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.

Trial registration: ClinicalTrials.gov NCT00145327.

Fig. 1

Enrollment, follow-up, and outcomes by randomized group. Complete follow-up is defined as availability of primary endpoint (year 3 to 6 change in femoral neck bone mineral density).

Fig. 2

Mean changes in bone mineral density (BMD) over 6 years of treatment. The numbers at the bottom of each panel show the number of available measurements at each time point. For the core study period, only values for those continuing in the extension study are shown.

Fig. 3

Mean changes in bone turnover markers over 6 years of treatment. The horizontal lines indicate premenopausal reference ranges, and the arrows indicate timing of infusions. The year 4.5 measurement was made 6 months after the most recent infusion, whereas the year 6 measurement was 12 months after the most recent infusion. Results represent geometric means.

Fig. 4

Incidence of fractures by treatment in the extension for morphometric vertebral fractures (A), nonvertebral fractures (B), and hip fractures (C). The dashed lines indicate the incidence in the core trial by core treatment for the corresponding fracture types. For B and C, the percentages given are the event rate from the Kaplan–Meier estimate at month 36 in the extension (bars) or core study (dashed lines).