porozendoОстеопороз и остеопатииOsteoporosis and Bone Diseases2072-26802311-0716Endocrinology Research Centre10.14341/osteo13148porozendo-13148Research ArticleНАУЧНЫЕ ОБЗОРЫREVIEWSОсложнения длительной терапии остеопороза бисфосфонатамиLong-term consequences of osteoporosis therapy with bisphosphonateshttps://orcid.org/0000-0001-6759-8367НикитинскаяО. А.NikitinskayaO. A.

Никитинская Оксана Анатольевна - к.м.н., ученый секретарь, старший научный сотрудник лаборатории остеопороза.

115522 Москва, Каширское шоссе, д. 34А

Researcher ID AAF-2616-2021, Scopus Author ID 6504217119

Oksana A. Nikitinskaya - MD, PhD.

115522, Kashirskoye shosse 34 A, Moscow

Researcher ID AAF-2616-2021, Scopus Author ID 6504217119

nikitinskayaox@yandex.ruФГБНУ «Научно-исследовательский институт ревматологии имени В.А. Насоновой»РоссияV.A. Nasonova Research Institute of RheumatologyRussian Federation2023180320242641419Copyright © Никитинская О.А., 20242024Никитинская О.А.Nikitinskaya O.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.osteo-endojournals.ru/jour/article/view/13148

Бисфосфонаты (БФ) — препараты, широко используемые в клинической практике для лечения остеопороза (ОП), доказавшие свою эффективность в снижении риска переломов. Длительное применение антирезорбтивной терапии привлекло внимание к двум чрезвычайно редким, хотя и тяжелым, нежелательным явлениям. Атипичный перелом бедренной кости (АПБ) и медикаментозный остеонекроз челюсти (МОНЧ) чаще встречаются у пациентов с высокими кумулятивными дозами и более длительной терапией. Риск АПБ зависит от длительности лечения и значительно повышен среди пациентов, получающих БФ более 8 лет. При отмене БФ риск может снизиться и вернуться к исходному уровню — уже через год после прекращения лечения он уменьшается более чем на 50%. Риск МОНЧ в меньшей степени зависит от длительности лечения, он чаще возникает у онкологических пациентов, получающих более высокие кумулятивные дозы БФ. У больных ОП, получающих БФ, на риск МОНЧ значимо влияют локальные травмы (стоматологические процедуры), местные инфекции и сопутствующие заболевания. На протяжении многих лет БФ демонстрировали безопасность и эффективность и свидетельствовали об увеличении МПК и снижении риска переломов, и эти преимущества перевешивают риски редких побочных эффектов.

Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis (OP) and reduce fragility fractures. The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. Аtypical femoral fracture (AFF) and medication-related osteonecrosis of the jaw (MRONJ) are more common in patients with high cumulative doses and longer duration of therapy. The risk of AFF depends on the duration of treatment and is significantly increased among patients receiving BPs for more than 8 years. The risk may decrease and return to the initial level with discontinuation of BPs, it decreases by more than 50% during one year after the discontinuation. The risk of MRONJ is less dependent on the duration of therapy, it occurs more often in patients with cancer who are receiving higher cumulative doses of BPs. The combination of local trauma, microbial contamination and concomitant diseases induces this condition in patients with OP who are receiving BPs. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, and these benefits overweight the risks of rare adverse events.

