{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:54:44Z","timestamp":1773816884605,"version":"3.50.1"},"reference-count":94,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDB\/04539\/2020"],"award-info":[{"award-number":["UIDB\/04539\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDP\/04539\/2020"],"award-info":[{"award-number":["UIDP\/04539\/2020"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["LA\/P\/0058\/2020"],"award-info":[{"award-number":["LA\/P\/0058\/2020"]}]},{"name":"Centre for Mechanical Engineering, Materials and Processes","award":["UID\/00285\/2025"],"award-info":[{"award-number":["UID\/00285\/2025"]}]},{"name":"Centre for Mechanical Engineering, Materials and Processes","award":["LA\/P\/0112\/2020"],"award-info":[{"award-number":["LA\/P\/0112\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is characterized by exposed necrotic bone that often progresses with increasing pain and impaired quality of life. Zoledronate, the most potent and widely used bisphosphonate, has been strongly associated with BRONJ development following invasive dental procedures. Given the rising incidence of BRONJ, understanding and implementing effective preventive strategies have become imperative. Biomaterials based on synthetic hydroxyapatite and beta-tricalcium phosphate have been investigated as potential preventive agents. Their therapeutic rationale is supported by two key principles: the well-documented chemical interaction of calcium phosphates with bisphosphonates when used as drug carriers, and the established clinical use of synthetic calcium phosphate biomaterials in dentistry for bone regeneration. This review examines the underlying mechanisms of this preventive therapeutic strategy and evaluates studies investigating synthetic calcium phosphate biomaterials for BRONJ prevention through zoledronate adsorption at jaw wound sites, thereby reducing soft tissue toxicity and promoting healing. The evidence supports the protective effect of these biomaterials as a scientifically grounded preventive approach for BRONJ.<\/jats:p>","DOI":"10.3390\/jfb17030145","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:13:14Z","timestamp":1773659594000},"page":"145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Calcium Phosphate Bone Substitutes in the Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw: A Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3914-2423","authenticated-orcid":false,"given":"Siri","family":"Paulo","sequence":"first","affiliation":[{"name":"Institute of Endodontics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4185-7871","authenticated-orcid":false,"given":"Ana Margarida","family":"Abrantes","sequence":"additional","affiliation":[{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Medical Imaging and Radiotherapy Department, Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, 3046-854 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0689-6007","authenticated-orcid":false,"given":"Mafalda","family":"Laranjo","sequence":"additional","affiliation":[{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9269-5417","authenticated-orcid":false,"given":"Carlos Miguel","family":"Marto","sequence":"additional","affiliation":[{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Institute of Integrated Clinical Practice, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Institute of Experimental Pathology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Laboratory for Evidence-Based Sciences and Precision Dentistry, University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6154-4173","authenticated-orcid":false,"given":"Anabela","family":"Paula","sequence":"additional","affiliation":[{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Institute of Integrated Clinical Practice, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Laboratory for Evidence-Based Sciences and Precision Dentistry, University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Trancoso","sequence":"additional","affiliation":[{"name":"Egas Moniz School of Health & Science, Department of Oral Surgery and Oral Medicine, Campus Universit\u00e1rio, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal"},{"name":"Centro de Investiga\u00e7\u00e3o Interdisciplinar Egas Moniz (CiiEM), Campus Universit\u00e1rio, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-1650","authenticated-orcid":false,"given":"Filomena","family":"Botelho","sequence":"additional","affiliation":[{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Institute