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The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis was examined by Black and colleagues in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT) [1]. The first extension study (EXT1) with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain. 


To investigate the longer-term efficacy and safety of zoledronic acid, a second extension (EXT2) was conducted to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in EXT1, were randomized to either zoledronic acid (Z9) ([I]n[/I] = 95) or placebo (Z6P3) ([I]n[/I] = 95) for three additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% CI -0.37% to 1.93%; [I]p[/I] = 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits.


  • Ewald Boschitsch
    KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria


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