Skip to main content
SpringerLink
Log in

Safety Considerations with Bisphosphonates for the Treatment of Osteoporosis

  • Review Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. This review provides an overview of the safety issues associated with the nitrogen-containing class of bisphosphonates and discusses the potential effect of these issues on adherence. The review specifically considers upper gastrointestinal (UGI) adverse events (AEs), renal toxicity, influenza-like illness, osteonecrosis of the jaw and evidence on how to treat or prevent these events.

In clinical trials, UGI AEs, including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms. However, postmarketing studies have highlighted UGI AEs as a concern. These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs. Some clinical trials with oral bisphosphonates have suggested that a decrease in the frequency of administration may lead to improvement in gastrointestinal tolerability. In the authors’ experience, the issue of UGI tolerability can be minimised by explaining to the patient and/or caregiver the importance of following administration instructions.

Intravenous (IV) bisphosphonates have been recently approved for use in osteoporosis, offering an alternative regimen for patients with osteoporosis. Earlier generation IV bisphosphonates (e.g. etidronate) have been associated with acute renal failure. Alternatively, late-generation IV bisphosphonates (i.e. ibandronate) have shown a better safety profile in relation to renal toxicity.

Influenza-like illness, often referred to as an acute-phase reaction, covers symptoms such as fatigue, fever, chills, myalgia and arthralgia. These symptoms are transitory and self-limiting and usually do not recur after subsequent drug administration. Symptoms of influenza-like illness have been associated with both IV and oral bisphosphonates.

Osteonecrosis of the jaw has also been associated with IV bisphosphonate treatment, particularly in patients treated with high doses. A small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this AE. As osteonecrosis of the jaw is difficult to treat and is often associated with dental procedures and poor oral hygiene, preventive measures seem to be the best management option for patients taking bisphosphonates.

Overall, the safety and tolerability profile of the nitrogen-containing bisphosphonates is good, and long-term treatment does not appear to carry a risk of serious AEs. By encouraging adherence to administration instructions physicians can minimise certain complications, such as UGI intolerability. By being aware of other potential safety issues, such as renal impairment, influenza-like illness and osteonecrosis of the jaw, physicians can detect these AEs early in the course of treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. 1The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004; 350: 1189–99

    Article  PubMed  CAS  Google Scholar 

  2. Chesnut III C, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241–9

    Article  CAS  Google Scholar 

  3. 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. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344–52

    Article  PubMed  CAS  Google Scholar 

  4. Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003; 9: 2643–58

    Article  PubMed  CAS  Google Scholar 

  5. South-Paul JE. Osteoporosis: part I. Evaluation and assessment. Am Fam Physician 2001; 63: 897–904

    PubMed  CAS  Google Scholar 

  6. National Osteoporosis Foundation. Physician’s guide to prevention and treatment of osteoporosis [online]. Available from URL: http://www.nof.org/_vti_bin/shtml.dll/physguide [Accessed 2005 Apr 15]

  7. Kuehn BM. Better osteoporosis management a priority: impact predicted to soar with aging population. JAMA 2005; 293: 2453–8

    Article  PubMed  CAS  Google Scholar 

  8. Hamilton B, McCoy K, Taggart H. Tolerability and compliance with risedronate in clinical practice. Osteoporos Int 2003; 14: 259–62

    PubMed  CAS  Google Scholar 

  9. Naylor G, Davies MH. Oesophageal stricture associated with alendronic acid. Lancet 1996; 348: 1030–1

    Article  PubMed  CAS  Google Scholar 

  10. Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 2004; 15: 1003–8

    Article  PubMed  Google Scholar 

  11. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000; 85: 4118–24

    Article  PubMed  CAS  Google Scholar 

  12. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Foxamax International Trial Study Group. Osteoporos Int 1999; 9: 461–8

    Article  PubMed  CAS  Google Scholar 

  13. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70mg once-weekly and alendronate 10mg daily in the treatment of osteoporosis: Alendronate Once-Weekly Study Group. Aging (Milano) 2000; 12: 1–12

    CAS  Google Scholar 

  14. 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. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344–52