of Biophysics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Medical Imaging and Radiotherapy Department, Polytechnic Institute of Coimbra, ESTESC-Coimbra Health School, 3046-854 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arm\u00e9nio","family":"Serra","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Faculty of Sciences and Technology, University of Coimbra, 3030-790 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5968-6161","authenticated-orcid":false,"given":"Manuel Marques","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Institute of Endodontics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-354 Coimbra, Portugal"},{"name":"Laboratory for Evidence-Based Sciences and Precision Dentistry, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"CEMMPRE\u2014Centre for Mechanical Engineering, Materials and Processes, Chemical Engineering Department, University of Coimbra, 3000-548 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bonr.2018.06.007","article-title":"Bisphosphonate Conjugation for Bone Specific Drug Targeting","volume":"9","author":"Farrell","year":"2018","journal-title":"Bone Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"300","DOI":"10.23736\/S0026-4806.18.05688-4","article-title":"Clodronate in the Management of Different Musculoskeletal Conditions","volume":"109","author":"Frediani","year":"2018","journal-title":"Minerva Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s12306-018-0548-6","article-title":"Antiresorptive Drug-Related Osteonecrosis of the Jaws, Literature Review and 5 Years of Experience","volume":"103","author":"Bernardi","year":"2019","journal-title":"Musculoskelet. Surg."},{"key":"ref_4","unstructured":"Santora, A.C., and Saag, K.G. (2023). Bisphosphonate. Firestein & Kelley\u2019s Textbook of Rheumatology, 2-Volume Set, Elsevier."},{"key":"ref_5","first-page":"92","article-title":"Osteoporosis: A Review of Treatment Options","volume":"43","author":"Tu","year":"2018","journal-title":"Pharm. Ther."},{"key":"ref_6","first-page":"336","article-title":"Aminobisphosphonates: Reconsideration 25 Years after Their Approval for the Treatment of Osteoporosis","volume":"159","year":"2022","journal-title":"Med. Cl\u00edn. (Engl. Ed.)"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100470","DOI":"10.1016\/j.jbo.2023.100470","article-title":"Management of Bone Metastasis with Zoledronic Acid: A Systematic Review and Bayesian Network Meta-Analysis","volume":"39","author":"Lorange","year":"2023","journal-title":"J. Bone Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ctrv.2011.09.003","article-title":"Direct and Indirect Anticancer Activity of Bisphosphonates: A Brief Review of Published Literature","volume":"38","author":"Gnant","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.drup.2005.07.001","article-title":"Metastases and Their Microenvironments: Linking Pathogenesis and Therapy","volume":"8","author":"Sierra","year":"2005","journal-title":"Drug Resist. Updates"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1038\/sj.bjc.6604382","article-title":"Risks and Benefits of Bisphosphonates","volume":"98","author":"Coleman","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.joms.2022.02.008","article-title":"American Association of Oral and Maxillofacial Surgeons\u2019 Position Paper on Medication-Related Osteonecrosis of the Jaws\u20142022 Update","volume":"80","author":"Ruggiero","year":"2022","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.eprac.2025.06.003","article-title":"Dental Implant Failure and Medication-Related Osteonecrosis of the Jaw Related to Dental Implants in Patients Taking Antiresorptive Therapy for Osteoporosis: A Systematic Review and Meta-Analysis","volume":"31","author":"Mirza","year":"2025","journal-title":"Endocr. Pract."