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Gastrointestinal Adverse Effects of Bisphosphonates

Etiology, Incidence and Prevention

  • Review Article
  • Published:
Treatments in Endocrinology

Abstract

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget’s disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians.

Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants.

From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.

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Table I

References

  1. Fleisch H. The use of bisphosphonates in osteoporosis. Br J Clin Pract 1994; 48: 323–6

    PubMed  CAS  Google Scholar 

  2. Fleisch H. Bisphosphonates: pharmacology. Semin Arthritis Rheum 1994; 23: 261–2

    Article  PubMed  CAS  Google Scholar 

  3. Watts NB. Treatment of osteoporosis with bisphosphonates. Rheum Dis Clin North Am 1994; 20: 717–34

    PubMed  CAS  Google Scholar 

  4. Black DM, Cummings SR, Karpe DB, et al. Randomized trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–41

    Article  PubMed  CAS  Google Scholar 

  5. Jeal W, Barradell LB, Mctavish D. Alendronate: a review of its pharmacological properties and therapeutic efficacy in postmenopausal osteoporosis. Drugs 1997; 43: 415–34

    Article  Google Scholar 

  6. Coleman RK, Houston S, Purohit OP, et al. A randomized phase II study of oral pamidronate for the treatment of bone metastases from breast cancer. Eur J Cancer 1998; 34: 820–4

    Article  PubMed  CAS  Google Scholar 

  7. Lufkin EG, Argueta R, Whitaker MD, et al. An unrecognized problem in gastrointestinal tolerability. Osteoporos Int 1994; 4: 320–2

    Article  PubMed  CAS  Google Scholar 

  8. Mackay FJ, Wilton LV, Pearce GL, et al. United Kingdom experience with alendronate and esophageal reactions. Br J Gen Clin Pract 1998; 48: 1161–2

    CAS  Google Scholar 

  9. Ettinger B, Pressman A, Schein J. Clinic visits and hospital admissions for care of acid-related upper gastrointestinal disorders in women using alendronate for esophagitis. Am J Manag Care 1998; 4: 1377–82

    PubMed  CAS  Google Scholar 

  10. Kelly R, Taggart H. Incidence of gastrointestinal side effects due to alendronate is high in clinical practice. BMJ 1997; 315: 1235

    Article  PubMed  CAS  Google Scholar 

  11. Maconi G, Porro GB. Multiple ulcerative esophagitis caused by alendronate. Am J Gastroenterol 1995; 90: 1889–90

    PubMed  CAS  Google Scholar 

  12. Graham DY, Malaty HM, Goodgame R. Primary amino-bisphosphonates: A new class of gastrotoxic drugs: comparison of alendronate and aspirin. Am J Gastroenterol 1997; 92(8): 1322–5

    PubMed  CAS  Google Scholar 

  13. Blank MA, Ems BL, Gibson GW, et al. In a novel preclinical model, primary amino bisphosphonates show a greater potential for gastric effects than a pyrindinyl bisphosphonate [abstract]. J Bone Miner Res 1995; 10: S454

    Google Scholar 

  14. Graham DY, Malaty HM. Alendronate gastric ulcers. Aliment Pharmacol Ther 1999; 13: 515–9

    Article  PubMed  CAS  Google Scholar 

  15. Lanza FL, Carlson MR. The effects of amino-versus alkyl-bisphosphonates on the healing of aspirin-induced stomach erosions in healthy subjects [abstract]. Am J Gastroenterol 1996; 91: 1916

    Google Scholar 

  16. Chestnut CH III, Haris ST. Short-term effect of alendronate on bone mass and bone remodeliing in postmenopausal women. Osteoporos Int 1993; 3Suppl 3: S17–9

    Article  Google Scholar 

  17. Schenk R, Eggli P, Fleisch H, et al. Quantitative morphometric evaluation of the inhibitory activity of new aminobisphosphonates on bone resorption in the rat. Calcif Tissue Int 1986; 38: 342–9

    Article  PubMed  CAS  Google Scholar 

  18. Balena R, Toolan BC, Shea M, et al. The effects of a 2-year treatment with the aminobisphosphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 1993; 92: 2577–86

