Arthritis und Rheuma 2015; 35(04): 217-222
DOI: 10.1055/s-0037-1618373
Osteologie
Schattauer GmbH

Unerwünschte Spätfolgen einer Bisphosphonattherapie

Unwanted side effects of a longterm bisphosphonate therapy
V. Koeppen
1   Interdiziplinäres Osteoporosezentrum, Klinik und Poliklinik für Unfallchirurgie, Klinikum rechts der Isar, Technische Universität München, München
,
R. Skripitz
2   Orthopädische Klinik, Universitätsmedizin Rostock, Rostock
› Author Affiliations
Further Information

Publication History

Publication Date:
27 December 2017 (online)

Zusammenfassung

Bei den Langzeitfolgen von Bisphosphonaten führen neben vermeintlicher Kanzerogenität und bisphosphonatassoziierten Kiefernekrosen insbesondere auch atypische Femurschaftfrakturen zu Verunsicherung. Kiefernekrosen treten fast ausschließlich unter onkologisch dosierter i. v.-Bisphosphonattherapie auf und können durch eine vorausschauende Zahnsanierung minimiert werden. Unter oraler Applikation und gewöhnlicher Dosis bei Osteoporose liegt die Inzidenz bei < 0,1 %. Eine Bisphosphonattherapie geht mit einem erhöhten Risiko für atypische Femurschaftfrakturen einher. Auch wenn die Gesamtinzidenz mit elf Frakturen pro 10 000 Personenjahren gering ist, steigt das Risiko unter fort-währender Medikation an. Die Chance hierauf ist nach vier bis fünf Jahren Bisphosphonattherapie über 100-Mal höher als ohne Therapie. Nach Absetzen der Bisphosphonate verringerte sich das Risiko rasch um 70 % pro Jahr. So denn das Nutzen-Risiko-Verhältnis zu Beginn der Therapie bei geeigneter Indikation noch sehr günstig ist, könnte dies bei prolongierter Therapie invertiert werden. Dementsprechend sollten sowohl die Indikation und Therapiedauer sowie mögliche Prodrome der Nebenwirkungen regelmäßig vom Arzt kontrolliert werden.

Summary

Among the side effects of long-term bisphosphonate medication there is osteonecrosis of the jaw and atypical femoral fractures. Osteonecrosis of the jaw essentially happens under oncological dosed, i. v. bisphophonate therapy and can be minimized by foresightful dental caretaking. Under oral application and common dose for osteoporosis the incidence lies by less than 0.1 %. Bisphosphonates are associated with an increased risk for atypical femoral fractures. Even though the total incidence is low with only 11 atypical fractures per 10 000 person-years, the risk increases dramatically with ongoing therapy. The chance of suffering an atypical femoral fracture after four to five years of therapy is over a hundred times higher than without bis -phosphonate medication. After discontinuation the risk decreases rapidly by 70 % per year. Under prolonged bisphosphonate therapy there is no certain further risk reduction of frailty fracture, but the risk of an atypical femoral fracture increases drastically. While the benefit of bisphophonates at the beginning of a well indicated therapy outweigh, their effect might be inverted with prolonged therapy. Indication and treatment duration, as well as possible prodroms of side effects must therefore be regularly checked on by the treating physician.

