{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:27:36Z","timestamp":1794029256742,"version":"4.8.0"},"reference-count":89,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,4]],"date-time":"2022-12-04T00:00:00Z","timestamp":1670112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Periprosthetic osteolysis remains a leading complication of total hip and knee arthroplasty, often resulting in aseptic loosening of the implant and necessitating revision surgery. Wear-induced particulate debris is the main cause initiating this destructive process. The purpose of this article is to review recent advances in understanding of how wear debris causes osteolysis, and emergent strategies for the avoidance and treatment of this disease. A strong activator of the peri-implant innate immune this debris-induced inflammatory cascade is dictated by macrophage secretion of TNF-\u03b1, IL-1, IL-6, and IL-8, and PGE2, leading to peri-implant bone resorption through activation of osteoclasts and inhibition of osteoblasts through several mechanisms, including the RANK\/RANKL\/OPG pathway. Therapeutic agents against proinflammatory mediators, such as those targeting tumor necrosis factor (TNF), osteoclasts, and sclerostin, have shown promise in reducing peri-implant osteolysis in vitro and in vivo; however, radiographic changes and clinical diagnosis often lag considerably behind the initiation of osteolysis, making timely treatment difficult. Considerable efforts are underway to develop such diagnostic tools, therapies, and identify novel targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/bioengineering9120764","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T06:29:09Z","timestamp":1670221749000},"page":"764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The Role of the Innate Immune System in Wear Debris-Induced Inflammatory Peri-Implant Osteolysis in Total Joint Arthroplasty"],"prefix":"10.3390","volume":"9","author":[{"given":"John Patrick","family":"Connors","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0218-1111","authenticated-orcid":false,"given":"John W.","family":"Stelzer","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M.","family":"Garvin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-2939","authenticated-orcid":false,"given":"Ian J.","family":"Wellington","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Solovyova","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2174\/1874325001105010080","article-title":"Epidemiology of Knee and Hip Arthroplasty: A Systematic Review","volume":"5","author":"Singh","year":"2011","journal-title":"Open Orthop. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Man, K., Jiang, L.-H., Foster, R., and Yang, X.B. (2017). Immunological Responses to Total Hip Arthroplasty. J. Funct. Biomater., 8.","DOI":"10.3390\/jfb8030033"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Jamari, J., Ammarullah, M.I., Santoso, G., Sugiharto, S., Supriyono, T., and van der Heide, E. (2022). In Silico Contact Pressure of Metal-on-Metal Total Hip Implant with Different Materials Subjected to Gait Loading. Metals, 12.","DOI":"10.3390\/met12081241"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s11999-009-0945-0","article-title":"The epidemiology of revision total knee arthroplasty in the United States","volume":"468","author":"Bozic","year":"2010","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1016\/j.arth.2013.07.024","article-title":"Why are total knee arthroplasties failing today\u2014Has anything changed after 10 years?","volume":"29","author":"Sharkey","year":"2014","journal-title":"J. Arthroplast."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2106\/JBJS.20.01235","article-title":"Lifetime Risk of Revision Hip Replacement Surgery in Australia Remains Low: A Population-Level Analysis Using National Registry Data","volume":"103","author":"Ackerman","year":"2021","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"302","DOI":"10.2106\/JBJS.17.01528","article-title":"Major Aseptic Revision Following Total Knee Replacement: A Study of 478,081 Total Knee Replacements from the Australian Orthopaedic Association National Joint Replacement Registry","volume":"101","author":"Jorgensen","year":"2019","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1055\/s-0033-1348098","article-title":"Imaging of hip arthroplasty","volume":"Volume 17","author":"Fritz","year":"2013","journal-title":"Seminars in Musculoskeletal Radiology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/000164701753532853","article-title":"The Swedish Knee Arthroplasty Register 1975\u20131997: An update with special emphasis on 41,223 knees operated on in 1988\u20131997","volume":"72","author":"Robertsson","year":"2001","journal-title":"Acta Orthop."