{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T03:30:10Z","timestamp":1784863810347,"version":"3.55.0"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel (CAPES)","doi-asserted-by":"publisher","award":["0001"],"award-info":[{"award-number":["0001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordination for the Improvement of Higher Education Personnel (CAPES)","doi-asserted-by":"publisher","award":["308408\/2023-3"],"award-info":[{"award-number":["308408\/2023-3"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Research Productivity Scholarship","doi-asserted-by":"publisher","award":["0001"],"award-info":[{"award-number":["0001"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Research Productivity Scholarship","doi-asserted-by":"publisher","award":["308408\/2023-3"],"award-info":[{"award-number":["308408\/2023-3"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomimetics"],"abstract":"<jats:p>Osteoporosis compromises bone quality and impairs implant osseointegration. Since an adequate bone bed is essential for implant stability and success, this study evaluated the effects of implant surface functionalization with zoledronic acid (ZOL), alone or combined with ruterpy (TERPY), on peri-implant bone healing in healthy (SHAM) and osteoporotic (OVX) rats. ZOL has antiresorptive properties, while TERPY exhibits osteoinductive potential. The hypothesis was that ZOL + TERPY would act synergistically by inhibiting bone resorption and promoting new bone formation. Sixty-six female Wistar rats (3 months old) were divided into six groups (n = 11) according to systemic condition (SHAM or OVX) and implant type: conventional (CONV), ZOL, or ZOL + TERPY. Surgeries (sham or bilateral ovariectomy) were performed on day 0, and implants were placed in the tibial metaphysis on day 90. Fluorochromes were administered on days 104 (calcein) and 114 (alizarin), and euthanasia was performed on day 118. Samples were analyzed histologically via confocal microscopy and micro-computed tomography (Micro-CT). The ZOL + TERPY groups demonstrated significantly accelerated peri-implant bone repair, showing greater bone formation and organization; improved BV\/TV, Tb.N, and I.S.; and reduced Tb.Sp and Po.Tot compared to CONV and ZOL-alone groups. In conclusion, ZOL + TERPY enhances and speeds bone healing, even under osteoporotic conditions.<\/jats:p>","DOI":"10.3390\/biomimetics10080547","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T15:53:37Z","timestamp":1755705217000},"page":"547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Titanium Implants Functionalized with Zoledronic Acid Associated with Ruterpy Accelerate Peri-Implant Repair in Healthy and Osteoporotic Rats"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6251-8604","authenticated-orcid":false,"given":"Laura Vidoto","family":"Paludetto","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isadora","family":"Breseghello","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina Cruz Tfaile","family":"Frasnelli","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e1bio Roberto de Souza","family":"Batista","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2787-6160","authenticated-orcid":false,"given":"Paulo Roberto","family":"Botacin","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0315-6161","authenticated-orcid":false,"given":"Cristina","family":"Antoniali","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7734-4069","authenticated-orcid":false,"given":"Paulo Noronha","family":"Lisboa-Filho","sequence":"additional","affiliation":[{"name":"Department of Physics and Meteorology, Bauru Sciences School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Bauru 17033-360, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-6966","authenticated-orcid":false,"given":"Roberta","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Ara\u00e7atuba Dental School, S\u00e3o Paulo State University J\u00falio de Mesquita Filho\u2014UNESP, Aracatuba 16015-050, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD US Health Disparities Collaborators (2022). Life expectancy by county, race, and ethnicity in the USA, 2000\u20132019: A systematic analysis of health disparities. Lancet, 400, 25\u201338.","DOI":"10.1016\/S0140-6736(22)00876-5"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/S0140-6736(18)32112-3","article-title":"Osteoporosis","volume":"393","author":"Compston","year":"2019","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S65","DOI":"10.1016\/0378-5122(96)01015-8","article-title":"Estrogen and bone metabolism","volume":"23","year":"1996","journal-title":"Maturitas"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1159\/000367692","article-title":"The endocrinology of ageing: A mini-review","volume":"61","author":"Jones","year":"2015","journal-title":"Gerontology"},{"key":"ref_5","first-page":"1","article-title":"Vital microscopy of bone marrow in rabbit","volume":"11","year":"1959","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pandey, C., Rokaya, D., and Bhattarai, B.P. (2022). Contemporary Concepts in Osseointegration of Dental Implants: A Review. BioMed Res. Int., 2022.","DOI":"10.1155\/2022\/6170452"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s00784-024-05929-3","article-title":"How far can we go? A 20-year meta-analysis of dental implant survival rates","volume":"28","author":"Kupka","year":"2024","journal-title":"Clin. Oral Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0022-3913(83)80101-2","article-title":"Osseointegration and its experimental background","volume":"50","year":"1983","journal-title":"J. Prosthet. Dent."