HORIZON-PFT

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Black DM, et al. "Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis". The New England Journal of Medicine. 2007. 356(18):1809-22.
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Clinical Question

Among postmenopausal women with osteoporosis, does annual infusion of zoledronic acid reduce rates of vertebral, hip, and other fractures compared to placebo?

Bottom Line

When compared to placebo, once-yearly infusion of zoledronic acid significantly reduced incident vertebral, hip, and other fractures among postmenopausal women with osteoporosis.

Major Points

Osteoporosis is increasingly common with every decade of life in postmenopausal women, affecting 7% of those age 50-59, 12% of those age 60-69, 26% of those age 70-79, and 35% of women age 80+.[1] Osteoporotic fractures are a major cause of disability for women and contribute $14 billion in annual costs in the US.[2] The time following a fracture is associated with excess risk in mortality. For example, the 1-year mortality after a hip fracture was 27% in one survey.[3] Bisphosphonates inhibit bone reabsorption and increase bone mineral density (BMD) and reduce fractures. Adherence to oral versions of these medications can be poor.

Guidelines

Design

  • Multicenter, randomized, double-blind, placebo-controlled trial
  • N=7,736
    • Zoledronic acid (n=3,875)
    • Placebo (n=3,861)
  • Setting: 60 study centers internationally[4]
  • Enrollment: 2002-2003
  • Follow-up: 3 years
  • Analysis: Not specified, presumably intention-to-treat
  • Primary outcomes:
    • New vertebral fracture among patients not taking concomitant osteoporosis meds
    • Hip fracture among all participants

Population

Inclusion Criteria

  • Postmenopausal women age 65-89 years
  • 1 of the following:
    • T score <-2.5 at femoral neck, with or without vertebral fracture
    • T score <-1.5 with ≥2 mild vertebral fractures or 1 moderate vertebral fracture on imaging
  • Completed a washout of any prior bisphosphonate (duration of washout was dependent on duration of prior use)
  • Concomitant use of certain osteoporosis medications was permitted, including HRT, raloxifene, calcitonin, tibolone, tamoxifen, dehydroepiandrosterone, ipriflavone, and medroxyprogesterone

Exclusion Criteria

  • Prior use of parathyroid hormone, sodium flouride, or strontium
  • Anabolic steroids or growth hormone in prior 6 months
  • Systemic corticosteroids in prior 12 months
  • Ca >2.75 or <2.00 mmol/L
  • CKD with CrCl <30 mL/min or 2+ protein on UA

Baseline Characteristics

From the placebo group.

  • Demographics: 73 years, Western Europe 30%, Eastern Europe 20%, North America or Oceania 20%, Latin America 16%, Asia 14%
  • Body measurements: BMI 25 kg/m2
  • T-score at femoral neck: <-2.5 71%, -2.5 to -1.5 28%, >-1.5 1%
  • Bone mineral density (g/cm2): Femoral neck 0.53, total hip 0.65, lumbar spine 0.79
  • Prior vertebral fracture: None 36%, 1 28%, ≥2 36%
  • Prior meds: HRT 21%, bisphosphonates 14%, calcitonin 11%, SERMs 11%, other 1.1%
  • Among the 21% of women in stratum 2, concomitant meds in >5%: Raloxifene 42%, calcitonin 17%, conjugated estrogens 12%, estradiol 8%

Interventions

  • Participants were divided into a stratum:
    • Stratum 1 - Not taking an osteoporosis med at baseline
    • Stratum 2 - Taking an osteoporosis med at baseline
  • Randomized to a group:
    • Zolendronic acid - 5 mg infused every 12 mo for 3 years
    • Placebo
  • All patients took oral calcium 1-1.5 g/day and vitamin D 400-1200 units/day

Outcomes

Presented as zolendronic acid vs. placebo. Outcomes are for all participants except where specified.

Primary Outcomes

New vertebral fracture
Among patients not taking concomitant osteoporosis meds (i.e., stratum 1) with a baseline radiograph and ≥1 follow-up xray, and a fracture.
3.3% vs. 10.9% (RR 0.30; 95% CI 0.24-0.38; P<0.001)
Hip fracture
1.4% vs. 2.5% (HR 0.59; 95% CI 0.42-0.83; P=0.002)

Secondary Outcomes

Nonvertebral fracture
8.0% vs. 10.7% (HR 0.75; 95% CI 0.64-0.87; P<0.001)
Any clinical fracture
8.4% vs. 12.8% (HR 0.67; 95% CI 0.58-0.77; P<0.001)
Clinical vertebral fracture
0.5% vs. 2.6% (HR 0.23; 95% CI 0.14-0.37; P<0.001)
≥2 morphometric vertebral fractures
Among patients not taking concomitant osteoporosis meds (i.e., stratum 1) with a baseline radiograph and ≥1 follow-up xray, and a fracture.
0.2% vs. 2.3% (RR 0.11; 95% CI 0.05-0.23; P<0.001)

Subgroup Analysis

Adverse Events

Any
95.5% vs. 93.9% (P=0.002)
The authors note that the higher rate with the study medication was primarily driven by post-infusion symptoms.
Serious: 29.2% vs. 30.1% (P=0.40)
Death: 3.4% vs. 2.9% (P=0.27)
Leading to discontinuation: 2.1% vs. 1.8% (P=0.41)
Osteonecrosis of the jaw: None reported.
Most symptom within 3 days of infusion
Pyrexia: 16.1% vs. 2.1% (P<0.001)
Myalgia: 9.5% vs. 1.7% (P<0.001)
FLI: 7.8% vs. 1.6% (P<0.001)
Headache: 7.1% vs. 2.3% (P<0.001)
Arthralgia: 6.3% vs. 2.0% (P<0.001)
Renal
Creatinine increase >0.5 mg/dL: 1.2% vs. 0.4% (P=0.001)
The authors note that these increases were transient and there were no differences in renal function at 3 years.
Urinary protein >2+: 0.5% vs. 0.2% (P=0.06)
CrCl <30 mL/min: 4.1% vs. 3.9% (P=0.69)
CVD-related
Any AF: 2.4% vs. 1.9% (P=0.12)
Serious AF-related event: 1.3% vs. 0.5% (P<0.001)
Stroke: 2.3% vs. 2.3% (P=0.94)
Stroke death: 0.5% vs. 0.3% (P=0.15)
MI: 1.0% vs. 1.2% (P=0.44)
CVD mortality: 1.0% vs. 0.9% (P=0.55)

Criticisms

Funding

Further Reading

  1. Wright NC et al. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J. Bone Miner. Res. 2014. 29:2520-6.
  2. Blume SW & Curtis JR Medical costs of osteoporosis in the elderly Medicare population. Osteoporos Int 2011. 22:1835-44.
  3. Panula J et al. Mortality and cause of death in hip fracture patients aged 65 or older: a population-based study. BMC Musculoskelet Disord 2011. 12:105.
  4. Clinicaltrials.gov listing for HORIZON-PFT