Effects of denosumab on insulin resistance in postmenopausal women with osteoporosis

-IR,The tumor necrosis factor (TNF)-related cytokine receptor activator of nuclear factor kappa B ligand (RANKL) has been proposed as an independent risk predictor of type 2 diabetes mellitus (DM) and experimental blockade of RANK signaling resulted in a marked improvement of glucose tolerance. Denosumab is an IgG2 human antibody that binds RANKL and prevents the interaction of RANKL with its receptor RANK, thus inhibiting osteoclast-mediated bone resorption, and reducing the risk of fractures. Denosumab may also affect osteocalcin (BGP) levels possibly interfering with insulin secretion, in accordance to the endocrine role of BGP. Our aim was to study the modifications of fasting glucose concentrations, insulin resistance and lipid profile in a set of non diabetic women treated with denosumab for postmenopausal osteoporosis. A total of 48 women were enrolled and received a single subcutaneous dose (60mg) of denosumab. At baseline and after 4, 12 ad 24 weeks insulin resistance was computed by homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol, triglycerides and HDL-cholesterol were also measured. At baseline and after 24 weeks, levels of BGP, C-telopeptide of type 1 collagen (CTX), as bone formation and resorption markers respectively were recorded. After denosumab administration, fasting plasma glucose was not significantly changed, and the same was observed for HOMA-IR , although a slight reduction of HOMA-IR was detected at 4 weeks (p<0.05). Lipid parameters remained unchanged at each time-points. A reduction of CTX (-63%, P<.0001) and BGP (-45%, P<.0001) were observed at the end of the study. At a multiple regression analysis, baseline levels of bone biomarkers were not predictive of HOMA-IR, and changes of BGP were not associated to markers of glucose metabolic control. A single dose of denosumab in osteoporotic otherwise healthy postmenopausal women was not associated to relevant modification of glucose homeostasis.