IBMS BoneKEy | BoneKEy Watch
Kondegowda et al. Could denosumab have value in treating diabetes?
DOI:10.1038/bonekey.2015.130
Kondegowda et al. explored the potential of osteoprotegerin (OPG), a key bone formation enhancer, for its role as a β-cell proliferation inhibitor. Mice injected daily with recombinant OPG showed a two to six-fold increase in β-cell proliferation, a 20% increase in β-cell mass and a significant improvement in glucose homeostasis. The normally recalcitrant adult human β-cells replicated after exposure to OPG; treatment with a dose as low as 0.05 μg/ml caused a three-fold increase in cell proliferation within 24 h.
Further studies revealed the mechanism involved: OPG increased phosphorylation of GSK3 and CREB in vitro in murine and human islets and appeared to stimulate β-cell proliferation by removing the RANKL/RANK brake that prevents cell division. Since the osteoporosis drug denosumab also inhibits hRANKL, the authors then investigated its effects on β-cell proliferation.
Denosumab did indeed cause human β-cell replication, in vivo and in vitro. A human islet transplanted into the kidney capsule of immunodeficient mice showed significantly increased proliferation one week after denosumab treatment with negligible β-cell cell death, in sharp contrast to control grafts.
Editor’s comment: Following on the work of Kiechl et al. this study further shows a potential role of RANKL-RANK pathway and its inhibitors, OPG and denosumab, on the control of glucose metabolism. So far, however, the FREEDOM trial has shown no convincing effects of denosumab on the development of diabetes or on fasting serum glucose. Whether a designated diabetes trial with denosumab as adjuvant therapy to oral anti-diabetics should be performed remains an interesting question.
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