title: The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT).
abstract: Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.
authors.affiliation: Department of Epidemiology and Biostastistics, University of California, San Francisco, CA 94107, USA. dblack@psg.ucsf.edu
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Black
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Christina
authors.initials: C
authors.lastname: Bucci-Rechtweg
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cauley
authors.forename: Felicia
authors.initials: F
authors.lastname: Cosman
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.forename: Trisha F
authors.initials: TF
authors.lastname: Hue
authors.forename: Kurt
authors.initials: K
authors.lastname: Lippuner
authors.forename: Peter
authors.initials: P
authors.lastname: Lakatos
authors.forename: Ping Chung
authors.initials: PC
authors.lastname: Leung
authors.forename: Zulema
authors.initials: Z
authors.lastname: Man
authors.forename: Ruvie Lou Maria
authors.initials: RL
authors.lastname: Martinez
authors.forename: Monique
authors.initials: M
authors.lastname: Tan
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Ruzycky
authors.forename: Guoqin
authors.initials: G
authors.lastname: Su
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000502:physiology; D004164:Diphosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015994:Incidence; D010024:Osteoporosis / Q000150:complications* / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000150:complications* / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; 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