},{"key":"ref_13","first-page":"e195","article-title":"Medication-Related Osteonecrosis of the Jaw Associated with Implant and Regenerative Treatments: Systematic Review","volume":"24","year":"2019","journal-title":"Med. Oral Patol. Oral Cir. Bucal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/JPER.21-0611","article-title":"Association between Periodontal Disease, Tooth Extraction, and Medication-Related Osteonecrosis of the Jaw in Women Receiving Bisphosphonates: A National Cohort-Based Study","volume":"94","author":"Kwoen","year":"2023","journal-title":"J. Periodontol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/jop.12963","article-title":"Association between Periodontitis and Medication-Related Osteonecrosis of the Jaw: A Systematic Review and Meta-Analysis","volume":"49","author":"Carballo","year":"2020","journal-title":"J. Oral Pathol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1002\/jbmr.379","article-title":"Periodontal Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in the Rat","volume":"26","author":"Aghaloo","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Stelea, C.G., Bologa, E., Boi\u0219teanu, O., Platon, A.L., Stelea, \u0218.O., Gele\u021bu, G.L., Onic\u0103, C.A., \u0218ulea, D., Ciofu, M.L., and Costan, V.V. (2025). Bisphosphonate-Related Osteonecrosis of the Jaw: A 10-Year Analysis of Risk Factors and Clinical Outcomes. J. Clin. Med., 14.","DOI":"10.20944\/preprints202505.1868.v1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.ijom.2015.01.026","article-title":"Treatment Strategies and Outcomes of Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) with Characterization of Patients: A Systematic Review","volume":"44","author":"Fliefel","year":"2015","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40729-021-00323-0","article-title":"Clinical Considerations for Medication-Related Osteonecrosis of the Jaw: A Comprehensive Literature Review","volume":"7","author":"Kawahara","year":"2021","journal-title":"Int. J. Implant Dent."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jpor.2014.08.001","article-title":"Osteonecrosis of the Jaw in Patients with Dental Prostheses Being Treated with Bisphosphonates or Denosumab","volume":"59","author":"Niibe","year":"2015","journal-title":"J. Prosthodont. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"151","DOI":"10.11005\/jbm.2015.22.4.151","article-title":"Medication Related Osteonecrosis of the Jaw: 2015 Position Statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons","volume":"22","author":"Kim","year":"2015","journal-title":"J. Bone Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s00774-016-0810-7","article-title":"Antiresorptive Agent-Related Osteonecrosis of the Jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw","volume":"35","author":"Yoneda","year":"2017","journal-title":"J. Bone Miner. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1054\/ijom.2002.0292","article-title":"Early Bone Healing Events in the Human Extraction Socket","volume":"31","author":"Devlin","year":"2002","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fogelman, I., Van Der Wall, H., and Gnanasegaran, G. (2012). Radionuclide and Hybrid Bone Imaging, Springer.","DOI":"10.1007\/978-3-642-02400-9"},{"key":"ref_25","first-page":"114","article-title":"The Healing Socket and Socket Regeneration","volume":"29","author":"Steiner","year":"2008","journal-title":"Compend. Contin. Educ. Dent."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.jcms.2019.06.004","article-title":"Gingival Fibroblasts and Medication-Related Osteonecrosis of the Jaw: Results by Real-Time and Wound Healing in Vitro Assays","volume":"47","author":"Yuan","year":"2019","journal-title":"J. Cranio-Maxillofac. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.2147\/DDDT.S456811","article-title":"Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate","volume":"18","author":"Zhu","year":"2024","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1111\/j.1365-2141.2008.07504.x","article-title":"Effect of Zoledronic Acid on Oral Fibroblasts and Epithelial Cells: A Potential Mechanism of Bisphosphonate-associated Osteonecrosis","volume":"144","author":"Scheper","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.joms.2008.01.026","article-title":"Inhibition of Oral Mucosal Cell Wound Healing by Bisphosphonates","volume":"66","author":"Landesberg","year":"2008","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00784-009-0266-4","article-title":"Influence of Bisphosphonates on Endothelial Cells, Fibroblasts, and Osteogenic Cells","volume":"14","author":"Walter","year":"2010","journal-title":"Clin. Oral Investig."