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/00003086-200010000-00012","article-title":"Alumina ceramic bearings for hip endoprostheses: The Austrian experiences","volume":"379","author":"Boehler","year":"2000","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_11","first-page":"67","article-title":"Studies of host response to orthopedic implants and biomaterials","volume":"9","author":"Santavirta","year":"1999","journal-title":"J. Long-Term Eff. Med. Implant."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1097\/00003086-199009000-00013","article-title":"Osteolysis in alloarthroplasty of the hip. The role of ultra-high molecular weight polyethylene wear particles","volume":"258","author":"Willert","year":"1990","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jamari, J., Ammarullah, M.I., Santoso, G., Sugiharto, S., Supriyono, T., Prakoso, A.T., Basri, H., and van der Heide, E. (2022). Computational Contact Pressure Prediction of CoCrMo, SS 316L and Ti6Al4V Femoral Head against UHMWPE Acetabular Cup under Gait Cycle. J. Funct. Biomater., 13.","DOI":"10.3390\/jfb13020064"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100060","DOI":"10.1016\/j.cmpbup.2022.100060","article-title":"The relation between body weight and wear in Total Hip Prosthesis: A finite element study","volume":"2","author":"Toh","year":"2022","journal-title":"Comput. Methods Programs Biomed. Updat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"185150","DOI":"10.1155\/2014\/185150","article-title":"The pathology of orthopedic implant failure is mediated by innate immune system cytokines","volume":"2014","author":"Landgraeber","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/jor.1100180321","article-title":"Tumor necrosis factor-\u03b1\/nuclear transcription factor-?B signaling in periprosthetic osteolysis","volume":"18","author":"Schwarz","year":"2000","journal-title":"J. Orthop. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.2106\/00004623-200107000-00031","article-title":"Specialty update: What\u2019s new in orthopaedic research","volume":"83","author":"Sandell","year":"2001","journal-title":"J. Bone Jt. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1097\/BRS.0000000000000549","article-title":"What is the optimum fusion technique for adult spondylolisthesis\u2014PLIF or PLF or PLIF plus PLF? A meta-analysis from 17 comparative studies","volume":"39","author":"Liu","year":"2014","journal-title":"Spine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ajpath.2015.09.006","article-title":"Macrophage Polarization in IL-10 Treatment of Particle-Induced Inflammation and Osteolysis","volume":"186","author":"Jiang","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2815","DOI":"10.1016\/j.actbio.2012.03.042","article-title":"Revision joint replacement, wear particles, and macrophage polarization","volume":"8","author":"Rao","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_21","first-page":"i-16","article-title":"Wear and osteolysis in total joint replacements","volume":"69","author":"Kadoya","year":"1998","journal-title":"Acta Orthop."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/jbm.820280111","article-title":"Macrophage\/particle interactions: Effect of size, composition and surface area","volume":"28","author":"Shanbhag","year":"1994","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Revell, P.A. (2008). Joint Replacement Technology, Woodhead Publishing.","DOI":"10.1201\/9781439833063"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"596870","DOI":"10.1155\/2012\/596870","article-title":"The Role of TLR and Chemokine in Wear Particle-Induced Aseptic Loosening","volume":"2012","author":"Gu","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3960\/jslrt.51.77","article-title":"Toll-like Receptor","volume":"51","author":"Takagi","year":"2011","journal-title":"J. Clin. Exp. Hematop."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5535","DOI":"10.1016\/j.biomaterials.2011.04.046","article-title":"Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles","volume":"32","author":"Pearl","year":"2011","journal-title":"Biomaterials"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32378","DOI":"10.1074\/jbc.M110.136895","article-title":"Bacterial Pathogen-associated Molecular Patterns Stimulate Biological Activity of Orthopaedic Wear Particles by Activating Cognate Toll-like Receptors","volume":"285","author":"Greenfield","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"558","DOI":"10.4049\/jimmunol.164.2.558","article-title":"Cutting Edge: Heat Shock Protein 60 Is a Putative Endogenous Ligand of the Toll-Like Receptor-4 Complex","volume":"164","author":"Ohashi","year":"2000","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/jbm.a.31235","article-title":"Toll-like receptors in the interface membrane around loosening total hip replacement implants","volume":"81A","author":"Takagi","year":"2007","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1359\/jbmr.2001.16.11.2082","article-title":"Adherent Endotoxin on Orthopedic Wear Particles Stimulates Cytokine Production and Osteoclast Differentiation","volume":"16","author":"Bi","year":"2001","journal-title":"J. Bone Miner. