Contents

Search

drug adverse effects of bisphosphonates

Adverse effects: 1) nausea/vomiting 2) erosive esophagitis a) not associated with increase risk of esophageal cancer or gastric cancer despite association with erosive esophagitis [14] b) associated with esophageal cancer in patients taking 10 or more prescriptions [15] c) evidence inconclusive on risk of esophageal cancer [19] - insufficient data to recommend endoscopic screening of asymptomatic patients [19] d) oral bisphosphates contraindicated in patients with esophageal varices 3) severe bone pain, myalgias & arthralgias may occur with bisphosphonates [1,8] a) these adverse effects may occur with standard doses from the start of therapy b) the pain may resolve with discontinuation c) alendronate & risedronate are specificically implicated, but this is probably generalizable to bisphosphates as a class. 4) osteonecrosis of the jaw [2,4,6,18,27] a) patients receiving intravenous bisphosphonates at highest risk b) many cases associated with infections following dental procedures, especially tooth extractions c) link between oral bisphosphonate use & jaw osteonecrosis; absolute risk is very low [18] d) Recommendations: 1] cancer patients should receive a dental examination prior to initiating therapy with intravenous bisphosphonates 2] extract any teeth that are nonrestorable prior to starting bisphosphonate 3] avoid invasive dental procedures while receiving intravenous bisphosphonate 4] for patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition 5) atypical subtrochanteric stress fractures [12] a) after prolonged bisphosphonate use, especially > 5 years - index fractures occur after a mean 9 years [23] - > 70% of patients with weight-bearing pain prior to atypical fracture [34] - 277 atypical femur fractures observed in 196,129 women over 10 years [35] - benefit exceeds risk 149:2 (whites) vs 91:8 (Asians) [35] b) suppression of bone turnover & accumulation of microdamage is a postulated mechanism [11] c) no clear association, but FDA is investigating [12] d) intermediate-term use of bisphosphonates does not elevate risk [13] e) overall risk < 0.08% over 3 years [13] f) after >= 5 years odds ratio = 2.74 (women) [16] g) relative risk increased by bisphosphonate use - benefits of bisphosphonate use exceed risks (if indicated) - relative risk large (> 30), absolute risk small [22] - risk falls rapidly after discontinuaton [17] 6) IV bisphosphonates may cause transient hypocalcemia [3] - treat hypocalcemia, vitamin D deficiency prior to starting IV bisphosphonates [25] 7) IV bisphosphonates may cause acute tubular necrosis [25] 8) ocular inflammation: uveitis & scleritis [3,21,22] a) symptoms may not resolve until bisphosphate discontinued b) RR - 1.45 for uveitis & 1.51 for scleritis [21] 9) association with atrial fibrillation ? [5] - FDA unable to find association [7] 10) not linked to gastrointestinal cancers [24] 11) increases bone mineral density, but also increases risk of hip fracture in primary hyperparathyroidism relative to observation (RR=1.5) [29] Management: - prophylaxis/prevention osteonecrosis of the jaw for bisphosphonates administered IV - dental consultation - no active oral infection - biannual dental care for - teeth cleaning - minizing periodontal inflammation - addressing caries - endodontic care for non restorable teeth