},{"key":"ref_31","first-page":"1553","article-title":"A Novel Bioassay Model to Determine Clinically Significant Bisphosphonate Levels","volume":"17","author":"Scheper","year":"2009","journal-title":"Support. Care Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bullock, G., Miller, C.A., McKechnie, A., and Hearnden, V. (2021). A Review Into the Effects of Pamidronic Acid and Zoledronic Acid on the Oral Mucosa in Medication-Related Osteonecrosis of the Jaw. Front. Oral Health, 2.","DOI":"10.3389\/froh.2021.822411"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1016\/j.joms.2010.07.017","article-title":"Osteonecrosis of the Jaw: Effect of Bisphosphonate Type, Local Concentration, and Acidic Milieu on the Pathomechanism","volume":"68","author":"Otto","year":"2010","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1007\/s00784-011-0596-x","article-title":"Bisphosphonate-Associated Osteonecrosis of the Mandible: Reliable Soft Tissue Reconstruction Using a Local Myofascial Flap","volume":"16","author":"Lemound","year":"2012","journal-title":"Clin. Oral Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1590\/S1678-77572011000400001","article-title":"A Systematic Review of Microsurgical Reconstruction of the Jaws Using Vascularized Fibula Flap Technique in Patients with Bisphosphonate-Related Osteonecrosis","volume":"19","author":"Sacco","year":"2011","journal-title":"J. Appl. Oral Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00784-017-2163-6","article-title":"The Effects of Ozone Application on Genotoxic Damage and Wound Healing in Bisphosphonate-Applied Human Gingival Fibroblast Cells","volume":"22","author":"Akdeniz","year":"2018","journal-title":"Clin. Oral Investig."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Porcaro, G., Caccianiga, P., Bader, A.A., Caccianiga, G., Porcaro, G., Caccianiga, P., Bader, A.A., and Caccianiga, G. (2022). Treatment of Medication-Related Osteonecrosis of the Jaw (MRONJ) with Er:YaG Laser and Ozone Therapy: A Case Series. Inventions, 7.","DOI":"10.3390\/inventions7040097"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10006-020-00831-0","article-title":"Laser Surgery in Management of Medication-Related Osteonecrosis of the Jaws: A Meta-Analysis","volume":"24","author":"Momesso","year":"2020","journal-title":"Oral Maxillofac. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1200\/JCO.19.02192","article-title":"Teriparatide Promotes Bone Healing in Medication-Related Osteonecrosis of the Jaw: A Placebo-Controlled, Randomized Trial","volume":"38","author":"Sim","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e469","DOI":"10.1097\/MJT.0000000000001182","article-title":"Teriparatide for the Treatment of Medication-Related Osteonecrosis of the Jaw","volume":"28","author":"Chopra","year":"2021","journal-title":"Am. J. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bullock, G., Miller, C., McKechnie, A., and Hearnden, V. (2020). Synthetic Hydroxyapatite Inhibits Bisphosphonate Toxicity to the Oral Mucosa in Vitro. Materials, 13.","DOI":"10.3390\/ma13092086"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chin, K.-Y., Ekeuku, S.O., and Trias, A. (2022). The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.878556"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ferreira, F., Faria, C., and Pozza, D.H. (2025). Autologous Platelet Concentrates in the Management of Medication-Related Osteonecrosis of the Jaw: A Systematic Review. Medicina, 61.","DOI":"10.3390\/medicina61081496"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.jcms.2024.01.007","article-title":"The Effectiveness of Autologous Platelet Concentrates in Prevention and Treatment of Medication-Related Osteonecrosis of the Jaws: A Systematic Review","volume":"52","author":"Nowak","year":"2024","journal-title":"J. Cranio-Maxillofac. Surg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3109\/10611869808995866","article-title":"Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. I.v. Effects of Osteotropic Estradiol on Bone Mineral Density and Uterine Weight in Ovariectomized Rats","volume":"5","author":"Fujisaki","year":"1998","journal-title":"J. Drug Target."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.actbio.2011.11.017","article-title":"Calcium Phosphate Ceramic Systems in Growth Factor and Drug Delivery for Bone Tissue Engineering: A Review","volume":"8","author":"Bose","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ijpharm.2013.01.031","article-title":"Drug Carriers in Osteoporosis: Preparation, Drug Encapsulation and Applications","volume":"445","author":"Miladi","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3541","DOI":"10.1016\/j.actbio.2012.06.022","article-title":"Controlling the Biological Function of Calcium Phosphate Bone Substitutes with Drugs","volume":"8","author":"Verron","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00884","DOI":"10.1016\/j.heliyon.2018.e00884","article-title":"The Use of Hydroxyapatite Bone Substitute Grafting for Alveolar Ridge Preservation, Sinus Augmentation, and Periodontal Bone Defect: A Systematic Review","volume":"4","author":"Dewi","year":"2018","journal-title":"Heliyon"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1016\/j.jeurceramsoc.2012.01.018","article-title":"Calcium Phosphate Porous Pellets as Drug Delivery Systems: Effect of Drug Carrier Composition on Drug Loading and in Vitro Release","volume":"32","author":"Baradari","year":"2012","journal-title":"J. Eur. Ceram. