Correspondence

Esophagitis and Alendronate

N Engl J Med 1996; 335:1069-1070October 3, 1996

Article

To the Editor:

Post-marketing reports of severe esophagitis associated with the use of alendronate sodium, reported in this issue of the Journal by de Groen et al.,1 prompted us to reexamine in detail adverse esophageal effects in our three-year osteoporosis studies (Nov. 30, 1995, issue).2 In these studies, 994 patients were randomly assigned to receive placebo, 5 or 10 mg of alendronate daily for three years, or 20 mg of alendronate for two years followed by 5 mg daily in year 3 (ratio of assignments to the four groups, 2:1:1:1, respectively). We used the same terms suggesting esophageal irritation that de Groen et al. used in their analysis of post-marketing reports, and like de Groen et al., we considered a serious adverse effect to involve hospitalization. However, the severity of adverse effects (mild, moderate, or severe, according to the intensity of the effect and its influence on the patient's functioning), as well as the causal relation to medication use, was rated by study investigators who were unaware of the treatment assignments. Patients were seen on average every three months (range, one to six), and dosing instructions (which formed the basis for the initial product labeling3) were usually reviewed at each visit. The incidence of adverse effects was compared among the treatment groups with the use of the unadjusted, two-tailed Tukey test for trend.4

The overall incidence of adverse upper gastrointestinal effects and of discontinuation of treatment due to such effects was similar in all four treatment groups (Table 1Table 1Adverse Esophageal Effects in Three-Year Studies of Alendronate in Patients with Osteoporosis.).2 Adverse esophageal effects were reported in 15 to 18 percent of the patients in the placebo and alendronate groups, and these events were considered serious or severe1 in approximately 1.5 percent of the patients in all four groups. Three patients (one in the placebo group and two in the group receiving 20 mg of alendronate for two years followed by 5 mg in the third year) required hospitalization, and an additional three patients (one in the placebo group and two in the 5-mg group) discontinued therapy because of a severe adverse esophageal effect. Three patients in the 10-mg group had esophageal ulcers. Each case was considered by the investigators to be related to the drug; only one ulcer was classified as severe (Table 1), and none of the patients required hospitalization. In two of the patients, the ulcers resolved despite continued therapy; in the third, alendronate was stopped. Dysphagia and ulcers persisted in this patient for one year and were attributed to idiopathic gastric acid hypersecretion. We thus found no evidence of an increased incidence of serious or severe adverse esophageal effects among patients taking alendronate, as compared with those taking placebo, in the three-year osteoporosis studies.

There are several reasons why we did not detect an increase in severe adverse esophageal effects in our placebo-controlled trials that was similar to the incidence reported by de Groen et al.1 These effects occur only in small numbers of patients; trial participants generally have fewer coexisting conditions; and most important, the patients in our studies had regularly scheduled follow-up visits, with frequent reinforcement of dosing instructions. Therefore, we recommend strict adherence to the current dosing instructions.5

Uri A. Liberman, M.D.
Beilinson Medical Center, 49100, Petah-Tikva, Israel

Laurence J. Hirsch, M.D.
Merck Research Laboratories, Rahway, NJ 07065

5 References

1. 1

   de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;335:1016-1021
   Full Text | Web of Science | Medline

2. 2

   Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443
   Full Text | Web of Science | Medline

3. 3

   Fosamax (alendronate sodium). West Point, Pa.: Merck, September 1995 (U.S. package insert).
   

4. 4

   Tukey JW, Ciminera JL, Heyse JF. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 1985;41:295-301
   CrossRef | Web of Science | Medline

5. 5

   Fosamax (alendronate sodium). West Point, Pa.: Merck, March 1996 (U.S. package insert).
   

Citing Articles (16)

Citing Articles

1. 1

   Taio Naniwa, Tomoyo Maeda, Tsutomu Mizoshita, Yoshihito Hayami, Maiko Watanabe, Shogo Banno, Rei Ito. (2008) Alendronate-Induced Esophagitis: Possible Pathogenic Role of Hypersensitivity to Alendronate. Internal Medicine 47:23, 2083-2085
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2. 2

   David C. McCarus. (2006) Fracture Prevention in Postmenopausal Osteoporosis: A Review of Treatment Options. Obstetrical & Gynecological Survey 61:1, 39-50
   CrossRef

3. 3

   Ted Xenodemetropoulos, Shawn Davison, George Ioannidis, Jonathan D Adachi. (2004) The Impact of Fragility Fracture on Health-Related Quality of Life. Drugs & Aging 21:11, 711-730
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4. 4

   Cathy Kessenich. (2003) An Approach to Postmenopausal Osteoporosis Treatment: A Case Study Review. Journal of the American Academy of Nurse Practitioners 15:12, 539-540
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5. 5

   Karl-Uwe Petersen, Daniel Jaspersen. (2003) Medication-induced oesophageal disorders. Expert Opinion on Drug Safety 2:5, 495-507
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6. 6

   F Lanza. (2003) Bisphosphonate mucosal injury—the end of the story?. Digestive and Liver Disease 35:2, 67-70
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7. 7

   Frank L. Lanza. (2002) Gastrointestinal Adverse Effects of Bisphosphonates. Treatments in Endocrinology 1:1, 37-43
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8. 8

   Byung-Joo Park, Jon Clouse, Deborah Shatin, Andy Stergachis. (2000) Incidence of adverse oesophageal and gastric events in alendronate users. Pharmacoepidemiology and Drug Safety 9:5, 371-376
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9. 9

   David Y Graham. (2000) Bisphosphonate gastrointestinal damage: perspective and research needs. Pharmacoepidemiology and Drug Safety 9:5, 377-381
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10. 10

    Daniel Jaspersen. (2000) Drug-Induced Oesophageal Disorders. Drug Safety 22:3, 237-249
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11. 11

    Henry G. Bone, Silvano Adami, Rene Rizzoli, Murray Favus, Philip D. Ross, Arthur Santora, Srinivasa Prahalada, Anastasia Daifotis, John Orloff, John Yates. (2000) Weekly administration of alendronate: Rationale and plan for clinical assessment. Clinical Therapeutics 22:1, 15-28
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12. 12

    GRAHAM, MALATY. (1999) Alendronate gastric ulcers. Alimentary Pharmacology and Therapeutics 13:4, 515-519
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13. 13

    Johann D. Ringe. (1998) The interpretation of preclinical data in predicting bisphosphonate response in the treatment of osteoporosis. Clinical Therapeutics 20:4, 648-660
    CrossRef

14. 14

    Castell, Donald O., . (1996) “Pill Esophagitis” — The Case of Alendronate. New England Journal of Medicine 335:14, 1058-1059
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15. 15

    de Groen, Piet C., Lubbe, Dieter F., Hirsch, Laurence J., Daifotis, Anastasia, Stephenson, Wendy, Freedholm, Debra, Pryor-Tillotson, Suzanne, Seleznick, Mitchel J., Pinkas, Haim, Wang, Kenneth K., . (1996) Esophagitis Associated with the Use of Alendronate. New England Journal of Medicine 335:14, 1016-1021
    Full Text

16. 16

    &NA;. (1996) Reducing alendronic acid-induced oesophagitis. Reactions Weekly &NA;:622, 2
    CrossRef