The Effect of Denosumab on Muscle and Strength and Insulin Sensitivity

NCT ID: NCT07271771

Last Updated: 2025-12-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-05-21
• Study Completion Date: 2027-03-01

Brief Summary

Randomized, placebo controlled prospective trial evaluating the effect of denosumab on insulin sensitivity and muscle strength.

Detailed Description

Denosumab is an antibody against receptor-activator of nuclear factor kappa-B ligand (RANKL) that prevents recruitment and differentiation of mature osteoclasts. Treatment with denosumab markedly decreases bone resorption, increases bone mineral density (BMD), and reduces the risk of vertebral as well as non-vertebral and hip fractures. Osteoclasts produce dipeptidyl peptidase-4 (DPP-4) that degrades glucagon-like peptide-1 (GLP-1) and GLP-1 stimulates insulin production. In accordance with this, animal models have shown a beneficial effect of denosumab on glucose metabolism. However, data from clinical studies in patients with osteoporosis are limited and the results inconsistent. In a small, randomised trial with 52 healthy postmenopausal women, treatment with denosumab for 12 months reduced DPP-4 and increased GLP-1 compared to placebo but no effect was seen on insulin or fasting glucose levels. In the same publication, the authors conducted a non-randomized, observational study in osteoporotic patients with diabetes mellitus or prediabetes that were treated with either denosumab, bisphosphonates, or calcium + vitamin D at the discretion of their physician. Here, treatment with denosumab significantly reduced fasting glucose after 6 months and HbA1c after 12 months compared to bisphosphonates or calcium + vitamin D. Similar findings were seen in another observational study with 20 patients with diabetes. On the other hand, a post hoc analysis of the FREEDOM trial did not find a general effect of denosumab on fasting glucose in postmenopausal women with self-reported diabetes or prediabetes, but only reported a small decrease in fasting glucose in denosumab treated women with diabetes not treated with antidiabetics. This is in line with three small observational studies, in which no clinically relevant effect of denosumab on fasting glucose, insulin level or homeostatic model assessment for insulin resistance (HOMA-IR) was identified.

Overall, the heterogeneity across the studies is large, most of the trials are observational studies and the results are inconsistent. Therefore, randomized, controlled trials are warranted to further elucidate this.

Denosumab has also been shown to improve muscle strength compared to placebo in animal models, however, data from human studies is limited. In an observational study, denosumab decreased the risk of falls and improved sarcopenia measures in 135 patients with osteoporosis compared to 272 patients treated with alendronate or zoledronate assessed at treatment initiation and after 5 years for denosumab and alendronate and 3 years for zoledronate. All outcome measures worsened one years after denosumab discontinuation. In another prospective observational study with 18 postmenopausal women, denosumab treatment for an average of three years improved appendicular lean mass and handgrip strength compared to treatment with bisphosphates or placebo. This is in line with two additional observational studies, in which denosumab improved muscle strength after 6 - 17 months compared to bisphosphonates or vitamin D.

None of the studies evaluating the effect of denosumab on muscle strength are randomised controlled trials, the outcome measures are different and the follow up visits few. Also, none of the studies controlled for exercise.

The investigators therefore want to conduct a randomized, placebo controlled prospective trial evaluating the effect of denosumab on insulin sensitivity and muscle strength.

Conditions

Osteoporosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Study group 1

Denosumab

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: DRUG

Denosumab 60 mg

Study group 2

Placebo

Group Type: PLACEBO_COMPARATOR

Saline (0.9% NaCl)

Intervention Type: DRUG

Placebo

Interventions

Denosumab

Denosumab 60 mg

Intervention Type: DRUG

Saline (0.9% NaCl)

Placebo

Intervention Type: DRUG

Other Intervention Names

Placebo

Eligibility Criteria

Inclusion Criteria

• Postmenopausal women (postmenopausal for at least two years)
• Age ≥ 40 years
• BMD T-score ≥ -2.0 (lumbar spine, total hip or femoral neck)
• At least 2 lumbar vertebrae that can be evaluated by dual-energy x-ray absorptiometry (DXA)
• Diabetes Mellitus type 2
• Treatment with metformin as monotherapy

Exclusion Criteria

• Treatment for osteoporosis at any time
• Other antidiabetic medication than metformin
• Low-energy vertebral fractures at any time
• Low-energy hip fracture at any time
• Ongoing treatment with systemic glucocorticoids
• Metabolic bone disease (for example osteogenesis imperfecta, Paget's disease of bone, hyperparathyroidism)
• Treatment affecting bone, calcium metabolism or muscle
• Active cancer within the last 5 years with the exception of basal cell skin cancer
• Estimated glomerular filtration rate (eGFR) ≤ 35 mL/min
• Unable to read and understand Danish
• Immobility

• Minimum Eligible Age: 40 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Sponsor: MD, Professor, DMSc, PhD Bente Lomholt Langdahl

UNKNOWN

Sponsor Role: collaborator

Aarhus University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Anne Sophie Sølling

MD, PhD, postdoc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bente Langdahl, MD, Professor, DMSc, PhD

Role: PRINCIPAL_INVESTIGATOR

Aarhus University Hospital

Locations

Aarhus University Hospital

Aarhus, , Denmark

Site Status: RECRUITING

Countries

Denmark

Central Contacts

Anne Sophie Sølling, MD, PhD

Role: CONTACT

annesoel@rm.dk

+45 22 30 05 24

Facility Contacts

Anne Sophie Sølling, MD, PhD

Role: primary

annesoel@rm.dk

+45 22 30 05 24

References

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Reference Type: BACKGROUND

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CTIS: 2024-510637-18-00

Identifier Type: OTHER

Identifier Source: secondary_id

CTIS: 2024-510637-18-00

Identifier Type: -

Identifier Source: org_study_id