Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment

Bisphosphonates have recently been introduced in the therapeutic armamentar ium for the long-term treatment of patients with multiple myeloma (MM). The se pyrophosphate analogs not only reduce the occurrence of skeletal-related events but also provide patients with a clinical benefit and improve the s urvival of some of them. We investigated the effects of two bisphosphonates , pamidronate and zoledronate, on both myeloma cells and bone marrow stroma l cells (BMSCs), We show here that both bisphosphonates induce both myeloma cell and BMSC apoptosis, Furthermore, at lower concentrations, they induce a significant inhibition (40% and 60%, respectively) of the constitutive p roduction of interleukin-6 (IL-6) by BMSCs, We have recently shown that BMS Cs produce MMP-1, the major metalloproteinase involved in the initiation of bone resorption, production up-regulated by IL-1 beta. Here, we demonstrat e that zoledronate significantly inhibits MMP-1 production by BMSCs stimula ted with IL-1 beta more efficiently than pamidronate. However, zoledronate and to a lesser extent pamidronate are responsible for an up-regulation of MMP-2 secretion by BMSCs, MMP-2 is involved both in bone resorption and in the metastatic process. In conclusion, the apoptosis of myeloma cells and B MSCs and the inhibition of both IL-6 and MMP-1 production induced by bispho sphonates, mainly zoledronate, could have antitumoral effects in patients w ith MM, However, the up-regulation of MMP-2 secretion observed in vitro sug gests a putative risk of tumor cell dissemination in vivo when using these new potent bisphosphonates. This potentially deleterious effect could be ab olished by combining bisphosphonates,vith metalloproteinase inhibitors.