Correspondence
Yearly Zoledronic Acid in Postmenopausal Osteoporosis
N Engl J Med 2007; 357:711-715August 16, 2007
- Article
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 once-yearly 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.
5 ReferencesRon N.J. de Nijs, M.D., Ph.D.
Antonius A.A. Westgeest, M.D., Ph.D.
Máxima Medical Center, 5631 BM Eindhoven, the Netherlands
r.denijs@mmc. nl 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
Sorscher SM . Electrolyte abnormalities with zoledronic acid therapy. Cancer J 2002;8:348-349
CrossRef | Web of Science | Medline3
Abbott LG ,Rude RK . Clinical manifestations of magnesium deficiency. Miner Electrolyte Metab 1993;19:314-322
Medline4
Whang R ,Hampton EM ,Whang DD . Magnesium homeostasis and clinical disorders of magnesium deficiency. Ann Pharmacother 1994;28:220-226
Web of Science | Medline5
Peter R ,Mishra V ,Fraser WD . Severe hypocalcaemia after being given intravenous bisphosphonate. BMJ 2004;328:335-336
CrossRef | Web of Science | Medline
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 (Figure 1Figure 1
Serial Changes in Mean Serum Calcium Levels in Patients with Stroke Treated with Zoledronic Acid or Placebo.). Calcium levels remained suppressed and had only partly recovered 10 days later. Two thirds of our treated patients also had phosphate levels below the lower limit of the normal range within 10 days.Reid et al. reported decreased calcium and phosphate levels in women with osteoporosis 1 month after infusion of zoledronic acid.3 Women who were treated with quarterly infusions (at a dose of 1 mg) had mean values of parathyroid hormone that were 30% higher than baseline values 3 months after their last infusion. Prolonged relative hypocalcemia and associated secondary hyperparathyroidism might underlie cardiac arrythmogenesis, as seen in the secondary hyperparathyroidism of patients undergoing hemodialysis.4 Further studies are needed to document the duration of relative hypocalcemia and its likely preventable determinants — for instance, vitamin D insufficiency — before treatment.
4 ReferencesKenneth E.S. Poole, B.M., Ph.D.
Stephen Kaptoge, Ph.D.
Jonathan Reeve, D.M., D.Sc.
University of Cambridge, Cambridge CB2 2QQ, United Kingdom
jonathan.reeve@srl. cam. ac. uk 1
Rosen CJ ,Brown S . Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. N Engl J Med 2003;348:1503-1504
Full Text | Web of Science | Medline2
Poole KE ,Loveridge N ,Rose CM ,Warburton EA ,Reeve J . A single infusion of zoledronate prevents bone loss after stroke. Stroke 2007;38:1519-1525
CrossRef | Web of Science | Medline3
Reid IR ,Brown JP ,Burckhardt P , et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-661
Full Text | Web of Science | Medline4
Kim HW ,Park CW ,Shin YS , et al. Calcitriol regresses cardiac hypertrophy and QT dispersion in secondary hyperparathyroidism on hemodialysis. Nephron Clin Pract 2006;102:c21-c29
CrossRef | Web of Science | Medline
To the Editor:
Black et al. report a significant increase in the risk of atrial fibrillation, classified as a serious adverse event, among patients treated with intravenous zoledronic acid. In a letter in the same issue of the Journal, Cummings et al. report a trend toward an increased risk of atrial fibrillation among patients treated with oral alendronate.1
To determine whether there was a similar effect with oral risedronate, we evaluated the incidence of nonadjudicated adverse events of atrial fibrillation and cerebrovascular accident and of death from these events in placebo-controlled, phase 3 clinical trials of risedronate for the treatment of osteoporosis. These trials followed approximately 15,000 patients for up to 3 years (Table 1Table 1
Demographic Characteristics and Incidence of Atrial Fibrillation, Cerebrovascular Accident, and Death among Patients with Osteoporosis Receiving Risedronate.).In the risedronate group, as compared with the placebo group, there was no significant difference in the incidence of atrial fibrillation (classified as an adverse event or a serious adverse event), cerebrovascular accident, or death associated with cardiovascular adverse events. The difference in the rate of death from cerebrovascular accident (P=0.003) was consistent with findings reported previously.2 These data do not support a causal association between atrial fibrillation and the use of risedronate.
Roger Karam, M.D.
Procter & Gamble Pharmaceuticals, Mason, OH 45040
karam.r@pg. com John Camm, M.D.
St. George's University of London, London SW17 0RE, United KingdomMichael McClung, M.D.
