Actual problems in dentistry Actual problems in dentistry Проблемы стоматологии 2077-7566 2412-9461 45641 10.18481/2077-7566-21-17-3-69-76 ХИРУРГИЧЕСКАЯ СТОМАТОЛОГИЯ И ИМПЛАНТОЛОГИЯ SURGICAL DENTISTRY AND IMPLANTOLOGY ХИРУРГИЧЕСКАЯ СТОМАТОЛОГИЯ И ИМПЛАНТОЛОГИЯ ESTIMATION OF PERIODONTAL MICROCIRCULATION, JAW AFTER INJECTION OF ANTI-RESORPTIVE DRUG IN EXPERIMENT ОЦЕНКА МИКРОЦИРКУЛЯЦИИ ПАРОДОНТА, ЧЕЛЮСТИ ПОСЛЕ ВВЕДЕНИЯ АНТИРЕЗОРБТИВНОГО ПРЕПАРАТА В ЭКСПЕРИМЕНТЕ Косач Герман Александрович Kosach German Alexandrovich german1kosach@gmail.com Петросян Александр Львович Petrosyan Alexander Lvovich 89119309875@mail.ru Ойсиева Карина Шариповна Oisieva Karina Sharipovna koisieva@mail.ru Кутукова Светлана Игоревна Kutukova Svetlana Igorevna dr.s.kutukova@gmail.com

кандидат медицинских наук;

candidate of medical sciences;

 Зубарева Анна Анатольевна Zubareva Anna Anatolievna a.zubareva@bk.ru

доктор медицинских наук;

doctor of medical sciences;

 Чефу Светлана Григорьевна Chefu Svetlana Grigorievna chefusveta@yandex.ru Яременко Андрей Ильич YAREMENKO ANDREY Ilyich ayaremenko@me.com

доктор медицинских наук;

doctor of medical sciences;

 Власов Тимур Дмитриевич Vlasov Timur Dmitrievich tvlavov@yandex.ru

доктор медицинских наук;

doctor of medical sciences;

 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова The First St. Petersburg State Medical University named after academician I. P. Pavlov СПб ГБУЗ "Городской клинический онкологический диспансер" Санкт - Петербург Россия City clinical oncology dispensary Saint Petersburg Russian Federation Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова Санкт-Петербург Россия First St. Petersburg State Medical University named after Academician I. P. Pavlov St. Petersburg Russian Federation 17 3 69 76 20 08 2021 https://dental-press.ru/en/nauka/article/45641/view

Предмет. Определение влияния медикаментозных препаратов в развитии различных заболеваний является обязательным условием адекватного комплексного лечения пациентов. В настоящее время отсутствует достаточное количество данных о влиянии антиостеокластических препаратов на состояние микроциркуляторного русла. Цель. В эксперименте на животных оценить влияние внутривенного введения деносумаба на микроциркуляцию пародонта, челюсти до и после операции удаления зуба. Методология. Исследование проводилось на 36 крысах линии Вистар на кафедре патофизиологиии с курсом клинической патофизиологии ПСПбГМУ им. акад. И. П. Павлова. Проводилось индуцирование остеонекроза челюстей крыс посредством удаления моляра нижней челюсти. Наблюдение проводилось с диагностическими исследованиями микроциркуляции (допплерография), костной структуры (3D компьютерная томография челюстей) с последующей статистической обработкой данных. Результаты. Выявлено, что максимальное уменьшение скорости кровотока и наибольший костный дефект определяется в группе крыс с максимальной дозировкой препарата моноклонального антитела деносумаб к сроку 4 недели, 0,5 мг/кг внутривенного введения. Также были получены данные о различии уменьшения скорости кровотока между гистологическими слоями нижней челюсти. Так, внутрикостный кровоток повреждался значительно больше, нежели слой слизистой оболочки десны. Выводы. Комбинированный метод допплерографии позволяет определить состояние кровотока на различных гистологических слоях. Так можно определить степень влияния различных фармакологических препаратов на скорость кровотока в локальной области без инвазивных вмешательств. Изучение моноклонального антитела является острой проблемой в мире хирургической стоматологической практики, что требует дальнейшего изучения.

