Bisphosphonates as antimyeloma drugs

Abstract

In patients with symptomatic multiple myeloma (MM), bisphosphonate (BP) treatment has been widely used to prevent bone loss and preserve skeletal health because of its proven effects on inhibiting osteoclast-mediated bone resorption. In addition to their effects on osteoclasts, it is becoming increasingly evident that BPs may have additional effects on the bone microenvironment and cells other than osteoclasts that may potentially inhibit the development and progression of MM. This review focuses on the pathophysiology of MM with an emphasis on the events that drive MM progression within the bone and the mechanisms by which BPs may inhibit specific processes. The underlying molecular mechanisms that drive the modulation of cellular fate and function and consequent physiological outcomes are described. Direct effects on myeloma cell growth and survival and the interactions between myeloma cells and the bone microenvironment are discussed. Clinical evidence of the antimyeloma effects of BPs is emerging and is also reviewed.

Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation

“…Animal studies show that zol inhibits soft-tissue tumour growth, decreases tumour cell proliferation, and enhances immune surveillance; and in vitro studies suggest that zol inhibits tumour cell dissemination in bone marrow 16,17 . Given those promising results, we conducted an open-label randomized controlled phase iii trial to examine the effect of zol on progression-free survival (pfs) and os in the same patient population treated using our institution's current standard of care, a high-dose induction regimen of dexamethasone, all-trans-retinoic acid, and interferon (dai) followed by asct.…”

Inhibition of Bone Remodeling in Young Mice by Bisphosphonate Displaces the Plasma Cell Niche into the Spleen

“…However, our comparative analysis of megakaryocyte numbers of osteopetrotic and osteosclerotic mice clearly suggests that bone resorption by osteoclasts is a prerequisite for the establishment of the megakaryocyte niche in the bone marrow. This property may have important therapeutic implications because it can partly explain the bisphosphonate-mediated antitumor activity observed in multiple myeloma even in the absence of established bone complications (44,45). In addition, these data suggest that long-term treatment with bone anabolic treatments would have less chance to affect immune responses than antiresorptive drugs.…”

Hypercalcemia Associated with Local and Ectopic Hormone Production

“…By suppressing osteoclast activity, bone resorption is reduced and fewer skeletal-related events occur including hypercalcemia. 134 Other drugs that target different molecules involved in the uncoupling of bone remodeling in MM such as denosumab are being tested in MM regimens.…”