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How soon after hip fracture surgery should a patient start bisphosphonates?

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Patients with an osteoporotic hip fracture suffer from profound morbidity and are at a heightened risk of death. It is therefore essential that they receive treatment with a bisphosphonate known to modify the subsequent risk of fracture at any site—eg, alendronate (Fosamax), risedronate (Actonel), or zoledronic acid (Reclast).

However, there is concern that starting a bisphosphonate too soon after surgery could disrupt bone remodeling and delay fracture repair.

Only one clinical study addressed the timing of bisphosphonate therapy after hip fracture repair. In this study, Eriksen et al1 performed a post hoc analysis of data from the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT)2 and concluded that the optimal time to give intravenous zoledronic acid is 2 to 12 weeks after surgical repair of the fracture.

In a frail, elderly patient with comorbidities, a single intravenous 5-mg dose of zoledronic acid guarantees adequate treatment, obviating issues of poor compliance and oral absorption and loss to follow-up. Sufficient levels of vitamin D and calcium should be ensured.

THE EVIDENCE

The original HORIZON-RFT study,2 published in 2007, compared intravenous zoledronic acid against placebo in elderly patients with osteoporotic hip fracture. Most of the patients were white women; their mean age was 74; 1,065 received intravenous zoledronic acid, and 1,062 received placebo. All received vitamin D and calcium.

The trial showed a clear reduction in the rate of recurrent fractures at other sites (a primary end point) and a reduction in the rate of all-cause mortality in patients treated within 90 days of fracture. A total of 424 fractures occurred in 231 patients. The risk of any new clinical fracture was 35% lower with treatment than with placebo (occurring in 8.6% vs 13.9% of patients, P = .001), and the number of deaths due to any cause was 28% lower with treatment than with placebo (occurring in 101 vs 141, P = .01).2

The mean time to fracture was 39.8 months in the treated group vs 36.4 in the placebo group. The fracture risk reduction began to be apparent by 12 months, and the reduction in mortality rate by 16 months.2

In a post hoc analysis of the trial, Eriksen et al1 attempted to ascertain the optimal time for therapy in terms of fracture risk and mortality reduction. Analyzing the data by 2-week intervals beginning after the surgical repair of the fracture, the authors found that only 56 patients (5.3%) had received zoledronic acid within 2 weeks of surgery and only 47 had received placebo, and they saw no advantage to intravenous zoledronic acid compared with placebo in these first 2 weeks with respect to bone mineral density, fracture risk, or risk of death. However, excluding this small subset, antifracture efficacy and reduction in mortality rate were present when patients were treated with zoledronic acid in the 2 to 12 weeks after hip fracture repair, and improvement in bone mineral density at the hip was noted at 12 months in all cohorts.

Colón-Emeric et al3 performed another post hoc analysis, attempting to explain the lower mortality rate seen in patients treated with zoledronic acid. It had been an unexpected finding, and determinants of mortality rate reduction were hampered by a limited knowledge of the true cause of death or the circumstances of care after fracture. The authors concluded that only 8% of the reduction in mortality rate evident early in the second year of treatment with zoledronic acid could be attributed to a reduction in fractures.3 Other mechanisms by which the mortality rate reduction occurred remained unclear.

Curiously, in another large randomized controlled trial of zoledronic acid, in women with postmenopausal osteoporosis, Black et al4 reported that more patients died in the treated group (130 of 3,862) than in the placebo group (112 of 3,852). This difference was not statistically significant, but neither was it explained.

A meta-analysis by Bolland et al5 examined the effect of other osteoporosis treatments on mortality rate, using randomized controlled trials that lasted more than 12 months and that reported more than 10 deaths. The authors concluded the following:

  • In the trials in which bisphosphonates reduced the mortality rate, the mortality rate in the placebo group was higher than 10 per 1,000 patient-years
  • The effect of osteoporosis treatment on the mortality rate in a frail, elderly population is evident using agents with proven efficacy in reducing vertebral and nonvertebral fractures, eg, alendronate, risedronate, and zoledronic acid.5

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