1) "...glucosamine sulfate shows an effect size superior to (or at least equal to) the commonly used analgesic or nonsteroidal anti-inflammatory drugs but has no rare or adverse effects" and 2) the majority of clinical trials assessing glucosamine reported a significant number of subjects who failed to respond to treatment, thereby questioning the benefit of glucosamine. a 2014 review and analysis conducted by the la universidad del zulia located in maracaibo, venezuela and funded by the venezuelan government's technological, humanistic, and scientific development council concluded that the preponderance of the available evidence indicates that glucosamine, specifically the sulfate form, has disease-modifying effects and provides symptomatic relief for at least some individuals suffering from oa. the report classified glucosamine as a symptomatic slow acting drugs for osteoarthritis (sysadoa) and states: although further research is required...glucosamine supplements have been more than sufficiently proven to display overtly beneficial risk-to-reward profiles, and they should remain fundamental components of oa therapy. a further meta-analysis published in december 2014 by the parker institute (copenhagen, denmark) sponsored by the oak foundation concluded that glucosamine sulfate, but not glucosamine hcl, did have a significant effect on osteoarthritis pain but only when one particular brand was used. once this effect size was corrected for bias and heterogeneity, the effect size became clinically unimportant. summary of results many randomized controlled trials have been conducted with mixed results. these trials have been summarized: in 2007, reichenbach et al. used explicit methods to conduct and report a systematic review of 20 trials and concluded "large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. use of chondroitin in routine clinical practice should therefore be discouraged." also in 2007, bruyere et al. without using explicit methodology for reviewing trials concluded "there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of oa." the effectiveness of glucosamine is controversial. most recent reviews found it to be equal to or only slightly better than placebo. a difference may exist between glucosamine sulfate and glucosamine hydrochloride, with glucosamine sulfate showing a benefit and glucosamine hydrochloride not. the osteoarthritis research society international recommends that glucosamine be discontinued if no effect is observed after six months and the national institute of clinical excellence no longer recommends its use although the arthritis foundation compares the effectiveness of glucosamine to traditional nsaid therapy. despite the difficulty in determining the efficacy of glucosamine, it remains a viable treatment option according to some experts. chondroitin is not recommended as a treatment for osteoarthritis. guidelines prior to recent studies prior to publication of the negative review by reichenbach and the equivocal gait trial, clinical practice guidelines recommended the use of chondroitin. the oarsi (osteoarthritis research society international) recommended chondroitin sulfate as the second-most-effective treatment for moderate cases of osteoarthritis (although the guidelines were published in 2008, the developers closed their search date in january 2006 – prior to the gait trial). in 2003, the european league against rheumatism (eular) supported the usefulness of chondroitin sulfate in the management of knee osteoarthritis and granted the highest level of evidence, 1a, and strength of the recommendation, a, to this product. gait trial (2006–2010) the major trial included in the two reviews above was the glucosamine/chondroitin arthritis intervention, or gait trial. gait was funded by the national institutes of health to test the effects of chondroitin and glucosamine on osteoarthritis of the knee. it reported initially in 2006, with further findings in 2008 and again in 2010. this multicenter, placebo-controlled, double-blind, six-month-long trial found that glucosamine plus chondroitin had no statistically significant effect on symptoms of osteoarthritis in the osteoarthritis patients studied. the study, in addition to an inactive placebo, also included an active control, the fda-approved prescription analgesic drug celecoxib. the researchers found that those taking the active control drug fared no better or worse than those taking glucosamine, glucosamine and chondroitin combined or the inactive placebo. however, in the moderate-to-severe pain subgroup, the combination of chondroitin and glucosamine was found to be clinically more effective (in 25% of the patients) in treating pain than celecoxib or chondroitin and glucosamine taken individually. due to small sample sizes in the sub-group (roughly 250 people), the researchers concluded that this needs further validation. the study also found chondroitin sulfate to have no significant effect in reducing joint swelling, effusion, or both. these results indicate that glucosamine and chondroitin do not effectively relieve pain in the overall group of osteoarthritis patients, though it may be an effective treatment for those suffering from moderate-to-severe pain. in a follow-up study, 572 patients from the gait trial continued the supplementation for two years. after two years of supplementation with glucosamine and chondroitin sulfate, alone or in combination, there was no benefit in slowing the loss of cartilage, in terms of joint space width, when compared to a placebo. however, no patient group, placebo or glucosamine alone, or in combination, experienced joint space width loss at even half the rate expected during this study, making it difficult to assess the clinical effectiveness of any treatment on the progression of oa. in another two-year follow-up study, there was no significant pain reduction or improved function when compared to either inactive placebo or celecoxib some of the researchers' ties to pfizer (which makes celecoxib) have brought into question the validity of the study. the lead author of the gait trial, allen d. sawitzke, md, expressed his disappointment with unexpectedly equivocal findings of the trial, noting in an interview with the arthritis foundation, that because of significant limitations, like a small sample size, the gait trial likely didn’t have enough power to determine whether glucosamine and chondroitin are effective treatments for knee osteoarthritis or not. the legs study (2007–2011) the long-term evaluation of glucosamine sulfate (legs) study ran between 2007 and 2011, to study whether glucosamine sulfate, chondroitin sulfate or a combination of both are effective treatments for chronic knee pain due to osteoarthritis. 502 patients (from 605 enrolled) were followed for two years. the main outcomes were disease progression, as measured by joint space narrowing (jsn) and knee pain (vas). the combination treatment did result in a small but statistically significant (0.1 mm) decrease in 2-year jsn compared with placebo but there was no difference in jsn between this group and the other treatment groups and no differences between any group for changes in knee pain. in summary, there was no significant symptomatic benefit detected for these dietary supplements, and a longer study would be required to test the efficacy of both supplements combined.