The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

By D. Black, I. Reid, S. Boonen, C. Bucci-Rechtweg, J. Cauley, F. Cosman, Steve Cummings, T. Hue, K. Lippuner, P. Lakatos and 7 more. Journal of Bone and Mineral Research, 2011

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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

Subfields: Oncology, Orthopedics and Sports Medicine, Surgery

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Citations in the corpus

UK clinical guideline for the prevention and treatment of osteoporosis (2017, background): “small decrease in BMD after a further 3 years without treatment [110].”
European guidance for the diagnosis and management of osteoporosis in postmenopausal women (2018, background): “‘drug holiday’, prospective and retrospective analyses report that the risk of new clinical fractures was 20–40% higher in subjects who stopped treatment [248, 249] and vertebral fracture risk was approximately doubled [226, 250].”
Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline. (2019, background): “For alendronate and zoledronic acid, two moderate-sized randomized, placebo-controlled trials (1099 and 1233 women, respectively) of long-term use (10 years vs 5 years for alendronate and 6 vs 3 years for zoledronic acid) (35, 36) form the primary evidence base.”
Clinician’s Guide to Prevention and Treatment of Osteoporosis (2014, background): “Evidence of efficacy beyond 5 years is limited, whereas rare safety concerns such as ONJ and atypical femur fractures become more common beyond 5 years [67, 92].”