medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2020-21-185-191medsovet-5983Research ArticleГИНЕКОЛОГИЯGYNECOLOGYПротективный эффект золедроновой кислоты при переходе от длительной терапии остеопороза деносумабомPotential protective effect of zoledronic acid when switching from long-term therapy of osteoporosis with denosumabhttps://orcid.org/0000-0002-7430-1207ЯкушевскаяО. В.YakushevskayaO. V.

к.м.н., научный сотрудник отделения гинекологической эндокринологии, 

117997, Москва, ул. Академика Опарина, д. 4

Cand. of Sci. (Med.), Researcher of the Department of Gynecological Endocrinology, 

4, Academician Oparin St., Moscow, 117997

aluckyone777@gmail.comНациональный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. академика В.И. КулаковаРоссияKulakov National Medical Research Center of Obstetrics, Gynecology and PerinatologyRussian Federation202015012021021185191Copyright © Якушевская О.В., 20212021Якушевская О.В.Yakushevskaya O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/5983

В соответствии с данными Федеральных клинических рекомендаций по диагностике, лечению и профилактике остеопороза при последнем применяют препараты с антирезорбтивным действием (деносумаб, бисфосфонаты), преимущественно подавляющие костную резорбцию, и анаболические соединения (терипаратид), усиливающие костеобразование. Вектор их фармакологического влияния способствует предотвращению потери минеральной плотности костной ткани и значимо снижает риск низкоэнергетических переломов позвонков и переломов других локализаций. Опыт клинических испытаний позволяет успешно проводить антирезорбтивную терапию некоторыми препаратами (деносумаб) до 10 лет, демонстрируя хорошую приверженность и переносимость. Бисфосфонаты (БФ) на длительное время задерживаются в костном матриксе и характеризуются периодом определенного последействия. Деносумаб и терипаратид проявляют свое влияние только в период непосредственного применения. По некоторым данным, при отмене терапии деносумабом в ситуации достижения таргетной цели увеличивается частота переломов тел позвонков, особенно у пациентов с предшествующими низкотравматичными переломами в анамнезе. В статье представлены основные положения Европейского общества кальцифицированных тканей, Европейского медицинского агентства, Российской ассоциации по остеопорозу относительно сроков проведения лечения и разбор клинических ситуаций, требующих назначения альтернативной антирезорбтивной терапии.

Согласно резолюции совета экспертов РАОП, для предотвращения увеличения риска переломов позвонков через 6 мес после последней подкожной инъекции деносумаба всем пациентам рекомендуется назначение БФ. Пероральные БФ следует принимать сразу, а введение золедроновой кислоты необходимо отсрочить еще на 65 дней после пропущенной инъекции деносумаба. 

In accordance with the data of the Federal Clinical Recommendations for the Diagnosis, Treatment and Prevention of Osteoporosis, with the latter, antiresorptive drugs (denosumab, bisphosphonates) are used, which mainly suppress bone resorption, and anabolic compounds (teriparatide), which enhance bone formation. The vector of their pharmacological effect helps to prevent BMD loss and significantly reduces the risk of low-energy vertebral fractures and fractures of other localizations. The experience of clinical trials makes it possible to successfully carry out antiresorptive therapy with some drugs (denosumab) for up to 10 years, demonstrating good adherence and tolerance. Bisphosphonates remain in the bone matrix for a long time and are characterized by a period of a certain aftereffect. Denosumab and teriparatide show their effect only during the period of direct use. According to some data, when denosumab therapy is canceled in a situation where the targeted goal is achieved, the incidence of vertebral fractures increases, especially in patients with a history of low-traumatic fractures. The article will present the main provisions of the European Calcified Tissues Society, the European Medical Agency, the Russian Association for Osteoporosis regarding the timing of treatment and an analysis of clinical situations requiring the appointment of alternative antiresorptive therapy. According to the resolution of the Council of Experts of the Russian Association on Osteoporosis, bisphosphonates are recommended for all patients to prevent an increased risk of vertebral fractures 6 months after patients had their last subcutaneous injection of denosumab. Oral bisphosphonates should be taken immediately, and zoledronic acid injection should be delayed for another 65 days following a missed denosumab injection.

