Effect of Denosumab on Glucose Homeostasis in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors: A Pilot Study

Abstract

Background. Aromatase inhibitors in women with breast cancer have been associated with cancer treatment-induced bone loss (CTIBL), increased fracture risk, and impairment of glucose metabolism. Denosumab (Dmab), a monoclonal antibody against RANKL, which is a key regulator of the osteoclast activity, is effective as an antiresorptive agent in the treatment of CTIBL. Since RANKL/RANK pathway may contribute to the pathogenesis of glucometabolic disorders, it has been suggested that Dmab may improve glucose homeostasis. Our pilot study evaluated the effect of a single administration of 60 mg Dmab on glucose metabolism in a cohort of women with breast cancer treated with aromatase inhibitors. Methods. Fifteen postmenopausal nondiabetic women were prospectively enrolled. Oral glucose tolerance test (OGTT) and metabolic parameters, including FGF21, were assessed at baseline and one month after Dmab injection. Midterm glucose control was evaluated by measuring glycated haemoglobin (HbA1c) levels 5 months after Dmab. Results. Parameters of glucose metabolism were not different one month after Dmab but circulating FGF21 levels significantly decreased (128.5 ± 46.8 versus 100.2 ± 48.8 pg/mL; p = 0.016 ). Considering patients with insulin resistance at baseline (HOMA-IR > 2.5 and Matsuda Index < 2.5; n = 5), reduced mean fasting insulin levels (16.3 ± 4.9 versus 13.5 ± 3.5 mcU/mL; p = 0.029 ) and increased insulin sensitivity index QUICKI (0.317 ± 0.013 versus 0.327 ± 0.009; p = 0.025 ) were found. Nonetheless, HbA1c increased 5 months after Dmab (36.0 ± 2.3 versus 39.6 ± 3.1 mmol/mol; p = 0.01 ). Conclusions. Although RANKL blockade induced a short-term positive effect on insulin sensitivity, particularly in insulin-resistant patients, a benefit on long-term glucose metabolism was not evident. In conclusion, Dmab is safe for glucose metabolism in aromatase inhibitor-treated women with breast cancer.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

“…Other small prospective evaluations in nondiabetic, postmenopausal women with osteoporosis treated with Dmab have not shown any significant changes in glucose metabolism parameters [ 57 , 58 ]. Recently, it was demonstrated that Dmab may induce a short-term positive effect on insulin resistance in postmenopausal women [ 20 ] and women with breast cancer treated with an aromatase inhibitor [ 59 ]. In agreement with this finding, Weivoda et al found that T2DM subjects treated with Dmab depicted both a significant reduction of dipeptidyl peptidase-4 and an elevation of glucagon-like peptide 1, leading to a greater improvement of HbA1c than subjects treated with Bps or calcium and vitamin D supplementation [ 60 ].…”

“…In agreement with this finding, Weivoda et al found that T2DM subjects treated with Dmab depicted both a significant reduction of dipeptidyl peptidase-4 and an elevation of glucagon-like peptide 1, leading to a greater improvement of HbA1c than subjects treated with Bps or calcium and vitamin D supplementation [ 60 ]. However, long-term beneficial effects have not been reported [ 59 ].…”

Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study

“…Bonnet et al showed improvement in muscle function associated with increased muscle mass and decreased antimyogenic and inflammatory gene expression in mice as well as improved grip force in postmenopausal women treated with Dmab (n = 18) [19]. Phu et al compared strength, balance, and physical performance in elderly patients receiving anti-resorptive therapy during a six-month observation period and found a significant increase in multidirectional mobility and a significant decrease in fear of falling with Dmab (n = 51) versus zoledronic acid (n = 28) [24]. Further clinical results confirmed the positive effects of both Dmab (n = 15) and BP (n = 25) on skeletal muscle mass and function in elderly patients with hip fractures, with no significant differences between treatment groups [25].…”

RANKL inhibition: a new target of treating diabetes mellitus?

“… 59 Notably, although some studies did not find the clinical effect of Dmab on glucose metabolism, they detected that it seems to improve hepatic insulin sensitivity. 28 , 60 In 2021, to determine whether Dmab can improve glycemic parameters, Pacheco-Soto et al 61 did a meta-analysis involving 1203 participants and found that Dmab could reduce FPG levels (standardized mean difference, SMD = −0.388 mg/dl, p = 0.017) and ameliorate insulin resistance (HOMA-IR: −0.223, p = 0.008) in the overall population, but without the change of HbA1c (SMD = −0.075%, p = 0.538). Further subgroup analysis showed that this beneficial effect on FPG (SMD = −0.636 mg/dl, p = 0.010) and insulin resistance (HOMA-IR: −0.573, p = 0.008) was more prominent in individuals with prediabetes or diabetes than in those with NGT, and the significant improvement of HbA1c (SMD = −0.292%, p < 0.005) can also be seen.…”