Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients? – a meta-analysis of randomized controlled trials

Open ArchivePublished:April 14, 2008DOI:https://doi.org/10.1016/j.joca.2008.03.001

      Summary

      Objective

      Meta-analysis of randomized controlled trials (RCTs) – of a hip powder of Rosa canina (rosehip) preparation for symptomatic treatment of osteoarthritis (OA), in order to estimate the empirical efficacy as a pain reducing compound.

      Method

      RCTs from systematic searches were included if they explicitly stated that OA patients were randomized to either rosehip or placebo. The primary outcome was reduction in pain calculated as effect size (ES), defined as the standardized mean difference (SMD). As secondary analysis the number of responders to therapy was analyzed as Odds Ratios (OR), and expressed as the Number Needed to Treat (NNT). Restricted Maximum Likelihood (REML) methods were applied for the meta-analyses using mixed effects models.

      Results

      The three studies (287 patients and a median trial-duration of 3 months) – all supported by the manufacturer (Hyben-Vital International) – showed a reduction in pain scores by rosehip powder (145 patients) compared to placebo (142 patients): ES of 0.37 [95% confidence interval (CI): 0.13–0.60], P=0.002. Test for homogeneity seemed to support that the efficacy was consistent across trials (I2=0%). Thus it seems reasonable to assume that the three studies were measuring the same overall effect. It seemed twice as likely that a patient allocated to rosehip powder would respond to therapy, compared to placebo (OR=2.19; P=0.0009); corresponding to a NNT of six (95% CI: 4–13) patients.

      Conclusions

      Although based on a sparse amount of data, the results of the present meta-analysis indicate that rosehip powder does reduce pain; accordingly it may be of interest as a nutraceutical, although its efficacy and safety need evaluation and independent replication in a future large-scale/long-term trial.