    Article  PubMed  CAS  Google Scholar 

  19. Blank MA, Ems BL, Gibson GW, et al. Nonclinical model for assessing gastric effects of bisphosphonates. Dig Dis Sci 1997; 42(2): 281–8

    Article  PubMed  CAS  Google Scholar 

  20. Lanza FL, Rack MF, Simon TJ, et al. Effects of alendronate on duodenal mucosa. Am J Gastroenterol 1998; 93(5): 753–7

    Article  PubMed  CAS  Google Scholar 

  21. Lowe CE, Depew WT, Vanner SJ, et al. Upper gastrointestinal toxicity of alendronate. Am J Gastroenterol 2000; 95(3): 634–40

    Article  PubMed  CAS  Google Scholar 

  22. Lanza FL, Schwartz H, Sahba B, et al. An endoscopic comparison of the effects of alendronate and risedronate on upper gastrointestinal mucosae. Am J Gastroenterol 2000; 95(11): 3112–7

    Article  PubMed  CAS  Google Scholar 

  23. Lanza FL, Hunt RH, Thomson ABR, et al. Endoscopie comparison of esophageal and gasroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 2000; 119: 631–8

    Article  PubMed  CAS  Google Scholar 

  24. Thomson ABR, Marshall JK, Hunt RH, et al. Incidence of gastric ulcers lower in postmenopausal women treated with risedronate than alendronate regardless of H. pylori status [abstract]. Gastrointest Endosc 2001; 53(5): AB202

    Google Scholar 

  25. Lanza FL, Sahba B, Schwartz H, et al. The upper gastrointestinal safety and tolerability of oral alendronate 70 mg once daily: a placebo-controlled endoscopy study. Am J Gastroenterol 2002 Jan; 97(1): 58–64

    Article  PubMed  CAS  Google Scholar 

  26. Graham DY, Smith JL, Dobbs SM, et al. Gastric adaptation occurs with aspirin administration in men. Dig Dis Sci 1983; 28: 1–6

    Article  PubMed  CAS  Google Scholar 

  27. Olivero JJ, Graham DY. Gastric adaptation to nonsteroidal anti-inflammatory drugs in a man. Scand J Gastroenterol Suppl 1992; 153: 53–8

    Article  Google Scholar 

  28. Black DM, Cummings ST, Karpf DB. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348(9041): 1535–41

    Article  PubMed  CAS  Google Scholar 

  29. Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal tract safety profile of alendronate. The fracture intervention trial. Arch Intern Med 2000; 160: 517–25

    Article  PubMed  CAS  Google Scholar 

  30. 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; 232(14): 1344–52

    Article  Google Scholar 

  31. Hosking D, Chilvers CED, Christiansen C, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 1998; 338(8): 485–92

    Article  PubMed  CAS  Google Scholar 

  32. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000; 343(9): 604–10

    Article  PubMed  CAS  Google Scholar 

  33. McClung M, Clemmensen B, Daifotis A, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. Ann Intern Med 1998; 15(4): 253–61

    Google Scholar 

  34. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year study results from the early postmenopausal intervention cohort study: a randomized controlled trial. Ann Intern Med 1999; 131(12): 935–42

    PubMed  CAS  Google Scholar 

  35. Tucci JR, Tonino RP, Emkey RD, et al. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996; 101: 488–501

    Article  PubMed  CAS  Google Scholar 

  36. Abdelmalek MF, Douglas DD. Alendronate-induced ulcerative esophagitis [letter]. Am J Gastroenterol 1996; 91: 1282–3

    PubMed  CAS  Google Scholar 

  37. Rimmer DE, Rawls DE. Improper alendronate administration and a case of pill esophagitis [letter]. Am J Gastroenterol 1996; 91: 2648–9

    PubMed  CAS  Google Scholar 

  38. Liberman UI, Hirsch LJ. Esophagitis and alendronate [letter]. N Engl J Med 1996; 335: 1069–70

    Article  PubMed  CAS  Google Scholar 

  39. Castell DO. ‘Pill esophagitis’ — the case of alendronate [editorial]. N Engl J Med 1996; 335: 1058–9

    Article  PubMed  CAS  Google Scholar 

  40. Pizzani E, Valenzuela G. Esophagitis associated with alendronate sodium. VA Med Q 1997; 124: 181–2

    PubMed  CAS  Google Scholar 

  41. Girelli CM, Reguzzoni G, Rocca F. Alendronate-induced esophagitis: a report of 2 cases. Recenti Prog Med 1997; 88: 223–5