Importance. Determining the influence of different medications in the development of different diseases is a prerequisite for adequate comprehensive treatment of patients. At present, there is insufficient data on the influence of anti-osteoclastic drugs on the microcirculation, which may have an impact. The aim. To study the effects of the monoclonal antibody denosumab on the development of osteonecrosis of the jaw of rats. Methodology. The study was carried out on 36 Wistar Line rats in the Department of Pathophysiology with the course of clinical pathophysiology First Pavlov State Medical University. The osteonecrorosis of the jaws of rats was induced by the extracted of a lower first molar. The observation was carried out with diagnostic studies of microcirculation (doppler), bone structure (3D computer tomography of jaws), followed by statistical processing of the data. Results. It has been shown that the greatest decrease in blood flow rate and the greatest bone defect is determined in the group of rats with the maximum dose of the monoclonal antibody preparation of denosumab by the time of 4 weeks, 0.5 mg/kg intravenous administration. Also, there has been evidence of a difference in blood flow reduction between the histological layers of the lower jaw. Thus, the intrabone blood flow was damaged much more, than the layer of mucous membrane of the gum. Conclusions. The combined method of dopplerography allows the determination of blood flow status on different histological layers. It is possible to determine the extent to which different pharmacological preparations influence the rate of blood flow in the local area without invasive interventions. The study of monoclonal antibodies is an acute problem in the world of surgical dental practice, which requires further study.

 Медикаментозно-ассоциированный остеонекроз челюсти деносумаб моноклональные антитела комбинированная допплерография Medication-related osteonecrosis of the jaw denosumab monoclonal antibodies combined doppler Нет Nil