      Key words

      Introduction

      Osteoarthritis (OA) is a common joint disorder and may occur in any synovial joint in the body, although the condition is most common in hands, knees, hips and spine
      • Dieppe P.A.
      • Lohmander L.S.
      Pathogenesis and management of pain in osteoarthritis.
      . The clinical problems, along with the pathological and radiographic changes, include joint pain, stiffness, movement with a restricted range and cracking of joints (crepitus)
      • Altman R.D.
      Criteria for classification of clinical osteoarthritis.
      . OA has traditionally been regarded as a non-inflammatory condition
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
      , but improved detection methods show that inflammatory pathways are up-regulated in OA
      • Abramson S.B.
      Inflammation in osteoarthritis.
      ; with, e.g., a low-level increase by groups in C-reactive protein (CRP)
      • Spector T.D.
      • Hart D.J.
      • Nandra D.
      • Doyle D.V.
      • Mackillop N.
      • Gallimore J.R.
      • et al.
      Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease.
      . Drug therapy in OA consists mainly of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Paracetamol is the oral analgesic of first choice, and if successful, the preferred long-term oral analgesic. However, NSAIDs must be considered in patients with no response to paracetamol
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.
      • Dieppe P.
      • et al.
      EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
      • Zhang W.
      • Doherty M.
      • Arden N.
      • Bannwarth B.
      • Bijlsma J.
      • Gunther K.P.
      • et al.
      EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      . Disease-modifying OA drug (DMOAD)-therapy remains to be developed in order to slow down disease progression as demonstrated by, e.g., a reduced joint space narrowing on plain X-rays
      • Abadie E.
      • Ethgen D.
      • Avouac B.
      • Bouvenot G.
      • Branco J.
      • Bruyere O.
      • et al.
      Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.
      .
      According to the consensus statement following the outcome measures in rheumatology (OMERACT) III conference, a core set of outcome measures for phase III clinical trials pointed towards four variables which should be evaluated in trials with patients suffering from either knee, hip, or hand OA: pain, physical function (i.e., disability), patient global assessment; and – for studies of 1 year or longer – joint imaging
      • Bellamy N.
      • Kirwan J.
      • Boers M.
      • Brooks P.
      • Strand V.
      • Tugwell P.
      • et al.
      Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III.
      . It is mandatory to perform continuous follow-up on clinical interventions, which are assessed on scales typically referred to as subjective
      • Tugwell P.
      • Shea B.
      • Boers M.
      • Brooks P.
      • Simon L.S.
      • Strand V.
      • et al.
      Evidence-Based Rheumatology.
      • Dougados M.
      Monitoring osteoarthritis progression and therapy.
      .
      A standardized hip powder of Rosa canina made from the seeds and husks of the fruits from a subtype of R. canina hip powder (i.e., rosehip), the common wild-briar hedgerow rose, has been evaluated in (short-term) randomized controlled trials (RCTs)
      • Chrubasik C.
      • Duke R.K.
      • Chrubasik S.
      The evidence for clinical efficacy of rose hip and seed: a systematic review.
      . According to the best-evidence synthesis, there are contradictory results with regard to scientific evidence for R. canina extracts
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      . Evidence from early in vitro studies indicates that R. canina hip powder preparations exert anti-inflammatory properties via reduced chemotaxis of peripheral blood neutrophils and monocytes in healthy subjects, and a reduction in CRP is seen after 4 weeks supplementation in patients with OA
      • Winther K.
      • Rein E.
      • Kharazmi A.
      The anti-inflammatory properties of rose-hip.
      • Kharazmi A.
      • Winther K.
      Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
      . The proposed mechanism of action has been focused on the preparations' anti-oxidative capacities, and a specific galactolipid (called GOPO) has been identified (in vitro) as anti-inflammatory, and as such possibly the reason for the preparation's proposed pain reducing property
      • Larsen E.
      • Kharazmi A.
      • Christensen L.P.
      • Christensen S.B.
      An antiinflammatory galactolipid from rose hip (Rosa canina) that inhibits chemotaxis of human peripheral blood neutrophils in vitro.
      . These considerations over active ingredients have recently been confirmed by others, as extracts of R. canina fruits have shown potent anti-inflammatory and anti-nociceptive activities
      • Orhan D.D.
      • Hartevioglu A.
      • Küpeli E.
      • Yesilada E.
      In vivo anti-inflammatory and antinociceptive activity of the crude extract and fractions from Rosa canina L. fruits.
      and R. canina hip powder extracts (an organic solvent) may inhibit both cyclooxygenase (COX)-1 and -2
      • Jager A.K.
      • Eldeen I.M.
      • van S.J.
      COX-1 and -2 activity of rose hip.
      . In a clinical trial it has been shown that R. canina hip powder may have some efficacy in hip and knee OA patients
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      .
      In the present systematic review on clinical efficacy of giving a R. canina hip powder preparation for symptomatic treatment of OA, with explicit meta-analysis of the available RCTs
      • Moher D.
      • Cook D.J.
      • Eastwood S.
      • Olkin I.
      • Rennie D.
      • Stroup D.F.
      Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses.
      – our primary aim was to obtain up-to-date, evidence-based estimates that could provide a detailed view of the symptomatic efficacy of R. canina compounds used in the treatment of OA. The results of this analysis may be crucial for the evaluation whether or not these preparations will be relevant for future large-scale (i.e., phase III) clinical trials.

      Materials and methods

      Study selection, assessment of eligibility criteria, data extraction, and statistical analysis were performed based on a predefined protocol according to the Cochrane Collaboration guidelines (http://www.cochrane.org/resources/handbook/index.htm).

       Retrieval of published studies

      RCTs of R. canina hip powder treatment vs placebo were identified through a systematic literature search in the following bibliographic databases: Medline via PubMed (mid 1950s to October 2007), EMBASE via WebSpirs (1980 to October 2007), CINAHL via WebSpirs (1982 to October 2007), Biosis Previews via WebSpirs (1980 to October 2007), Web of Science (1945–54 to October 2007), Scifinder (1907 to October 2007), Scopus (1966 to October 2007), and the Cochrane Library from 1966 to October 2007. Following the searches, reference lists of original reports and review articles retrieved through the described searches, were thoroughly checked for further relevant studies. Finally, we searched conference abstracts over the past 2 years via the established international societies of rheumatology, i.e., the OsteoArthritis Research Society International (OARSI), EUropean League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Since the available studies were expected to be few, a broad, less specific search strategy was applied: (Rosehip OR “Rose hip” OR “Rosa canina” OR “dog rose” OR Rosaceae OR Litozin OR hyben OR GOPO OR i-flex) AND (OA OR osteoarthrosis). Controlled, randomized and clinical trials were deliberately not part of an explicit search strategy, since we wished to find any work dealing with R. canina hip powder in the treatment of OA. With the awareness of a higher proportion of noise in the chosen searches, full references were reviewed for possible RCTs, and full text references were obtained for further scrutiny, where relevant.