    PubMed  CAS  Google Scholar 

  42. Levine J, Nelson D. Esophageal stricture associated with alendronate therapy. Am J Med 1997; 102: 489–91

    Article  PubMed  CAS  Google Scholar 

  43. Ribeiro A, DeVault KR, Wolfe III JT, et al. Case report -alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998; 47(6): 525–8

    Article  PubMed  CAS  Google Scholar 

  44. Macedo G, Azavedo F, Ribeiro T. Ulcerative esophagitis caused by etidronate. Gastrointest Endosc 2001; 53: 250–1

    Article  PubMed  CAS  Google Scholar 

  45. deGroen PC, Lubbe DF, Hirsch LJ, et al. Alendronate caused esophagitis, but rarely. N Engl J Med 1996; 335: 1016–21

    Article  CAS  Google Scholar 

  46. Lilley LL, Guanci R. Avoiding alendronate-related esophageal irritation. Am J Nurs 1977; 97: 12–4

    Google Scholar 

  47. ACTONEL® (Risedronate sodium tablets) prescribing information. Proctor & Gamble Pharmaceuticals, 2000 Apr

  48. FOSOMAX® (Alendronate sodium tablets) prescribing information. Whitehouse Station (NJ): Merck & Company, Inc., 2000 Oct

  49. Lanza FL. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol 1998; 93(11): 2037–46

    Article  PubMed  CAS  Google Scholar 

  50. Marshall JK, Rainsford KD, James C, et al. A randomized controlled trial to assess alendronate-associated injury of the upper gastrointestinal tract. Aliment Pharmacol Ther 2000; 14: 1451–7

    Article  PubMed  CAS  Google Scholar 

  51. Wallace JL, Dicay M, McKnight W, et al. N-bisphosphosphonates cause gastric epithelial injury independent of effects on the microcirculation. Aliment Pharmacol Ther 1999; 13: 1675–82

    Article  PubMed  CAS  Google Scholar 

  52. Elliott SN, McKnight W, Davies NM, et al. Alendronate induces gastric injury and delays healing in rodents. Life Sci 1998; 62: 77–91

    Article  PubMed  CAS  Google Scholar 

  53. Lichtenberger LM, Romero JJ, Blank MA. Effect of bisphosphonates on the surface hydrophobicity and phosphatidylcholine concentration of gastric mucosa [abstract]. Gastroenterology 1999; 116: A237

    Article  Google Scholar 

  54. Geddes AD, D’Souza SM, Ebetino FH, et al. Structure-activity relationships and therapeutic implications. In: Heersche JNM. Kanis JA, editors. Bone and mineral research. Vol 8. Amsterdam: Elsevier Science, 1994: 265–306

    Google Scholar 

  55. Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets -possible mechanisms. Dig Dis Sci 1998; 43: 1998–2002

    Article  PubMed  CAS  Google Scholar 

  56. Levine J, Nelson D. Esophageal stricture associated with alendronate therapy. Am J Med 1997; 102: 4898–0

    Article  Google Scholar 

  57. Lanza FL. Bisphosphonates: oesaphageal and gastric toxicity —Fact or fiction. Ital J Gastroenterol Hepatol 1998; 30: 143–5

    PubMed  CAS  Google Scholar 

  58. Lader BZ, Kroneberg HM. Editorial: Gastroenterologists and choosing the right bisophosphonate. Gastroenterology 2000; 119: 866–9

    Article  Google Scholar 

  59. Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med 2001; 161: 107–10

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Section of Gastroenterology, Baylor College of Medicine, Houston, Texas, USA

    Frank L. Lanza

  2. Houston Institute for Clinical Research, 7777 Southwest Freeway, Suite 762, Houston, Texas, 77074, USA

    Frank L. Lanza

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Lanza, F.L. Gastrointestinal Adverse Effects of Bisphosphonates. Mol Diag Ther 1, 37–43 (2002). https://doi.org/10.2165/00024677-200201010-00004

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