Advertisement
Mayo Clinic Proceedings Home

Risk of Jaw Osteonecrosis After Intravenous Bisphosphonates in Cancer Patients and Patients Without Cancer

Published:November 19, 2016DOI:https://doi.org/10.1016/j.mayocp.2016.09.015

      Abstract

      Objective

      To compare the risk of jaw osteonecrosis after intravenous (IV) bisphosphonate administered to patients with cancer vs patients without cancer.

      Patients and Methods

      We conducted a retrospective cohort study of a 5% national sample of Medicare patients administered IV bisphosphonate from January 1, 2008, through December 31, 2013, for cancer vs noncancer indications. Probable jaw osteonecrosis was estimated with an algorithm including diagnoses, surgical procedures, and imaging studies. A non-IV bisphosphonate comparison group included patients prescribed an oral bisphosphonate for 30 days or less.

      Results

      During follow-up, 40 (0.42%) out of 9482 patients with cancer developed probable jaw osteonecrosis compared with 8 (0.05%) out of 16,046 patients without cancer. In a Cox multivariable survival analysis controlling for patient characteristics and number of IV zoledronic infusions, patients without cancer had a hazard ratio of 0.17 (95% CI, 0.06-0.46) for developing jaw osteonecrosis compared with those with cancer. The lower rate of jaw osteonecrosis in patients without cancer was also confirmed in a number of sensitivity analyses.

      Conclusion

      The low rate of jaw osteonecrosis in patients with osteoporosis who receive IV bisphosphonate should be weighed against the benefit of those agents in preventing hip and other fractures.

      Abbreviations and Acronyms:

      ICD-9-CM (International Classification of Disease, Ninth Revision, Clinical Modification), IV (intravenous)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Black D.M.
        • Rosen C.J.
        Postmenopausal osteoporosis.
        N Engl J Med. 2016; 374: 254-262
        • Modi A.
        • Siris E.S.
        • Tang J.
        • Sen S.
        Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy.
        Curr Med Res Opin. 2015; 31: 757-765
      1. The American Society for Bone and Mineral Research, the National Osteoporosis Foundation and the National Bone Health Alliance. Statement: nation's scientific and medical bone health experts call for action on dangers of not treating osteoporosis more aggressively. http://www.asbmr.org/About/PressReleases/Detail.aspx?cid=e22b66f7-337a-46f7-93cc-f6b29479b9e1. Accessed June 21, 2016.

        • Crandall C.J.
        • Newberry S.J.
        • Diamant A.
        • et al.
        Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review.
        Ann Intern Med. 2014; 161: 711-723
        • Black D.M.
        • Delemas P.D.
        • Eastell R.
        • et al.
        • HORIZON Pivotal Fracture Trial
        Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.
        N Engl J Med. 2007; 356: 1809-1822
        • Yun H.
        • Curtis J.R.
        • Guo L.
        • et al.
        Patterns and predictors of osteoporosis medication discontinuation and switching among Medicare beneficiaries.
        BMC Musculoskelet Disord. 2014; 15: 112
        • Wysowski D.K.
        • Greene P.
        Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012.
        Bone. 2013; 57: 423-428
        • Jha S.
        • Wang Z.
        • Laucis N.
        • Bhattacharyya T.
        Trends in media reports, oral bisphosphonate prescriptions, and hip fractures 1996-2012: an ecological analysis.
        J Bone Miner Res. 2015; 30: 2179-2187
      2. Kolata G. Fearing drugs' rare side effects, millions take their chances with osteoporosis. The New York Times. June 1, 2016. http://www.nytimes.com/2016/06/02/health/osteoporosis-drugs-bones.html. Accessed June 21, 2016.

        • Wang Z.
        • Bhattacharyya T.
        Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996-2007.
        J Bone Miner Res. 2011; 26: 553-560
      3. Kolata G. Drug for bones is newly linked to jaw disease. The New York Times. June 2, 2006. http://www.nytimes.com/2006/06/02/health/02jaw.html. Accessed June 21, 2016.

      4. Parker-Pope T. New cautions about long-term use of bone drugs. The New York Times. May 9, 2012. http://well.blogs.nytimes.com/2012/05/09. Accessed June 21, 2016.

      5. Singer N. High stakes for Merck in litigation on fosamax. The New York Times. September 2, 2009. http://www.nytimes.com/2009/09/03/business/03drug.html. Accessed June 21, 2016.

