to monitor progress and collect data on the primary and secondary endpoints. The end-of-study visit will occur at month 12, marking the completion of the participant's involvement in the trial. The trial is categorized as low intervention, with all medications used being approved by the EMA for the treatment of osteoporosis and administered at approved doses.

The clinical trial involves the administration of **denosumab**, a human monoclonal antibody, as the experimental medication. Denosumab is provided in a pharmaceutical form identified as PHF00231MIG. The active substance, denosumab, is a protein of non-specified origin, with synonyms including AMG 162, HLX14, TVB-009, and MAB-22. The medication is administered subcutaneously at a dosage of 60 mg per administration. The dosing schedule is set to a maximum of 60 mg per day, with the treatment period extending up to 12 months. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes **saline** as a placebo comparator. Saline is administered in the form of a solution for injection, specifically 0.9% sodium chloride. The placebo is also delivered via subcutaneous injection, with a maximum daily dose of 0.9 ml. The total dose per administration is 0.9 ml, and the treatment period for the placebo group is similarly set to a maximum of 12 months. The use of saline as a placebo allows for the evaluation of denosumab's effects on insulin sensitivity and muscle strength in a controlled manner. Compliance with the placebo administration is similarly monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include changes in muscle mass and muscle strength, as well as changes in insulin sensitivity, measured by HbA1c, HOMA-IR, fasting glucose, and oral glucose tolerance test (OGTT) from baseline to month 12. Secondary endpoints will evaluate changes in DPP-4 and GLP-1 levels, carboxy-terminal collagen crosslinks (CTX), procollagen type I N-terminal propeptide (PINP), lumbar spine bone mineral density (BMD), and advanced glycation end products (AGEs) from baseline to month 12. Additionally, changes in muscle strength and insulin sensitivity will be assessed at months 1 and 3.

The trial will employ validated laboratory tests and dual-energy x-ray absorptiometry (DXA) to measure these parameters. Efficacy assessments will be conducted at specified timepoints, including baseline, month 1, month 3, and month 12. The trial is designed as a randomized, placebo-controlled, prospective study to evaluate the effect of **denosumab** on insulin sensitivity and muscle strength in postmenopausal women with type 2 diabetes mellitus. The study will utilize a human monoclonal antibody, administered subcutaneously, with a maximum treatment period of 12 months.