However, as the reduced RANKL/OPG ratio reported is slightly modulated by extracellular calcium, further studies are required to clarify whether the extracellular calcium modulated RANKL/OPG ratio produced in osteoblasts would be compensated by other major signals like cytokines secreted from breast cancer cells during bone metastasis, and therefore plays minor effects in the whole vicious cycle. The gene discussed is TNFSF11; the disease is breast cancer.