The Effect of Denosumab on Muscle and Strength and Insulin Sensitivity

Overview

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.

Interventions

• Drug Denosumab
  Denosumab 60 mg
• Drug Saline (0.9% NaCl)
  Placebo

Primary outcome measures

• Insulin sensitivity: HbA1c [Time frame: 12 months]
• Insulin sensitivity: HOMA-IR [Time frame: 12 months]
• Insulin sensitivity: fasting glucose [Time frame: 12 months]
• Insulin sensitivity: oral glucose tolerance test [Time frame: 12 months]
• Muscle mass [Time frame: 12 months]
• Muscle strength [Time frame: 12 months]

Secondary outcome measures (11)

• DPP-4 [Time frame: 12 months]
• GLP-1 [Time frame: 12 months]
• Bone turnover markers: CTX [Time frame: 12 months]
• Bone turnover markers: PINP [Time frame: 12 months]
• Bone Mineral Density [Time frame: 12 months]
• Advanced glycation end products (AGEs) [Time frame: 12 months]
• Muscle strength [Time frame: Month 1 and 3]
• Insulin sensitivity: Hb1Ac month 1 and 3 [Time frame: Month 1 and 3]
• Insulin sensitivity: HOMA-IR month 1 and 3 [Time frame: Month 1 and 3]
• insulin sensitivity: fasting glucose month 1 and 3 [Time frame: Month 1 and 3]
• Insulin sensitivity: OGTT month 1 and 3 [Time frame: Month 1 and 3]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 1 center

• Aarhus University Hospital — Aarhus

Publications

• Anastasilakis AD, Papapoulos SE, Polyzos SA, Appelman-Dijkstra NM, Makras P. Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial. J Bone Miner Res. 2019 Dec;34(12):2220-2228. doi: 10.1002/jbmr.3853. Epub 2019 Oct 14. PMID 31433518
• Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, Liu Y, San Martin J. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008 Aug;43(2):222-229. doi: 10.1016/j.bone.2008.04.007. Epub 2008 Apr 26. PMID 18539106
• Rupp T, von Vopelius E, Strahl A, Oheim R, Barvencik F, Amling M, Rolvien T. Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study. Osteoporos Int. 2022 Oct;33(10):2177-2184. doi: 10.1007/s00198-022-06470-3. Epub 2022 Jun 25. PMID 35751664
• Phu S, Bani Hassan E, Vogrin S, Kirk B, Duque G. Effect of Denosumab on Falls, Muscle Strength, and Function in Community-Dwelling Older Adults. J Am Geriatr Soc. 2019 Dec;67(12):2660-2661. doi: 10.1111/jgs.16165. Epub 2019 Sep 4. No abstract available. PMID 31483858
• Miedany YE, Gaafary ME, Toth M, Hegazi MO, Aroussy NE, Hassan W, Almedany S, Nasr A, Bahlas S, Galal S; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021 Oct;40(10):4225-4232. doi: 10.1007/s10067-021-05757-w. Epub 2021 May 19. PMID 34008069
• Rossini A, Frigerio S, Dozio E, Trevisan R, Perseghin G, Corbetta S. Effect of Denosumab on Glucose Homeostasis in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors: A Pilot Study. Int J Endocrinol. 2020 Nov 6;2020:1809150. doi: 10.1155/2020/1809150. eCollection 2020. PMID 33204260
• Lasco A, Morabito N, Basile G, Atteritano M, Gaudio A, Giorgianni GM, Morini E, Faraci B, Bellone F, Catalano A. Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis. Calcif Tissue Int. 2016 Feb;98(2):123-8. doi: 10.1007/s00223-015-0075-5. Epub 2015 Oct 24. PMID 26498169
• Passeri E, Benedini S, Costa E, Corbetta S. A Single 60 mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women. Int J Endocrinol. 2015;2015:352858. doi: 10.1155/2015/352858. Epub 2015 Mar 19. PMID 25873952

Identifiers

NCT: NCT07271771 · CTIS: 2024-510637-18-00 · CTIS: 2024-510637-18-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