Oregon Osteoporosis Center, Portland, OR 97213Dr. Camm reports receiving consulting fees from Procter & Gamble, Merck, and Novartis; and Dr. McClung, research grants and consulting fees from Amgen, Lilly, Merck, Novartis, Procter & Gamble, Roche, and Sanofi-Aventis and lecture fees from Lilly, Merck, and Sanofi-Aventis. No other potential conflict of interest relevant to this letter was reported.
2 References1
Cummings SR ,Schwartz AV ,Black DM . Alendronate and atrial fibrillation. N Engl J Med 2007;356:1895-1896
Full Text | Web of Science | Medline2
Steinbuch M ,D'Agostino RB ,Mandel JS , et al. Assessment of mortality in patients enrolled in a risedronate clinical trial program: a retrospective cohort study. Regul Toxicol Pharmacol 2002;35:320-326
CrossRef | Web of Science | Medline
To the Editor:
The report by Black et al. adds an important new dimension to the management of postmenopausal osteoporosis. However, a number of trials have already shown the efficacy of bisphosphonates in preventing osteoporotic fractures.1-3 Since Black et al. have been in the forefront of research in this area,1,2 we are concerned about their choice of a placebo-controlled trial to show the usefulness of zoledronic acid in osteoporosis. In our view, only a lack of evidence regarding the effectiveness of a trial drug should justify conducting a placebo-controlled trial. We believe that the data available before the start of the study by Black et al., in 2002,4 should have led to a trial comparing oral (daily, weekly, or monthly) bisphosphonates with yearly parenteral zoledronic acid. Such a trial would have been more pertinent, both clinically and ethically.
4 ReferencesMarwan A. Najib, M.R.C.P.
Imran Aziz, F.R.C.P.
Royal Albert Edward Infirmary, Wigan WN1 2NN, United Kingdom
imran.aziz@wwl. nhs. uk 1
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 | Medline2
Cummings SR ,Black DM ,Thompson DE , et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082
CrossRef | Web of Science | Medline3
Harris ST ,Watts NB ,Genant HK , et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999;282:1344-1352
CrossRef | Web of Science | Medline4
Harris ST . Bisphosphonates for the treatment of postmenopausal osteoporosis: clinical studies of etidronate and alendronate. Osteoporos Int 2001;12:Suppl 3:S11-S16
CrossRef | Web of Science | Medline
To the Editor:
In the editorial by Compston1 accompanying the article by Black et al., there is a sentence that is misleading. With respect to zoledronic-acid treatment in postmenopausal women, Compston writes that “the absence of long-term adverse effects on renal function is reassuring,” citing a letter I wrote to the Journal in 2003.2 In that letter, I wrote that some patients taking zoledronic acid had long-term renal effects — namely renal deterioration progressing to renal failure, the need for dialysis, and even death. The renal failure was caused by acute tubular necrosis, which is not always reversible.3
A re-review of the cases I discussed in my letter showed that 22 patients continued to have elevated serum creatinine levels at the time of recovery, as compared with the levels at baseline. Five of these patients were treated with dialysis. Thirteen patients had received only one dose of zoledronic acid before having renal failure. In this group, six patients underwent dialysis. Two of these patients died, in addition to a third patient. Furthermore, five patients continued to have elevated serum creatinine levels after discontinuation of zoledronic acid.
The Food and Drug Administration continues to have concerns about the safety of zoledronic acid. In January 2005, the product labeling was updated to include medication dosing based on the baseline creatinine clearance.4
4 ReferencesJennie T. Chang, Pharm.D.
Food and Drug Administration, Silver Spring, MD 20993
jennie.chang@fda. hhs. gov 1
Compston J . Treatments for osteoporosis -- looking beyond the HORIZON. N Engl J Med 2007;356:1878-1880
Full Text | Web of Science | Medline2
Chang JT ,Green L ,Beitz J . Renal failure with the use of zoledronic acid. N Engl J Med 2003;349:1676-1678
Full Text | Web of Science | Medline3
Markowitz GS ,Fine PL ,Stack JI , et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003;64:281-289
CrossRef | Web of Science | Medline4
Zometa product label. East Hanover, NJ: Novartis Pharmaceuticals, 2002. (Accessed July 26, 2007, at http://www.us.zometa.com/info/about/index.jsp.)
