NPC Archive Item: Annual bisphosphonate infusion for secondary prevention of osteoporotic fracture reduces total fracture risk and death rate but not hip fracture risk

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Lyles K et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357. Published on line on September 17th 2007. (the HORIZON recurrent fracture trial)

What is the story here?
Osteoporosis is associated with much morbidity and mortality – in particular the burden of illness associated with hip fracture is huge. Current interventions are far from ideal in terms of evidence of benefit. There are also problems with adherence to prescribed oral bisphosphonate regimens. The HORIZON study looks at a once a year infusion of zoledronic acid in women who have had a low-impact hip fracture.

What does this study claim?
In people who have suffered a low-impact hip fracture, annual infusion of zoledronic acid reduced the rate of all new clinical fractures over two years by 35% (NNT= 19) and all-cause mortality by 28% (NNT=27) compared with placebo. However, the treatment did not significantly reduce the rate of hip fractures – these are the type of fractures with the greatest clinical impact. For more details of the study, see below

How does this relate to other studies?
Oral bisphosphonates are recommended by NICE as options for the secondary prevention of osteoporotic fractures in certain women. However, as the authors of the editorial accompanying the HORIZON trial say, no other controlled trial has found any osteoporosis medication to be effective in preventing fractures in people who have already suffered a hip fracture. We know that concordance with bisphosphonates is low: adherence rates were reported in one study as 32% for daily alendronate and 48% for weekly alendronate.

So what?
Zoledronic acid 5mg for infusion is available in the UK but is not yet licensed for management of osteoporosis. However, it did receive a positive opinion from the EMEA in July 2007 so a product license should be imminent. Novartis is reported as stating that it expects zoledronic acid to be available in the UK before the end of the year for the treatment of postmenopausal osteoporosis in women at risk of fracture. Weekly alendronate costs the NHS £63.31 per year at September 2007 Drug Tariff prices. The current BNF gives a price of £283.74 for the 5 mg infusion, to which must be added staff and administration costs.

Continue to manage osteoporosis in line with NICE guidance (which is due to be updated any time now). Zoledronic acid may become an option for women who truly cannot adhere to oral bisphoshonate regimens, once it is licensed. (UPDATE – this product was licensed on 12.10.2007 – see here for details.

What were the details of the study?
This was a double-blind, multi-centre randomised, controlled trial. Allocation concealment was not stated. Median follow up was 1.9 years.

2127 patients aged 50 years or older (mean 74 years, mostly white women) who had had surgical repair of a hip fracture sustained after minimal trauma. Ongoing treatment with oral bisphosphonates or teriparatide was excluded, but hormone replacement therapy, use of hip protectors or treatment with calcitonin, selective oestrogeon-recepter modulators or tibolone was allowed at the discretion of the investigator. The two groups were well matched with regard to race, age, sex, bone mineral density and T-score but no information is given about co-morbidity eg cardiovascular risk factors.

Intravenous zoledronic acid infusion first administered within 90 days of hip repair and then annually

Placebo infusion. Both groups also received daily oral calcium (1 to 1.5 g/d) plus daily vitamin D (800 to 1200 IU/d)

The primary outcome was the cumulative rate of new clinical fracture at 24 months.
• The rate for any fracture was 13.9% in the placebo group and 8.6% in the zoledronic acid group [Hazard Ratio 0.65 (95%CI 0.50 to 0.84), NNT= 19, P=0.001].
• The rate for non-vertebral fracture was 10.7% and 7.6% respectively [HR(95%CI) = 0.73(0.55 to 0.98), NNT=32, P=0.03]
• The difference in rates of hip fractures (3.5% vs 2.0%) was not statistically significant (P=0.18).
• The rate of death from any cause was lower in the zoledronic acid group than the placebo group [9.6% vs 13.3%, HR(95%CI) = 0.72 (0.56 to 0.93), NNT=, P=0.01]

The study was sponsored by Novartis, who manufacture zoledronic acid.