бисфосфонатыостеопорозатипичный перелом бедрамедикаментозный остеонекроз челюстиbisphosphonateosteoporosisatypical femoral fractureosteonecrosis of the jawReferencesCompston J. Practical guidance for the use of bisphosphonates in osteoporosis. Bone. 2020; 136:115330. doi: https://doi.org/10.1016/j.bone.2020.115330Compston J. Practical guidance for the use of bisphosphonates in osteoporosis. Bone. 2020; 136:115330. doi: https://doi.org/10.1016/j.bone.2020.115330Белая Ж.Е., Белова К.Ю., Бирюкова Е.В., и др. Федеральные клинические рекомендации по диагностике, лечению и профилактике остеопороза. — Остеопороз и остеопатии. — 2021. — Т.24. — №2. — С. 4–47. doi: https://doi.org/10.14341/osteo12930Belaya ZE, Belova Kyu. Biryukova EV, Dedov II, et al. Federal clinical guidelines for diagnosis, treatment and prevention of osteoporosis. Osteoporosis and bone diseases. 2021;24(2):4-47. (In Russ.) doi: https://doi.org/10.14341/osteo12930Black DM, Abrahamsen B, Bouxsein ML, et al. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev. 2019;40(2):333-368. doi: https://doi.org/10.1210/er.2018-00001Black DM, Abrahamsen B, Bouxsein ML, et al. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev. 2019;40(2):333-368. doi: https://doi.org/10.1210/er.2018-00001Ayers C, Kansagara D, Lazur B, et al. Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):182-195. doi: https://doi.org/10.7326/M22-0684Ayers C, Kansagara D, Lazur B, et al. Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med. 2023 Feb;176(2):182-195. doi: https://doi.org/10.7326/M22-0684Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90(3):1294–1301. doi: https://doi.org/10.1210/jc.2004-0952Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90(3):1294–1301. doi: https://doi.org/10.1210/jc.2004-0952Shane 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):2267–94Shane 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):2267–94Shane 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):1–23Shane 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):1–23Khow KS, Shibu P, Yu SC, Chehade MJ, Visvanathan R. Epidemiology and Postoperative Outcomes of Atypical Femoral Fractures in Older Adults: A Systematic Review. J Nutr Health Aging. 2017; 21:83–91. doi: https://doi.org/10.1007/s12603-015-0652-3.2016/12/22Khow KS, Shibu P, Yu SC, Chehade MJ, Visvanathan R. Epidemiology and Postoperative Outcomes of Atypical Femoral Fractures in Older Adults: A Systematic Review. J Nutr Health Aging. 2017; 21:83–91. doi: https://doi.org/10.1007/s12603-015-0652-3.2016/12/22Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012 Dec;27(12):2544-50. doi: https://doi.org/10.1002/jbmr.1719Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012 Dec;27(12):2544-50. doi: https://doi.org/10.1002/jbmr.1719Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020; 383:743-53. doi: https://doi.org/10.1056/NEJMoa1916525Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020; 383:743-53. doi: https://doi.org/10.1056/NEJMoa1916525Pearce O, Edwards T, Al-Hourani K, Kelly M, Riddick A. Evaluation and management of atypical femoral fractures: an update of current knowledge. Eur J Orthop Surg Traumatol. 2021;31:825–840. doi: https://doi.org/10.1007/s00590-021-02896-3Pearce O, Edwards T, Al-Hourani K, Kelly M, Riddick A. Evaluation and management of atypical femoral fractures: an update of current knowledge. Eur J Orthop Surg Traumatol. 2021;31:825–840. doi: https://doi.org/10.1007/s00590-021-02896-3Lloyd AA, Gludovatz B, Riedel C, et al. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci. 2017;114(33):8722–7. doi: https://doi.org/10.1073/pnas.1704460114Lloyd AA, Gludovatz B, Riedel C, et al. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci. 2017;114(33):8722–7. doi: https://doi.org/10.1073/pnas.1704460114Farlay D, Rizzo S, Ste-Marie LG, Michou L, et al. Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture. J Bone Miner Res. 2021 Jun;36(6):1031-1041. doi: https://doi.org/10.1002/jbmr.4244Farlay D, Rizzo S, Ste-Marie LG, Michou L, et al. Duration-Dependent Increase of Human Bone Matrix Mineralization in Long-Term Bisphosphonate Users with Atypical Femur Fracture. J Bone Miner Res. 2021 Jun;36(6):1031-1041. doi: https://doi.org/10.1002/jbmr.4244Morin SN, Wall M, Belzile EL, et al. Assessment of femur geometrical parameters using EOS™ imaging technology in patients with atypical femur fractures; preliminary results. Bone. 2016; 83:184–9. doi: https://doi.org/10.1016/j.bone.2015.10.016Morin SN, Wall M, Belzile EL, et al. Assessment of femur geometrical parameters using EOS™ imaging technology in patients with atypical femur fractures; preliminary results. Bone. 2016; 83:184–9. doi: https://doi.org/10.1016/j.bone.2015.10.016Tsuchie H, Miyakoshi N, Kasukawa Y, et al. Evaluation of the Nature and Etiologies of Risk Factors for Diaphyseal Atypical Femoral Fractures. Med Princ Pract. 