"Zoledronic Acid and Fracture Risk Reduction".The New England Journal of Medicine. 2007. 356(18):1809-1822.PubMed•Full text•PDFContents1Clinical Question2Bottom Line3Major Points4Guidelines5Design6Population6.1Inclusion Criteria6.2Exclusion Criteria6.3Baseline Characteristics7Interventions8Outcomes8.1Primary Outcomes8.2Secondary Outcomes8.3Bone Mineral Density and Biochemical Markers8.4Adverse Events9Criticisms10Funding11Further ReadingClinical QuestionDoes an annual infusion of zoledronic acid over a 3-year period reduce the risk of vertebral and hip fractures in postmenopausal women with osteoporosis?Bottom LineAnnual infusions of zoledronic acid over a 3-year period significantly reduced the risks of vertebral, hip, and other fractures, improved bone mineral density and bone metabolism markers, and had a favorable safety profile in postmenopausal women with osteoporosis.Major PointsFractures due to osteoporosis are a significant cause of morbidity in postmenopausal women. Bisphosphonates, which inhibit bone resorption, are common treatments but poor adherence is an issue. This study evaluated the efficacy and safety of annual infusions of zoledronic acid over a 3-year period in reducing fracture risk in postmenopausal women with osteoporosis.GuidelinesNo current guideline recommendations available.DesignMulticenter, double-blind, placebo-controlled, randomized trial.Participants: 7,765 randomized postmenopausal women with osteoporosis.Setting: Multiple international centers.Enrollment: 2002-2003 with follow-up until June 2006.Analysis: Intention-to-treat.Primary outcomes: New vertebral fracture and hip fracture.PopulationInclusion CriteriaPostmenopausal women aged 65-89 years.Bone mineral density T score of −2.5 or less at the femoral neck or a T score of −1.5 or less with radiologic evidence of at least two mild or one moderate vertebral fractures.Previous usage of oral bisphosphonates was allowed with specific washout periods.Exclusion CriteriaPrior use of parathyroid hormone, sodium fluoride, anabolic steroids, or growth hormone within specified time frames.Patients with certain serum calcium levels or creatinine clearances, and positive urine dipsticks for protein.Baseline CharacteristicsMean age: 73 years.European and North and South American and Asian participants.Baseline T scores below −2.5: 72%.Baseline vertebral fractures: 63%.Taking osteoporosis medications at baseline: 21%.InterventionsOne group received a 15-minute intravenous administration of zoledronic acid (5 mg) at baseline, 12 months, and 24 months.All patients received oral daily calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU).OutcomesPrimary OutcomesZoledronic acid reduced the relative risk of morphometric vertebral fracture by 70% as compared with placebo (3.3% vs. 10.9%; relative risk, 0.30; 95% CI, 0.24 to 0.38).The risk of hip fracture was reduced by 41% with zoledronic acid (1.4% vs. 2.5%; hazard ratio, 0.59; 95% CI, 0.42 to 0.83).Secondary OutcomesNonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons).Bone Mineral Density and Biochemical MarkersSignificant increases in bone mineral density at the total hip, lumbar spine, and femoral neck were observed in the zoledronic acid group.Biochemical markers of bone turnover decreased significantly in the treatment group.Adverse EventsSymptoms such as fever, influenza-like symptoms, myalgia, headache, and arthralgia were more common post dose in the zoledronic-acid group but decreased with subsequent infusions.An increased incidence of serious atrial fibrillation was noted in the zoledronic-acid group (1.3% vs. 0.5%; P<0.001).There were no significant differences in overall death and other serious adverse events between the groups.Osteonecrosis of the jaw was rare, with only one case each in the zoledronic-acid and placebo groups.CriticismsAn increase in serious atrial fibrillation in the zoledronic-acid group requires further exploration in other trials and analyses.FundingSupported by Novartis Pharma.Disclosures from various authors include grants, consulting, and lecturing fees from Novartis and other pharmaceutical companies.Further ReadingDetailed references and further reading are included in the full text of the article.