Aljohani S., Gaudin R., Weiser J., Tröltzsch M., Ehrenfeld M., Kaeppler G., Smeets R., Otto S. Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series // J Craniomaxillofac Surg. - 2018;46(9):1515-1525. https://doi.org/10.1016/j.jcms.2018.05.046 Aljohani S., Gaudin R., Weiser J., Tröltzsch M., Ehrenfeld M., Kaeppler G., Smeets R., Otto S. Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series // J Craniomaxillofac Surg. - 2018;46(9):1515-1525. https://doi.org/10.1016/j.jcms.2018.05.046 McDonald M.M., Kim A.S., Mulholland B.S., Rauner M. New Insights Into Osteoclast Biology // JBMR Plus. - 2021;30;5(9):e10539. https://doi.org/10.1002/jbm4.10539 McDonald M.M., Kim A.S., Mulholland B.S., Rauner M. New Insights Into Osteoclast Biology // JBMR Plus. - 2021;30;5(9):e10539. https://doi.org/10.1002/jbm4.10539 Bone H.G., Wagman R.B., Brandi M.L., Brown J.P., Chapurlat R., Cummings S.R., Czerwiński E., Fahrleitner-Pammer A., Kendler D.L., Lippuner K., Reginster J.Y., Roux C., Malouf J., Bradley M.N., Daizadeh N.S., Wang A., Dakin P., Pannacciulli N., Dempster D.W., Papapoulos S. 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. https://doi.org/10.1016/S2213-8587(17)30138-9 Bone H.G., Wagman R.B., Brandi M.L., Brown J.P., Chapurlat R., Cummings S.R., Czerwiński E., Fahrleitner-Pammer A., Kendler D.L., Lippuner K., Reginster J.Y., Roux C., Malouf J., Bradley M.N., Daizadeh N.S., Wang A., Dakin P., Pannacciulli N., Dempster D.W., Papapoulos S. 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. https://doi.org/10.1016/S2213-8587(17)30138-9 Migliorini F., Maffulli N., Colarossi G., Eschweiler J., Tingart M., Betsch M. Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis // J Orthop Surg Res. - 2021;27;16(1):533. https://doi.org/10.1186/s13018-021-02678-x. Migliorini F., Maffulli N., Colarossi G., Eschweiler J., Tingart M., Betsch M. Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis // J Orthop Surg Res. - 2021;27;16(1):533. https://doi.org/10.1186/s13018-021-02678-x. Egloff-Juras C., Gallois A., Salleron J., Massard V., Dolivet G., Guillet J., Phulpin B. Denosumab-related osteonecrosis of the jaw: A retrospective study // J Oral Pathol Med. - 2018;47(1):66-70.https://doi.org/10.1111/jop.12646. Egloff-Juras C., Gallois A., Salleron J., Massard V., Dolivet G., Guillet J., Phulpin B. Denosumab-related osteonecrosis of the jaw: A retrospective study // J Oral Pathol Med. - 2018;47(1):66-70.https://doi.org/10.1111/jop.12646. Fassio A., Bertoldo F., Idolazzi L., Viapiana O., Rossini M., Gatti D. Drug-induced osteonecrosis of the jaw: the state of the art // Reumatismo. - 2017;22;69(1):9-15. https://doi.org/10.4081/reumatismo.2017.983 Fassio A., Bertoldo F., Idolazzi L., Viapiana O., Rossini M., Gatti D. Drug-induced osteonecrosis of the jaw: the state of the art // Reumatismo. - 2017;22;69(1):9-15. https://doi.org/10.4081/reumatismo.2017.983 Hadaya D., Soundia A., Gkouveris I. et al. Antiresorptive-Type and Discontinuation-Timing Affect ONJ Burden // Journal of Dental Research. - 2021;100(7):746-753. https://doi.org/10.1177/0022034520986804 Hadaya D., Soundia A., Gkouveris I. et al. Antiresorptive-Type and Discontinuation-Timing Affect ONJ Burden // Journal of Dental Research. - 2021;100(7):746-753. https://doi.org/10.1177/0022034520986804 Hoefert S., Yuan A., Munz A., Grimm M., Elayouti A., Reinert S. Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ) //J Craniomaxillofac Surg. - 2017;45(4):570-578.https://doi.org/10.1016/j.jcms.2017.01.013. Hoefert S., Yuan A., Munz A., Grimm M., Elayouti A., Reinert S. Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ) //J Craniomaxillofac Surg. - 2017;45(4):570-578.https://doi.org/10.1016/j.jcms.2017.01.013. Khan A., Morrison A., Cheung A., Hashem W., Compston J. Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015 // Osteoporos Int. - 2016;27(3):853-859. https://doi.org/10.1007/s00198-015-3335-3 Khan A., Morrison A., Cheung A., Hashem W., Compston J. Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015 // Osteoporos Int. - 2016;27(3):853-859. https://doi.org/10.1007/s00198-015-3335-3 Lorusso L., Pieruzzi L., Gabriele M., Nisi M., Viola D., Molinaro E., Bottici V., Elisei R., Agate L. Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates // J Endocrinol Invest. - 2021;21. https://doi.org/10.1007/s40618-021-01634-0. Lorusso L., Pieruzzi L., Gabriele M., Nisi M., Viola D., Molinaro E., Bottici V., Elisei R., Agate L. Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates // J Endocrinol Invest. - 2021;21. https://doi.org/10.1007/s40618-021-01634-0. Kostenuik P.J., Nguyen H.Q., McCabe J., Warmington K.S., Kurahara C., Sun N., Chen C., Li L., Cattley R.C., Van G., Scully S., Elliott R., Grisanti M., Morony S., Tan H.L., Asuncion F., Li X., Ominsky M.S., Stolina M., Dwyer D., Dougall W.C., Hawkins N., Boyle W.J., Simonet W.S., Sullivan J.K. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL // J Bone Miner Res. - 2009;24(2):182-195. doi: 10.1359/jbmr.081112. PMID: 19016581 Kostenuik P.J., Nguyen H.Q., McCabe J., Warmington K.S., Kurahara C., Sun N., Chen C., Li L., Cattley R.C., Van G., Scully S., Elliott R., Grisanti M., Morony S., Tan H.L., Asuncion F., Li X., Ominsky M.S., Stolina M., Dwyer D., Dougall W.C., Hawkins N., Boyle W.J., Simonet W.S., Sullivan J.K. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL // J Bone Miner Res. - 2009;24(2):182-195. doi: 10.1359/jbmr.081112. PMID: 19016581 Kanis J.A., Cooper C., Rizzoli R., Reginster J.Y. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women // Osteoporos Int. - 2019;30(1):3-44. https://doi.org/10.1007/s00198-018-4704-5. Kanis J.A., Cooper C., Rizzoli R., Reginster J.Y. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women // Osteoporos Int. - 2019;30(1):3-44. https://doi.org/10.1007/s00198-018-4704-5. Lenasi H., Potočnik N., Petrishchev N., Papp M., Egorkina A., Girina M., Skedina M., Kovaleva A. The measurement of cutaneous blood flow in healthy volunteers subjected to physical exercise with ultrasound Doppler imaging and laser Doppler flowmetry // Clin Hemorheol Microcirc. - 2017;65(4):373-381. doi: 10.3233/CH-16204. PMID: 27983546. Lenasi H., Potočnik N., Petrishchev N., Papp M., Egorkina A., Girina M., Skedina M., Kovaleva A. The measurement of cutaneous blood flow in healthy volunteers subjected to physical exercise with ultrasound Doppler imaging and laser Doppler flowmetry // Clin Hemorheol Microcirc. - 2017;65(4):373-381. doi: 10.3233/CH-16204. PMID: 27983546. Alsalih A., Dam A., Lindberg P., Truedsson A. Medication-Related Osteonecrosis of the Jaws Initiated by Zoledronic Acid and Potential Pathophysiology // Dent J (Basel). - 2021;30;9(8):85. https://doi.org/10.3390/dj9080085. Alsalih A., Dam A., Lindberg P., Truedsson A. Medication-Related Osteonecrosis of the Jaws Initiated by Zoledronic Acid and Potential Pathophysiology // Dent J (Basel). - 2021;30;9(8):85. https://doi.org/10.3390/dj9080085. Akther F., Razan M.R., Shaligram S., Graham J.L., Stanhope K.L., Allen K.N., Vázquez-Medina J.P., Havel P.J., Rahimian R. Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses // Front Physiol. - 2021;22;12:616317.https://doi.org/10.3389/fphys.2021.616317 Akther F., Razan M.R., Shaligram S., Graham J.L., Stanhope K.L., Allen K.N., Vázquez-Medina J.P., Havel P.J., Rahimian R. Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses // Front Physiol. - 2021;22;12:616317.https://doi.org/10.3389/fphys.2021.616317 Querrer R., Ferrare N., Melo N., Stefani C.M., Dos Reis P.E.D., Mesquita C.R.M., Borges G.A., Leite A.F., Figueiredo P.T. Differences between bisphosphonate-related and denosumab-related osteonecrosis of the jaws: a systematic review // Support Care Cancer. - 2021;29(6):2811-2820. https://doi.org/10.1007/s00520-020-05855-6 Querrer R., Ferrare N., Melo N., Stefani C.M., Dos Reis P.E.D., Mesquita C.R.M., Borges G.A., Leite A.F., Figueiredo P.T. Differences between bisphosphonate-related and denosumab-related osteonecrosis of the jaws: a systematic review // Support Care Cancer. - 2021;29(6):2811-2820. https://doi.org/10.1007/s00520-020-05855-6 Eleutherakis-Papaiakovou E., Bamias A. Antiresorptive treatment-associated ONJ // Eur J Cancer Care (Engl). - 2017;26(6). https://doi.org/10.1111/ecc.12787. Eleutherakis-Papaiakovou E., Bamias A. Antiresorptive treatment-associated ONJ // Eur J Cancer Care (Engl). - 2017;26(6). https://doi.org/10.1111/ecc.12787. Loyson T., Van Cann T., Schöffski P., Clement P.M., Bechter O., Spriet I., Coropciuc R., Politis C., Vandeweyer R.O., Schoenaers J., Dumez H., Berteloot P., Neven P., Nackaerts K., Woei-A-Jin F.J.S.H., Punie K., Wildiers H., Beuselinck B. Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab // Acta Clin Belg. - 2018;73(2):100-109. https://doi.org/10.1080/17843286.2017.1348001. Loyson T., Van Cann T., Schöffski P., Clement P.M., Bechter O., Spriet I., Coropciuc R., Politis C., Vandeweyer R.O., Schoenaers J., Dumez H., Berteloot P., Neven P., Nackaerts K., Woei-A-Jin F.J.S.H., Punie K., Wildiers H., Beuselinck B. Incidence of osteonecrosis of the jaw in patients with bone metastases treated sequentially with bisphosphonates and denosumab // Acta Clin Belg. - 2018;73(2):100-109. https://doi.org/10.1080/17843286.2017.1348001. Thanakun S., Pornprasertsuk-Damrongsri S., Na Mahasarakham C.P., Techatanawat S., Izumi Y. Increased Plasma Osteocalcin, Oral Disease, and Altered Mandibular Bone Density in Postmenopausal Women // Int J Dent. - 2019;24;2019:3715127. https://doi.org/10.1155/2019/3715127. Thanakun S., Pornprasertsuk-Damrongsri S., Na Mahasarakham C.P., Techatanawat S., Izumi Y. Increased Plasma Osteocalcin, Oral Disease, and Altered Mandibular Bone Density in Postmenopausal Women // Int J Dent. - 2019;24;2019:3715127. https://doi.org/10.1155/2019/3715127. Rugani P., Walter C., Kirnbauer B., Acham S., Begus-Nahrman Y., Jakse N. Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma // Dent J (Basel). - 2016;27;4(4):32. https://doi.org/10.3390/dj4040032. Rugani P., Walter C., Kirnbauer B., Acham S., Begus-Nahrman Y., Jakse N. Prevalence of Medication-Related Osteonecrosis of the Jaw in Patients with Breast Cancer, Prostate Cancer, and Multiple Myeloma // Dent J (Basel). - 2016;27;4(4):32. https://doi.org/10.3390/dj4040032. Chen J., Chen Q., Hu B., Wang Y., Song J. Effectiveness of alendronate as an adjunct to scaling and root planing in the treatment of periodontitis: a meta-analysis of randomized controlled clinical trials // J Periodontal Implant Sci. - 2016;46(6):382-395. https://doi.org/10.5051/jpis.2016.46.6.382. Chen J., Chen Q., Hu B., Wang Y., Song J. Effectiveness of alendronate as an adjunct to scaling and root planing in the treatment of periodontitis: a meta-analysis of randomized controlled clinical trials // J Periodontal Implant Sci. - 2016;46(6):382-395. https://doi.org/10.5051/jpis.2016.46.6.382. Williams D.W., Lee C., Kim T. et al. Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κb ligand antibody in mice // Am J Pathol. - 2014;184(11):3084-3093. Doi:10.1016/j.ajpath.2014.07.010 Williams D.W., Lee C., Kim T. et al. Impaired bone resorption and woven bone formation are associated with development of osteonecrosis of the jaw-like lesions by bisphosphonate and anti-receptor activator of NF-κb ligand antibody in mice // Am J Pathol. - 2014;184(11):3084-3093. Doi:10.1016/j.ajpath.2014.07.010