Bisphosphonates and Atypical Femoral Shaft Fractures

N Engl J Med 2011; 365:377July 28, 2011


To the Editor:

Schilcher et al. (May 5 issue)1 report the findings of a cohort analysis that examined the risk of atypical femoral fractures with bisphosphonate use. They found a statistically significant increase in such fractures, with an absolute risk of 5 per 10,000 patient-years, similar to that reported in other studies.2 They conclude that their results are reassuring for patients taking bisphosphonates, since “the magnitude of the absolute risk [is] small.” This level of absolute risk appears identical to the absolute risks reported for hormone-replacement therapy (HRT) by the Women's Health Initiative investigators,3 yet those investigators described the risks of HRT as “substantial,” even though many of those increased risks appeared more likely to be due to chance rather than the intervention when subsequent analyses were undertaken or appropriate statistics were applied.4 This report from the Women's Health Initiative led to substantial reduction in the use of HRT (up to 50% worldwide), even though the results indicated neither harm nor benefit for more than 99% of participants. But Schilcher et al. say that they find the data on the risk of bisphosphonate use to be reassuring. Am I missing something?

John C. Stevenson, F.R.C.P.
Royal Brompton Hospital, London, United Kingdom

Dr. Stevenson reports receiving research grants from Eli Lilly, Janssen-Cilag, Novo Nordisk, Organon-Schering-Plough, Schering, Shire, Solvay, and Wyeth; serving on the advisory boards of Novo Nordisk, Procter & Gamble, and Pfizer-Wyeth; and receiving consulting fees from AstraZeneca, Bayer-Schering, Novo Nordisk, Orion, Procter & Gamble, Servier, Solvay, Theramex, and Pfizer-Wyeth.

No other potential conflict of interest relevant to this letter was reported.

4 References

Author/Editor Response

Any judgment about the magnitude of a risk must be seen in relation to other risks and benefits. Women with osteoporosis run a high risk of fracture, which is substantially reduced by bisphosphonate therapy.1 The numbers needed to treat with bisphosphonates for 3 years are 91 for hip fractures and 14 for radiologic vertebral fractures.1 Without consideration of duration of use, we found that the number needed to harm given 3 years of treatment was 667 — that is, the benefits with the therapy outweigh the risks. The absolute risk of stress (atypical) fracture in our study tended to be higher with a longer duration of bisphosphonate use. With more than 2 years of treatment, the difference in absolute risk as compared with no treatment was 8 per 10,000 women per year of treatment. This estimate corresponds to a number needed to harm of 417 for a 3-year treatment period. Thus, theoretically, for each stress fracture caused, at least 30 vertebral and about 5 hip fractures will be prevented. This is reassuring. However, without a proper indication, the benefit–risk ratio with bisphosphonate use may not be advantageous.

Jörg Schilcher, M.D.
Linköping University, Linköping, Sweden

Karl Michaëlsson, M.D., Ph.D.
Uppsala University, Uppsala, Sweden

Per Aspenberg, M.D., Ph.D.
Linköping University, Linköping, Sweden

Since publication of their article, the authors report no further potential conflict of interest.