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01-09-2009 | Short Communication

Low-Energy Femoral Fractures Associated with the Long-Term Use of Bisphosphonates

A Case Series from a Swiss University Hospital

Authors: Kuntheavy Ing-Lorenzini, Jules Desmeules, Olivier Plachta, Domizio Suva, Pierre Dayer, Professor Robin Peter

Published in: Drug Safety | Issue 9/2009

Abstract

Background: Bisphosphonates are effective and well tolerated anti-resorptive drugs used for the treatment of osteoporosis. However, some concerns about their potential long-term negative effects are emerging.

Objective: We report a series of patients with a history of bisphosphonate treatment admitted to our institution with a low-energy subtrochanteric fracture.

Patients and methods: Eight patients fulfilling these two criteria within the last 2 years were included in our retrospective analysis. All cases were reported to the Swiss National Pharmacovigilance Centre.

Results: All patients presented with a typical radiological pattern consisting of a cortical thickening at the lateral femoral subtrochanteric cortex with a horizontal fracture line originating precisely at this level. Four patients eventually developed a stress fracture or complete fracture of the contralateral femur. Two patients demonstrated delayed healing of their fracture. Five patients had been on alendronate therapy for a period ranging from 16 months to 8 years, two had been on ibandronate for 4 months and 1 year, respectively, after changing from alendronate, and one patient had been on pamidronate until 1 year before the fracture occurred. Seven patients were also receiving long-term proton pump inhibitor (PPI) treatment which could have contributed to the increased risk of fracture. Four patients were receiving both PPI and long-term corticosteroid treatment. The hypothesis of a negative pharmacodynamic interaction between bisphosphonates, PPIs and corticosteroids which could lead to a decrease in bone strength after long-term use needs further investigation.

Conclusion: Prescribers should be aware of the possibility of these rare adverse reactions and the prolonged use of bisphosphonates should be reconsidered until long-term robust safety data are available.

Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008 Jan 23; (1): CD001155

Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008 Jan 23; (1): CD004523 784

Wells GA, Cranney A, Peterson J, et al. Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008 Jan 23; (1): CD003376

Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007 Mar; 119 Suppl. 2: S150–62PubMedCrossRef

Ott SM. Fractures after long-term alendronate therapy. J Clin Endocrinol Metab 2001 Apr; 86(4): 1835–6PubMedCrossRef

Lee P, van der Wall H, Seibel M J. Looking beyond low bone mineral density: multiple insufficiency fractures in a woman with post-menopausal osteoporosis on alendronate therapy. J Endocrinol Invest 2007 Jul–Aug; 30(7): 590–7PubMed

Cheung RK, Leung KK, Lee KC, et al. Sequential nontraumatic femoral shaft fractures in a patient on long-term alendronate. Hong Kong Med J 2007 Dec; 13(6): 485–9PubMed

Armamento-Villareal R, Napoli N, Panwar V, et al. Suppressed bone turnover during alendronate therapy for high-turnover osteoporosis. N Engl J Med 2006 Nov 9; 355(19): 2048–50PubMedCrossRef

Schneider JP. Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics 2006 Jan; 61(1): 31–3PubMed

10.

Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005 Mar; 90(3): 1294–301PubMedCrossRef

11.

Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 2007 Mar; 89(3): 349–53PubMedCrossRef

12.

Kwek EB, Goh SK, Koh JS, et al. An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 2008 Feb; 39(2): 224–31PubMedCrossRef

13.

Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008 Mar 20; 358(12): 1304–6PubMedCrossRef

14.

Neviaser AS, Lane JM, Lenart BA, et al. Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 2008 May–Jun; 22(5): 346–50PubMedCrossRef

15.

Kelly WN, Arellano FM, Barnes J, et al., on behalf of the International Society for Pharmacoepidemiology; International Society of Pharmacovigilance. Guidelines for submitting adverse event reports for publication. Drug Saf 2007; 30(5): 367–73PubMedCrossRef

16.

Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002 Jun 1; 359(9321): 1929–36PubMedCrossRef

17.

Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. HORIZON Pivotal Fracture Trial. N Engl J Med 2007 May 3; 356(18): 1809–22PubMedCrossRef

18.

Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535–41PubMedCrossRef

19.

Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998; 280: 2077–82PubMedCrossRef

20.

Black DM, Reiss TF, Nevitt MC, et al. Design of the Fracture Intervention Trial. Osteoporos Int 1993; 3: S29–39PubMedCrossRef

21.

Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial Long-Term Extension. J Bone Miner Res 2004; 19: 1259–69PubMedCrossRef

22.

Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. FLEX Research Group. JAMA 2006 Dec 27; 296(24): 2927–38PubMedCrossRef

23.

Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 2004 Mar 18; 350(12): 1189–99PubMedCrossRef

24.

Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 2006 Oct 15; 12(20 Pt 2): 6222–30sCrossRef

25.

Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 2007 Nov; 86(11): 1022–33PubMedCrossRef

26.

Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009 Jan 1; 360(1): 53–62PubMedCrossRef

27.

Glowacki J. The deceiving appearances of osteoclasts. N Engl J Med 2009 Jan 1; 360(1): 80–2PubMedCrossRef

28.

Strewler GJ. Decimal point: osteoporosis therapy at the 10-year mark. N Engl J Med 2004 Mar 18; 350(12): 1172–4PubMedCrossRef

29.

Ott S. New treatments for brittle bones. Ann Intern Med 2004 Sep 7; 141(5): 406–7PubMed

30.

Carey JJ. What is a ‘failure’ of bisphosphonate therapy for osteoporosis. Cleve Clin J Med 2005 Nov; 72(11): 1033–9PubMedCrossRef

31.

Erviti J, Gorricho J. Use of alendronate after 5 years of treatment [letter]. JAMA 2007 May 9; 297(18): 1979PubMed

32.

Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005 Mar; 90(3): 1897–9PubMedCrossRef

33.

Mashiba T, Turner CH, Hirano T, et al. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 2001 May; 28(5): 524–31PubMedCrossRef

34.

Yang KH, Won JH, Yoon HK, et al. High concentrations of pamidronate in bone weaken the mechanical properties of intact femora in a rat model. Yonsei Med J 2007 Aug 31; 48(4): 653–8PubMedCrossRef

35.

Jeal W, Barradell LB, McTavish D. Alendronate: a review of its pharmacological properties and therapeutic efficacy in postmenopausal osteoporosis. Drugs 1997 Mar; 53(3): 415–34PubMedCrossRef

36.

WHO Collaborating Centre for International Drug Monitoring. Caveat document. Accompanying statement to data released from the WHO Collaborating Centre [online]. Available from URL: http://www.who-umc.org/graphics/9510.pdf [Accessed 2009 January 23]

37.

Yang YX, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006 Dec 27; 296(24): 2947–53PubMedCrossRef

38.

Yu EW, Blackwell T, Ensrud KE, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008 Oct; 83(4): 251–9PubMedCrossRef

39.

Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008 Aug 12; 179(4): 319–26PubMedCrossRef

40.

Blank JB, Cawthon PM, Carrion-Petersen ML, et al. Overview of recruitment for the Osteoporotic Fractures in Men Study (MrOS). Contemp Clin Trials 2005; 26: 557–68PubMedCrossRef

41.

Orwoll E, Blank JB, Barrett-Connor E, et al. Design and baseline characteristics of the Osteoporotic Factures in Men (MrOS) study: a large observational study of the determinants of facture in older men. Contemp Clin Trials 2005; 26: 569–85PubMedCrossRef

42.

Cummings SR, Nevitt MC, Browner WS, et al. Study of osteoporotic fractures research group: risk factors for hip facture in White women. N Engl J Med 1995; 332: 767–73PubMedCrossRef

43.

Richards JB, Goltzman D. Proton pump inhibitors: balancing the benefits and potential fracture risks. CMAJ 2008 Aug 12; 179(4): 306–7PubMedCrossRef

44.

Van Staa TP, Leufkens HGM, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13(10): 777–87PubMedCrossRef

45.

Strom B. Study designs available for pharmacoepidemiology. In: Strom B, editor. Pharmacoepidemiology. 2nd ed. Chichester: John Wiley & Sons Ltd, 1994: 15–27

Title: Low-Energy Femoral Fractures Associated with the Long-Term Use of Bisphosphonates
A Case Series from a Swiss University Hospital
Authors: Kuntheavy Ing-Lorenzini
Jules Desmeules
Olivier Plachta
Domizio Suva
Pierre Dayer
Professor Robin Peter
Publication date: 01-09-2009
Publisher: Springer International Publishing
Published in: Drug Safety / Issue 9/2009
Print ISSN: 0114-5916
Electronic ISSN: 1179-1942
DOI: https://doi.org/10.2165/00002018-200932090-00002

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Low-Energy Femoral Fractures Associated with the Long-Term Use of Bisphosphonates

A Case Series from a Swiss University Hospital

Abstract

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Abstract

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