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/jbm.a.32474","article-title":"The roles of monocytic heat shock protein 60 and Toll-like receptors in the regional inflammation response to wear debris particles","volume":"92A","author":"Hao","year":"2009","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s10753-012-9454-5","article-title":"Inhibition of Titanium Particle-Induced Inflammation by the Proteasome Inhibitor Bortezomib in Murine Macrophage-Like RAW 264.7 Cells","volume":"35","author":"Mao","year":"2012","journal-title":"Inflammation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.molimm.2009.09.023","article-title":"Endosomal damage and TLR2 mediated inflammasome activation by alkane particles in the generation of aseptic osteolysis","volume":"47","author":"Maitra","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1182\/blood.V90.3.909","article-title":"Chemokines","volume":"90","author":"Rollins","year":"1997","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1146\/annurev.pharmtox.42.091901.115838","article-title":"Structure, function, and inhibition of chemokines","volume":"42","author":"Fernandez","year":"2002","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1074-7613(00)80165-X","article-title":"Chemokines: A New Classification System and Their Role in Immunity","volume":"12","author":"Zlotnik","year":"2000","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1146\/annurev.immunol.24.021605.090529","article-title":"Chemokine: Receptor Structure, Interactions, and Antagonism","volume":"25","author":"Allen","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1006\/cyto.1999.0647","article-title":"Monocyte migration inhibitory factor synthesis and gene expression in particle-activated macrophages","volume":"12","author":"Lind","year":"2000","journal-title":"Cytokine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1302\/0301-620X.81B1.0810155","article-title":"Induction of macrophage C-C chemokine expression by titanium alloy and bone cement particles","volume":"81","author":"Nakashima","year":"1999","journal-title":"J. Bone Jt. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1002\/jor.21548","article-title":"Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles","volume":"30","author":"Gibon","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/jbm.a.32744","article-title":"Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging","volume":"9999A","author":"Ren","year":"2010","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11999-010-1645-5","article-title":"Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis","volume":"469","author":"Ren","year":"2010","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1186\/ar2170","article-title":"Aseptic loosening of total joint replacements: Mechanisms underlying osteolysis and potential therapies","volume":"9","author":"Darwech","year":"2007","journal-title":"Arthritis Res. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/jbm.a.31467","article-title":"Human macrophage response to UHMWPE, TiAlV, CoCr, and alumina particles: Analysis of multiple cytokines using protein arrays","volume":"84A","author":"Kaufman","year":"2007","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_46","first-page":"853","article-title":"Biological responses of human mesenchymal stem cells to titanium wear debris particles","volume":"30","author":"Argintar","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1002\/jbm.a.32803","article-title":"Effects of orthopedic polymer particles on chemotaxis of macrophages and mesenchymal stem cells","volume":"94A","author":"Huang","year":"2010","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/jbm.a.32390","article-title":"Titanium induced production of chemokines CCL17\/TARC and CCL22\/MDC in human osteoclasts and osteoblasts","volume":"92","author":"Cadosch","year":"2010","journal-title":"J. Biomed. Mater. Res.\u2014Part A"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/978-0-387-89520-8_9","article-title":"RANK(L) as a Key Target for Controlling Bone Loss","volume":"Volume 647","author":"Leibbrandt","year":"2009","journal-title":"Therapeutic Targets of the TNF Superfamily"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0169-6009(08)80211-5","article-title":"The expression of osteoclast markers on foreign body giant cells","volume":"27","author":"Kadoya","year":"1994","journal-title":"Bone Miner."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1302\/0301-620X.74B1.1732267","article-title":"Resorption of bone by inflammatory cells derived from the joint capsule of hip arthroplasties","volume":"74","author":"Athanasou","year":"1992","journal-title":"J. Bone Jt. Surg."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/(SICI)1096-9896(199705)182:1<92::AID-PATH813>3.0.CO;2-E","article-title":"Osteoclasts are capable of particle phagocytosis and bone resorption","volume":"182","author":"Wang","year":"1997","journal-title":"J. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1302\/0301-620X.79B5.0790849","article-title":"Biomaterial Particle Phagocytosis by Bone-Resorbing Osteoclasts","volume":"79","author":"Wang","year":"1997","journal-title":"J. Bone Jt. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1054\/arth.2001.28719","article-title":"The potential role of the osteoblast in the development of periprosthetic osteolysis: Review of in vitro osteoblast responses to wear debris, corrosion products, and cytokines and growth factors","volume":"16","author":"Vermes","year":"2001","journal-title":"J. Arthroplast."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0142-9612(02)00324-1","article-title":"Prosthetic particles modify the expression of bone-related proteins by human osteoblastic cells in vitro","volume":"24","author":"Zreiqat","year":"2002","journal-title":"Biomaterials"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"107","DOI":"10.2106\/00004623-199701000-00011","article-title":"Suppression of osteoblast function by titanium particles","volume":"79","author":"Yao","year":"1997","journal-title":"J. Bone Jt. Surg.\u2014Ser. A"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0736-0266(00)00030-9","article-title":"Effect of polymer molecular weight and addition of calcium stearate on response of MG63 osteoblast-like cells to UHMWPE particles","volume":"19","author":"Dean","year":"2001","journal-title":"J. Orthop. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/(SICI)1097-4636(19990905)46:3<399::AID-JBM13>3.0.CO;2-B","article-title":"The cytotoxic effect of titanium particles phagocytosed by osteoblasts","volume":"46","author":"Pioletti","year":"1999","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/S0142-9612(99)00250-1","article-title":"The effects of calcium phosphate cement particles on osteoblast functions","volume":"21","author":"Pioletti","year":"2000","journal-title":"Biomaterials"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5803","DOI":"10.1016\/j.biomaterials.2004.01.053","article-title":"The influence of wear particles in the expression of osteoclastogenesis factors by osteoblasts","volume":"25","author":"Pioletti","year":"2004","journal-title":"Biomaterials"},{"key":"ref_61","first-page":"319","article-title":"Pathology of the bone-implant interfaces","volume":"9","author":"Revell","year":"1999","journal-title":"J. Long-Term Eff. Med. Implant."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1002\/art.22134","article-title":"The role of fibroblasts and fibroblast-derived factors in periprosthetic osteolysis","volume":"54","author":"Koreny","year":"2006","journal-title":"Arthritis Care Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.artd.2022.02.003","article-title":"Bisphosphonates in Total Joint Arthroplasty: A Review of Their Use and Complications","volume":"14","author":"McDonald","year":"2022","journal-title":"Arthroplast. Today"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.279.5350.509","article-title":"Rho GTPases and the Actin Cytoskeleton","volume":"279","author":"Hall","year":"1998","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7829","DOI":"10.1073\/pnas.0601643103","article-title":"The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs","volume":"103","author":"Kavanagh","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","first-page":"235","article-title":"Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates","volume":"296","author":"Dunford","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2106\/JBJS.D.01772","article-title":"Effect of Bisphosphonates on Periprosthetic Bone Mineral Density After Total Joint Arthroplasty","volume":"87","author":"Bhandari","year":"2005","journal-title":"J. Bone Jt. Surg."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.2106\/00004623-200311000-00009","article-title":"The Effect of Alendronate on Bone Mineral Density in the Distal Part of the Femur And Proximal Part of the Tibia After Total Knee Arthroplasty","volume":"85","author":"Wang","year":"2003","journal-title":"J. Bone Jt. Surg."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.arth.2015.09.005","article-title":"Lower Total Knee Arthroplasty Revision Risk Associated With Bisphosphonate Use, Even in Patients With Normal Bone Density","volume":"31","author":"Namba","year":"2016","journal-title":"J. Arthroplast."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"d7222","DOI":"10.1136\/bmj.d7222","article-title":"Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: Population based retrospective cohort study","volume":"343","author":"Javaid","year":"2011","journal-title":"BMJ"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1007\/s00167-018-5333-4","article-title":"The use of bisphosphonates after joint arthroplasty is associated with lower implant revision rate","volume":"27","author":"Ro","year":"2018","journal-title":"Knee Surg. Sport. Traumatol. Arthrosc."