 
  • Literatur

  • 1 Wark JD, Bensen W, Recknor C. et al Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg. Osteoporos Int 2012; 23 (02) 503-512.
  • 2 Reid IR. Efficacy, effectiveness and side effects of medications used to prevent fractures. J Intern Med 2015; 277 (06) 690-706.
  • 3 Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360 (17) 1789; author reply 1791-1792.
  • 4 Woo S, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144 (10) 753-761.
  • 5 Ward WG, Carter CJ, Wilson SC, Emory CL. Femoral Stress Fractures Associated With Long-term Bisphosphonate Treatment. Clin Orthop Relat Res 2012; 470 (03) 759-765.
  • 6 Siris ES, Oster MW, Bilezikian JP. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360 (17) 1791; author reply 1791-1792.
  • 7 Shaheen NJ. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360 (17) 1790-1791 author reply 1791-1792.
  • 8 Solomon DH, Patrick A, Brookhart MA. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360 (17) 1789-1790 author reply 1791-1792.
  • 9 Ribeiro A, DeVault KR, Wolfe JT, Stark ME. Alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998; 47 (06) 525-528.
  • 10 Khosla S, Burr D, Cauley J. et al Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22 (10) 1479-1491.
  • 11 Borromeo GL, Brand C, Clement JG. et al A large case-control study reveals a positive association between bisphosphonate use and delayed dental healing and osteonecrosis of the jaw. J Bone Miner Res 2014; 29 (06) 1363-1368.
  • 12 Ruggiero SL, Dodson TB, Assael LA. et al American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws - 2009 update. J Oral Maxillofac Surg 2009; 67 (5 Suppl) 2-12.
  • 13 Lo JC, O’Ryan FS, Gordon NP. et al Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010; 68 (02) 243-253.
  • 14 Kwon J, Park E, Jung S. et al. A Large National Cohort Study of the Association between Bisphosphonates and Osteonecrosis of the Jaw in Patients with Osteoporosis: A Nested Case-control Study. J Dent Res 2015 [Epub ahead of print]
  • 15 Koy S, Schubert M, Koy J. et al Bisphosphonat-assoziierte Kiefernekrosen. Schmerz 2015; 29 (02) 171-178.
  • 16 Paulo S, Abrantes AM, Laranjo M. et al Bisphosphonate-related osteonecrosis of the jaw: specificities. Oncol Rev 2014; 8 (02) 254
  • 17 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 09041 1535-1541.
  • 18 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: The Fracture Intervention Trial Long-term Extension (FLEX): A Randomized Trial. JAMA 2006; 296 (24) 2927-2938.
  • 19 Eastell R, Black DM, Boonen S. et al Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab 2009; 94 (09) 3215-3225.
  • 20 Khosla S, Bilezikian JP, Dempster DW. et al Benefits and Risks of Bisphosphonate Therapy for Osteoporosis. Journal of Clinical Endocrinology & Metabolism 2012; 97 (07) 2272-2282.
  • 21 Shane E, Burr D, Ebeling PR. et al Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010; 25 (11) 2267-2294.
  • 22 Tang SY, Zeenath U, Vashishth D. Effects of non-enzymatic glycation on cancellous bone fragility. Bone 2007; 40 (04) 1144-1151.
  • 23 Boskey AL, Spevak L, Weinstein RS. Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int 2009; 20 (05) 793-800.
  • 24 Ettinger B, Burr D, Ritchie R. Proposed pathogenesis for atypical femoral fractures: Lessons from material research. Bone 2013; 55 (02) 495-500.
  • 25 Recker RR, Ste-Marie L, Langdahl B. et al Effects of intermittent intravenous ibandronate injections on bone quality and micro-architecture in women with postmenopausal osteoporosis: the DIVA study. Bone 2010; 46 (03) 660-665.
  • 26 Stepan JJ, Burr DB, Pavo I. et al Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone 2007; 41 (03) 378-385.
  • 27 Armamento-Villareal R, Napoli N, Diemer K. et al Bone Turnover in Bone Biopsies of Patients with Low-Energy Cortical Fractures Receiving Bisphosphonates: A Case Series. Calcif Tissue Int 2009; 85 (01) 37-44.
  • 28 Abrahamsen B, Einhorn TA. Beyond a reasonable doubt? Bisphosphonates and atypical femur fractures. Bone 2012; 50 (05) 1196-1200.
  • 29 Kwek EBK, Goh SK, Koh JSB. et al An emerging pattern of subtrochanteric stress fractures: A long-term complication of alendronate therapy?. Injury 2008; 39 (02) 224-231.
  • 30 Koeppen VA, Schilcher J, Aspenberg P. Dichotomous location of 160 atypical femoral fractures. Acta Orthop 2013; 84 (06) 561-564.
  • 31 Schilcher J, Koeppen V, Ranstam J. et al Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone 2013; 52 (01) 389-392.
  • 32 Somford MP, Draijer FW, Thomassen BJW. et al Bilateral Fractures of the Femur Diaphysis in a Patient With Rheumatoid Arthritis on Long-Term Treatment With Alendronate: Clues to the Mechanism of Increased Bone Fragility. Journal of Bone and Mineral Research 2009; 24 (10) 1736-1740.
  • 33 Wang X, Shen X LX. Age-related Changes in the Collagen Network and Toughness of Bone. Bone 2002; 31 (01) 1-7.
  • 34 Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 2014; 371 (10) 974-976.
  • 35 Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop 2015; 86 (01) 100-107.
  • 36 Dell RM, Adams AL, Greene DF. et al Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012; 27 (12) 2544-2550.
  • 37 Verborgt O, Gibson GJ, Schaffler MB. Loss of Osteocyte Integrity in Association with Microdamage and Bone Remodeling After Fatigue In Vivo. Journal of Bone and Mineral Research 2000; 15 (01) 60-67.