    Article  PubMed  CAS  Google Scholar 

  15. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000; 11: 83–91

    Article  PubMed  CAS  Google Scholar 

  16. Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002; 71: 103–11

    Article  PubMed  CAS  Google Scholar 

  17. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003; 115: 209–16

    Article  PubMed  Google Scholar 

  18. United States Department of Health and Human Services. Bone health and osteoporosis: a report of the Surgeon General [online]. Available from URL: http://www.hhs.gov/surgeongeneral/library/bonehealth/content.html [Accessed 2005 Apr 28]

  19. 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: 653–61

    Article  PubMed  CAS  Google Scholar 

  20. Bounameaux HM, Schifferli J, Montani JP, et al. Renal failure associated with intravenous diphosphonates. Lancet 1983; 1: 471–2

    Article  PubMed  CAS  Google Scholar 

  21. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349: 1676–9

    Article  PubMed  CAS  Google Scholar 

  22. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115–7

    Article  PubMed  Google Scholar 

  23. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996; 335: 1016–21

    Article  PubMed  Google Scholar 

  24. Reszka AA, Halasy-Nagy J, Rodan GA. Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation. Mol Pharmacol 2001; 59: 193–202

    PubMed  CAS  Google Scholar 

  25. MCA/CSM. Reminder: severe oesophageal reactions with alendronate sodium (Fosamax). CurrProbl Pharmacovig 1998; 24: 11–4

    Google Scholar 

  26. Levin TR, Schmittdiel JA, Kunz K, et al. Costs of acid-related disorders to a health maintenance organization. Am J Med 1997; 103: 520–8

    Article  PubMed  CAS  Google Scholar 

  27. 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 

  28. Taggart H, Bolognese M, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002; 77: 262–70

    Article  PubMed  CAS  Google Scholar 

  29. Lanza F, 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: 3112–7

    Article  PubMed  CAS  Google Scholar 

  30. Lanza FL, Hunt RH, Thomson AB, et al. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 2000; 119: 631–8

    Article  PubMed  CAS  Google Scholar 

  31. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once-weekly alendronate 70mg compared with once-weekly 763 risedronate 35mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 2005; 20: 141–51

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  33. 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 

  34. Chestnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241–9

    Article  Google Scholar 

  35. Reginster J-Y, Wilson KM, Dumont E, et al. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study. J Clin Endocrinol Metab 2005; 90: 5018–24

    Article  PubMed  CAS  Google Scholar 

  36. Harris ST, Watts NB, Li Z, et al. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin 2004; 20: 757–64

    Article  PubMed  CAS  Google Scholar 

  37. Reginster J-Y, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study. Ann Rheum Dis 2006; 65: 654–61

    Article  PubMed  CAS  Google Scholar 

  38. Coleman RE. Bisphosphonates: clinical experience. Oncologist 2004; 9: 14–27

    Article  PubMed  CAS  Google Scholar 

  39. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–68

    Article  PubMed  CAS  Google Scholar 

  40. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 2004; 100: 2613–21

    Article  PubMed  CAS  Google Scholar 

  41. Lyubimova NV, Kushlinsky NE, Lichinitser MR, et al. Renal safety of intravenous ibandronic acid in breast cancer patients with metastatic bone disease. Clin Drug Invest 2003; 23: 707–16

    Article  CAS  Google Scholar 

  42. Diel I, Body JJ, Bergaström B. Low nephrotoxicity of ibandronate: evidence from clinical trials in metastatic bone disease [abstract]. Bone 2004; 34: S77

    Google Scholar 

  43. Neugebauer G, Koehler W, Akinkunmi L, et al. Influence of peak ibandronic acid concentrations after 6mg iv administration with shortened infusion time (15 and 30 minutes) on renal safety in man [abstract no. 486]. Proc Annu Meet Am Soc Clin Oncol 2001; 20: 122A

    Google Scholar 

  44. Delmas PD, Emkey R, Gilbride J, et al. Oral ibandronate has a similar gastrointestinal (GI) safety profile to placebo in patients with a history of GI disorders or receiving concomitant NSAIDS [abstract no. P267]. Osteoporos Int 2003; 14: S74