менопаузапостменопаузальный остеопорозденосумаббисфосфонатытерипаратидзоледроновая кислотаантирезорбтивная терапияmenopausepostmenopausal osteoporosisdenosumabbisphosphonatesteriparatidezoledronic acidresoclastinantiresorptive therapyReferencesБелая Ж.Е., Bilezikian J.P., Ершова О.Б., Лесняк О.М., Марченкова Л.А., Родионова С.С. и др. Возможности длительной терапии постменопаузального остеопороза: обзор результатов последних клинических исследований деносумаба и резолюция совета экспертов Российской ассоциации по остеопорозу (РАОП). Остеопороз и остеопатии. 2018;21(1):17–22. doi: 10.14341/osteo9760.Belaya Z.E., Bilezikian J.P., Ershova O.B., Lesnyak O.M., Marchenkova L.A., Rodionova S.S. et al. Long-term treatment options for postmenopausal osteoporosis: results of recent clinical studies of Denosumab. Osteoporoz i osteopatii = Osteoporosis and Bone Diseases. 2018;21(1):17–22. (In Russ.) doi: 10.14341/osteo9760.Prevrhal S., Krege J.H., Chen P., Genant H., Black D.M. Teriparatide vertebral fracture risk reduction determined by quantitative and qualitative radiographic assessment. Curr Med Res Opin. 2009;25(4):921–928. doi: 10.1185/03007990902790993.Prevrhal S., Krege J.H., Chen P., Genant H., Black D.M. Teriparatide vertebral fracture risk reduction determined by quantitative and qualitative radiographic assessment. Curr Med Res Opin. 2009;25(4):921–928. doi: 10.1185/03007990902790993.Neer R.M., Arnaud C.D., Zanchetta J.R., Prince R., Gaich G.A., Reginster J.Y. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434–1441. doi: 10.1056/NEJM200105103441904.Neer R.M., Arnaud C.D., Zanchetta J.R., Prince R., Gaich G.A., Reginster J.Y. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434–1441. doi: 10.1056/NEJM200105103441904.Jiang Y., Zhao J.J., Mitlak B.H., Wang O., Genant H.K., Eriksen E.F. Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res. 2003;18(11):1932–1941. doi: 10.1359/jbmr.2003.18.11.1932.Jiang Y., Zhao J.J., Mitlak B.H., Wang O., Genant H.K., Eriksen E.F. Recombinant human parathyroid hormone (1–34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res. 2003;18(11):1932–1941. doi: 10.1359/jbmr.2003.18.11.1932.Fahrleitner-Pammer A., Langdahl B.L., Marin F., Jakob F., Karras D., Barrett A. Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS). Osteoporos Int. 2011;22(10):2709–2719. doi: 10.1007/s00198-010-1498-5.Fahrleitner-Pammer A., Langdahl B.L., Marin F., Jakob F., Karras D., Barrett A. Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS). Osteoporos Int. 2011;22(10):2709–2719. doi: 10.1007/s00198-010-1498-5.Obermayer-Pietsch B.M., Marin F., McCloskey E.V., Hadji P., Farrerons J., Boonen S. et al. Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res. 2008;23(10):1591– 1600. doi: 10.1359/jbmr.080506.Obermayer-Pietsch B.M., Marin F., McCloskey E.V., Hadji P., Farrerons J., Boonen S. et al. Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res. 2008;23(10):1591– 1600. doi: 10.1359/jbmr.080506.Cummings S.R., San Martin J., McClung M.R., Siris E.S., Eastell R., Reid I.R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. doi: 10.1056/NEJMoa0809493.Cummings S.R., San Martin J., McClung M.R., Siris E.S., Eastell R., Reid I.R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. doi: 10.1056/NEJMoa0809493.Miller P.D., Bolognese M.A., Lewiecki E.M., McClung M.R., Ding B., Austin M. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222–229. doi: 10.1016/j.bone.2008.04.007.Miller P.D., Bolognese M.A., Lewiecki E.M., McClung M.R., Ding B., Austin M. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222–229. doi: 10.1016/j.bone.2008.04.007.Simon J., Recknor C., Moffett A.H. Jr., Adachi J.D., Franek E., Lewiecki E.M. et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of the radius, and wrist fracture. Menopause. 