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.5312\/wjo.v6.i2.311","article-title":"Impact of osteoporosis in dental implants: A systematic review","volume":"6","author":"Giro","year":"2015","journal-title":"World J. Orthop."},{"key":"ref_10","first-page":"206","article-title":"Osteoporosis\u2019 effects on dental implants osseointegration and survival rate: A systematic review of clinical studies","volume":"56","author":"Shibli","year":"2025","journal-title":"Quintessence Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/sj.ebd.6401307","article-title":"Is osteoporosis a risk factor for implant survival orfailure?","volume":"19","author":"Grisa","year":"2018","journal-title":"Evid.-Based Dent."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1007\/s00784-023-05005-2","article-title":"Do dental implants placed in patients with osteoporosis have higher risks of failure and marginal bone loss compared to those in healthy patients? A systematic review with meta-analysis","volume":"27","author":"Lemos","year":"2023","journal-title":"Clin. Oral Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ijom.2017.05.021","article-title":"Dental implants in patients with osteoporosis: A systematic review with meta-analysis","volume":"47","author":"Kudo","year":"2018","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_14","first-page":"905","article-title":"Efeito do estado osteopor\u00f3tico na sobreviv\u00eancia de implantes dent\u00e1rios de tit\u00e2nio","volume":"23","author":"Holahan","year":"2008","journal-title":"Int. J. Oral Maxillofac. Implant."},{"key":"ref_15","first-page":"17455057231176655","article-title":"An overview of the management of osteoporosis in the aging female population","volume":"19","author":"Amin","year":"2023","journal-title":"Women\u2019s Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e220334","DOI":"10.20945\/2359-4292-2022-0334","article-title":"Long-term consequences of osteoporosis therapy with bisphosphonates","volume":"68","author":"Gehrke","year":"2023","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_17","first-page":"D3626","article-title":"Zoledroninezuur zinvol bij osteopenie? [Zoledronic acid; useful in osteopenia?]","volume":"163","author":"Smit","year":"2019","journal-title":"Ned. Tijdschr. Geneeskd."},{"key":"ref_18","first-page":"1564","article-title":"Zoledronic acid and fracture risk: A meta-analysis of 12 randomized controlled trials","volume":"25","author":"He","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.bone.2004.10.004","article-title":"Calcium phosphate drug delivery system: Influence of local zoledronate release on bone implant osteointegration","volume":"36","author":"Peter","year":"2005","journal-title":"Bone"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.bone.2008.10.054","article-title":"Effect of combined local treatment with ovariectomized rats","volume":"44","author":"Gao","year":"2009","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.22203\/eCM.v016a02","article-title":"Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study","volume":"16","author":"Stadelmann","year":"2008","journal-title":"Eur. Cell Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2106\/JBJS.I.00518","article-title":"Locally delivered bisphosphonate for enhancement of bone formation and implant fixation","volume":"91","author":"Bobyn","year":"2009","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00198-012-2258-5","article-title":"Promotion of peri-implant bone healing by systemically administered parathyroid hormone (1-34) and zoledronic acid adsorbed onto the implant surface","volume":"24","author":"Li","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1166\/jbn.2018.2635","article-title":"Sustained release of zoledronic acid from mesoporous TiO2-layered implant enhances implant osseointegration in osteoporotic condition","volume":"14","author":"Liu","year":"2018","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"333","DOI":"10.22203\/eCM.v037a20","article-title":"Systemic sclerostin antibody treatment increases osseointegration and biomechanical competence of zoledronic- acid-coated dental implants in a rat osteoporosis model","volume":"37","author":"Korn","year":"2019","journal-title":"Eur. Cell Mater."