Author/Editor Response
Poole et al. and de Nijs and Westgeest note the potential relationship between clinically important changes in electrolytes and the occurrence of cardiac arrhythmias. We also evaluated electrolyte changes in the HORIZON trial. There were significant differences between study groups in the change in serum calcium from the level before the first infusion of zoledronic acid to the level 9 to 11 days after the infusion, but the magnitude of the difference was relatively small (a reduction of 0.2±0.5 mg per deciliter in the zoledronic-acid group vs. an increase of 0.03±0.4 in the placebo group). No difference was evident at 12 months, and no significant changes occurred with subsequent doses. In the zoledronic-acid group, the change in calcium levels after the first infusion did not differ between women with atrial fibrillation and those without atrial fibrillation. Over the 3 years of the study, mean serum calcium levels increased in both study groups, although the mean increase was slightly larger in the placebo group than in the zoledronic-acid group. The difference in the mean serum calcium level between study groups 9 to 11 days after the initial infusion (0.2 mg per deciliter) was less than that observed by Poole et al. at 10 days (0.6 mg per deciliter).1
In our study, a similar pattern was seen for phosphorous: 9 to 11 days after the initial infusion, there was a slightly larger decrease in the zoledronic-acid group than in the placebo group, but in the zoledronic-acid group, phosphorus levels did not differ between women with atrial fibrillation and those without atrial fibrillation. Magnesium and potassium levels did not differ between the two study groups and were similar in women with and those without atrial fibrillation.
As discussed in our article, episodes of atrial fibrillation did not cluster in time immediately after any infusion, when serum electrolytes are most affected. Taken together, these findings support our speculation that if the observed increase in atrial fibrillation was in fact related to the administration of zoledronic acid, it was probably not due to changes in serum electrolytes.
We welcome the data from Karam et al. on risedronate and look forward to the publication of data on other bisphosphonates to further elucidate this finding.
The investigators and industry sponsor of our trial incorporated ethical considerations regarding placebo controls, such as those raised by Najib and Aziz, into the study design. The protocol specified that patients had to be unable or unwilling to take oral bisphosphonates. All women were counseled regarding the risk of fracture and the availability of approved osteoporosis medications. One innovation of the trial was that women who were receiving nonbisphosphonate treatments for osteoporosis (including hormone therapy, raloxifene, and calcitonin) were included (“stratum 2”), and all patients were free to begin any of these treatments during the study while continuing to receive the study treatment. Furthermore, we monitored patients for excessive bone loss or multiple fractures, and women who met either criterion were again counseled about alternative treatment options. We agree that a trial with an active comparator would be of great clinical interest, but the numbers required for such a trial to demonstrate equivalence or superiority with respect to the risk of fracture are prohibitive (20,000 to 30,000 patients).
1 ReferencesDennis Black, Ph.D.
University of California, San Francisco, San Francisco, CA 94107
dblack@psg.ucsf. edu Erik Eriksen, M.D.
Novartis Pharma, CH-4002 Basel, SwitzerlandDeborah Sellmeyer, M.D.
University of California, San Francisco, San Francisco, CA 941071
Poole KE ,Loveridge N ,Rose CM ,Warburton EA ,Reeve J . A single infusion of zoledronate prevents bone loss after stroke. Stroke 2007;38:1519-1525
CrossRef | Web of Science | Medline
Author/Editor Response
In my editorial, the reference to Dr. Chang's letter was not intended to support the absence of long-term adverse renal effects associated with zoledronic acid but, rather, to provide a context in which the long-term renal safety in the HORIZON study could be regarded as reassuring. As Dr. Chang points out, long-term adverse effects of zoledronic acid on renal function have been documented in a small number of patients and remain a potential concern.
Juliet Compston, M.D., F.R.C.P.
University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, United Kingdom- Citing Articles (4)
Citing Articles
1
Patricia A. Howard, Brian J. Barnes, James L. Vacek, Warren Chen, Sue-Min Lai. (2010) Impact of Bisphosphonates on the Risk of Atrial Fibrillation. American Journal Cardiovascular Drugs 10:6, 359-367
CrossRef2
Weng-Foung Huang, Yi-Wen Tsai, Yu-Wen Wen, Fei-Yuan Hsiao, Ken N. Kuo, Chia-Rung Tsai. (2010) Osteoporosis treatment and atrial fibrillation. Menopause 17:1, 57-63
CrossRef3
K. Poole, . (2008) Comment on: Hypovitaminosis D among rheumatology outpatients in clinical practice: reply. Rheumatology 48:2, 204-204
CrossRef4
Roland D Chapurlat. (2008) Single annual injectable treatment for postmenopausal osteoporosis. Expert Opinion on Drug Delivery 5:5, 583-591
CrossRef
