Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC38010.15690/vramn.v69i11-12.1194SHORT MESSAGESКРАТКИЕ СООБЩЕНИЯTHE COMBINED USE OF BISPHOSPHONATES AND STRONTIUM RANELATE WITH OSSEOSUBSTITUTING MATERIALSКОМБИНИРОВАННОЕ ПРИМЕНЕНИЕ БИСФОСФОНАТОВ И СТРОНЦИЯ РАНЕЛАТА С ОСТЕОЗАМЕЩАЮЩИМИ МАТЕРИАЛАМИKhlusovI. A.ХлусовИ. А.
Russian Federation

доктор медицинских наук, профессор кафедры морфологии и общей патологии Сибир- ского государственного медицинского университета, профессор кафедры теоретической и экспериментальной физики Национального исследовательского Томского политехнического университета Адрес: 634050, Томск, ул. Московский тракт, д. 2, тел.: +7 (3822) 53-24-71

khlusov63@mail.ruVengerovskiiA. I.ВенгеровскийА. И.
Russian Federation

доктор медицинских наук, профессор, заведующий кафедрой фармакологии Сибирского государственного медицинского университета Адрес: 634050, Томск, ул. Московский тракт, д. 2, тел.: +7 (3822) 55-34-95

pharm-sibgmu@rambler.ruNovitskiiV. V.НовицкийВ. В.
Russian Federation

доктор медицинских наук, профессор, академик РАН, заведующий кафедрой пато- физиологии Сибирского государственного медицинского университета Адрес: 634050, Томск, ул. Московский тракт, д. 2, тел.: +7 (3822) 55-36-13

patfizssmu@yandex.ruSiberian State Medical University, Tomsk, Russian Federation National Research Tomsk Polytechnic University, Russian FederationСибирский государственный медицинский университет, Томск, Российская Федерация Национальный исследовательский Томский политехнический университет, Томск, Российская ФедерацияSiberian State Medical University, Tomsk, Russian FederationСибирский государственный медицинский университет, Томск, Российская Федерация171220146911-12Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук12813207082015Copyright ©; 1970, "Paediatrician" Publishers LLCCopyright ©; 1970, Издательство "Педиатръ"1970"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/380

In review the possibility of biomaterials osseointegration improvement with help of bisphosphonates or strontium ranelate is discussed. For this purpose, they are added to hydroxyapatite used for implants coating, or are included as a component of bulk calcium phosphate materials. Strontium is employed as a compound of biodegradable metal alloys, also. Combined use of carrier (implant) with bisphosphonates or strontium ranelate promotes controlling local delivery of pharmaceutical molecules into lesion, enhances the therapy efficiency, and decreases a dose and systemic toxicity of the drugs. Bisphosphonates and strontium ranelate increase the mass, a count and thickness of bone trabeculas, improve the bone biomechanical properties in the place of implants fixation, and diminish the bone fracture risk. Main studies are devoted to pharmacologic mechanisms of implants osseointegration improvement. Bisphosphonates as isoprenoid lipids chemical analogues diminish by concurrent principle theosteoclasts farnesyl pyrophosphate synthase activity and inhibit the prenylation. Unprenylated small GTPases don’t fasten onto osteoclasts membrane that weakens cellular resorptive activity and accelerates their apoptosis. Strontium ranelate enhances osteoblasts replicative activity and suppresses their apoptosis, also retards osteoclasts resorptive function and accelerates their apoptosis. Its effects are conditioned by activating Wnt-signaling pathway by means of calcium-sensing receptor and by changing the RANKL/RANK/OPG system.

