Role of the MM microenvironment in osteoclast activation. Adherence of MM cells to bone marrow stromal cells (BMSCs) enhances the production of RANKL and IL-6, whereas it suppresses the production of OPG (the decoy receptor of RANKL). RANK/RANKL interaction results in osteoclast differentiation, proliferation, and activation, leading to increased bone resorption (increased levels of TRACP-5b and NTX).