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However, the evidence of their efficacy is poor and their outcomes presented a great heterogeneity. Therefore, the aim of this study is to systematically review the main effects of bisphosphonate use on synovial joint tissues and biochemical markers in preclinical studies over the past two decades (2000\u20132020). Three databases (Pubmed, Scopus, and Web of Science) were searched, and after screening, twenty-six studies with five different types of bisphosphonates were included in the review. The animal model selected, the type of bisphosphonate used, the therapy duration, and the main effects of individual drugs on synovial tissues were evaluated. Additionally, the quality and risk of bias assessments were performed using the Animals in Research Reporting In Vivo Experiments guidelines and the Systematic Review Centre for Laboratory animal Experimentation tool. Studies showed high variability in experimental designs. Consequently, the comparison of the findings in order to draw specific conclusions about the effectiveness of the drugs is complicated. However, the results of this systematic review suggested that bisphosphonates seemed to reduce the osteoarthritic changes in a dose-dependent manner showing better chondroprotective effects at high doses. Besides, a time-dependent efficacy was also detected in terms of cartilage status. One can conclude that the disease stage of the time-point of treatment initiation may constitute a key factor in the antiresorptive drug efficacy. Generally, we noted that bisphosphonate administration seemed to show positive subchondral bone conservation and fewer biomarker alterations. However, they did not appear to suppress the osteophyte development and their chondroprotective effect is highly variable among the studies. Bisphosphonates appeared to show a positive anti-inflammatory effect on the synovial membrane. However, only a few included publications were focused on their investigation. Regarding the therapy duration, there is a significant lack of evidence on evaluating their effectiveness in preclinical long-term studies and further experimental studies may be needed to examine the pharmacological response in these circumstances. This systematic review might help to clarify the efficacy of bisphosphonates and their function as disease-modifying treatments in osteoarthritis.<\/jats:p>","DOI":"10.1186\/s13075-021-02446-6","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T05:03:15Z","timestamp":1613970195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Bisphosphonates as disease-modifying drugs in osteoarthritis preclinical studies: a systematic review from 2000 to 2020"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2576-7438","authenticated-orcid":false,"given":"Silvia","family":"Fern\u00e1ndez-Mart\u00edn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"L\u00f3pez-Pe\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Permuy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Gonz\u00e1lez-Cantalapiedra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"2446_CR1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/art.20051","volume":"50","author":"DT Felson","year":"2004","unstructured":"Felson DT, Neogi T. 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