Langzeitsicherheit von Bisphosphonaten

Zusammenfassung

Bisphosphonate sind derzeit die am häufigsten verwendeten Medikamente bei metabolischen Knochenerkrankungen, insbesondere bei Osteoporose, die Wirksamkeit ist durch Studien gut belegt. Bisphosphonate führen bei Osteoporose zu einer Reduktion des Knochenmineralverlusts und zu einer Senkung des Frakturrisikos. Neben den bekannten Kurzzeit-Nebenwirkungen wurden bei einer Langzeittherapie mit Bisphosphonaten potentielle Sicherheitsrisiken und Nebenwirkungen festgestellt. Zu diesen sehr seltenen Langzeitnebenwirkungen zählen: Kieferosteonekrose, atypische Femurfraktur, Muskel- und Skelettschmerzen, Vorhofflimmern und Ösophaguskarzinom. Dabei ergab sich teilweise keine eindeutige Kausalität aber eine Evidenz für ein vermehrtes, wenn auch sehr seltenes Auftreten. Eine Awareness gegenüber diesen Nebenwirkungen ist jedoch erforderlich. Bei leitliniengerechter Indikationsstellung und adäquater Prophylaxe, z. B. im Falle einer möglichen Kiefernekrose, überwiegen bei den meisten Patienten die Vorteile einer Bisphosphonattherapie gegenüber den möglichen Risiken. Unter Berücksichtigung des individuellen Frakturrisikos ist nach 3–5 Jahren Behandlung eine Therapiepause (drug holiday ) möglich, um die Gefahr von Nebenwirkungen zu reduzieren.

Abstract

Bisphosphonates are currently the most commonly used drugs in metabolic bone disease, especially in osteoporosis, and efficacy is well documented in studies. The aim of this review, based on existing studies, is to summarize the positive and negative aspects of a long-term therapy with bisphosphonates. Bisphosphonates in osteoporosis lead to a reduction in bone mineral loss and a reduction in fracture risk at the spine, hip and other nonvertebral sites. In addition to the known short-term side effects (irritation oft the esophagus, acute-phase reactions or renal toxicity), potential safety risks and adverse events have been identified in long-term bisphosphonate therapy. These very rare long-term side effects include: osteonecrosis of the jaw, atypical femur fracture, muscle and skeletal pain, atrial fibrillation and esophageal cancer. In some cases, there was no clear causality but there is evidence for an increased, albeit very rare, occurrence. However, an awareness of these adverse events is required. For guideline-appropriate indication and adequate prophylaxis, e. g. in the case of possible necrosis of the jaw, in most patients the benefits of bisphosphonate therapy outweigh the potential risks. Since bisphosphonates have a longer residence time in the bone, taking into account the individual fracture risk after 3–5 years of treatment, a therapy break of 2–3 years (drug holiday) is possible to reduce the long-term risks.