       Inclusion and exclusion criteria

      We included RCTs comparing a preparation containing R. canina hip powder with a placebo intervention. Studies were selected if the included patients were (explicitly) described as having clinical or radiographic evidence of OA. Two reviewers (RDA, HB) crosschecked and agreed on diagnostic criteria in each trial. We excluded studies in conditions such as non-OA joint pain, rheumatoid arthritis (RA), pain due to surgery or injury, and studies with mixed patient groups such as those with both OA and RA, unless the subgroup data for OA were available. No language restrictions applied.

       Quality assessment

      The quality of studies was assessed based on randomization, masking and withdrawal. The complete reports of the RCTs that were selected for inclusion in the meta-analysis were scored by two reviewers for quality (RC, EMB) using a validated instrument
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • Jenkinson C.
      • Reynolds D.J.
      • Gavaghan D.J.
      • et al.
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      . The score was given as follows: if the study was described as randomized (+1); if the study was described as double masked (+1); if there was a (detailed) description of withdrawals and attrition rates/detailed outcome data and the analysis was performed according to the intention-to-treat (ITT) principle (+1). In addition, if the random allocation and the double blinding were properly described and appropriately put into practice, each item received 1 point extra. Conversely, if the methods (randomization and masking) were not considered appropriate, 1 point was subtracted from each item.

       Data extraction and outcome measures

      Two reviewers (RC, EMB) undertook data extraction independently. Disagreements were resolved by discussion. A customized form was used to record the following: authors of the study, year of publication, trial design, study length, number of patients randomized (i.e., the ITT population, Ntotal), the number of patients for whom detailed outcome data was available for meta-analysis in each group (E/exposed=R. canina hip powder and C/control=placebo) included in the individual-study statistical tests (NE and NC, respectively), average patient age, sex, site of OA. Note that in order to estimate the relative number of responders to therapy, we included the ITT population (based on the NE−ITT and NC−ITT, respectively) in the denominator. The number of responders per se, was assessed as the number of patients in each trial defined by the authors as being a responder; the number of responders in both the R. canina hip powder and placebo group were based on the same criterion
      • Dougados M.
      Monitoring osteoarthritis progression and therapy.
      .
      As it seemed relevant to consider the available efficacy in cross-over trials as being subjected to carry-over bias
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      , we only report (i.e., include) data from the first period. The primary outcome measure was the magnitude of pain reduction
      • Huskisson E.C.
      Measurement of pain.
      . The secondary outcomes were the reported changes in the average level of applied painkillers; the extracted (or estimated) reported number of responders per group following intervention
      • Dougados M.
      Monitoring osteoarthritis progression and therapy.
      . Disability and patient's global assessment following therapy
      • Bellamy N.
      • Kirwan J.
      • Boers M.
      • Brooks P.
      • Strand V.
      • Tugwell P.
      • et al.
      Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III.
      were not included as outcomes in the present meta-analysis, since we expected that these endpoints would not have been reported consistently.