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Paludetto, L.V., Monteiro, N.G., Breseghello, I., de Souza Batista, F.R., Antoniali, C., Lisboa-Filho, P.N., and Okamoto, R. (2024). Smart Delivery of Biomolecules Interfering with Peri-Implant Repair in Osteoporotic Rats. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25168963"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Inoue, B.K.N., Paludetto, L.V., Monteiro, N.G., Batista, F.R.S., Kitagawa, I.L., da Silva, R.S., Antoniali, C., Lisboa Filho, P.N., and Okamoto, R. (2023). Synergic Action of Systemic Risedronate and Local Rutherpy in Peri-implantar Repair of Ovariectomized Rats: Biomechanical and Molecular Analysis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216153"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE Guidelines 2.0: Updated Guidelines for Reporting Animal Research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Neto, F.C., Breseghello, I., Paludetto, L.V., Frasnelli, S.C., de Souza Batista, F.R., Blay, A., Boni, A., J\u00fanior, F.C., and Okamoto, R. (2025). Effect of Er:YAG laser bone bed milling, with or without photobiomodulation, on the bone repair process of additive manufacturing implants in rats. J. Photochem. Photobiol., 26\u201327.","DOI":"10.1016\/j.jpap.2025.100260"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1007\/s00198-020-05431-y","article-title":"Teriparatide improves microarchitectural characteristics of peri-implant bone in orchiectomized rats","volume":"31","author":"Grandfield","year":"2020","journal-title":"Osteoporos. Int."},{"key":"ref_31","unstructured":"Yogui, F.C. (2020). Caracteriza\u00e7\u00e3o e Avalia\u00e7\u00e3o Randomizada de Superf\u00edcies de Liga de Tit\u00e2nio Modificada por Hidroxiapatita e Hidroxia- 635 Patita Incorporada com Estr\u00f4ncio em Ratas Saud\u00e1veis e Osteopor\u00f3ticas. [Master\u2019s Thesis, Universidade Estadual Paulista \u2018\u2019Julio de Mesquita Filho\u2019\u2019]."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1034\/j.1600-0765.2002.01601.x","article-title":"Effects of ovariectomy on trabecular structures of rat alveolar bone","volume":"37","author":"Tanaka","year":"2002","journal-title":"J. Periodontal Res."},{"key":"ref_33","unstructured":"Long, J.A., and Evans, H.M. (1922). The Oestrus Cycle in the Rat and Its Related Phenomena, University of California Press."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.5897\/AJPP2013.3817","article-title":"Antiosteoporotic effect of Coelatura aegyptiaca shell powder on ovariectomized rats","volume":"7","author":"Sayed","year":"2013","journal-title":"Afr. J. Pharm. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro- computed tomography","volume":"25","author":"Bouxsein","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1053\/sonc.2002.37421","article-title":"Preclinical pharmacology of zoledronic acid","volume":"29","author":"Green","year":"2002","journal-title":"Semin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3934\/molsci.2020003","article-title":"How can nitric oxide help osteogenesis?","volume":"7","author":"Nascimento","year":"2020","journal-title":"AIMS Mol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.addr.2012.03.002","article-title":"Local Delivery of Nitric Oxide: Targeted Delivery of Therapeutics to Bone and Connective Tissues","volume":"64","author":"Storm","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Liu, W., Meng, Z., and Wang, G. (2022). The Efficacy of Nitrates for Bone Health: A Systematic Review and Meta-Analysis of Observational and Randomized Controlled Studies. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.833932"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s00198-007-0540-8","article-title":"Mechanisms of action of bisphosphonates: Similarities and differences and their potential influence on clinical efficacy","volume":"19","author":"Russell","year":"2008","journal-title":"Osteoporos. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1749-6632.2009.05230.x","article-title":"Nitric oxide and bone","volume":"1192","author":"Wimalawansa","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2205336","DOI":"10.1002\/advs.202205336","article-title":"Nitric Oxide-Releasing Bioinspired Scaffold for Exquisite Regeneration of Osteoporotic Bone via Regulation of Homeostasis","volume":"10","author":"Lee","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S8756-3282(98)00070-2","article-title":"Nitric oxide synthase expression in bone cells","volume":"23","author":"Fox","year":"1998","journal-title":"Bone"}],"container-title":["Biomimetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2313-7673\/10\/8\/547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:31:43Z","timestamp":1760034703000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2313-7673\/10\/8\/547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,20]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["biomimetics10080547"],"URL":"https:\/\/doi.org\/10.3390\/biomimetics10080547","relation":{},"ISSN":["2313-7673"],"issn-type":[{"value":"2313-7673","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,20]]}}}