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.actamat.2012.10.039","article-title":"Bioceramics for Drug Delivery","volume":"61","author":"Arcos","year":"2013","journal-title":"Acta Mater."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Shu, T., Wang, S., Liu, Z., Cheng, Y., Li, A., and Pei, D. (2022). The Osteoinductivity of Calcium Phosphate-Based Biomaterials: A Tight Interaction with Bone Healing. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.911180"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"99","DOI":"10.4028\/www.scientific.net\/KEM.377.99","article-title":"Calcium Phosphates\/Biphosphonates Combinations\u2026Towards a Therapeutic Synergy","volume":"377","author":"Bujoli","year":"2008","journal-title":"Key Eng. Mater."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1097\/00003086-200002000-00003","article-title":"Bone Graft Materials. An Overview of the Basic Science","volume":"371","author":"Bauer","year":"2000","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.archoralbio.2003.12.004","article-title":"Hydroxyapatite Solubility in Simple Inorganic Solutions","volume":"49","author":"Chen","year":"2004","journal-title":"Arch. Oral Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/0021-9797(78)90016-4","article-title":"A New Two-Site Model for Hydroxyapatite Dissolution in Acidic Media","volume":"67","author":"Fox","year":"1978","journal-title":"J. Colloid Interface Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/j.msec.2012.12.075","article-title":"Chemical Characterization of Hydroxyapatite Obtained by Wet Chemistry in the Presence of V, Co, and Cu Ions","volume":"33","author":"Moseke","year":"2013","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6150","DOI":"10.1016\/j.biomaterials.2006.08.025","article-title":"Human Bone Marrow Stromal Cells: In Vitro Expansion and Differentiation for Bone Engineering","volume":"27","author":"Ciapetti","year":"2006","journal-title":"Biomaterials"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.bsecv.2022.05.002","article-title":"Calcium Phosphate Cements Improved by Addition of Carbonated Hydroxyapatite Type B","volume":"62","author":"Ruiz","year":"2023","journal-title":"Bolet\u00edn Soc. Espa\u00f1ola Cer\u00e1mica Vidr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.addr.2012.07.009","article-title":"How Smart Do Biomaterials Need to Be? A Translational Science and Clinical Point of View","volume":"65","author":"Holzapfel","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1023\/B:JMSM.0000021102.68509.65","article-title":"Relationship between Bioceramics Sintering and Micro-Particles-Induced Cellular Damages","volume":"15","author":"Lu","year":"2004","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/0142-9612(91)90025-6","article-title":"Cellular Activity of Osteoblasts in the Presence of Hydroxyapatite: An in Vitro Experiment","volume":"12","author":"Gregoire","year":"1991","journal-title":"Biomaterials"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.actbio.2008.11.022","article-title":"Calcium Phosphate-Based Particles Influence Osteogenic Maturation of Human Mesenchymal Stem Cells","volume":"5","author":"Bensiamar","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1248\/bpb.20.1183","article-title":"Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. V. Biological Disposition and Targeting Characteristics of Osteotropic Estradiol","volume":"20","author":"Fujisaki","year":"1997","journal-title":"Biol. Pharm. Bull."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1016\/j.addr.2012.01.008","article-title":"Calcium Phosphate Cements as Drug Delivery Materials","volume":"64","author":"Ginebra","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"399","DOI":"10.4028\/www.scientific.net\/KEM.284-286.399","article-title":"A Novel Drug Delivery System for Bisphosphonates: Innovative Strategy for Local Treatment of Bone Resorption","volume":"284\u2013286","author":"Josse","year":"2005","journal-title":"Key Eng. Mater."