       Statistical analysis

      As a preliminary review of the available data
      • Christensen R.
      • Sørensen L.B.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Rose-hip in osteoarthritis (OA): a meta-analysis.
      supported the notion that the available cross-over trials had been reporting carry-over bias
      • Elbourne D.R.
      • Altman D.G.
      • Higgins J.P.
      • Curtin F.
      • Worthington H.V.
      • Vail A.
      Meta-analyses involving cross-over trials: methodological issues.
      , we chose to include only data from the first period, as any pooled efficacy meta-analysis including data from both periods would imply a risk of (accumulating) carry-over bias
      • Curtin F.
      • Elbourne D.
      • Altman D.G.
      Meta-analysis combining parallel and cross-over clinical trials. III: the issue of carry-over.
      . For each of the continuous outcomes (i.e., pain and rescue medications), we calculated the test statistics based on the available data, using standard formulae
      • Altman D.G.
      • Bland J.M.
      Interaction revisited: the difference between two estimates.
      . Based on these statistics and the number of observations in each group, we were able to estimate the standardized mean difference (SMD) for each study
      • Normand S.L.
      Meta-analysis: formulating, evaluating, combining, and reporting.
      – which was applied as effect size (ES)
      • Cohen J.
      Statistical Power Analysis for the Behavioral Sciences.
      . The corresponding variance (SE2) was calculated based on the individual study SMD and the number of patients included (SE2=1/NE+1/NC+SMD2/[2{NE+NC}])
      • Normand S.L.
      Meta-analysis: formulating, evaluating, combining, and reporting.
      . As the unadjusted (Cohen's) SMD in principle does not treat the variance (SE2) as an estimate, we applied (i.e., via multiplication) the Hedges' bias-correction (J=13/[4×df1]; i.e., df=NE+NC2) by default – adjusting for small sample bias
      • Hedges L.V.
      Distribution theory for Glass's estimator of effect size and related estimators.
      . SMDs were signed so that positive values (>0) indicated a benefit of R. canina hip powder: clinically, |ES|0.2 is considered small, |ES|0.5 is moderate (and would probably be recognized clinically
      • Norman G.R.
      • Sloan J.A.
      • Wyrwich K.W.
      Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation.
      ), and |ES|0.8 is large
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.
      • Dieppe P.
      • et al.
      EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
      • Zhang W.
      • Doherty M.
      • Arden N.
      • Bannwarth B.
      • Bijlsma J.
      • Gunther K.P.
      • et al.
      EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      • Kazis L.E.
      • Anderson J.J.
      • Meenan R.F.
      Effect sizes for interpreting changes in health status.
      • Zhang W.
      • Doherty M.
      • Leeb B.F.
      • Alekseeva L.
      • Arden N.K.
      • Bijlsma J.W.
      • et al.
      EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      . The Odds Ratio (OR) was estimated for the dichotomous efficacy data (i.e., responders to therapy)
      • Bland J.M.
      • Altman D.G.
      Statistics notes: the odds ratio.
      . To combine the individual study results we did (generic inverse variance) meta-analyses via mixed effects model procedures using SAS software (version 9.1.3, by SAS Institute Inc., Cary, NC, USA)
      • Littell R.C.
      • Milliken G.A.
      • Stroup W.W.
      • Wolfinger R.D.
      • Schabenberger O.
      SAS for Mixed Models.
      . We applied the restricted maximum likelihood (REML) method
      • Patterson H.D.
      • Thompson R.
      Recovery of inter-block information when block sizes are unequal.
      • Wang M.C.
      • Bushman B.J.
      Integrating Results through Meta-Analytic Review Using SAS Software.
      to estimate the between study variance and the combined efficacy
      • Normand S.L.
      Meta-analysis: formulating, evaluating, combining, and reporting.
      • van Houwelingen H.C.
      • Arends L.R.
      • Stijnen T.
      Advanced methods in meta-analysis: multivariate approach and meta-regression.
      . The heterogeneity (between trials) was examined with a standard Q test (testing the hypothesis of homogeneity: χ(k−1)2)
      • Cochran W.G.
      The combination of estimates from different experiments.
      . However, as measures of the extent of heterogeneity might be considered preferable to test of its presence, we evaluated possible inconsistency between effect measures via the I2 statistic
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      – which can be interpreted as the percentage of variability in effect estimates due to heterogeneity
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      . As it is often sensible to use one statistic for meta-analysis and re-express the results using a second more easily interpretable statistic
      , we estimated the Number Needed to Treat (NNT), with 95% confidence intervals (CI) on the basis of the combined OR value
      • Christensen R.
      • Kristensen P.K.
      • Bartels E.M.
      • Bliddal H.
      • Astrup A.
      Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.
      , since this method enables direct translation into clinical practice
      • Tugwell P.
      • Shea B.
      • Boers M.
      • Brooks P.
      • Simon L.S.
      • Strand V.
      • et al.
      Evidence-Based Rheumatology.
      • Osiri M.
      • Suarez-Almazor M.E.
      • Wells G.A.
      • Robinson V.
      • Tugwell P.
      Number needed to treat (NNT): implication in rheumatology clinical practice.
      • Kristensen L.E.
      • Christensen R.
      • Bliddal H.
      • Geborek P.
      • Danneskiold-Samsoe B.
      • Saxne T.
      The number needed to treat for adalimumab, etanercept and infliximab based on ACR50 response in three randomized controlled trials on established rheumatoid arthritis: a systematic literature review.
      ; applying the overall event rate in the placebo group as a proxy for baseline risk
      • Cates C.J.
      Simpson's paradox and calculation of number needed to treat from meta-analysis.
      • Altman D.G.
      • Deeks J.J.
      Meta-analysis, Simpson's paradox, and the number needed to treat.
      . The software “Visual Rx” is designed to calculate NNT (and NNH) from the pooled results of a meta-analysis and produce a graphical display of the result
      • Edwards A.
      • Elwyn G.
      • Mulley A.
      Explaining risks: turning numerical data into meaningful pictures.
      : http://www.nntonline.net/ebm/visualrx/try.asp
      • Visual Rx
      Version 1.0–1.7. Copyright© 2000–2003.
      .

