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The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or dosage forms, the prescription product achieves higher plasma and synovial fluid concentrations that are above the threshold for a pharmacologically relevant effect, and may therefore justify its distinct therapeutic characteristics.<\/jats:p>","DOI":"10.1177\/1759720x12437753","type":"journal-article","created":{"date-parts":[[2012,3,8]],"date-time":"2012-03-08T21:48:47Z","timestamp":1331243327000},"page":"167-180","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":45,"title":["Crystalline glucosamine sulfate in the management of knee osteoarthritis: efficacy, safety, and pharmacokinetic properties"],"prefix":"10.1177","volume":"4","author":[{"given":"Lucio C.","family":"Rovati","sequence":"first","affiliation":[{"name":"Chief Scientific Officer, Rottapharm|Madaus, Via Valosa di Sopra, 9, 20900 Monza (MB), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Girolami","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, Rottapharm|Madaus, Monza, Italy and Department of Pharmacovigilance and Drug Safety, Rottapharm|Madaus, Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Persiani","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, Rottapharm|Madaus, Monza, Italy and Department of Translational Sciences and Pharmacokinetics, Rottapharm|Madaus, Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2012,3,8]]},"reference":[{"key":"bibr1-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2011.03.014"},{"key":"bibr2-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1586\/ecp.09.17"},{"key":"bibr3-1759720X12437753","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1002\/1529-0131(200111)44:11<2531::AID-ART433>3.0.CO;2-J","volume":"44","author":"Altman R.D.","year":"2001","journal-title":"Arthritis Rheum"},{"key":"bibr4-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118349"},{"key":"bibr5-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1053\/joca.1998.0146"},{"key":"bibr6-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2005.036368"},{"key":"bibr7-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.38273.626655.63"},{"key":"bibr8-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.3310\/hta13520"},{"key":"bibr9-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2009.07.005"},{"key":"bibr10-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2007.06.011"},{"key":"bibr11-1759720X12437753","first-page":"939265","author":"Chiusaroli R.","year":"2011","journal-title":"Int J Rheumatol"},{"key":"bibr12-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052771"},{"key":"bibr13-1759720X12437753","doi-asserted-by":"publisher","DOI":"10.1016\/S1063-4584(02)00351-5"},{"key":"bibr14-1759720X12437753","unstructured":"De Wan M., Volpi G.; inventors. 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