Fracture Prevention with Zoledronate in Older Women with Osteopenia

Clinical Question

In female patients with osteopenia, do bisphosphonates compared to no therapy at all provide better preventative treatment for fractures?

Bottom Line

In female, postmenopausal patients 65 years of age or older with osteopenia, vertebral or non-vertebral fractures were significantly reduced when treated with Zoledronate 5 mg.

Major Points

Most fractures in postmenopausal women occur in those with osteopenia so therapies that are effective in women with osteopenia. This study conducted involved women with osteopenia who were 65 years of age or older. They were randomly assigned to receive four infusions of either Zoledronate 5 mg or normal saline at 18 month intervals. A dietary calcium intake of 1 g per day was advised but calcium supplements were not provided. In patients with osteopenia, receiving zoledronate 5 mg administered four times in 18 month intervals prevented fractures in 1 out of every 15 patients with osteopenia (NNT=15 patients). The mean age of the patients selected with osteopenia was 71 (w/ plus/minus of 5 years) years of age. Patients who were not on vitamin D supplements prior received 2.5mg or ergocalciferol prior to the RCT and 1.5mg during the trial. The trial lasted 6 years and had a total of 2000 women over the age of 65. The trial ended as soon a fracture occurred. The zoledronate group had a significantly lower fragility fracture occurrence (P value< 0.001, 95% CI: 0.50-0.79).

Guidelines

Clinician's Guide to Prevention and Treatment of Osteoporosis

• In patients with hip or vertebral fractures, osteoporotic with a T-score of less than or equal to 2.5 and in postmenopausal women, the current FDA approved first line treatment for osteoporosis are bisphosphonates (alendronate, ibandronate, risedronate, zoledronate)
• Therapy duration varies for whichever bisphosphonate is selected. After initial dosing regimen is complete (1-2 years of therapy), a BMD (Bone Mineral Density) test and vertebral imaging should be completed.
• In all patients with decreased bone density, it is recommended that:
  • Diet should have 1000-1200 mg of calcium
  • Supplement with Vitamin D (800-1000 IU/day)
  • Physical, weight-bearing activities in moderation

Fracture Prevention with Zoledronate in Older Women with Osteopenia

• 2000 postmenopausal women of age 65 or greater (mean age of 71) who were ambulatory and had a total hip or femoral neck T-score of -1.0 to -2.5 at either hip.
• 96% of patients completed 6 year follow up or died (intention to treat analysis)
• Zoledronate and placebo did not differ for serious adverse events and was concluded that in older postmenopausal women with osteopenia, zoledronate reduced nonvertebral or vertebral fragility fractures at 6 years.

Design

Randomized, double blind, placebo controlled trial. N=1000 for placebo group and N=1000 for zoledronate. Participants were to report fractures, adverse events, and changes in medications. Reporting was supposed to be done using a quarterly questionnaire. Patients were enrolled in the study for six years, some from 2009-2016, and some from 2011-2018. For follow up, patients either attended the final visit after 6 years or had telephone consultation that permitted ascertainment of fractures and adverse events. Analyses were based on intention to treat principle. The prespecified primary outcome was measuring the time to first recurrence of fragility fracture from the start of therapy.

Population

Inclusion Criteria

• Ambulatory postmenopausal women
• >65 years old
• T score of either -1.0 to -2.5

Exclusion Criteria

• Glomerular Filtration rate of less than 30 mL per minute (Renal Impairment)
• Major systemic disease
• Cancer in the previous 2 years
• Metabolic Bone disease
• Regular use of bone active drugs in the previous year

