Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

Background: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the> circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9> (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in> patients with bone metastasis (BMTS) and the possible correlation with the symptomatic> response induced by this drug in these patients were evaluated. Patients and Methods:> Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the> plasma of 30 patients with painful bone metastases from breast or prostate cancer> undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects> (HS) of both genders (12 female and 30 male) served as the control group. The> symptomatic response to ZA was assessed by the visual analog scale score (VAS).> Results: The median MMP-2 and MMP-9 pretreatment levels were more elevated in BMTS as> compared to HS (p¡Ü0.0001). Conversely, uPA levels were lower in BMTS p=0.0033; no> significant difference was observed for Cath B. ZA administration was associated with> a symptomatic response (VAS score¡Ü4) in 25/30 patients (83.3%) (p<0.0001). This> phenomenon paralleled a decrease of Cath B and MMP-2 plasma concentrations from> baseline values on week 12 (p=0.05). A similar trend, although not statistically> significant, was also noted for MMP-9 and uPA. However, no direct relationship was> observed between the analgesic effect induced by ZA and changes in the circulating> levels of these enzymes. Conclusion: These data show that ZA administration may> provide relief from bone pain in patients with diffuse skeletal metastases and confirm> a possible implication of cysteine proteinases and matrix metalloproteinases in bone> metastasis formation, but not in the pathogenesis of metastatic bone pain.