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1016\/j.biomaterials.2004.05.019","article-title":"Novel Biomaterials for Bisphosphonate Delivery","volume":"26","author":"Josse","year":"2005","journal-title":"Biomaterials"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1021\/cm702584d","article-title":"Reaction of Zoledronate with Beta-Tricalcium Phosphate for the Design of Potential Drug Device Combined Systems","volume":"20","author":"Fayon","year":"2008","journal-title":"Chem. Mater."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Bigi, A., Boanini, E., Bigi, A., and Boanini, E. (2018). Calcium Phosphates as Delivery Systems for Bisphosphonates. J. Funct. Biomater., 9.","DOI":"10.3390\/jfb9010006"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jct.2016.02.005","article-title":"Thermodynamic Study of the Interaction between Calcium and Zoledronic Acid by Calorimetry","volume":"97","author":"Sauzet","year":"2016","journal-title":"J. Chem. Thermodyn."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"015005","DOI":"10.1088\/1748-6041\/7\/1\/015005","article-title":"The Chemical Composition of Synthetic Bone Substitutes Influences Tissue Reactions in Vivo: Histological and Histomorphometrical Analysis of the Cellular Inflammatory Response to Hydroxyapatite, Beta-Tricalcium Phosphate and Biphasic Calcium Phosphate Cer","volume":"7","author":"Ghanaati","year":"2012","journal-title":"Biomed. Mater."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Paulo, S., Laranjo, M., Abrantes, A.M., Casalta-Lopes, J., Santos, K., Gon\u00e7alves, A.C., Paula, A.B., Marto, C.M., Sarmento-Ribeiro, A.B., and Carrilho, E. (2019). Synthetic Calcium Phosphate Ceramics as a Potential Treatment for Bisphosphonate-Related Osteonecrosis of the Jaw. Materials, 12.","DOI":"10.3390\/ma12111840"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Paulo, S., Laranjo, M., Paula, A., Abrantes, A.M., Martins, J., Marto, C.M., Coelho, A., Casalta-Lopes, J., Carvalho, L., and Carrilho, E. (2020). Calcium Phosphate Ceramics Can Prevent Bisphosphonate-Related Osteonecrosis of the Jaw. Materials, 13.","DOI":"10.3390\/ma13081955"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Mikai, A., Ono, M., Tosa, I., Nguyen, H.T.T., Hara, E.S., Nosho, S., Kimura-Ono, A., Nawachi, K., Takarada, T., and Kuboki, T. (2020). BMP-2\/\u03b2-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197028"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Tanaka, Y., Aung, K.T., Ono, M., Mikai, A., Dang, A.T., Hara, E.S., Tosa, I., Ishibashi, K., Ono-Kimura, A., and Nawachi, K. (2021). Suppression of Bone Necrosis around Tooth Extraction Socket in a MRONJ-like Mouse Model by E-RhBMP-2 Containing Artificial Bone Graft Administration. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312823"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"16510","DOI":"10.1038\/s41598-022-20128-4","article-title":"Beta Tricalcium Phosphate, Either Alone or in Combination with Antimicrobial Photodynamic Therapy or Doxycycline, Prevents Medication-Related Osteonecrosis of the Jaw","volume":"12","author":"Hadad","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Sacco, R., Sartoretto, S.C., de Brito Resende, R.F., de Albuquerque Calasans-Maia, J., Rossi, A.M., de Souza Lima, V.H., de Almeida Barros Mour\u00e3o, C.F., Granjeiro, J.M., Yates, J., and Calasans-Maia, M.D. (2022). The Use of Hydroxyapatite Loaded with Doxycycline (HADOX) in Dentoalveolar Surgery as a Risk-Reduction Therapeutic Protocol in Subjects Treated with Different Bisphosphonate Dosages. Medicina, 59.","DOI":"10.3390\/medicina59010046"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1177\/19433875211048367","article-title":"The Role of Bone Grafts in Preventing Medication-Related Osteonecrosis of the Jaw: Histomorphometric, Immunohistochemical, and Clinical Evaluation in Animal Model","volume":"15","author":"Balbas","year":"2022","journal-title":"Craniomaxillofac. Trauma Reconstr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"16032","DOI":"10.1038\/s41598-023-43315-3","article-title":"Impact of Beta-Tricalcium Phosphate on Preventing Tooth Extraction-Triggered Bisphosphonate-Related Osteonecrosis of the Jaw in Rats","volume":"13","author":"Funayama","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6648","DOI":"10.3390\/ijms25126648","article-title":"Local