2021;30(5):430-436. doi: https://doi.org/10.1159/000517484. doi: 10.1159/000517484Tsuchie H, Miyakoshi N, Kasukawa Y, et al. Evaluation of the Nature and Etiologies of Risk Factors for Diaphyseal Atypical Femoral Fractures. Med Princ Pract. 2021;30(5):430-436. doi: https://doi.org/10.1159/000517484. doi: 10.1159/000517484Pearce O, Edwards T, Al-Hourani K, et al. Evaluation and management of atypical femoral fractures: an update of current knowledge. Eur J Orthop Surg Traumatol. 2021;31:825–840. doi: https://doi.org/10.1007/s00590-021-02896-3Pearce O, Edwards T, Al-Hourani K, et al. Evaluation and management of atypical femoral fractures: an update of current knowledge. Eur J Orthop Surg Traumatol. 2021;31:825–840. doi: https://doi.org/10.1007/s00590-021-02896-3Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86(1):100‐107. doi: https://doi.org/10.3109/17453674.2015.1004149Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86(1):100‐107. doi: https://doi.org/10.3109/17453674.2015.1004149Roca-Ayats N, Balcells S, Garcia-Giralt N, et al. GGPS1 mutation and atypical femoral fractures with bisphosphonates. N Engl J Med. 2017;376(18):1794–5. doi: https://doi.org/10.1056/NEJMc1612804Roca-Ayats N, Balcells S, Garcia-Giralt N, et al. GGPS1 mutation and atypical femoral fractures with bisphosphonates. N Engl J Med. 2017;376(18):1794–5. doi: https://doi.org/10.1056/NEJMc1612804Pérez-Núñez I, Pérez-Castrillón JL, Zarrabeitia MT, et al. Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study. Mol Cell Biochem. 2015;409(1):45–50. doi: https://doi.org/10.1007/s11010-015-2510-3Pérez-Núñez I, Pérez-Castrillón JL, Zarrabeitia MT, et al. Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study. Mol Cell Biochem. 2015;409(1):45–50. doi: https://doi.org/10.1007/s11010-015-2510-3Zhou W, van Rooij JGJ, Ebeling PR, et al. The Genetics of Atypical Femur Fractures-a Systematic Review. Curr Osteoporos Rep. 2021 Apr;19(2):123-130. doi: https://doi.org/10.1007/s11914-021-00658-yZhou W, van Rooij JGJ, Ebeling PR, et al. The Genetics of Atypical Femur Fractures-a Systematic Review. Curr Osteoporos Rep. 2021 Apr;19(2):123-130. doi: https://doi.org/10.1007/s11914-021-00658-yAnastasilakis AD, Pepe J, Napoli N, et al. Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS. J Clin Endocrinol Metab. 2022 Apr 19;107(5):1441-1460. doi: https://doi.org/10.1210/clinem/dgab888Anastasilakis AD, Pepe J, Napoli N, et al. Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS. J Clin Endocrinol Metab. 2022 Apr 19;107(5):1441-1460. doi: https://doi.org/10.1210/clinem/dgab888Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws AAoO and Maxillofacial S. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007 Mar;65(3):369-76. doi: https://doi.org/10.1016/j.joms.2006.11.003Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws AAoO and Maxillofacial S. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007 Mar;65(3):369-76. doi: https://doi.org/10.1016/j.joms.2006.11.003Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol. 2008 Dec;19(12):2091-2. doi: https://doi.org/10.1093/annonc/mdn653Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol. 2008 Dec;19(12):2091-2. doi: https://doi.org/10.1093/annonc/mdn653Ruggiero SL, Dodson TB, Aghaloo T, et al. American Association of Oral and Maxillofacial Surgeons’ position paper on medication-related osteonecrosis of the Jaws-2022 update. J Oral Maxillofac Surg. 2022 May;80(5):920-943. doi: https://doi.org/10.1016/j.joms.2022.02.008Ruggiero SL, Dodson TB, Aghaloo T, et al. American Association of Oral and Maxillofacial Surgeons’ position paper on medication-related osteonecrosis of the Jaws-2022 update. J Oral Maxillofac Surg. 2022 May;80(5):920-943. doi: https://doi.org/10.1016/j.joms.2022.02.008Nicolatou-Galitis O, Kouri M, Papadopoulou E, et al. Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer. 2019;27(2):383-394. doi: https://doi.org/10.1007/s00520-018-4501-xNicolatou-Galitis O, Kouri M, Papadopoulou E, et al. Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer. 2019;27(2):383-394. doi: https://doi.org/10.1007/s00520-018-4501-xEguia A, Bagán-Debón L, Cardona F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal. 2020;25(1):e71-e83. doi: https://doi.org/10.4317/medoral.23191Eguia A, Bagán-Debón L, Cardona F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal. 2020;25(1):e71-e83. doi: https://doi.org/10.4317/medoral.23191Pabst AM, Ziebart T, Koch FP, et al. The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes-- in vitro study. Clin Oral Investig. 2012 Feb;16(1):87-93. doi: https://doi.org/10.1007/s00784-010-0507-6Pabst AM, Ziebart T, Koch FP, et al. The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes-- in vitro study. Clin Oral Investig. 2012 Feb;16(1):87-93. doi: https://doi.org/10.1007/s00784-010-0507-6Kobayashi Y, Hiraga T, Ueda A, et al. Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab. 2010 Mar;28(2):165-75. doi: https://doi.org/10.1007/s00774-009-0128-9Kobayashi Y, Hiraga T, Ueda A, et al. Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice. J Bone Miner Metab. 2010 Mar;28(2):165-75. doi: https://doi.org/10.1007/s00774-009-0128-9Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007 Sep;41(3):318-20. doi: https://doi.org/10.1016/j.bone.2007.04.196Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007 Sep;41(3):318-20. doi: https://doi.org/10.1016/j.bone.2007.04.196Santini D, Vincenzi B, Galluzzo S, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. https://doi.org/. 2007 Aug 1;13(15 Pt 1):4482-6. doi: https://doi.org/10.1158/1078-0432.CCR-07-0551Santini D, Vincenzi B, Galluzzo S, et al. Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. https://doi.org/. 2007 Aug 1;13(15 Pt 1):4482-6. doi: https://doi.org/10.1158/1078-0432.CCR-07-0551Khan AA, Morrison A, Kendler DL, et al.; International Task Force on Osteonecrosis of the Jaw. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ. J Clin Densitom. 2017;20(1):8-24. doi: https://doi.org/10.1016/j.jocd.2016.09.005Khan AA, Morrison A, Kendler DL, et al.; International Task Force on Osteonecrosis of the Jaw. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the International Task Force on ONJ. J Clin Densitom. 2017;20(1):8-24. doi: https://doi.org/10.1016/j.jocd.2016.09.005Khosla 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. doi: https://doi.org/10.1359/jbmr.0707onjKhosla 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. doi: https://doi.org/10.1359/jbmr.0707onjFuggle NR, Curtis B, Clynes M, et al. The treatment gap: The missed opportunities for osteoporosis therapy. Bone. 2021 Mar; 144:115833. doi: https://doi.org/10.1016/j.bone.2020.115833Fuggle NR, Curtis B, Clynes M, et al. The treatment gap: The missed opportunities for osteoporosis therapy. Bone. 2021 Mar; 144:115833. doi: https://doi.org/10.1016/j.bone.2020.115833Amigues C, Fresse A, Roux CH, et al. Zoledronate and osteonecrosis of the jaw in osteoporosis: incidence and risk factors. Aalysis of the French Pharmacovigilance Database. Joint Bone Spine. 2023 Jun 2;90(6):105599. doi: https://doi.org/10.1016/j.jbspin.2023.105599Amigues C, Fresse A, Roux CH, et al. Zoledronate and osteonecrosis of the jaw in osteoporosis: incidence and risk factors. Aalysis of the French Pharmacovigilance Database. Joint Bone Spine. 2023 Jun 2;90(6):105599. doi: https://doi.org/10.1016/j.jbspin.2023.105599Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 2010 Feb;68(2):243-53. doi: https://doi.org/10.1016/j.joms.2009.03.050Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 2010 Feb;68(2):243-53. doi: https://doi.org/10.1016/j.joms.2009.03.050Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015; 30:934–944. doi: https://doi.org/10.1002/jbmr.2442Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2015; 30:934–944. doi: https://doi.org/10.1002/jbmr.2442Fusco V, Cabras M, Erovigni F, et al. A multicenter observational study on medication-related osteonecrosis of the jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy. Med Oral Patol Oral Cir Bucal. 2021;26(4):e466-e473. doi: https://doi.org/10.4317/medoral.24318Fusco V, Cabras M, Erovigni F, et al. A multicenter observational study on medication-related osteonecrosis of the jaw (MRONJ) in advanced cancer and myeloma patients of a cancer network in North-Western Italy. Med Oral Patol Oral Cir Bucal. 2021;26(4):e466-e473. doi: https://doi.org/10.4317/medoral.24318

The authors declare that there are no conflicts of interest present.