Bisphosphonates have been suggested to be partially chondroprotective in animal models of arthritis. The aim of this study was to assess the short-term effect of the bisphosphonate zoledronate on type II collagen degradation in patients with Paget's disease of bone. Twenty-six patients with active Paget's disease who were a part of a double-blind, placebo-controlled, randomized study comparing the effects of several doses of a single injection of zoledronate, a potent bisphosphonate, were studied. Type II collagen destruction was assessed by urinary levels of type II collagen C-telopeptide (CTX-II) using a new immunoassay. Bone resorption was assessed by measuring the urinary excretion of nonisomerized type I collagen C-telopeptide (alpha CTX-I). Biochemical markers were measured at baseline and 5, 10, 30, and 60 days after injection. At baseline, no significant increase of CTX-II was observed in patients with Paget's disease compared with a group of 27 gender-and age-matched controls, in contrast to the ninefold (p < 0.0001) increase of urinary alpha CTX-I. After a single intravenous injection of zoledronate (200 or 400 microg), urinary CTX-II transiently decreased by a median of 25% 5 days after the injection of zoledronate (p = 0.0023 vs. placebo), then increased to pretreatment levels after 10 days. In contrast, urinary alpha CTX-I decreased within 5 days with a maximal decrease of 51% at day 10 (p < 0.001 vs. baseline and placebo), and levels remained suppressed during the 2 months of the study. Zoledronate not only reduces bone turnover but also directly decreases type II collagen degradation in patients with Paget's disease, suggesting that bisphosphonates may have chondroprotective effects in humans. Measurement of type II collagen breakdown by a new urinary biochemical marker may be useful for in vivo assessment of the effects of drugs that potentially inhibit cartilage destruction.