The Effect of Denosumab on Muscle and Strength and Insulin Sensitivity

The Effect of Denosumab on Muscle and Strength and Insulin Sensitivity

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

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.

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