        • Ruggiero S.L.
        • Dodson T.B.
        • Fantasia J.
        • et al.
        • American Association of Oral and Maxillofacial Surgeons
        American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update.
        J Oral Maxillofac Surg. 2014; 72 (Erratum in: J Oral Maxillofac Surg. 2015;73(9):1879. J Oral Maxillofac Surg. 2015;73(7):1440): 1938-1956
        • Wilkinson G.S.
        • Kuo Y.F.
        • Freeman J.L.
        • Goodwin J.S.
        Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis.
        J Natl Cancer Inst. 2007; 99: 1016-1024
        • Boonen S.
        • Black D.M.
        • Colon-Emeric C.S.
        • et al.
        Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older.
        J Am Geriatr Soc. 2010; 58: 292-299
        • Baillargeon J.
        • Kuo Y.F.
        • Lin Y.L.
        • Wilkinson G.S.
        • Goodwin J.S.
        Osteonecrosis of the jaw in older osteoporosis patients treated with intravenous bisphosphonates.
        Ann Pharmacother. 2011; 45: 1199-1206
        • Lyles K.W.
        • Colon-Emeric C.S.
        • Magaziner J.S.
        • et al.
        • for the HORIZON Recurrent Fracture Trial
        Zoledronic acid in reducing clinical fractures and mortality after hip fracture.
        N Engl J Med. 2007; 357: 1799-1809
        • Mavrokokki T.
        • Cheng A.
        • Stein B.
        • Goss A.
        Nature and frequency of bisphosphonate-associated osteonecrosis of the jaw in Australia.
        J Oral Maxillofac Surg. 2007; 65: 415-423
        • Kahn A.A.
        • Rios L.P.
        • Sandor G.K.
        • et al.
        Bisphosphonate associated osteonecrosis of the jaw.
        J Rheumatol. 2011; 38: 1396-1402
        • McClung M.R.
        • Lewiecki E.M.
        • Cohen S.B.
        • et al.
        • AMG 162 Bone Loss Study Group
        Denosumab in postmenopausal women with low bone mineral density.
        N Engl J Med. 2006; 354: 821-831
        • Elixhauser A.
        • Steiner C.
        • Harris D.R.
        • Coffey R.M.
        Comorbidity measures for use with administrative data.
        Med Care. 1998; 36: 8-27
        • Lin D.Y.
        • Wei L.J.
        • Ying Z.
        Checking the Cox model with cumulative sums of martingale-based residuals.
        Biometrika. 1993; 80: 557-572
        • Bergdahl J.
        • Jambring F.
        • Ehrenstein V.
        • et al.
        Evaluation of an algorithm ascertaining cases or osteonecrosis of the jaw in the Swedish National Patient Register.
        Clin Epidemiol. 2013; 5: 1-7
        • Vlad S.C.
        • Felson D.T.
        • Miller D.R.
        Can health care databases be used to identify incident cases of osteonecrosis?.
        Arthritis Res Ther. 2009; 11: R89
        • Gammelager H.
        • Erichsen R.
        • Antonsen S.
        • et al.
        Positive predictive value of the International Classification of Diseases, 10th revision, codes to identify osteonecrosis of the jaw in patients with cancer.
        Cancer Epidemiol. 2012; 36: 381-383
        • Zavras A.I.
        • Zhu S.
        Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it Osteonecrosis?.
        J Oral Maxillofac Surg. 2006; 64: 917-923
        • Zhang J.
        • Yun H.
        • Wright N.C.
        • Kilgore M.
        • Saag K.G.
        • Delzell E.
        Potential and pitfalls of using large administrative claims data to study the safety of osteoporosis therapies.
        Curr Rheumatol Rep. 2011; 13: 273-282
        • Tennis P.
        • Rothman K.J.
        • Bohn R.L.
        • et al.
        Incidence of osteonecrosis of the jaw among users of bisphosphonates with selected cancers or osteoporosis.
        Pharmacoepidemiol Drug Saf. 2012; 21: 810-817
        • Vasconcelos A.C.
        • de Azambuja Berti-Couto S.
        • Figueiredo M.A.
        • Salum F.G.
        • Lopes T.G.
        • Cherubini K.
        Laboratory methods and biomarkers in the evaluation of bisphosphonate effects on body tissues: a literature review.
        J Oral Pathol Med. 2013; 42: 557-586
        • Naylor K.
        • Eastell R.
        Bone turnover markers: use in osteoporosis.
        Nat Rev Rheumatol. 2012; 8: 379-389
        • Hochberg M.C.
        • Thompson D.E.
        • Black D.M.
        • et al.
        • FIT Research Group
        Effect of alendronate on the age-specific incidence of symptomatic osteoporotic fractures.
        J Bone Miner Res. 2005; 20: 971-976
        • Boonen S.
        • McClung M.R.
        • Eastell R.
        • El-Hajj Fuleihan G.
        • Barton I.P.
        • Delmas P.
        Safety and efficacy of risedronate in reducing fracture risk in osteoporotic women aged 80 and older: implications for the use of antiresorptive agents in the old and oldest old.
        J Am Geriatr Soc. 2004; 52: 1832-1839
        • Reid I.R.
        • Black D.M.
        • Eastell R.
        • et al.
        • HORIZON Pivotal Fracture Trial and HORIZON Recurrent Fracture Trial Steering Committees
        Reduction in the risk of clinical fractures after a single dose of zoledronic acid 5 milligrams.
        J Clin Endocrinol Metab. 2013; 98: 557-563

      Linked Article

      • Bisphosphonates and Osteonecrosis of the Jaw
        Mayo Clinic ProceedingsVol. 92Issue 7
        • Preview
          In the January 2017 issue of Mayo Clinic Proceedings, Goodwin et al1 provide reassuring information on the incidence of osteonecrosis of the jaw (ONJ) in patients treated with intravenous bisphosphonates. Although the causal relationship between this class of bone antiresorptive medications and ONJ has long been known, this specific complication of osteoporosis treatment appears to be a rarity. Nevertheless, the perception among patients and some health care professionals is that ONJ is a relatively common occurrence.
        • Full-Text
        • PDF