{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T15:55:29Z","timestamp":1768838129561,"version":"3.49.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T00:00:00Z","timestamp":1542067200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T00:00:00Z","timestamp":1542067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>It has been recognized that the operative stabilization of osteoporotic fractures should be followed up with an appropriate osteoporosis treatment in order to decrease the risk of repeated fractures. Despite the good clinical results of strontium ranelate (SrRan) towards the osteoporosis treatment, high drug doses and long treatment period cause an increased risk of serious side effects. Novel local SrRan\/poly(lactic acid) (SrRan\/PLA) delivery systems containing from 3.57\u2009\u00b1\u20090.28\u2009wt% to 24.39\u2009\u00b1\u20090.91\u2009wt% of active substance were developed. In order to resemble the naturally occurring processes, osteogenic media (OM) was used as a release medium for long term (121 days) <jats:italic>in vitro<\/jats:italic> drug release studies and UV\/VIS method for the determination of SrRan content in OM was developed and validated. Biomimetic calcium phosphate precipitates were found on the surface and in the pores of prepared delivery system after microcapsule exposure to OM for 121 days as well as SrRan particles, indicating that the release of the drug have not been completed within 121 days. <jats:italic>In vitro<\/jats:italic> cell viability evaluation approved no cytotoxic effects of microcapsule suspensions and extracts.<\/jats:p>","DOI":"10.1038\/s41598-018-35197-7","type":"journal-article","created":{"date-parts":[[2018,11,7]],"date-time":"2018-11-07T13:03:55Z","timestamp":1541595835000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Development of local strontium ranelate delivery systems and long term in vitro drug release studies in osteogenic medium"],"prefix":"10.1038","volume":"8","author":[{"given":"Dagnija","family":"Loca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasija","family":"Smirnova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janis","family":"Locs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arita","family":"Dubnika","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Vecstaudza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liga","family":"Stipniece","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elina","family":"Makarova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maija","family":"Dambrova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,11,13]]},"reference":[{"key":"35197_CR1","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/joim.12369","volume":"277","author":"M Lorentzon","year":"2015","unstructured":"Lorentzon, M. & Cummings, S. R. Osteoporosis: The evolution of a diagnosis. J. Intern. Med. 277, 650\u2013661, https:\/\/doi.org\/10.1111\/joim.12369 (2015).","journal-title":"J. Intern. Med."},{"key":"35197_CR2","doi-asserted-by":"publisher","first-page":"117","DOI":"10.2147\/CIA.S85551","volume":"12","author":"S Walters","year":"2017","unstructured":"Walters, S., Khan, T., Ong, T. & Sahota, O. Fracture liaison services: improving outcomes for patients with osteoporosis. Clin. Interv. Aging. 12, 117\u2013127, https:\/\/doi.org\/10.2147\/CIA.S85551 (2017).","journal-title":"Clin. Interv. Aging."},{"key":"35197_CR3","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.ijpharm.2016.01.050","volume":"512","author":"HL Quinn","year":"2016","unstructured":"Quinn, H. L., Hughes, C. M. & Donnelly, R. F. Novel methods of drug administration for the treatment and care of older patients. Int. J. Pharm. 512, 366\u2013373, https:\/\/doi.org\/10.1016\/j.ijpharm.2016.01.050 (2016).","journal-title":"Int. J. Pharm."},{"key":"35197_CR4","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/S0025-6196(11)60752-0","volume":"84","author":"KA Kennel","year":"2009","unstructured":"Kennel, K. A. & Drake, M. T. Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management. Mayo Clin. Proc. 84, 632\u2013638, http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2704135\/ (2009).","journal-title":"Mayo Clin. Proc."