Correspondence
Zoledronate, Fractures, and Mortality after Hip Fracture
N Engl J Med 2008; 358:967-969February 28, 2008
- Article
To the Editor:
The increased use of composite end points in clinical studies makes it harder for clinicians to translate the findings into treatment decisions. The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial, reported by Lyles et al. (Nov. 1 issue)1 is no exception.
In this study, the primary end point was new clinical fractures, which included burdensome but relatively less severe fractures, such as vertebral fractures, and potentially life-threatening hip fractures. The absolute risk reduction for the primary end point was a significant 5.3%. However, the risk reduction for the clinically important hip fractures was only 1.5%, which failed to reach statistical significance. This means that a clinician will treat about 67 patients for 2 years to prevent one hip fracture (number needed to treat, 67). In doing so, he or she will expose an extra 10 elderly patients to postinfusion symptoms (number needed to harm, 10).
Clinicians who want to prevent hip fractures are forced to glue together these pieces of information to see what this trial adds to their knowledge. It is time to use primary end points in clinical trials that make sense in the doctor's office.
1 ReferencesPieter van den Berg, M.D., Ph.D.
Erasmus Medical Center, 3000 CA Rotterdam, the Netherlands
p.vandenberg. 1@erasmusmc. nl 1
Lyles KW ,Colon-Emeric CS ,Magaziner JS , et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799-1809
Full Text | Web of Science | Medline
To the Editor:
The study by Lyles et al. was adequately powered, and the results showed a clear reduction in the rate of fractures,1 but although mentioned, confounders such as concomitant treatment with calcitonin, selective estrogen-receptor modulators, and hormone-replacement therapy were not reported specifically or with percentages of patients involved for each agent. Clearly, such concomitant medications might have had an effect on the results.2
In addition, although an increased rate of atrial fibrillation in association with this medication has been a concern since the HORIZON trial and the Food and Drug Administration's announcement, it is interesting to see that in this particular study, the incidence did not differ between the medication and placebo groups.3
3 ReferencesCesar A. Lopez, M.D.
Zahra Tasneem, M.D.
Lincoln Medical and Mental Health Center, Bronx, NY 10451
doctorcesarlopez@yahoo.com 1
Wittes J . Sample size calculations for randomized controlled trials. Epidemiol Rev 2002;24:39-53
CrossRef | Web of Science | Medline2
Gass M ,Dawson-Hughes B . Preventing osteoporosis-related fractures: an overview. Am J Med 2006;119:Suppl 1:S3-S11
CrossRef | Medline3
Black DM ,Delmas PD ,Eastell R , et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822
Full Text | Web of Science | Medline
To the Editor:
Lyles et al. report a mortality benefit with zoledronate. This interesting finding requires an appropriate context, since mortality was neither a primary nor a secondary end point. Time-to-event analyses should be performed on the basis of the intention-to-treat principle1; this analysis should have included the survival status of the 367 patients who discontinued the trial. It seems to us that excluding 17.3% of the patients from the intention-to-treat population (possibly at greater risk of death) could lead to a chance finding of a mortality benefit due to the risk of informative censoring.2 No apparent mortality benefit was observed in the first 16 months of the trial, when most of the patients had been followed for a median of 1.9 years.
Furthermore, if the mortality benefit was related to the fracture benefit, why was this benefit not observed in the HORIZON study,3 which was larger and had a longer follow-up (3 years) and which showed a significant fracture reduction?
If we assume that the mortality benefit was due to fracture reduction, then we would conclude, as did Calis and Pucino in the editorial accompanying the report by Lyles et al.,4 that other therapies that reduce fracture should have a mortality benefit.
4 ReferencesRoger Karam, M.D.
Hussein Al-Khalidi, Ph.D.
Michael Steinbuch, Ph.D.
Procter & Gamble Pharmaceuticals, Mason, OH 45040
karam.r@pg. com 1
Lachin JM . Statistical considerations in the intent-to-treat principle. Control Clin Trials 2000;21:167-189[Erratum, Control Clin Trials 2000;21:526.]
CrossRef | Medline2
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. 2nd ed. Hoboken, NJ: John Wiley, 2002.
3
Black DM ,Delmas PD ,Eastell R , et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822
Full Text | Web of Science | Medline4
Calis KA ,Pucino F . Zoledronic acid and secondary prevention of fractures. N Engl J Med 2007;357:1861-1862
Full Text | Web of Science | Medline
Author/Editor Response
Although we recognize the limitations of composite end points, as noted by van den Berg, we used symptomatic fractures detected during routine care, which are associated with increased morbidity, mortality, and functional impairment, and we reported major subtypes individually. Although the reduction in hip fractures did not reach statistical significance, the number needed to treat of 71 is comparable to the hip-fracture reduction in other bisphosphonate trials,1,2 and our study was not powered to show significant differences between treatment groups for this end point. Although postdose symptoms are problematic, they are generally limited to the first infusion,1 and we argue that their clinical importance is not equal to that of avoiding a symptomatic fracture (number needed to treat, 17) or an additional death (number needed to treat, 27).
In response to Lopez and Tasneem, when this study was designed, the only therapies that had been proven to reduce the risk of nonvertebral fractures were alendronate and risedronate.2,3 Thus, we believed that permitting the use of non-bisphosphonate therapies would not have an important influence on the overall outcome. In the recently reported study by Black et al.,1 there was no difference in the incidence of hip, nonvertebral, or all clinical fractures between subjects who received and those who did not receive concomitant therapy. Concomitant use of osteoporosis medication was only 10%, equally balanced between the groups, and was therefore unlikely to affect the results.
The comments by Karam et al. are also important to consider. However, we wish to clarify several points. First, the time-to-death analysis was a prespecified safety analysis that was described in both the protocol and the statistical-analysis plan (provided in the online Supplementary Appendix to our article). Second, as shown in Fig. 1 of the article, no patients were excluded from the analysis of time to death. Although 17% of patients discontinued the trial early, these patients were equally distributed between the study groups and were included in the death analysis until their last point of contact before discontinuation. Third, we wish to reiterate that the reasons for the death benefit are probably multifactorial. As Karam et al. point out, separation of the mortality curves occurs after a year, indicating that the benefit may accrue by acting on some system that changes only slowly. We are currently assessing whether the benefit is explained by differing infection rates, cardiovascular events, or changes in bone mineral density. Finally, the baseline risk of death in this patient population was substantially different from that in previous zoledronic acid trials1 and may account for some of the variance in results.
3 ReferencesCathleen S. Colon-Emeric, M.D., M.H.Sc.
Duke University Medical Center, Durham, NC 27710Kenneth W. Lyles, M.D.
Durham Veterans Affairs Medical Center, Durham, NC 27705Peter Mesenbrink, Ph.D.
Novartis Pharmaceuticals, East Hanover, NJ 07936for the HORIZON Recurrent Fracture Trial
1
Black DM ,Delmas PD ,Eastell R , et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822
Full Text | Web of Science | Medline2
Black DM ,Cummings SR ,Karpf DB , et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541
CrossRef | Web of Science | Medline3
Cranney A ,Waldegger L ,Zytaruk N , et al. Risedronate for the prevention and treatment of postmenopausal osteoporosis. Cochrane Database Syst Rev 2003;4:CD004523-CD004523
Medline