2013;20(2):130–1377. doi: 10.1097/gme.0b013e318267f909.Simon J., Recknor C., Moffett A.H. Jr., Adachi J.D., Franek E., Lewiecki E.M. et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of the radius, and wrist fracture. Menopause. 2013;20(2):130–1377. doi: 10.1097/gme.0b013e318267f909.Boonen S., Adachi J.D., Man Z., Cummings S.R., Lippuner K., Törring O. et al. Тreatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96(6):1727–1736. doi: 10.1210/jc.2010-2784.Boonen S., Adachi J.D., Man Z., Cummings S.R., Lippuner K., Törring O. et al. Тreatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96(6):1727–1736. doi: 10.1210/jc.2010-2784.Ferrari S., Adachi J.D., Lippuner K., Zapalowski C., Miller P.D., Reginster J.Y. et al. Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int. 2015;26(12):2763–2771. doi: 10.1007/s00198-015-3179-x.Ferrari S., Adachi J.D., Lippuner K., Zapalowski C., Miller P.D., Reginster J.Y. et al. Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int. 2015;26(12):2763–2771. doi: 10.1007/s00198-015-3179-x.Bone H.G., Wagman R.B., Brandi M.L, Brown J.P., Chapurlat R., Cummings S.R. et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–523. doi: 10.1016/S2213-8587(17)30138-9.Bone H.G., Wagman R.B., Brandi M.L, Brown J.P., Chapurlat R., Cummings S.R. et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–523. doi: 10.1016/S2213-8587(17)30138-9.2015 ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheumatol. 2015;67(Suppl. 10):1–4046. doi: 10.1002/art.39448.2015 ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheumatol. 2015;67(Suppl. 10):1–4046. doi: 10.1002/art.39448.Von Keyserlingk C., Hopkins R., Anastasilakis A., Toulis K., Goeree R., Tarride J-E., Xie F. Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. Semin Arthritis Rheum. 2011;41(2):178–186. doi: 10.1016/j.semarthrit.2011.03.005.Von Keyserlingk C., Hopkins R., Anastasilakis A., Toulis K., Goeree R., Tarride J-E., Xie F. Clinical efficacy and safety of denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. Semin Arthritis Rheum. 2011;41(2):178–186. doi: 10.1016/j.semarthrit.2011.03.005.Cummings S.R., Ferrari S., Eastell R., Gilchrist N., Jensen J.B., McClung M. et al. Vertebral fracture after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–198. doi: 10.1002/jbmr.3337.Cummings S.R., Ferrari S., Eastell R., Gilchrist N., Jensen J.B., McClung M. et al. Vertebral fracture after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190–198. doi: 10.1002/jbmr.3337.Tsourdi E., Langdahl B., Cohen-Solal M., Aubry-Rozier B., Eriksen E.F., Guañabens N. et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. 2017;105:11–17. doi: 10.1016/j.bone.2017.08.003.Tsourdi E., Langdahl B., Cohen-Solal M., Aubry-Rozier B., Eriksen E.F., Guañabens N. et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone. 2017;105:11–17. doi: 10.1016/j.bone.2017.08.003.Lehmann T., Aeberli D. Possible protective effect of switching from denosumab to zoledronic acid on vertebral fractures. Osteoporos Int. 2017;28(10):3067–3068. doi: 10.1007/s00198-017-4108-y.Lehmann T., Aeberli D. Possible protective effect of switching from denosumab to zoledronic acid on vertebral fractures. Osteoporos Int. 2017;28(10):3067–3068. doi: 10.1007/s00198-017-4108-y.Horne A.M., Mihov B., Reid I.R. Bone Loss After Romosozumab/ Denosumab: Effects of Bisphosphonates. Calcif Tissue Int. 2018;103(1):55–61. doi: 10.1007/s00223-018-0404-6.Horne A.M., Mihov B., Reid I.R. Bone Loss After Romosozumab/ Denosumab: Effects of Bisphosphonates. Calcif Tissue Int. 2018;103(1):55–61. doi: 10.1007/s00223-018-0404-6.Freemantle N., Satram-Hoang S., Tang E.T., Kaur P., Macarios D., Siddhanti S. et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012;23(1):317–326. doi: 10.1007/s00198-011-1780-1.Freemantle N., Satram-Hoang S., Tang E.T., Kaur P., Macarios D., Siddhanti S. et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int. 2012;23(1):317–326. doi: 10.1007/s00198-011-1780-1.

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