title: 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 Yearly-Pivotal Fracture Trial (HORIZON-PFT), 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 = 95) and Z6P3 (n = 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 -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 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.
authors.affiliation: University of California, San Francisco, CA, USA.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Black
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Felicia
authors.initials: F
authors.lastname: Cosman
authors.forename: Ping Chung
authors.initials: PC
authors.lastname: Leung
authors.forename: Peter
authors.initials: P
authors.lastname: Lakatos
authors.forename: Kurt
authors.initials: K
authors.lastname: Lippuner
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Trisha F
authors.initials: TF
authors.lastname: Hue
authors.forename: Amitava
authors.initials: A
authors.lastname: Mukhopadhyay
authors.forename: Monique
authors.initials: M
authors.lastname: Tan
authors.forename: R Paul
authors.initials: RP
authors.lastname: Aftring
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D016723:Bone Remodeling; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000188:drug therapy*; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D010446:Peptide Fragments; D011347:Procollagen; C047202:procollagen Type I N-terminal peptide; D000077211:Zoledronic Acid
keywords: ANTIRESORPTIVES; BIOCHEMICAL MARKERS OF BONE TURNOVER; FRACTURE PREVENTION; OSTEOPOROSIS; RANDOMIZED CLINICAL TRIALS