The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT)

Abstract

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once YearlyÀPivotal Fracture Trial (HORIZONÀPFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n ¼ 95) and Z6P3 (n ¼ 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was À0.54% in Z9 vs. À1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: À0.37%, 1.93%; p ¼ 0.183). BTMs 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 almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

Denosumab after 8 years

“…However, there is a wide range of values of C-telopeptide, indicating that >50 % of patients have bone resorption rates well within the postmenopausal normal range at the time they are due for re-dosing. This appears to contrast with similar data from alendronate and zoledronate, which seem to produce more consistent suppression of resorption [3,10]. Also contrasting with bisphosphonates is the continued increase in bone density with long-term use, albeit not at the same rate observed in the first 1-2 years of treatment.…”

“…This equates to an incidence of ∼4/10,000 patient-years. By comparison, there was one case of ONJ in both the zoledronate and placebo groups in Black et al [13], 1 during 1914 patients-years of observation in the study extensions [10,14], and no cases in the other phase 3 zoledronate study [15]. These data do not suggest a difference in incidences of this problem with these two medications.…”

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

“…It results in a reduction in CTX by 2 weeks and when it is given for 6 years as in the Horizon Study, the suppression of CTX and PINP is maintained (26). PINP was found to be even better than CTX and BMD in the horizon study at identifying clinical (fracture) efficacy and responders (27).…”

Osteoporosis and the Orthopedist

“…The benefits however, might outweigh the risks [13]. Reports on the complications of odd fractures appear conflicting.…”