Literature examining the use of the dietary supplements, especially glucosamine and chondroitin sulfate, to treat osteoarthritis has increased substantially over the last five years. Reviews describe their effects on symptoms [13
] and to a lesser extent on structural modification.[7
] Unfortunately, the duration of most of the symptomatic studies is relatively short, especially when compared to the duration of use expected for these agents in patients affected by OA of the knee. Systematically collected data on safety of these agents are also limited by short study durations as well. The prior report from GAIT examined the primary outcome in the overall study population of 1583 patients at 24 weeks.[6
] This report describes the efficacy and safety over two years of exposure to the therapies.
The patients reported in this two-year cohort from GAIT are, as would be expected of OA patients in general, predominantly female, overweight and over 45 years of age. As shown in , improvement in pain and function over 24 months was observed in all groups, and no therapy was statistically superior to placebo. However, patients treated with celecoxib and with glucosamine monotherapy had the greatest improvement. shows an improved sensitivity to change relative to placebo for the OMERACT/OARSI outcome measure as compared to a 20% reduction in WOMAC Pain score. Overall our results are in agreement with the Cochrane review of glucosamine, which found glucosamine ineffective for treatment of pain in studies that used a WOMAC Pain outcome.[15
] Interestingly, in the Cochrane analysis, studies which used the Lequesne index as an outcome measure showed glucosamine sulfate to be superior to placebo. Two trials, including the parent to this study (GAIT), reported that use of glucosamine hydrochloride, did not show a benefit compared to placebo.[6
] While meta-analyses have supported benefit for OA pain from use of chondroitin sulfate [19
], we did not see evidence for such a benefit. A protocol for a Cochrane review of chondroitin sulfate for OA has been defined, but a completed analysis has not been reported.
Remarkably few published reports of efficacy data exist in OA of the knee beyond six months duration. Those studies that are published typically use patient global pain measures rather than validated composite indexes. For example, naproxen was shown equal to diclofenac for 26 weeks based on continuation of use and patient reports of pain at rest [21
], while two year data for naproxen using a 5 point Likert scale showed it to be statistically similar to acetaminophen.[22
] Sustained release diclofenac was also studied for two years and shown similar to placebo as assessed by patient report on a 5 point Likert scale.[23
] Use of celecoxib to treat OA for one year has been reported. [24
] Celecoxib has demonstrated efficacy as compared to placebo at 12 weeks as a mean reduction in WOMAC pain score [25
], and was effective at 24 weeks in the primary GAIT study.[6
] The ancillary study reported here suggests a waning of benefit with longer usage like has been described for NSAIDs in general.
AEs were mild and occurred in all groups over the two-year period. Only five SAEs were thought to be related to study agents. While there were concerns that glucosamine might exacerbate diabetes or asthma, three-year studies from Europe and these data do not substantiate those concerns.[26
] A two-year study with safety data for celecoxib comes from a trial on prevention of adenomatous polyps. [26
] Another longer-term study of celecoxib use was in ankylosing spondylitis (one year).[27
] Reports of the relative safety of celecoxib are supported by our findings, which show no difference from the safety profile of placebo. While the number of participants using celecoxib in this study is modest, it is noteworthy that no adverse events related to gastrointestinal bleeding were reported and no difference in cardiovascular events as compared to use of placebo was demonstrated.
Perhaps the most interesting finding is the pronounced and persistent clinical improvement shown in , which shows an improved WOMAC Pain and WOMAC Function score for all treatment groups, including placebo. The improvement is seen early and persists throughout the two-year study period. This response cannot easily be dismissed as regression to the mean as it persists throughout the entire 24-month duration of follow-up. Patients in flare studies may demonstrate regression toward the mean, but this study did not require flare criteria for entry, and patients did not systematically discontinue medications prior to entry. If the agents indeed had therapeutic benefit to account for the change, then the placebo group's improvement is difficult to explain, as it is identical to the other arms. While a benefit of being closely followed by a study team is reported, it is not typically of this magnitude or of this extended duration.
In another two year study in OA evaluating risedronate as a possible structure modifying agent in OA, there was a very similar benefit demonstrated in all treatment groups as well as in the placebo group, which was detected at the first efficacy time point at six months, and persistent through the two years of the study.[28
] Risedronate decreases biochemical markers of cartilage degradation, but does not decrease symptoms or slow radiographic progression in patients with medial compartment OA of the knee.[29
] While the study allowed patients to take background analgesics, all patients were required to discontinue NSAIDs and analgesics in a proscribed manner prior to all clinical assessments to allow for a possible flare to better detect a treatment effect of the study medications. While in this study regression to the mean is a possibility, baseline levels of pain were also low (mean WOMAC pain 42.4), making it more difficult to detect a treatment effect due to a floor effect of the outcome measurement. Also, a significant expectation bias on the part of participants as reflected in the very high completion rate at two years (76.4%) might have contributed.
As evidenced by both of these longer-term studies demonstrating similarly sustained placebo benefits, further evaluation of the factors involved is warranted and will be important in designing future OA trials. The current study is limited by its design as an ancillary preplanned continuation of a randomized controlled trial in which all of the initially randomized patients were not eligible to participate. There was significant dropout manifested as discontinuation of medication use as well as missed assessments. Recognizing that selective dropout can bias study findings, specific analytical methods were applied to mitigate this problem.
In conclusion, findings from this study provide important longer-term safety information on the use of glucosamine and chondroitin sulfate given alone or in combination and the use of celecoxib in a two-year placebo-controlled trial for treatment of OA of the knee. All of the tested therapies appeared to be generally safe and well tolerated over a two-year period. A clinically detectable symptomatic benefit was seen as early as 24 weeks in all groups, including placebo, and was sustained over two years of study. Although none of the agents were statistically superior to placebo, celecoxib and glucosamine gave the highest odds of benefit for improved pain and function, but with widely overlapping confidence intervals for all treatments.
What is Already Known
It is already known that successful longer-term medical treatment of asteoarthritis (OA) of the knee is limited.
It is estimated that only 15-20% will continue to receive a given non-steroidal anti-inflammatory drug after 1 year of use, because of a combination of loss of efficacy and/or accumulated toxicities.
Relatively long-term efficacy and safety data for glucosamine and chonroitinsulfate alone, and especially in combination, are also limited.
What this Study ADDS?
This study adds long-term data to the efficacy and safety data not only for the nutraceuticals but also for the coxib-celecoxib.
All data were obtained using dosages typically used to treat OA of the knee and gathered prospectively.
Only one other report of celecoxib use in OA of greater than 1-years duration has been reported.