},{"key":"35197_CR5","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/j.ijpharm.2013.01.031","volume":"445","author":"K Miladi","year":"2013","unstructured":"Miladi, K., Sfar, S., Fessi, H. & Elaissari, A. Drug carriers in osteoporosis: Preparation, drug encapsulation and applications. Int. J. Pharm. 445, 181\u2013195, https:\/\/doi.org\/10.1016\/j.ijpharm.2013.01.031 (2013).","journal-title":"Int. J. Pharm."},{"issue":"7","key":"35197_CR6","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.ijom.2017.03.009","volume":"46","author":"S.V. Kellesarian","year":"2017","unstructured":"Kellesarian, S. V. et al. Role of local alendronate delivery on the osseointegration of implants: a systematic review and meta-analysis, Int. J. Oral Maxillofac. Surg. https:\/\/doi.org\/10.1016\/j.ijom.2017.03.009 (2017).","journal-title":"International Journal of Oral and Maxillofacial Surgery"},{"key":"35197_CR7","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1007\/s00774-013-0494-1","volume":"31","author":"JJ Stepan","year":"2013","unstructured":"Stepan, J. J. Strontium ranelate: in search for the mechanism of action. J. Bone Miner. Metab. 31, 606\u2013612, https:\/\/doi.org\/10.1007\/s00774-013-0494-1 (2013).","journal-title":"J. Bone Miner. Metab."},{"key":"35197_CR8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1177\/1759720X13483187","volume":"5","author":"L Cianferotti","year":"2013","unstructured":"Cianferotti, L., D\u2019Asta, F. & Brandi, M. L. A review on strontium ranelate long-term antifracture efficacy in the treatment of postmenopausal osteoporosis. Ther. Adv. Musculoskelet. Dis. 5, 127\u2013139, https:\/\/doi.org\/10.1177\/1759720X13483187 (2013).","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"35197_CR9","doi-asserted-by":"publisher","first-page":"5883","DOI":"10.1016\/j.biomaterials.2013.04.031","volume":"34","author":"OZ Andersen","year":"2013","unstructured":"Andersen, O. Z. et al. Accelerated bone ingrowth by local delivery of strontium from surface functionalized titanium implants. Biomaterials. 34, 5883\u20135890, https:\/\/doi.org\/10.1016\/j.biomaterials.2013.04.031 (2013).","journal-title":"Biomaterials."},{"key":"35197_CR10","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.pharmthera.2012.07.009","volume":"136","author":"Z Saidak","year":"2012","unstructured":"Saidak, Z. & Marie, P. J. Strontium signaling: Molecular mechanisms and therapeutic implications in osteoporosis. Pharmacol. Ther. 136, 216\u2013226, https:\/\/doi.org\/10.1016\/j.pharmthera.2012.07.009 (2012).","journal-title":"Pharmacol. Ther."},{"key":"35197_CR11","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1016\/j.msec.2017.05.042","volume":"78","author":"M Pilmane","year":"2017","unstructured":"Pilmane, M., Salma-Ancane, K., Loca, D., Locs, J. & Berzina-Cimdina, L. Strontium and strontium ranelate: Historical review of some of their functions. Mater. Sci. Eng. C. 78, 1222\u20131230, https:\/\/doi.org\/10.1016\/j.msec.2017.05.042 (2017).","journal-title":"Mater. Sci. Eng. C."},{"key":"35197_CR12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s00223-011-9499-8","volume":"89","author":"R Rizzoli","year":"2011","unstructured":"Rizzoli, R. et al. Adverse Reactions and Drug\u2013Drug Interactions in the Management of Women with Postmenopausal Osteoporosis. Calcif. Tissue Int. 89, 91\u2013104, https:\/\/doi.org\/10.1007\/s00223-011-9499-8 (2011).","journal-title":"Calcif. Tissue Int."},{"key":"35197_CR13","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1056\/NEJMoa022436","volume":"350","author":"PJ Meunier","year":"2004","unstructured":"Meunier, P. J. et al. The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis. N. Engl. J. Med. 350, 459\u2013468, https:\/\/doi.org\/10.1056\/NEJMoa022436 (2004).","journal-title":"N. Engl. J. Med."},{"key":"35197_CR14","doi-asserted-by":"publisher","first-page":"157 LP","DOI":"10.1136\/annrheumdis-2012-202453","volume":"72","author":"FPJG Lafeber","year":"2013","unstructured":"Lafeber, F. P. J. G. & van Laar, J. M. Strontium ranelate: ready for clinical use as disease-modifying osteoarthritis drug? Ann. Rheum. Dis. 72, 157 LP\u2013161, http:\/\/ard.bmj.com\/content\/72\/2\/157.abstract (2013).","journal-title":"Ann. Rheum. Dis."