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1016\/j.biomaterials.2007.04.024","article-title":"Anabolic effects of bisphosphonates on peri-implant bone stock","volume":"28","author":"Eckhardt","year":"2007","journal-title":"Biomaterials"},{"key":"ref_73","first-page":"1492","article-title":"Does alendronate inhibit the progression of periprosthetic osteolysis?","volume":"29","author":"Rubash","year":"2004","journal-title":"Trans ORS"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13045-018-0615-3","article-title":"Wnt signaling in multiple myeloma: A central player in disease with therapeutic potential","volume":"11","author":"Spaan","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.1007\/s11999-014-3765-9","article-title":"Are Biologic Treatments a Potential Approach to Wear- and Corrosion-related Problems?","volume":"472","author":"Smith","year":"2014","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e195","DOI":"10.1016\/S2665-9913(20)30394-5","article-title":"Effect of denosumab on osteolytic lesion activity after total hip arthroplasty: A single-centre, randomised, double-blind, placebo-controlled, proof of concept trial","volume":"3","author":"Mahatma","year":"2021","journal-title":"Lancet Rheumatol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Sk\u00f6ldenberg, O., Rysinska, A., Eisler, T., Salemyr, M., Bod\u00e9n, H., and Muren, O. (2016). Denosumab for treating periprosthetic osteolysis; study protocol for a randomized, double-blind, placebo-controlled trial. BMC Musculoskelet. Disord., 17.","DOI":"10.1186\/s12891-016-1036-5"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/S0140-6736(21)02646-5","article-title":"Drug therapy for osteoporosis in older adults","volume":"399","author":"Reid","year":"2022","journal-title":"Lancet"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"19883","DOI":"10.1074\/jbc.M413274200","article-title":"Sclerostin Binds to LRP5\/6 and Antagonizes Canonical Wnt Signaling","volume":"280","author":"Li","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"41614","DOI":"10.1074\/jbc.M110.153890","article-title":"Distinct Modes of Inhibition by Sclerostin on Bone Morphogenetic Protein and Wnt Signaling Pathways","volume":"285","author":"Krause","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4012","DOI":"10.1002\/art.37697","article-title":"Sclerostin antibody prevents particle-induced implant loosening by stimulating bone formation and inhibiting bone resorption in a rat model","volume":"64","author":"Liu","year":"2012","journal-title":"Arthr. Care Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.3892\/ijmm.2012.1145","article-title":"MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis through downregulation of RANK\/RANKL in a murine osteolysis model","volume":"30","author":"Chen","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41467-020-20194-0","article-title":"Structural basis for nuclear import selectivity of pioneer transcription factor SOX2","volume":"12","author":"Jagga","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1177\/147323001003800616","article-title":"Effects of a Cannabinoid Receptor 2 Selective Antagonist on the Inflammatory Reaction to Titanium Particles In Vivo and In Vitro","volume":"38","author":"Zhou","year":"2010","journal-title":"J. Int. Med. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1525-1594.2012.01568.x","article-title":"Inhibition of the PI3K\/AKT Pathway Reduces Tumor Necrosis Factor-Alpha Production in the Cellular Response to Wear Particles In Vitro","volume":"37","author":"Huang","year":"2013","journal-title":"Artif. Organs"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bone.2010.09.024","article-title":"Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening","volume":"48","author":"Aspenberg","year":"2011","journal-title":"Bone"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1002\/jor.24044","article-title":"Discovery of biomarkers to identify peri-implant osteolysis before radiographic diagnosis","volume":"36","author":"Ross","year":"2018","journal-title":"J. Orthop. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1007\/s00402-004-0695-0","article-title":"Increased bone turnover as reflected by biochemical markers in patients with potentially unstable fixation of the tibial component","volume":"124","author":"Li","year":"2004","journal-title":"Arch. Orthop. Trauma Surg."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/9\/12\/764\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:33:45Z","timestamp":1760146425000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/9\/12\/764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,4]]},"references-count":89,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["bioengineering9120764"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering9120764","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,4]]}}}