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Cited by 700Bone health and osteoporosis researchBone health and treatmentsMenopause: Health Impacts and Treatments

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The effect of 3 versus 6 years of Zoledronic acid treatment of osteoporosis: A randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)

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Black, Dennis M, Reid, Ian R, Boonen, Steven, Bucci-Rechtweg, Christina, Cauley, Jane A, Cosman, Felicia, Cummings, Steven R, Hue, Trisha F, Lippuner, Kurt, Lakatos, Peter, Leung, Ping Chung, Man, Zulema, Martinez, Ruvie Lou Maria, Tan, Monique, Ruzycky, Mary Ellen, Su, Guoqin, Eastell, Richard·2012·Journal of Bone and Mineral Research
DOI 10.1002/jbmr.1494PMC PMC3427916
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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

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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. 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).CC BY · PubMed Central
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. 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.CC BY · PubMed Central
Fig. 3 Mean changes in bone turnover markers over 6 years of treatment. The horizontal lines indicate premenopausal reference ranges,36 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. 3 Mean changes in bone turnover markers over 6 years of treatment. The horizontal lines indicate premenopausal reference ranges,36 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.CC BY · PubMed Central
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).
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).CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Black, 2004, A 5-year randomized trial of the long-term efficacy and safety of alendronate: the FIT Long-term EXtension (FLEX), J Bone Miner Res., 19
  2. Cosman, 2011, After 3 years of IV zoledronic acid administration, who is at highest risk for subsequent vertebral fractures and who should remain on treatment?, J Bone Miner Res., 26

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Authors
Black, D. M., Reid, I. R., Boonen, S., Bucci-Rechtweg, C., Cauley, J. A., Cosman, F., Cummings, S. R., Hue, T. F., Lippuner, K., Lakatos, P., Leung, P. C., Man, Z., Martinez, R. L. M., Tan, M., Ruzycky, M. E., Su, G., & Eastell, R.
Affiliations
  • University of California, San Francisco (US)
  • University of Auckland (NZ)
  • KU Leuven (BE)
  • Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
  • University of Pittsburgh (US)
  • Helen Hayes Hospital (US)
  • California Pacific Medical Center (US)
  • University Hospital of Bern (CH)
  • Semmelweis University (HU)
  • Chinese University of Hong Kong (HK)
  • Centro Médico TIEMPO, Buenos Aires, Argentina
  • University of Sheffield (GB)
Corresponding author
Black, Dennis M
ORCID
Venue
Journal of Bone and Mineral Research
Publisher
Oxford University Press (OUP)
Published
2011-12-08
Volume
27
Issue
2
Pages
243-254
ISSN
  • 0884-0431 (ISSN-L)
  • 1523-4681
DOI
10.1002/jbmr.1494
PMC
PMC3427916
OpenAlex
W2106406207
Cited by
700
References
40
Citations by year
2026: 18 · 2025: 37 · 2024: 29 · 2023: 45 · 2022: 40 · 2021: 58 · 2020: 53 · 2019: 49 · 2018: 48 · 2017: 54 · 2016: 61 · 2015: 62 · 2014: 50 · 2013: 49 · 2012: 35
FWCI
49.40
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Journal of Bone and Mineral Research (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UL1TR000005)
  • University of California, San Francisco
  • Novartis Pharma
  • National Center for Research Resources (UL1RR024153)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Oncology › Bone health and treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
Keywords
zoledronic acid, osteoporosis, postmenopausal women, long-term treatment, bone mineral density, femoral neck, vertebral fractures, fracture risk, bone turnover markers, serum creatinine, atrial fibrillation, stroke, hypertension, bisphosphonates, adverse events
MeSH terms
Zoledronic Acid, Aged, Diphosphonates, Female, Follow-Up Studies, Humans, Imidazoles, Osteoporosis, Peptide Fragments, Procollagen, Time Factors, Biomarkers, Bone Density, Incidence, Bone Remodeling, Treatment Outcome, Bone Density Conservation Agents, Osteoporotic Fractures

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