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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).

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.

SUBMITTER: Black DM

PROVIDER: S-EPMC3427916 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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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).

Black Dennis M DM Reid Ian R IR Boonen Steven S Bucci-Rechtweg Christina C Cauley Jane A JA Cosman Felicia F Cummings Steven R SR Hue Trisha F TF Lippuner Kurt K Lakatos Peter P Leung Ping Chung PC Man Zulema Z Martinez Ruvie Lou Maria RL Tan Monique M Ruzycky Mary Ellen ME Su Guoqin G Eastell Richard R

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20120201 2

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 we ...[more]

PMID: 22161728

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Project description:The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5?mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p?=?.0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p?=?.0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR)?=?0.94, 95% confidence interval (CI) 0.90-0.99] or limited activity owing to back pain (RR?=?0.94, 95% CI 0.87-1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR?=?0.58, 95% CI 0.47-0.72) and 7 or more limited-activity days owing to a fracture (RR?=?0.67, 95% CI 0.58-0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture.

Project description:Eighty-five percent of institutionalized elderly people have osteoporosis and bone fracture rates 8 to 9 times higher than rates observed among community-dwelling elderly people. Nevertheless, most of these persons are left untreated and are excluded from pivotal osteoporosis trials.To determine the efficacy and safety of zoledronic acid to treat osteoporosis in frail elderly women in long-term care facilities.We conducted a 2-year, randomized, placebo-controlled, double-blinded study from December 2007 through March 2012. Included were 181 women 65 or older with osteoporosis, including those with cognitive impairment, immobility, and multimorbidity, who were living in nursing homes and assisted-living facilities.One 5-mg dose of zoledronic acid or placebo intravenously and daily calcium and vitamin D supplementation.Hip and spine bone mineral density (BMD) at 12 and 24 months and adverse events.There were no baseline differences in mean (SE) age (85.4 [0.6] years), BMD, or functional or cognitive status, but the treatment group included more participants with frailty, falls history, diabetes, and anticonvulsant medication use. Values for BMD were available for 87% of participants at 12 months and 73% at 24 months. Mean (SE) BMD changes were greater in the treatment group: 3.2 (0.7) and 3.9 (0.7) percentage-point differences in the total hip at 12 and 24 months, respectively (P?<?.01 for both comparisons), and 1.8 (0.7) and 3.6 (0.7) percentage-point differences at the spine (P?<?.01); adjusted analyses were similar. The treatment and placebo groups' fracture rates were 20% and 16%, respectively (OR, 1.30; 95% CI, 0.61-2.78); mortality rates were 16% and 13% (OR, 1.24; 95% CI, 0.54-2.86). Groups did not differ in the proportion of single fallers (28% vs 24%; OR, 1.24; 95% CI, 0.64-2.42; P?=?.52), but more participants in the treatment group had multiple falls (49% vs 35%; OR, 1.83; 95% CI, 1.01-3.33; P?=?.047); however, this difference was no longer significant when adjusted for baseline frailty.In this group of frail elderly women with osteoporosis, 1 dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant increases in fracture and mortality rates in the treatment group needs further study. Since it is not known whether such therapy reduces the risk of fracture in this cohort, any change in nursing home practice must await results of larger trials powered to assess fracture rates.clinicaltrials.gov Identifier: NCT00558012.

Dataset Information

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

Publications

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

Similar Datasets

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