      Results

       Characteristics of trials

      The Quality of Reporting of Meta-analyses (QUOROM)-recommended flowchart
      • Moher D.
      • Cook D.J.
      • Eastwood S.
      • Olkin I.
      • Rennie D.
      • Stroup D.F.
      Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses.
      in Fig. 1 displays the eligibility details of the studies identified by the combined search strategy. Studies with clearly irrelevant objectives/designs as well as abstracts and reviews/theme articles, were separated from possible studies for inclusion: initially the search strategy revealed 37 potential references, which were considered at abstract level. When removing obviously residual literature and abstracts later reported in full, we retrieved 15 studies for further scrutiny – including critical assessment of the reported references
      • Chrubasik C.
      • Duke R.K.
      • Chrubasik S.
      The evidence for clinical efficacy of rose hip and seed: a systematic review.
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      • Winther K.
      • Rein E.
      • Kharazmi A.
      The anti-inflammatory properties of rose-hip.
      • Kharazmi A.
      • Winther K.
      Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
      • Larsen E.
      • Kharazmi A.
      • Christensen L.P.
      • Christensen S.B.
      An antiinflammatory galactolipid from rose hip (Rosa canina) that inhibits chemotaxis of human peripheral blood neutrophils in vitro.
      • Orhan D.D.
      • Hartevioglu A.
      • Küpeli E.
      • Yesilada E.
      In vivo anti-inflammatory and antinociceptive activity of the crude extract and fractions from Rosa canina L. fruits.
      • Jager A.K.
      • Eldeen I.M.
      • van S.J.
      COX-1 and -2 activity of rose hip.
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Nobaek S.
      • Johansson M.L.
      • Molin G.
      • Ahrne S.
      • Jeppsson B.
      Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome.
      • Rossnagel K.
      • Willich S.N.
      Value of complementary medicine exemplified by rose-hips.

      Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      • Ernst E.
      Complementary or alternative therapies for osteoarthritis.
      • Chrubasik J.E.
      • Roufogalis B.D.
      • Chrubasik S.
      Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain.
      .
      Figure thumbnail gr1
      Fig. 1Flow chart of the search strategy and selection of trials.
      Among these, five papers were excluded as a consequence of being reviews
      • Chrubasik C.
      • Duke R.K.
      • Chrubasik S.
      The evidence for clinical efficacy of rose hip and seed: a systematic review.
      • Ameye L.G.
      • Chee W.S.
      Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
      • Rossnagel K.
      • Willich S.N.
      Value of complementary medicine exemplified by rose-hips.
      • Ernst E.
      Complementary or alternative therapies for osteoarthritis.
      • Chrubasik J.E.
      • Roufogalis B.D.
      • Chrubasik S.
      Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain.
      ; one study only considered intestinal microflora in patients with irritable bowel syndrome
      • Nobaek S.
      • Johansson M.L.
      • Molin G.
      • Ahrne S.
      • Jeppsson B.
      Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome.
      ; three studies were categorized as in vitro
      • Larsen E.
      • Kharazmi A.
      • Christensen L.P.
      • Christensen S.B.
      An antiinflammatory galactolipid from rose hip (Rosa canina) that inhibits chemotaxis of human peripheral blood neutrophils in vitro.
      • Orhan D.D.
      • Hartevioglu A.
      • Küpeli E.
      • Yesilada E.
      In vivo anti-inflammatory and antinociceptive activity of the crude extract and fractions from Rosa canina L. fruits.
      • Jager A.K.
      • Eldeen I.M.
      • van S.J.
      COX-1 and -2 activity of rose hip.
      . Among the remaining six potentially relevant studies
      • Winther K.
      • Rein E.
      • Kharazmi A.
      The anti-inflammatory properties of rose-hip.
      • Kharazmi A.
      • Winther K.
      Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.

      Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      two were excluded as a consequence of being controlled trials, reported as case-control trials with explicit focus on in vitro-inflammatory properties
      • Winther K.
      • Rein E.
      • Kharazmi A.
      The anti-inflammatory properties of rose-hip.
      , and inhibition of chemotaxis and chemiluminescence
      • Kharazmi A.
      • Winther K.
      Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
      , respectively. This left four trials
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.

      Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      potentially relevant for inclusion in the meta-analysis
      • Christensen R.
      • Sørensen L.B.
      • Bartels E.M.
      • Astrup A.
      • Bliddal H.
      Rose-hip in osteoarthritis (OA): a meta-analysis.
      . However, following personal contact with Dr Winther and Dr Rein, it appeared that the patent registration from Rein et al.

      Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

      was based on an unpublished subgroup-analysis of the Norwegian study
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      and was, quote: “a rehash of a another study”. Accordingly, we were able to include three (assumed) mutually independent RCTs
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      .
      Table I shows the baseline characteristics of the included studies. All trials were supported by Hyben-Vital International (Tullebølle, Langeland, Denmark): one study was performed in an outpatient clinic in Norway
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      , while the two others included patients (from outpatient clinics) in Denmark
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      . Overall, the trials randomized 306 OA patients to either R. canina hip powder or placebo, allocating 153 patients to each group. The Danish trials
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      applied a cross-over design, and excluded patients with other rheumatic diseases than OA, and those who received glucosamine or intra-articular glucocorticoids 6 weeks prior to the study. The Norwegian study
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      included OA patients with pain for at least 6 months, who were on a waiting list for either hip or knee surgery, or on a list for final evaluation for surgery. As presented in Table I the majority of the participating patients were women (62%) suffering from knee OA (61%) with a median age of 66 years.
      Table ISummary of baseline characteristics of all participants in the eligible trials
      StudyYearQSInterventionDesignDuration (months)ITTWomen (%)Joint affectedAge (years)BMI (kg/m2)Definite sample size
      NENC
      Warholm20034Hyben-Vital®, 2×5×0.5 g/day=5 g/dayPG410065 (65.0%)K: 56, H: 44 (56% KOA)65.2±11.1n.a.4848
      Rein20044Hyben-Vital®, 2×5×0.5 g/day=5 g/dayCO311271 (63.4%)K: 59, H: 46, N: 18, S: 14, Ha: 40 (53% KOA)67.0±11.727.3±5.05047
      Winther20055LitoZin®, 2×5×0.5 g/day=5 g/dayCO39454 (57.4%)K: 58, H: 21, K&H: 15 (78% KOA)65.6±n.a. [range: 38–92]27.0±n.a. [range: 19–41]4747
      OverallMedian: 4, Mean: 4.3, SD: 0.55 g Rosehip powder/day32.7% PGMedian: 3, Mean: 3.3, SD: 0.5306190 (62.1%)K: 188 (61.4% KOA)Median: 65.6n.a.145142
      Data are number (%) or mean±SD. QS: Jadad Quality Score (range: 0–5); PG and CO indicate Parallel-Group and Cross-Over Trial design, respectively. BMI: body-mass index; K: knee OA; H: hip OA; N: neck OA; S: shoulder OA; Ha: hand OA. NE and NC are the number of patients included in the analyses in the exposed and control groups (i.e., rosehip and placebo), respectively. n.a.: Data not available.

       Pain reduction

      As presented in Fig. 2(A): the meta-analysis of the three studies reporting changes in pain scores produced a statistically significant (P=0.0019) combined ES of 0.37 (95% CI: 0.13–0.60) – favoring R. canina hip powder compared to placebo. Test for homogeneity seemed to support that the efficacy was consistent across trials (Q=0.18; I2=0%). Thus, it seems reasonable to assume that the three (mutually independent) studies measured the same overall effect. Apparently the pain reducing property of R. canina hip powder seemed more pronounced in the population examined in the study by Warholm et al.
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      , which included patients who were on a waiting list for either hip or knee surgery, or on a list for final evaluation for surgery.
      Figure thumbnail gr2
      Fig. 2Efficacy of R. canina hip powder (i.e., Rosehip) compared to placebo in OA patients presented as SMDs and OR. (A) Change (i.e., reduction) in self-reported pain; (B) change (i.e., reduction) in self-reported use of analgesics; (C) the number of patients defined/estimated as being a responder. Every square represents the individual study's effect measure with 95% CI indicated by horizontal lines. Square sizes are proportional to the precision of the estimate. The overall estimate from the meta-analysis and its CI are shown at the bottom of each subplot (A–C), represented as a diamond. The center of the diamond represents the pooled point estimate, and its horizontal lines represent the CI.

