Zoledronic Acid Early Increases Serum Osteoprotegerin in Early Stage Multiple Myeloma.

Abstract

Myeloma cells are able to induce an imbalance in the OPG/RANKL system in bone environment, and due to osteoclastic activation this is responsible for myeloma bone disease. Recent in vitro and in vivo evidence suggests that bisphosphonates exerts activity on myeloma cells, which could be of therapeutic interest particularly in patients in initial phases of multiple myeloma.We evaluated 26 patients with smoldering myeloma (stage IA) to assess basal levels of circulating cytokines as OPG, RANKL and macrophage inflammatory protein-1 alpha MIP-1α and serum markers of bone turnover at baseline and at 2, 4, 6 months and compared to 58 healthy subjects as control group. Moreover we treated 16 of those patients with a potent bisphosphonate, zoledronic acid (ZA), to find out if its antiosteoclastic activity can be related to changes in circulating levels of RANKL, OPG and (MIP-1α). Results showed serum levels of OPG significantly lower and an increase of RANKL:OPG ratio in MM patients respect to controls. A significant correlation was found between RANKL/OPG ratio and serum CTX (r=0.45;p<0.05). Patients with MM treated with zoledronic acid did not show significant changes in serum and urinary calcium as well as serum creatinine compared to untreated patients. An early and significant reduction of serum CTX was found in treated patients, while bone ALP decreased later and not significantly. Interestingly ZA increased serum OPG and reduced RANKL:OPG ratio (4,8±2,6 vs 2,9±0,8 ; p<0.05).The positive effect of zoledronic acid on bone tissue was confirmed by the increased in lumbar spine BMD at 6 months (+3.8%± 2.6 vs baseline; p<0.05). Larger studies are urgently needed to better clarify the significance of these findings.