},{"key":"35197_CR15","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1517\/14740338.2014.939169","volume":"13","author":"J-Y Reginster","year":"2014","unstructured":"Reginster, J.-Y. Cardiac concerns associated with strontium ranelate. Expert Opin. Drug Saf. 13, 1209\u20131213, https:\/\/doi.org\/10.1517\/14740338.2014.939169 (2014).","journal-title":"Expert Opin. Drug Saf."},{"key":"35197_CR16","doi-asserted-by":"publisher","first-page":"8116","DOI":"10.1021\/ja062286z","volume":"128","author":"F Balas","year":"2006","unstructured":"Balas, F., Manzano, M., Horcajada, P. & Vallet-Reg\u00ed, M. Confinement and Controlled Release of Bisphosphonates on Ordered Mesoporous Silica-Based Materials. J. Am. Chem. Soc. 128, 8116\u20138117, https:\/\/doi.org\/10.1021\/ja062286z (2006).","journal-title":"J. Am. Chem. Soc."},{"key":"35197_CR17","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.ijpharm.2015.01.020","volume":"480","author":"J Bae","year":"2015","unstructured":"Bae, J. & Park, J. W. Preparation of an injectable depot system for long-term delivery of alendronate and evaluation of its anti-osteoporotic effect in an ovariectomized rat model. Int. J. Pharm. 480, 37\u201347, https:\/\/doi.org\/10.1016\/j.ijpharm.2015.01.020 (2015).","journal-title":"Int. J. Pharm."},{"key":"35197_CR18","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1080\/02652040701439807","volume":"24","author":"EH Nafea","year":"2007","unstructured":"Nafea, E. H., El-Massik, M. A., El-Khordagui, L. K., Marei, M. K. & Khalafallah, N. M. Alendronate PLGA microspheres with high loading efficiency for dental applications. J. Microencapsul. 24, 525\u2013538, https:\/\/doi.org\/10.1080\/02652040701439807 (2007).","journal-title":"J. Microencapsul."},{"key":"35197_CR19","doi-asserted-by":"publisher","first-page":"368","DOI":"10.3389\/fphar.2018.00368","volume":"9","author":"Z Mao","year":"2018","unstructured":"Mao, Z. et al. Osteoinductivity and Antibacterial Properties of Strontium Ranelate-Loaded Poly(Lactic-co-Glycolic Acid) Microspheres With Assembled Silver and Hydroxyapatite Nanoparticles. Front. Pharmacol. 9, 368, https:\/\/doi.org\/10.3389\/fphar.2018.00368 (2018).","journal-title":"Front. Pharmacol."},{"key":"35197_CR20","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.colsurfb.2016.03.033","volume":"143","author":"BP Nair","year":"2016","unstructured":"Nair, B. P., Sindhu, M. & Nair, P. D. Polycaprolactone-laponite composite scaffold releasing strontium ranelate for bone tissue engineering applications. Colloids Surfaces B Biointerfaces. 143, 423\u2013430, https:\/\/doi.org\/10.1016\/j.colsurfb.2016.03.033 (2016).","journal-title":"Colloids Surfaces B Biointerfaces."},{"key":"35197_CR21","first-page":"93","volume":"57","author":"ME Mondelo","year":"1997","unstructured":"Mondelo, M. E. et al. Preclinical toxicology of bisphosphonates. Med. (B Aires). 57, 93\u2013100 (1997).","journal-title":"Med. (B Aires)."},{"key":"35197_CR22","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.msec.2017.03.235","volume":"78","author":"N Babanejad","year":"2017","unstructured":"Babanejad, N., Farhadian, A., Omrani, I. & Nabid, M. R. Design, characterization and in vitro evaluation of novel amphiphilic block sunflower oil-based polyol nanocarrier as a potential delivery system: Raloxifene-hydrochloride as a model. Mater. Sci. Eng. 78, 59\u201368, https:\/\/doi.org\/10.1016\/j.msec.2017.03.235 (2017).","journal-title":"Mater. Sci. Eng."},{"key":"35197_CR23","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.msec.2017.03.147","volume":"76","author":"M Pasqualone","year":"2017","unstructured":"Pasqualone, M., Andreetta, H. A. & Cortizo, M. S. Risedronate transdermal delivery system based on a fumaric copolymer for therapy of osteoporosis, Mater. Sci. Eng. C. 76, 652\u2013658, https:\/\/doi.org\/10.1016\/j.msec.2017.03.147 (2017).","journal-title":"Sci. Eng. C."},{"key":"35197_CR24","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.jpba.2008.05.028","volume":"48","author":"CK Zacharis","year":"2008","unstructured":"Zacharis, C. K. & Tzanavaras, P. D. Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: A review of analytical methods. J. Pharm. Biomed. Anal. 48, 483\u2013496, https:\/\/doi.org\/10.1016\/j.jpba.2008.05.028 (2008).","journal-title":"J. Pharm. Biomed. Anal."