В обзоре рассмотрена возможность улучшения остеоинтеграции биосовместимых материалов с помощью бисфосфонатов или стронция ранелата. Эти лекарственные средства добавляют к гидроксиапатиту, используемому для покрытия имплантатов, включают в состав кальцийфосфатных материалов. Стронций является также компонентом биодеградируемых сплавов. Бисфосфонаты и стронция ранелат увеличивают массу, число и толщину костных трабекул, улучшают биомеханические свойства кости в месте введения имплантатов, снижают риск переломов. Большое число исследований посвящено механизмам фармакологического улучшения остеоинтеграции имплантатов. Бисфосфонаты как химические аналоги изопреноидных липидов по конкурентному принципу уменьшают в остеокластах активность фарнезилдифосфатсинтазы и тормозят пренилирование. Непренилированные малые ГТФазы не прикрепляются к мембране остеокластов, что ослабляет их резорбтивную функцию и ускоряет апоптоз. Стронция ранелат, активируя при участии кальцийчувствительного рецептора Wnt-сигнальный путь и изменяя функции системы RANKL/RANK/OPG, повышает репликационную активность и подавляет апоптоз остеобластов, а также тормозит резорбтивную функцию и ускоряет апоптоз остеокластов.

bisphosphonatesstrontium ranelateimplantsbone deficienciesosseointegrationбисфосфонатыстронция ранелатимплантатыостеоинтеграция1. Barradas A.M., Yuan H., van Blitterswijk C.A. Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms. Eur. Cell. Mat. 2011; 21 (3): 407–429.2. Hernigou P., Homma Y. Tissue bioengineering in orthopedics Clin. Cases Miner. Bone Metab. 2012; 9 (1): 21–23.3. Racher T.D., Khosla S., Hofbauer L.C. New horizons in osteoporosis. Lancet. 2011; 377 (9773): 1276–1287.4. Bhat S., Kumar A. Biomaterials and bioengineering tomorrow’s healthcare. Biomater. 2013; 3 (2): 247–257.5. Lu H.D., Wheeldon I.R., Banta S. Catalytic biomaterials: engineering organophosphate hydrolase to form self-assembling enzymatic hydrogels. Protein Eng. Des. Sel. 2010; 23 (7): 559–566.6. Balaconis M.K., Clark H.A. Biodegradable optode-based nanosensors for in vivo monitoring. Anal. Chem. 2012; 84 (13): 5787– 5793.7. Carli A., Reuven A., Zukor D.J., Antoniou J. Adverse soft-tissue reactions around non-metal-on-metal total hip arthroplasty — a systematic review of the literature. Bull. N.Y. Hos. Jt. Dis. 2011; 69 (Suppl. 1): 47–51.8. Gortchacow M., Wettstein M., Pioletti D., Müller-Gerbl M. Simultaneous and multisite measure of micromotion, subsidence and gap to evaluate femoral stem stability. J. Biomech. 2012; 45 (7): 1232–1238.9. Jakobsen T., Baas J., Bechtold J.E., Elmengaard B. The effect of soaking allograft in bisphosphonate: a pilot dose-response study. Clin. Ortho Relat. Res. 2010; 468 (3): 867–874.10. Babiker H. Bone graft materials in fixation of orthopaedic implants. Dan. Med. J. 2013; 60 (7): 4680–4686.11. Anderson J.M., Rodriguez A., Chang D.T. Foreign body reaction to biomaterials. Semin. Immunol. 2008; 20 (2); 86–100.12. Noordin S., Masri B. Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions. Can. J. Surg. 2012; 55 (6): 408–417.13. Morais J.M., Papadimitrakopoulos F., Burgess D.J. Biomaterials/ tissue interactions: possible solutions to overcome foreign body response. AAPS J. 2010; 12 (2): 188–196.14. Хлусов И.А., Венгеровский А.И., Нечаев К.А., Дворниченко М.В., Саприна Т.В. Применение бисфосфонатов при несовершенном остеогенезе у детей. Клиническая фармакология и терапия. 2013; 22 (2): 78–82.15. Cremers S., Papapoulos S. Pharmacology of bisphosphonates. Bone. 2011; 49 (1): 42–49.16. Dominguez L.J., Di Bella G., Belvedere M., Barbagallo M. Physiology of the aging bone and mechanisms of action of bisphosphonates. Biogerontology. 