In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate-treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for beta-C-terminal telopeptides of type 1 collagen (beta-CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino-terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid-treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of beta-CTX within 9-11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.