Treatment with a single annual infusion of zoledronic acid 5 mg (ZOL) for 3 years has been shown to be effective in increasing bone mineral density (BMD) and decreasing fractures. In order to investigate the long-term effects of ZOL, we performed a 3-year extension of the HORIZON-PFT to 6 years. A total of 1233 women who received ZOL for 3 years in the core study were randomly allocated to 3 additional years of ZOL (Z6, n=616) or blinded placebo (Z3P3, n=617). Primary endpoint was percentage change in femoral neck (FN) BMD at year 6 relative to year 3. Secondary endpoints included other BMD sites, bone turnover markers, fractures and safety. FN BMD results are shown in the figure below. In the Z6 group, FN BMD remained constant in years 36 while it decreased slightly in the Z3P3 group (between treatment difference at year 6=1.04%, 95% CI: 0.431.65%, P=0.0009), and similar results were seen for total hip, trochanter and lumbar spine BMD. New vertebral morphometric fractures were lower in the Z6 group compared with the Z3P3 group (relative risk reduction of 52%, 95% CI: 1074%, P=0.03), while there were no differences between groups in clinical, non-vertebral, hip, and clinical vertebral fractures. Biochemical markers remained constant in the Z6 group but rose slightly in the Z3P3 group, remaining below pretreatment levels in both groups. The overall incidence of adverse events was similar in both groups. A numerical increase in atrial fibrillation SAEs (2.0% in Z6 vs 1.1% in Z3P3) was not statistically significant (P=0.26). No new safety concerns were identified. The BMD results, together with the fracture results, suggest that patients at high risk of fracture, particularly vertebral fracture, should continue on annual ZOL therapy.