Baseline Characteristics

• Age - 71 (placebo 71)
• Ethnic Group - 95%(placebo 94%) European, 1.7%(placebo 1.4%) Maori, 0.7%(placebo 1.5%) Pacific Islander, 1.5%(placebo 2.4%) East Asian, 0.5%(placebo 0.5%) Indian, 0.2%(placebo 0.2%) Other
• Height - 160 cm (placebo 160 cm)
• Weight - 69 kg (placebo 69 kg)
• Body-mass Index - 26.8 (placebo 26.9)
• Dietary Calcium Intake - 871 mg per day (placebo 882 mg per day)
• History of nonvertebral fracture after 45 years of age - 23.7% (placebo 23.8%)
• Prevalent Vertebral Fracture - 13.7% (placebo 12.6%)
• Median 10 year risk of osteoporotic fracture - 9-16% (placebo 9-15%)
• Median 10 year risk of hip fracture - 1.5-3.9% (placebo 1.5-3.8%)
• Bone mineral density (g/cm3) - Lumbar spine: 1.07(placebo 1.08), Total hip: 0.85(placebo 0.85), Femoral Neck: 0.81(placebo 0.81), Total Body: 1.06 (placebo 1.06)
• Bone Density T Score - Lumbar Spine: -0.91(placebo -0.87), Total Hip: -1.27 (placebo -1.24), Femoral Neck: -1.64 (placebo -1.63), Total Body: -0.81 (placebo -0.80)
• Current Smoker - 23% (placebo 33%)

Interventions

• Both groups were given 2.5 mg of cholecalciferol 1 week prior to treatment (Vitamin D3) and 1.25mg weekly during treatment (controlled)
• Blinding of placebo and zoledronate was completed by packing them within a identical container with the same I.V formulation.
  • Experimental Group: 1000 patients were given four infusions of 5mg zoledronate for 18 month intervals. The patients were treated for 6 years until first occurrence of bone fracture.
  • Control Group: 1000 patients were blindly given four infusions of normal saline for 18 months. The patients were treated for 6 years until first occurrence of bone fracture.

Outcomes

Comparisons are placebo vs. intervention.

Primary Outcomes

• Fragility Fractures: 19% Placebo vs 12.2% Intervention ( HR: 0.63, 95% CI 0.50-0.79)=Significant
• Symptomatic Fractures: 21.4% Placebo vs 16.3% Intervention (HR 0.73, 95% CI 0.60-0.90)=Significant

Secondary Outcomes

• Vertebral Fractures: 4.9% Placebo vs 2.3% Intervention (HR: 0.45, 95% CI 0.27-0.73)
• Non-Vertebral Fractures:
  • Fragility: 14.8% Placebo vs 10.1% Intervention (HR: 0.66 95% CI 0.51-0.85)
    • Forearm or Wrist: 6.3% Placebo vs. 3.6% Intervention (HR: 0.56, 95% CI 0.37-0.85)
  • No significant reduction in hip fractures

Subgroup Analysis

The subgroup analysis determined a significant difference in location of fracture between patients receiving Zoledronate and those receiving the placebo. In patients receiving the zoledronate, there was a significant reduction in fragility (OR 30.2, 95% CI 26-34.9), hip (OR 2.0, 95% CI 1.1-3.5), and forearm/wrist fractures (OR 11.6, 95% CI 9.0-14.6).

Adverse Events

• Cancer: 21.5% vs 14.7% (OR 0.67 95% CI 0.50-0.89)
• Cancer was the only adverse drug event that was significantly more probable in those receiving the placebo when in comparison to the zoledronate treatment.

Criticisms

• The guidelines used for this experimental treatment within the presented RTC was FDA approved. (Internal)
• Study cannot be applied to an entire population. Only postmenopausal women 65 years or older with certain T score parameters were studied. (Internal)
• Secondary Analyses and sensitivity analyses were not adjusted for multiplicity and heterogeneity. (Internal)
• The study contained 94-95% women with European decent. Not much data can be determined in those of non-European descent from the study. (Internal)
• No treatment recommendation if patient is renally impaired which is the case for many geriatric patients. (Internal?)

Funding

• Funding for trial was presented by the Health Research Council of New Zealand.
• The Zoledronate infusion was provided by Novartis.