Myeloma bone disease. A. Myeloma cells secrete osteoclast activating factors (IL-6, IL-3) that stimulate osteoclast induced bone resorption. B. Stromal cells stimulate osteoclasts by increasing the RANK L production. C. Myeloma cells directly inhibit osteoblast differentiation by expressing osteoblast inhibitory factors (Dickkopf-1, secreted frizzled-related protein 2 (sFRP2)), which are blocked by anti-myeloma agent bortezomib (BMIB). Zoledronic acid (ZA), temozolomide (TM) and denosumab (DMAB) inhibit osteoclast bone resorption. OC=Osteoclast, OB=Osteoblast, SC=Stromal cell.