},{"key":"35197_CR25","doi-asserted-by":"publisher","first-page":"208","DOI":"10.4028\/www.scientific.net\/KEM.721.208","volume":"721","author":"A Smirnova","year":"2017","unstructured":"Smirnova, A., Loca, D., Stipniece, L., Locs, J. & Pura, A. Encapsulation of Strontium Ranelate in Poly(Lactic Acid) Matrix. Key Eng. Mater. 721, 208\u2013212, https:\/\/doi.org\/10.4028\/www.scientific.net\/KEM.721.208 (2017).","journal-title":"Key Eng. Mater."},{"issue":"3","key":"35197_CR26","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1039\/C6RA25314H","volume":"7","author":"Zhuoxian Mai","year":"2017","unstructured":"Mai, Z. et al. Electrospray biodegradable microcapsules loaded with curcumin for drug delivery systems with high bioactivity. RSC Adv. 1724\u20131734 https:\/\/doi.org\/10.1039\/C6RA25314H (2017).","journal-title":"RSC Advances"},{"key":"35197_CR27","unstructured":"International Organization for Standardization Biological Evaluation of Medical Devices - Part 5: Tests for in vitro cytotoxicity. ISO 10993-5 24\u201327 (2009)."},{"key":"35197_CR28","unstructured":"Divi, M. K. P., Rao, M. A. N. & Nowshuddin, S. Polymorph of strontium ranelate and a process for its preparation, https:\/\/www.google.com\/patents\/US20110275834 (2011)."},{"key":"35197_CR29","first-page":"135","volume":"68","author":"I Vukovi\u0107-Kwiatkowska","year":"2014","unstructured":"Vukovi\u0107-Kwiatkowska, I., Kaczmarek, H. & Dzwonkowski, J. Innovative composites of poly (lactic acid) for the production of packaging foils. Chemik. 68, 135\u2013140 (2014).","journal-title":"Chemik."},{"key":"35197_CR30","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.aca.2014.07.021","volume":"843","author":"D Saviello","year":"2014","unstructured":"Saviello, D., Pouyet, E., Toniolo, L., Cotte, M. & Nevin, A. Synchrotron-based FTIR microspectroscopy for the mapping of photo-oxidation and additives in acrylonitrile\u2013butadiene\u2013styrene model samples and historical objects. Anal. Chim. Acta. 843, 59\u201372, https:\/\/doi.org\/10.1016\/j.aca.2014.07.021 (2014).","journal-title":"Anal. Chim. Acta."},{"key":"35197_CR31","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.matlet.2015.01.129","volume":"146","author":"J Locs","year":"2015","unstructured":"Locs, J., Narkevica, I., Bugovecka, L., Ozolins, J. & Berzina-Cimdina, L. Apatite-forming ability of thermally treated titania with various phase compositions. Materials Letters. 146, 69\u201372, https:\/\/doi.org\/10.1016\/j.matlet.2015.01.129 (2015).","journal-title":"Materials Letters."},{"key":"35197_CR32","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cger.2016.08.003","volume":"33","author":"P Alejandro","year":"2017","unstructured":"Alejandro, P. & Constantinescu, F. A Review of Osteoporosis in the Older Adult. Clin. Geriatr. Med. 33, 27\u201340, https:\/\/doi.org\/10.1016\/j.cger.2016.08.003 (2017).","journal-title":"Clin. Geriatr. Med."},{"key":"35197_CR33","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrendo.2011.146","volume":"8","author":"JS Chen","year":"2012","unstructured":"Chen, J. S. & Sambrook, P. N. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol. 8, 81\u201391, https:\/\/doi.org\/10.1038\/nrendo.2011.146 (2012).","journal-title":"Nat Rev Endocrinol."},{"key":"35197_CR34","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/S0889-857X(05)70195-2","volume":"6","author":"L Mosekilde","year":"2011","unstructured":"Mosekilde, L., T\u00f8rring, O. & Rejnmark, L. Emerging anabolic treatments in osteoporosis. Curr. Drug Saf. 6, 62\u201374, https:\/\/doi.org\/10.1016\/S0889-857X(05)70195-2 (2011).","journal-title":"Curr. Drug Saf."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35197-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35197-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35197-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T11:25:19Z","timestamp":1671621919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-35197-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,13]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["35197"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-35197-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,13]]},"assertion":[{"value":"22 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"16754"}}