Bone anabolic agents for the treatment of multiple myeloma

Abstract

The majority of patients with multiple myeloma develop bone osteolytic lesions, which may lead to severe complications, including pain and fractures. The pathogenesis of bone disease depends on uncoupled bone remodeling, characterized by increased bone resorption due to upregulation of osteoclast activity and decreased bone formation due to osteoblast inhibition. In myeloma, impaired osteoblast differentiation and increased apoptosis have been described. Responsible for these effects are integrin-mediated adhesion to tumor cells and soluble factors, including WNT antagonists, BMP2 inhibitors and numerous cytokines. Based on the evidence of osteoblast suppression in myeloma, bone anabolic agents have been developed and are currently undergoing clinical evaluation. Due to bidirectional inhibitory effects characterizing tumor cells and osteoblasts interactions, agents targeting osteoblasts are expected to reduce tumor burden along with improvement of bone health. This review summarizes the current knowledge on osteoblast inhibition in myeloma and provides an overview on the clinical grade agents with bone anabolic properties, which represent new promising therapeutic strategies in myeloma.

Fig. 1

Mechanisms of OB inhibition by MM cells. MM cells inhibit OB differentiation by deregulating the WNT and BMP2 signaling pathway via the secretion of inhibitory cytokines, such as DKK1 or Activin. In addition, integrin-mediated cell interactions are responsible for impaired osteoblastogenesis. Inhibition of OB function and induction of apoptosis play also a role in MM-mediated OB impairment