    Google Scholar 

  45. Civitelli R, Emkey R, Zaidi M, et al. Safety of intravenous ibandronate injections in postmenopausal osteoporosis: DIVA 2-year findings. Paper presented at the 12th annual meeting of the International Society for Clinical Densitometry; 2006 Feb 1–4; San Diego (CA)

  46. Ringe JD, Dorst A, Faber H, et al. Three-monthly ibandronate bolus injection offers favourable tolerability and sustained efficacy advantage over two years in established corticosteroid-induced osteoporosis. Rheumatology 2003; 42: 743–9

    Article  PubMed  CAS  Google Scholar 

  47. Procter & Gamble Pharmaceuticals, Inc. Actonel® (risedronate sodium tablets) [package insert]. Cincinnati (OH): Procter & Gamble Pharmaceuticals, Inc., May 2005

  48. Merck & Co., Inc. Fosamax® (alendronate sodium) tablets and oral solution [package insert]. Whitehouse Station (NJ): Merck & Co., Inc., 2005 Jul

  49. Adami S, Zamberlan N. Adverse effects of bisphosphonates: a comparative review. Drug Saf 1996; 14: 158–70

    Article  PubMed  CAS  Google Scholar 

  50. Hewitt R, Lissina A, Green A, et al. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 2005; 139: 101–11

    Article  PubMed  CAS  Google Scholar 

  51. Thompson K, Rogers MJ. Statins prevent bisphosphonate-induced gamma, delta-T-cell proliferation and activation in vitro. J Bone Miner Res 2004; 19: 278–88

    Article  PubMed  CAS  Google Scholar 

  52. Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002; 32: 94–124

    PubMed  Google Scholar 

  53. Migliorati C, Casiglia J, Epstein J, et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 2005; 136: 1658–68

    PubMed  CAS  Google Scholar 

  54. Department of Health and Human Services, Public Health Service, Food and Drug Administration. ODS Postmarketing Safety Review May 6 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDA-TAB3.pdf. [Accessed 2006 Feb 24]

  55. Strewler GJ. Decimal point: osteoporosis therapy at the 10-year mark. N Engl J Med 2004; 350: 1172–4

    Article  PubMed  CAS  Google Scholar 

  56. Rodan G, Reszka A, Golub E, et al. Bone safety of long-term bisphosphonate treatment. Curr Med Res Opin 2004; 20: 1291–300

    Article  PubMed  CAS  Google Scholar 

  57. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90: 1294–301

    Article  PubMed  CAS  Google Scholar 

  58. Steinbuch M, D’Agostino R, Mandel J, et al. Assessment of mortality in patients enrolled in a risedronate clinical trial program: a retrospective cohort study. Regul Toxicol Pharmacol 2002; 35: 320–6

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Dr Strampel has no financial relationships to disclose. Dr Emkey has acted as a consultant or speaker for Roche, Merck & Co., GlaxoSmithKline, Procter & Gamble and Amgen. Dr Civitelli has received research support from Eli-Lilly & Co., Roche and Procter & Gamble; he has acted as a consultant for both Merck & Co. and Roche, receives financial support for speaking on behalf of Merck & Co. and Roche, and has stock ownership in Merck & Co., Eli-Lilly & Co. and Wyeth. Editorial assistance was provided by Aidan Parte of Envision Pharma, Inc., and this assistance was funded by Roche Laboratories.

Author information

Authors and Affiliations

  1. Michigan State University College of Osteopathic Medicine, A309 East Fee Hall, East Lansing, Michigan, 48824-1316, USA

    William Strampel

  2. Emkey Arthritis and Osteoporosis Clinic, Wyomissing, Pennsylvania, USA

    Ronald Emkey

  3. Washington University School of Medicine, St Louis, Missouri, USA

    Roberto Civitelli

Authors
  1. William Strampel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald Emkey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roberto Civitelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William Strampel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Strampel, W., Emkey, R. & Civitelli, R. Safety Considerations with Bisphosphonates for the Treatment of Osteoporosis. Drug-Safety 30, 755–763 (2007). https://doi.org/10.2165/00002018-200730090-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200730090-00003

Keywords

Search

Navigation