2011; 12 (5): 397–408.17. Drake M.T., Bart L., Clarke B.L., Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin. Proc. 2008; 83 (9): 1032–1045.18. Graham R., Russell G. Bisphosphonates: the first 40 years. Bone. 2011; 49 (1): 2–19.19. Russell R.G. Bisphosphonates: from bench to bedside. Ann. N.Y. Acad. Sci. 2006; 1068 (3): 367–401.20. Yewle J.N., Puleo D.A., Bachas L.G. Enhanced affinity bifunctional bisphosphonates for targeted delivery of therapeutic agents to bone. Bioconjug. Chem. 2011; 22 (12): 2496–2506.21. Dunford J.E., Kwaasi A.A., Rogers M.J., Barnett B.L. Structureactivity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. J. Med. Chem. 2008; 51 (18): 2187–2195.22. Риггз Б., Мелтон Дж. Остеопороз. СПб.: БИНОМ, Невский диалект. 2000. 560 c.23. Ohgi K., Kajiya H., Okamoto F., Nagaoka Y. A novel inhibitory mechanism of nitrogen-containing bisphosphonate on the activity of Cl- extrusion in osteoclasts. Naunyn Schmiedebergs Arch. Pharmacol. 2013; 386 (7): 589–598.24. Coxon F., Thompson K., Roelofs A.J., Ebetino F.H. Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone. 2008; 42 (5): 848–860.25. Fisher J.E., Rosenberg E., Santora A.C., Reszka A.A. In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption. Calcif. Tissue Int. 2013; 92 (6): 531–538.26. Ueno A., Terkawi M.A., Yokoyama M., Cao S. Farnesyl pyrophosphate synthase is a potential molecular drug target of risedronate in Babesia bovis. Parasitol. Int. 2013; 62 (2): 189–192.27. Rogers M.J., Crockett J.C., Coxon F., Mönkkönen J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone. 2011; 49 (1): 34–41.28. Dunford J.E., Rogers M.J., Ebetino F.H., Phipps R.J. Inhibition of protein prenylation by bisphosphonates causes sustained activation of rac, Cdc42 and rho GTPases. J. Bone Miner. Res. 2006; 21 (4): 684–694.29. Coxon F.P., Taylor A. Vesicular trafficking in osteoclasts. Semin Cell Dev. Biol. 2008; 19 (5): 424–433.30. Roelofs A.J., Thompson K., Ebetino F.H., Rogers M.J. Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. Curr. Pharm. Des. 2010; 16 (27): 2950–2960.31. Plotkin L.I., Manolagas S.C., Bellido T. Dissociation of the proapoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone. 2006; 39 (2): 443–452.32. Idris A.I., Rojas J., Greig I.R., Van’t Hof R.J. Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif. Tissue Int. 2008; 82 (3): 191–201.33. Xiong Y., Yang H.J., Feng J., Shi Z.L. Effects of alendronate on the proliferation and osteogenic differentiation of MG-63 cells. J. Int. Med. Res. 2009; 37 (2): 407–416.34. Bobyn J.D., McKenzie K., Karabasz D., Krygier J.J. Locally delivered bisphosphonate for enhancement of bone formation and implant fixation. J. Bone Joint Surg. Am. 2009; 91 (Suppl. 6): 23–31. 35. Matuszewski Ł., Turżańska K., Matuszewska A., Jabłoński M. Effect of implanted bisphosphonate-enriched cement on the trabecular microarchitecture of bone in a rat model using microcomputed tomography. Int. Ortho. 2013; 37 (6): 1187–1193.36. Liu X., Bao C., Hu J., Yin G. Effects of clodronate combined with hydroxyapatite on multi-directional differentiation of mesenchymal stromal cells. Arch. Med. Sci. 2010; 6 (5); 670–677.37. Liu J.T., Liao W.J., Tan W.C., Lee J.K. Balloon kyphoplasty versus vertebroplasty for treatment of osteoporotic vertebral compression fracture: a prospective, comparative, and randomized clinical study. Osteoporos. Int. 2010; 21 (3): 359–364.38. Sibai T., Morgan E.F., Einhorn T.A. Anabolic agents and bone quality. Clin. Ortho Relat. Res. 2011; 469 (8): 2215–2224.39. Hamdy N.A. