Is Phytalgic® a goldmine for osteoarthritis patients or is there something fishy about this nutraceutical? A summary of findings and risk-of-bias assessment

A food supplement containing fish oils, urtica dioica, zinc, and vitamin E (Phytalgic®) for osteoarthritis (OA) has now been tested in a placebo-controlled trial for 3 months and according to the authors has a very large clinical effect, considerably larger than that of any other known product. Even experts endorsing nutraceuticals for OA symptoms would probably agree that a nutraceutical with an effect size above 0.5 is rarely seen. Despite our concerns about the fact that trial registration took place after the study was completed and the likelihood that patients would note the taste of fish, a circumstance that would lead to detection bias, we consider these data promising though with a high risk of bias.

registration foresee a random assignment of 41 patients to one group and 40 to the other group when it is a consequence of excluding 14 non-eligible patients, as presented in the CONSORT (CONsolidated Standards of Reporting Trials) Statement?
Th e authors present data for Phytalgic® [1] which are considerably more promising than expected and thus should be scrutinized for clinical eff ect and possible bias [3]. According to the authors, Phytalgic® consists of capsules containing fi sh oils, urtica dioica, zinc, and vitamin E. Jacquet and colleagues [1] randomly assigned some 81 OA patients to receive either Phytalgic® or a matching placebo consisting of 'non-fi sh oil' . Participants were an average of 57 years of age (range of 28 to 84 years) at entry, had either knee or hip OA, and were regular users of nonsteroidal anti-infl ammatory drugs (NSAIDs) or analgesics. Th e primary outcome of this 3-month trial was use of NSAIDs or analgesics at follow-up. According to ClinicalTrials.gov [2], Jacquet and colleagues [1] considered the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) function scale a secondary outcome measure, and none of the other WOMAC subscales is mentioned in the trial registration. In accordance with recent standards on how to evaluate the results of OA trials [3,4], Figure 1 presents a summary of fi ndings as generic eff ect sizes (ESs) based on the standardized mean diff erence, comparing the experimental drug (Phytalgic®) with a placebo, for each of the continuous outcomes measured on diff erent scales.
Th e results of this trial were remarkable. For example, the ES for pain reduction was -1.27, which corresponds to a very large ES and indicates that Phytalgic® is 76% more effi cacious than intra-articular corticosteroid therapy for knee OA [4]. We fi nd that very hard to believe.
During the last decade, the use of nutraceuticals has generated a great deal of interest. In our experience from trials [5] and in the results of meta-analyses on ASU

Abstract
A food supplement containing fi sh oils, urtica dioica, zinc, and vitamin E (Phytalgic®) for osteoarthritis (OA) has now been tested in a placebo-controlled trial for 3 months and according to the authors has a very large clinical eff ect, considerably larger than that of any other known product. Even experts endorsing nutraceuticals for OA symptoms would probably agree that a nutraceutical with an eff ect size above 0.5 is rarely seen. Despite our concerns about the fact that trial registration took place after the study was completed and the likelihood that patients would note the taste of fi sh, a circumstance that would lead to detection bias, we consider these data promising though with a high risk of bias.  [7], and diacerein (ES = -0.24) [8], we have never seen anything as effi cacious as Phytalgic® [3]. Th e same thing applies in the glucosamine area. It is now becoming evident that preparations with glucosamine hydrochloride do not ameliorate OA [9], and results of trials on diff erent glucosamine sulfate preparations are very confl icted with lots of inconsistency [3,9]. Th e glucosamine sulfate product from Rottapharm Madaus (Monza, Italy) is one exception to this [10]. While trials of this particular preparation showed promise in the early days with large clinical eff ects on OA in smaller studies, later and presumably more strictly led RCTs with less bias have claimed results that are more moderate, with an anticipated overall ES on pain of -0.33 standard deviation units (95% confi dence interval -0.49 to -0.17) [10]. Even OA experts who endorse nutra ceuticals (for example, glucosamine) would probably agree that a nutraceutical with an ES above 0.5 is rarely seen.
Th ere is empirical evidence that OA trials may be aff ected by selection and detection bias [11]. Allegedly, few patients noted the taste of fi sh oil during 12 weeks of taking such capsules three times per day. We argue that a fi shy taste in the mouth might certainly cause detection bias. Assessment of the trial reporting in terms of risk of bias, the use of random assignment, and subsequent concealment of allocation would qualify as adequate (that is, low risk of selection bias); it seems reasonable that at baseline the patients in the study groups were similar with respect to prognostic factors. Th e reporting of double-blinding supports a low risk of performance bias as the authors state that the manufacturer provided both the Phytalgic® and placebo capsules and that it claimed that they were identical and indistinguishable. We argue, however, that it might be diffi cult to hide the taste of fi sh oil during a 3-month trial, probably as diffi cult as it is to hide the taste of ginger [5]. Finally, deviations from protocol and loss to follow-up often lead to the exclusion of patients after they have been allocated to treatment groups, and this may introduce attrition bias [12]. We are concerned about the fact that the trial registration was done after study completion (April 2008). Th us, we would categorize the risk of attrition bias as being at best unclear as there is a possibility that some patients were excluded from the analyses. Although the authors performed their analyses according to the intention-totreat principle on what they claim is the correct sample size, we worry about the fact that the attrition rate was 10% (4/40) in the placebo group, whereas only 2% (1/41) withdrew from Phytalgic®.
With that said, we are now faced with some very promising results of Phytalgic® [1], and further experience is needed to show whether this product on a larger scale will become a relevant treatment option for OA [3,7]. As previously pointed out, the largest studies and the studies that are strictly monitored by good clinical practices are

Effect Size (95% CI) Variable
usually directly sponsored by the product manufacturers [10]. A fully independent analysis of a product like Phytalgic® would require funding from offi cial organizations (for example, the National Institutes of Health, which indeed needs reshuffl ing of its priorities). Th ese initial data on Phytalgic® would seem to justify such action. If these data are confi rmed, a goldmine has been struck and OA therapy is in for dramatic changes.