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Yearly Zoledronic Acid in Postmenopausal Osteoporosis To the Editor: In their report on the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, Black et al. (May 3 issue)1 conclude that a onceyearly infusion of zoledronic acid reduces the risk of vertebral, hip, and other fractures. Although this is a well-designed and well-done study, we are concerned about the increase in atrial fibrillation in patients treated with zoledronic acid. Hypocalcemia as a cause was ruled out. There is no report of hypokalemia during the study. Another electrolyte imbalance, hypomagnesemia, is reported as a side effect of zoledronic acid2 and can cause cardiac arrhythmias.3,4 It would be interesting to know the incidence of hypomagnesemia during the HORIZON study, mainly among the patients with atrial fibrillation. Forty-nine patients in the zoledronic-acid group had transient hypocalcemia at days 9 to 11 after the infusion. There are several case reports describing hypocalcemia during treatment with zoledronic acid, inducing a compensatory increase in parathyroid hormone.5 In the study by Black et al., however, we are not informed about the mean change in calcium and parathyroid hormone concentrations during treatment. Ron N.J. de Nijs, M.D., Ph.D. Antonius A.A. Westgeest, M.D., Ph.D. Máxima Medical Center 5631 BM Eindhoven, the Netherlands
[email protected]
To the Editor: Black et al. do not have a satisfactory explanation for their report of an increased incidence of serious atrial fibrillation in patients receiving zoledronic acid. Rapid atrial fibrillation, severe hypocalcemia, and a marked increase in the serum parathyroid hormone level were presenting features in a woman with hypovitaminosis D who had been treated with 60 mg of pamidronate 3 weeks before the episode, as reported in the Journal in 2003.1 Clinically, hypocalcemia may lower the ejection fraction, leading to myocardial dysfunction. The report by Black et al. contains little evidence that serum calcium was maintained at pretreatment levels after the administration of zoledronic acid, beyond the statement that the drug had “little or no effect” on levels 9 to 11 days after infusion. We previously reported that zoledronic acid (at a dose of 4 mg) lowered serum calcium levels, usually into the lowest quartile of the reference range.2 This finding was evident from the second day (Fig. 1). Calcium levels remained suppressed this week’s letters 711
Yearly Zoledronic Acid in Postmenopausal Osteoporosis
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1. Black DM, Delmas PD, Eastell R, et al. Once-yearly zole-
dronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-22. 2. Sorscher SM. Electrolyte abnormalities with zoledronic acid therapy. Cancer J 2002;8:348-9. 3. Abbott LG, Rude RK. Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993;19:314-22. 4. Whang R, Hampton EM, Whang DD. Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother 1994;28:220-6. 5. Peter R, Mishra V, Fraser WD. Severe hypocalcaemia after being given intravenous bisphosphonate. BMJ 2004;328:335-6.
n engl j med 357;7 www.nejm.org august 16, 2007
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Mean Serum Calcium Level (mg/dl)
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Zoledronic acid (15 patients) 0
2
4
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Figure 1. Serial Changes in Mean Serum Calcium Levels in Patients with Stroke Treated with Zoledronic Acid or Placebo. The dashed line indicates the lower limit of the laboratory reference range for calcium at 8.4 mg per deciliter (P