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford). 2009; 48 (Suppl. 4): 9–13.40. Fonseca J.E. Rebalancing bone turnover in favor of formation with strontium ranelate: implications for bone strength. Rheumatology (Oxford). 2008; 47 (Suppl. 4): 17–19.41. Magno A.L., Ward B.K., Ratajczak T. The calcium-sensing receptor: a molecular perspective. Endocr. Rev. 2011; 32 (1): 3–30.42. Xue Y., Xiao Y., Liu J., Karaplis A.C. The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice. Am. J. Physiol. Endocrinol. Metab. 2012; 302 (7): 841–851.43. Hurtel-Lemaire A.S., Mentaverri R.,. Caudrillier A., Cournarie F. The calcium-sensing receptor is involved in strontium ranelate induced osteoclast apoptosis. New insights into the associated signaling pathways. J. Biol. Chem. 2009; 284 (1): 575–584.44. Rucci N. Molecular biology of bone remodeling. Clin. Cases Miner. Bone Metab. 2008; 5 (1): 49–56.45. Rybchyn M.S., Slater M., Conigrave A.D., Mason R.S. An Aktdependent increase in canonical Wnt signaling and a decrease in sclerostin protein levels are involved in strontium ranelate induced osteogenic effects in human osteoblasts. J. Biol. Chem. 2011; 286 (27): 23771–23779.46. Fromigue O., Hay E., Barbara A., Marie J. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J. Biol. Chem. 2010; 285 (28): 25251–25258.47. Boyce B.F., Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch. Biochem. Biophys. 2008; 473 (3): 139–146.48. Tat S.T., Pelletier J., Velasco C.R., Padrines M. New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target. Keio J. Med. 2009; 58 (1): 29–40.49. Kearns A.E., Khosla S., Kostenuik J. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr. Rev. 2008; 29 (2): 155–192.50. Хлусов И.А., Венгеровский А.И., Нечаев К.А., Дворниченко М.В., Кулагина И.В., Саприна Т.В. Эффекты стронция ранелата в культуре мононуклеарных лейкоцитов. Экспериментальная и клиническая фармакология. 2013; 7 (1): 35–38.51. Yang G.L., Song L.N., Jiang Q.H., Wang X.X. Effect of strontium-substituted nanohydroxyapatite coating of porous implant surfaces on implant osseointegration in a rabbit model. Int. J. Oral Maxillofac. Implants. 2012; 27 (6): 1332–1339.52. Chung C.J., Long H.Y. Systematic strontium substitution in hydroxyapatite coatings on titanium via micro-arc treatment and their osteoblast/osteoclast responses. Acta. Biomater. 2011; 7 (11): 4081–4087.53. Li Y., Wen C., Mushahary D., Sravanthi R. Mg–Zn–Sr alloys as biodegradable implant materials. Acta. Biomater. 2012; 8 (8): 3177–3188.54. Berglund I.S., Brar H.S., Dolgova N., Acharya A. Synthesis and characterization of Mg–Ca–Sr alloys for biodegradable orthopedic implant applications. J. Biomed. Mater. Res. 2012; 100 (6): 1524–1534.55. Ballo A.M., Xia W., Palmquist A., Lindahl C. Bone tissue reactions to biomimetic ion-substituted apatite surfaces on titanium implants. J. R. Soc. Interface. 2012; 9 (72): 1615–1624.56. Forsgren J., Engqvist H. A novel method for local administration of strontium from implant surfaces. J. Mater. Sci. Mater. Med. 2010; 21 (5): 1605–1609.57. Sung J.H., Shuler M.I. In vitro microscale systems for systematic drug toxicity study. Bioprocess Biosyst. Eng. 2010; 33 (1): 5–19.58. Хлусов И.А., Рязанцева Н.В., Венгеровский А.И., Нечаев К.А., Якушина В.Д., Дворниченко М.В., Шаркеев Ю.П., Легостаева Е.В., Новицкий В.В. Модулирующее влияние матриц с кальцийфосфатным покрытием на цитотоксичность стронция ранелата и ибандроновой кислоты in vitro. Бюллетень экспериментальной биологии и медицины. 2013; 157 (2): 177–181.