Properties

DRUGS: bisphosphonate FORM: drug adverse effects bisphosphonate

References

  1. Prescriber's Letter 12(4): 2005 Bone, Muscle, and Joint Problems with Bisphosphonates Detail-Document#: 210403 (subscription needed) http://www.prescribersletter.com
  2. Internal Medicine News, April 15, 2005 - Prescriber's Letter 12(5): 2005 Bisphosphonate-associated Jaw Osteonecrosis Detail-Document#: 210511 (subscription needed) http://www.prescribersletter.com - FDA Safteywatch http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#zometa2
  3. Prescriber's Letter 12(5): 2005 New Formulation: Ibandronate (Boniva) Injection Detail-Document#: 220304 (subscription needed) http://www.prescribersletter.com
  4. Prescriber's Letter 13(8): 2006 Bisphosphonates and Jaw Bone Damage Detail-Document#: 220801 (subscription needed) http://www.prescribersletter.com - Favia G et al. Osteonecrosis of the jaw correlated to bisphosphonate therapy in non-oncologic patients: Clinicopathological features of 24 patients. J Rheumatol 2009 Dec; 36:2780 http://dx.doi.org/10.3899/jrheum.090455 PMID: 19884275
  5. Prescriber's Letter 14(6): 2007 New Developments With Bisphosphonate Therapy Detail-Document#: 230613 (subscription needed) http://www.prescribersletter.com - Prescriber's Letter 15(6): 2008 Bisphosphonates and the Risk of Atrial Fibrillation Detail-Document#: 240605 (subscription needed) http://www.prescribersletter.com
  6. Wilkinson GS et al, Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: A population-bases analysis. J Natl Cancer Inst 2007, 99:1016 PMID: 17596574
  7. FDA Medwatch http://www.fda.gov/medwatch/safety/2007/safety07.htm#Bisphosphonates
  8. FDA Medwatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates
  9. FDA Medwatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#bisphosphonates2
  10. Prescriber's Letter 16(3): 2009 Summary of the Latest Guidelines on Bisphosphonate-Induced Osteonecrosis Detail-Document#: 250303 (subscription needed) http://www.prescribersletter.com
  11. Capeci CM and Tejwani NC. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am 2009 Nov; 91:2556. PMID: 19884427 - Lenart BA et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: A case control study. Osteoporos Int 2009 Aug; 20:1353. PMID: 19066707
  12. FDA Medwatch Oral Bisphosphonates: Ongoing Safety Review of Atypical Subtrochanteric Femur Fractures http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm204127.htm - Black DM et al Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur N Engl J Med. 2010 Mar 24. PMID: 20335571 http://content.nejm.org/cgi/content/full/NEJMoa1001086
  13. Black DM et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 2010 Mar 24; PMID: 20335571 http://dx.doi.org/10.1056/NEJMoa1001086
  14. Cardwell CR et al Exposure to Oral Bisphosphonates and Risk of Esophageal Cancer JAMA. 2010;304(6):657-663. PMID: 20699457 http://jama.ama-assn.org/cgi/content/short/304/6/657 doi:10.1001/jama.2010.1098 - Wysowski DK Reports of Esophageal Cancer with Oral Bisphosphonate Use N Engl J Med 2009; 360:89-90 PMID: 19118315 http://www.nejm.org/doi/full/10.1056/NEJMc0808738 - Abrahamsen B et al More on Reports of Esophageal Cancer with Oral Bisphosphonate Use N Engl J Med 2009; 360:1789-1792 PMID: 19387022 http://www.nejm.org/doi/full/10.1056/NEJMc096026
  15. Green J et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: Case-control analysis within a UK primary care cohort. BMJ 2010 Sep 2; 341:c4444. PMID: 20813820
  16. Park-Wyllie LY et al, Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women JAMA. 2011;305(8):783-789 PMID: 21343577 http://jama.ama-assn.org/content/305/8/783.full
  17. Schilcher J et al. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011 May 5; 364:1728. PMID: 21542743
  18. Barasch A et al. Risk factors for osteonecrosis of the jaws: A case-control study from the CONDOR Dental PBRN. J Dent Res 2011 Apr; 90:439 PMID: 21317246 - Fellows JL et al. ONJ in two dental practice-based research network regions. J Dent Res 2011 Apr; 90:433. PMID: 21317245
  19. FDA MedWatch: 07/21/2011 Oral Osteoporosis Drugs (bisphosphonates): Drug Safety Communication - Potential Increased Risk of Esophageal Cancer http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm264087.htm
  20. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
  21. Etminan M et al Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study CMAJ 2012 May 15; 184:E431. PMID: 22470169 http://www.cmaj.ca/content/early/2012/04/02/cmaj.111752.full.pdf+html
  22. Meier RPH et al. Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch Intern Med. 2012 Jun 25;172(12):930-6. PMID: 22732749 http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinternmed.2012.1796 - Bauer DC. Atypical femoral fracture risk in patients treated with bisphosphonates. Arch Intern Med. 2012 Jun 25;172(12):936-7. PMID: 22732750 http://archinte.jamanetwork.com/article.aspx?doi=10.1001/archinternmed.2012.1827
  23. Schneider JP et al. Atypical femur fractures: 81 individual personal histories. J Clin Endocrinol Metab 2012 Dec; 97:4324 PMID: 23076349
  24. Vinogradova Y et al. Exposure to bisphosphonates and risk of gastrointestinal cancers: Series of nested case-control studies with QResearch and CPRD data. BMJ 2013 Jan 16; 346:f114. PMID: 23325866
  25. Medical Knowledge Self Assessment Program (MKSAP) 16, 18 American College of Physicians, Philadelphia 2012, 2018
  26. Fehm T, Felsenberg D, Krimmel M et al Bisphosphonate-associated osteonecrosis of the jaw in breast cancer patients: recommendations for prevention and treatment. Breast. 2009 Aug;18(4):213-7. PMID: 19651512
  27. Shannon J, Shannon J, Modelevsky S, Grippo AA. Bisphosphonates and osteonecrosis of the jaw. J Am Geriatr Soc. 2011 Dec;59(12):2350-5. Review. PMID: 22091898
  28. Crandall CJ et al Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures: An Updated Systematic Review. Ann Intern Med. Published online 9 September 2014 PMID: 25199883 http://annals.org/article.aspx?articleid=1902273
  29. Yeh MW, Zhou H, Adams AL et al The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study. Ann Intern Med. Published online 5 April 2016 PMID: 27043778 http://annals.org/article.aspx?articleid=2511009
  30. Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta- analysis. J Bone Miner Res. 2013 Aug;28(8):1729-37. Review. PMID: 23408697 Free PMC Article
  31. Schilcher J et al. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011 May 5; 364:1728. PMID: 21542743
  32. Shane E, Burr D, Abrahamsen B, Adler RA et al Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014 Jan;29(1):1-23. Review. PMID: 23712442 Free Article
  33. Tan SH, Saseendar S, Tan BH, Pawaskar A, Kumar VP. Ulnar fractures with bisphosphonate therapy: a systematic review of published case reports. Osteoporos Int. 2015 Feb;26(2):421-9. Review. PMID: 25227921
  34. Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
  35. Black DM et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med 2020 Aug 20; 383:743. PMID: 32813950 https://www.nejm.org/doi/10.1056/NEJMoa1916525