E-RhBMP-2\/\u03b2-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model","volume":"25","author":"Dang","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.pdpdt.2009.10.008","article-title":"Photodynamic Therapy for Localized Infections\u2014State of the Art","volume":"6","author":"Dai","year":"2009","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S8756-3282(00)00358-6","article-title":"Direct Stimulation of Osteoclastic Bone Resorption by Bone Morphogenetic Protein (BMP)-2 and Expression of BMP Receptors in Mature Osteoclasts","volume":"27","author":"Kaneko","year":"2000","journal-title":"Bone"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0168-1656(01)00425-4","article-title":"Renaturation and Purification of Bone Morphogenetic Protein-2 Produced as Inclusion Bodies in High-Cell-Density Cultures of Recombinant Escherichia coli","volume":"94","author":"Vallejo","year":"2002","journal-title":"J. Biotechnol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.joms.2008.12.002","article-title":"Imaging Findings in Bisphosphonate-Related Osteonecrosis of Jaws","volume":"67","author":"Arce","year":"2009","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1259\/dmfr\/27458726","article-title":"Clinical and Diagnostic Imaging of Bisphosphonate-Associated Osteonecrosis of the Jaws","volume":"35","author":"Chiandussi","year":"2006","journal-title":"Dentomaxillofac. Radiol."},{"key":"ref_86","first-page":"1385","article-title":"Bone Scintigraphy and SPECT\/CT of Bisphosphonate-Induced Osteonecrosis of the Jaw","volume":"50","author":"Dore","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.archoralbio.2003.12.003","article-title":"Quantitative Assessment of Post-Extraction Healing and Alveolar Ridge Remodelling of the Mandible in Female Rats","volume":"49","author":"Elsubeihi","year":"2004","journal-title":"Arch. Oral Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1902\/jop.2006.050367","article-title":"Accuracy of Cone Beam Computed Tomography for Periodontal Defect Measurements","volume":"77","author":"Misch","year":"2006","journal-title":"J. Periodontol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.bone.2013.08.005","article-title":"Prospective Biomarker Evaluation in Patients with Osteonecrosis of the Jaw Who Received Bisphosphonates","volume":"57","author":"Kim","year":"2013","journal-title":"Bone"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.archoralbio.2010.07.005","article-title":"Quantitative Scintigraphic Analysis of Pulp Revascularization in Autotransplanted Teeth in Dogs","volume":"55","author":"Ferreira","year":"2010","journal-title":"Arch. Oral Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"128","DOI":"10.4236\/ojst.2013.32024","article-title":"Comparison of the Apical Seal on Filled Root Canals with Topseal\u00ae vs MTA Fillapex\u00ae Sealers: A Quantitative Scintigraphic Analysis","volume":"3","author":"Ferreira","year":"2013","journal-title":"Open J. Stomatol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Marques-Ferreira, M., Abrantes, A.M., Paula, A., Laranjo, M., Pires, A.S., Caramelo, F., Segura-Egea, J.J., Brito, A., Carvalho, L., and Botelho, M.F. (2023). The Role of Apical Periodontitis Disease in the Development of Bisphosphonate-Related Osteonecrosis of the Jaw: An Animal Study. Dent. J., 11.","DOI":"10.3390\/dj11070168"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1111\/jop.12156","article-title":"Histomorphologic Characteristics of Bisphosphonate-related Osteonecrosis of the Jaw","volume":"43","author":"Koerdt","year":"2014","journal-title":"J. Oral Pathol. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.bonr.2017.03.001","article-title":"Spatial Heterogeneity in the Canalicular Density of the Osteocyte Network in Human Osteons","volume":"6","author":"Repp","year":"2017","journal-title":"Bone Rep."}],"container-title":["Journal of Functional Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/3\/145\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T05:56:33Z","timestamp":1773813393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4983\/17\/3\/145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":94,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["jfb17030145"],"URL":"https:\/\/doi.org\/10.3390\/jfb17030145","relation":{},"ISSN":["2079-4983"],"issn-type":[{"value":"2079-4983","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]}}}