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. (ClinicalTrials.gov identifier: NCT00145327). © 2012 American Society for Bone and Mineral Research.

A Retrospective Longitudinal Database Study of Persistence and Compliance with Treatment of Osteoporosis in Hungary

“…The study also assessed associations between compliance, baseline covariates and the risks of fracture, fracture-related hospitalization and death in this patient cohort over time. physicians' decisions not to repeat this treatment, perhaps on the basis of evidence which suggests residual antifracture benefits following yearly infusions [32,33]. Similarly, discontinuation of teriparatide may not be indicative of poor medication-taking behaviour as this agent should not be used for more than 24 months over a patient's lifetime [34].…”

Increased risk of stroke among hip fracture patients: a nationwide cohort study

“…This study adjusted the risk between bisphosphonates and stroke. Although bisphosphate use was unrelated to stroke risk in our study, the cardiovascular safety of bisphosphonates for the treatment of osteoporosis remains a concern [29][30][31][32]. Further research on the dosage and course of various bisphosphonates, as well as the risk of stroke after hip fracture and surgery is warranted.…”

Long-term administration of quarterly IV ibandronate is effective and well tolerated in postmenopausal osteoporosis: 5-year data from the DIVA study long-term extension

“…Long-term effects on BMD have been reported with 10 and 7 years of continuous treatment with the oral bisphosphonates alendronate [12] and risedronate [13], respectively, and 6 years of IV zoledronate [14]. Similarly, the Monthly Oral iBandronate In LadiEs (MOBILE) study has demonstrated that monthly treatment with 150 mg oral ibandronate provides sustained BMD gains and is well tolerated for up to 5 years in women with postmenopausal osteoporosis [15].…”