Schlüsselwörter

Bisphosphonate - Langzeitsicherheit - Benefits - Nebenwirkungen

Key words

bisphosphonates - long-term safety - benefits - adverse events

• Literatur

• 1 Khosla S, Bilezikian JP, Dempster DW. et al. Benefits an Risks of Bisphosphonate Therapy for Osteoporosis. J Clin Endocrinol Metab 2012; 97: 2272-2282
• 2 McClung M, Harris ST, Miller PD. et al. Bisphosphonate Therapy for Osteoporosis: Benefits, Risks, and Drug Holiday. Am J Med 2013; 126: 13-20
• 3 Watts NB. Long-term risks of bisphosphonate therapy. Arq Bras Endocrinol Metab 2014; 58: 523-529
• 4 Adler RA, El-Hajj Fuleihan G, Bauer DC. et al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016; 31: 16-35
• 5 Brown JP. Antiresorptives: Safety Concerns – Clinical Perspective. Toxicol Pathol 2017; 45: 859-863
• 6 Favus MJ. Bisphosphonates for Osteoporosis. N Engl J Med 2010; 363: 2027-2035
• 7 Bellido T, Plotkin LI. Novel actions of bisphosponates in bone: Preservation of osteoblast and osteocyte viability. Bone 2011; 49: 50-55
• 8 Bone HG, Hosking D, Devogelaer JP. et al. Ten years‘ experience with aledronate for osteoporosis in postmenopausal women. New Engl J Med 2004; 350: 1189-1199
• 9 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. JAMA 2006; 296: 2927-2938
• 10 Black DM, Reid IR, Boonen S. et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012; 27: 243-254
• 11 Mellström DD, Sörensen OH, Goemaere S. et al. Seven years of treatment with risedronat in women with postmenopausal osteoporosis. Calcif Tissue Int 2004; 75: 462-468
• 12 Black DM, Cummings SR, Karpf DB. et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535-1541
• 13 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 Efficiacy With Risedronate Therapy (VERT) Study Group. JAMA 1999; 282: 1344-1352
• 14 Black DM, Delmas PD, Eastell R. et al. Once-yearly zoledronic acid for treatment of osteoporosis. N Engl J Med 2007; 356: 1809-1822
• 15 Chesnut CH III, Skag A, Christiansen C. et al. Effect of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241-1249
• 16 Lyles KW, Colon-Emeric CS, Magaziner JS. et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357: 1799-1809
• 17 Sambrook PN, Cameron ID, Chen JS. et al. Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. Osteoporos Int 2011; 22: 2551-2556
• 18 Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis oft the jaws: a growing epidemic (letter). J Oral Maxillofac Surg 2003; 61: 1115-1117
• 19 Felsenberg D, Lopez S, Gabbert T. et al. Osteonekrose des Kiefers bei Osteoporosepatienten. Osteologie 2012; 21: 207-212
• 20 Otto S, Pautke C, Schieker M. Bisphosphonat-assoziierte Kiefernekrosen. Osteologie 2012; 21: 291-295
• 21 Khan AA, Morrison A, Hanley DA. et al. Diagnosis and management of osteonecrosis oft he jaw: a systematic review and international consensus. J Bone Miner Res 2015; 30: 3-23
• 22 Reid IR. Osteonecrosis oft he jaw – Who gets it, and why?. Bone 2009; 44: 4-10
• 23 Prophylaxe, Diagnostik und Therapie der Osteoporose bei postmenopausalen Frauen und bei Männern. Leitlinie des Dachverbandes der Deutschsprachigen Wissenschaftlichen Osteologischen Gesellschaften e. V.. 2017 http://www.dv-osteologie.org/dvo_leitlinien/dvo-leitlinie-2017
• 24 Felsenberg D. Osteonekrose des Kiefers, Editorial. Osteologie 2012; 21: 60
• 25 Odvina CV, Zerwekh JE, Rao DS. et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90: 1294-1301
• 26 Adler RA. Management of endocrine disease. Atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with antiresorptive therapy. Eur J Endocrinol 2018; 178: R81-R87
• 27 Shane E, Burr D, Abrahamsen B. 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; 29: 1-23
• 28 Roca-Ayats N, Balcells S, Garcia-Giralt N. et al. GGPS1 mutation and atypical femoral fractures with bisphosphonates. N Engl J Med 2017; 376: 1794-1795
• 29 Dell RM, Adams AL, Greene DF. et al. Incidence of atypical nontraumatic diaphyseal fractures oft the femur. J Bone Miner Res 2012; 27: 2544-2550
• 30 Wang Z, Bhattacharyya T. Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among US elderly, 1996–2007. J Bone Miner Res 2011; 26: 553-560
• 31 Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005; 165: 346-347
• 32 Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. (letter). N Engl J Med 2009; 360: 89-90
• 33 Green J, Czanner G, Reeves G et a. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010; 341: c4444
• 34 Cardwell CR, Abnet CC, Cantwell MM. et al. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 2010; 304: 657-663
• 35 Suresh E, Pazianas M, Abrahamsen B. Safety issues with bisphosphonate therapy for osteoporosis. Rheumatology 2014; 53: 19-31
• 36 Kanis JA, McCloskey EV, Johansson H. et al. Development and use of FRAX in osteoporosis. Osteoporos Int 2010; 21 Suppl (02) S407-S413