Pathophysiology of myeloma bone disease and the suggested sites of action of bortezomib. (1) Myeloma cells produce RANKL and (2) cause stromal cells to overexpress RANKL. Bortezomib reduces levels of RANKL. (3) OPG is the soluble RANKL antagonist. (4) Myeloma cells inhibit OPG production and also bind circulating OPG by syndecan-1, thus facilitating its internalization and degradation. Bortezomib restores the RANKL/OPG balance. (5) Myeloma cells express MIP-1α, MIP-1β, and SDF-1α, which recruit osteoclast precursors and enhance osteoclast activity. (6) Myeloma cells secrete Dkk1 and sFRP-2, which inhibit osteoblast differentiation and function. Bortezomib inhibits Dkk1 expression and increases osteoblast differentiation and activity. (7) The resulting enhanced bone resorption releases cytokines and growth factors that in turn promote myeloma cell proliferation and survival. Adapted from Heider et al7 with permission.