       Use of rescue medication

      As presented in Fig. 2(B): the meta-analysis of the three studies reporting changes in the use of ‘rescue medication’ produced a statistically significant (P=0.018) combined ES of 0.28 (95% CI: 0.05–0.51) – favoring R. canina hip powder compared to placebo. Test for homogeneity seemed to support that the efficacy was consistent across trials (Q=1.25; I2=0%). Thus it seems reasonable to assume that the three (mutually independent) studies measured the same overall effect. Apparently R. canina hip powder did not reduce the patients' consumption of painkillers in the population reported by Warholm et al. (i.e., ES<0.2)
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      , while based on the diaries of the consumption of ‘rescue medication’ investigated in the study by Winther et al.
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      – the use of R. canina hip powder resulted in a significantly reduced use of analgesics, compared to placebo.

       Number of responders to therapy

      In order to assess this secondary outcome, the arbitrary “responders to therapy”, the following data was extracted: (1) Warholm et al. used a simple yes-or-no questionnaire (about relief of pain) after 4 months therapy in both groups
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      (R. canina hip powder: 31/50 vs placebo: 21/50); (2) Rein et al. defined a responder as one who showed at least one category of pain improvement
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      (R. canina hip powder: 31/56 vs placebo: 18/56); (3) Winther et al. used any reduction in western ontario and mcmaster (WOMAC) score for joint pain after the initial 3 weeks of treatment as a response criterion – however, they did not report any explicit numbers following 3 months treatment
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      . We assessed the number of responders (any reduction in WOMAC pain) in each group following a Monte-Carlo simulation based on the reported means and standard deviations (SDs) (i.e., table 3
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      ) assuming that a univariate normal distribution apply
      • Fan X.
      • Felsövalyi À
      • Sivo S.A.
      • Keenan S.C.
      SAS for Monte Carlo Studies: a Guide for Quantitative Researchers.
      (R. canina hip powder: 32/47 vs placebo: 26/47). As presented in Fig. 2(C): the meta-analysis of the studies reporting the number of patients responding to therapy as a dichotomized (yes/no) count, produced a statistically highly significant (P=0.00089) combined OR of 2.19 (95% CI: 1.38–3.48) – favoring R. canina hip powder compared to placebo; i.e., it is more than twice as likely that a patient allocated to R. canina hip powder will respond to therapy, compared to placebo. Test for homogeneity seemed to support that the observed efficacy was consistent across trials (Q=0.52; I2=0%), supporting the assumption that the three (mutually independent) studies were measuring the same overall effect. In absolute terms: the total number of responders (across the three trials) on R. canina hip powder and placebo was 94/153 (61.4%) and 65/153 (42.5%), respectively. On the basis of the average number of responders within the placebo groups, the combined OR corresponded to a NNT of six (95% CI: 4–13) patients.

       Adverse events and safety considerations

      Focusing on adverse events, there seemed to be the same amount of mild cases of gastrointestinal discomfort after intervention vs control
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      . The same number of patients seemed to experience ‘acid regurgitation’ in both the study by Rein et al.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      and Winther et al.
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      : one case in each group (R. canina hip powder and placebo) – both leading to discontinuation. In the study by Winther et al.
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      , mild unwanted effects (reported as being non-significant) that did not cause withdrawal, were explicitly reported; based on these data we re-calculated empirical OR-values with 95% (“exact”
      • Agresti A.
      A survey of exact inference for contingency tables.
      ) confidence limits for these rare incident cases
      • Thomas D.G.
      Algorithm AS 36: exact confidence limits for the odds ratio in a 2×2 table.
      : (1) ‘Frequent voiding’ [OR=3.07 (0.24–162.65)]; (2) ‘Diarrhea’ [OR=1.00 (0.07–14.07)]; (3) ‘Constipation’ [OR=2.02 (0.10–120.54)]; (4) ‘Short episode of mild urticaria’ [OR=2.02 (0.10–120.51)].

      Discussion

      The main result of our analysis was a small to moderate short-term efficacy of preparations with R. canina hip powder with a small but clinically relevant reduction of pain in OA patients. However, the available data are sparse, since we had only three clinical trials evaluating the efficacy in 145 patients after use of R. canina hip powder for 3–4 months. One assumption that is prudent in order to make statistical inference following meta-analysis, is that the eligible studies included can be assumed to be mutually independent, which might be an issue within the context of clinical efficacy of R. canina hip powder. Dr Rein had access to the original data from Warholm et al.
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      – enabling a patent registration

      Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

      prior to the publication by Rein et al.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      ; recalling that Dr Winther was the co-author on this paper
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      before the Winther et al. paper was published in 2005
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      . However, meta-analyses are depending on the international peer-review system, which has been applied in all of the included papers
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      . A combined analysis (i.e., meta-analysis) of homogeneous results, quantifies the magnitude of clinical efficacy per se
      • Thompson S.G.
      • Pocock S.J.
      Can meta-analyses be trusted?.
      . Thus, it seems possible that the empirical magnitude of clinical efficacy following use of R. canina hip powder is comparable to other nutraceuticals available
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.
      . Our meta-analysis supports the conclusion previously stated by Chrubasik: “Moderate evidence exists for the use of a powder of the seeds and husks of a Rosa canina subspecies in patients suffering from osteoarthritis
      • Chrubasik C.
      • Duke R.K.
      • Chrubasik S.
      The evidence for clinical efficacy of rose hip and seed: a systematic review.
      .
      We are confident that the efficacy estimate is robust per se, as it is based on very consistent findings (I2=0%) – thus, a new trial (of the same duration) would be expected to result in a similar magnitude of small to moderate clinical efficacy (ES0.4). In an (assumed) average knee OA population
      • Tubach F.
      • Ravaud P.
      • Baron G.
      • Falissard B.
      • Logeart I.
      • Bellamy N.
      • et al.
      Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement.
      • Tubach F.
      • Ravaud P.
      • Baron G.
      • Falissard B.
      • Logeart I.
      • Bellamy N.
      • et al.
      Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state.
      , this ES would correspond to a mean reduction in the visual analog scale (VAS) for pain (0–100 mm) of 6 mm; i.e., approximately 10% pain reduction. Apparently the use of R. canina hip powder leads to a significant reduction in the use of rescue medication, corresponding to a small clinical efficacy. This does not allow more detailed interpretation, although it seems likely that a reduction in analgesics could have an impact on a major public health scale
      • Woolf A.D.
      Healthcare services for those with musculoskeletal conditions: a rheumatology service. Recommendations of the European Union of Medical Specialists Section of Rheumatology/European Board of Rheumatology 2006.
      . When focusing on the explicit, although arbitrary outcome ‘responders to therapy’, it seems that an OR of 2.19 corresponding to an ES of 0.43
      • Chinn S.
      A simple method for converting an odds ratio to effect size for use in meta-analysis.
      – indicates a small to moderate clinical efficacy
      • Jordan K.M.
      • Arden N.K.
      • Doherty M.
      • Bannwarth B.
      • Bijlsma J.W.
      • Dieppe P.
      • et al.
      EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
      • Zhang W.
      • Doherty M.
      • Arden N.
      • Bannwarth B.
      • Bijlsma J.
      • Gunther K.P.
      • et al.
      EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      • Zhang W.
      • Doherty M.
      • Leeb B.F.
      • Alekseeva L.
      • Arden N.K.
      • Bijlsma J.W.
      • et al.
      EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
      . When translated into the number of patients who would need R. canina hip powder therapy (compared to placebo) in order to “treat” one patient, the combined estimated NNT was six patients. The magnitude of R. canina hip powder as a pain reducing agent is more pronounced than the primary analgesic of choice in clinical practice, paracetamol/acetaminophen, which compared to placebo has an ES of 0.13 (95% CI: 0.04–0.22), and thus of questionable clinical significance
      • Towheed T.
      • Maxwell L.
      • Judd M.
      • Catton M.
      • Hochberg M.
      • Wells G.
      Acetaminophen for osteoarthritis.
      . Hence R. canina hip powder might have an impact as an over-the-counter (OTC) preparation in the future. The patients studied in the present meta-analysis (see Table I)
      • Winther K.
      • Apel K.
      • Thamsborg G.
      A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      • Rein E.
      • Kharazmi A.
      • Winther K.
      A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
      represent a fairly homogenous OA population with a clinically relevant age distribution. The exact degree of OA (i.e., radiographic data) was not given in the studies, in one study
      • Warholm O.
      • Skaar S.
      • Hedman E.
      • Mølmen H.M.
      • Eik L.
      The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      , however, patients were presumably end-stage, which might be the reason for a continuous use of pain medication in this study, in spite of a significant effect of R. canina hip powder on self-reported pain.
      An increasing interest has been noted over the last years for dietary supplements for OA
      • Ernst E.
      Complementary or alternative therapies for osteoarthritis.
      with a special emphasis on glucosamine and chondroitine
      • McAlindon T.E.
      • LaValley M.P.
      • Gulin J.P.
      • Felson D.T.
      Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis.
      • Richy F.
      • Bruyere O.
      • Ethgen O.
      • Cucherat M.
      • Henrotin Y.
      • Reginster J.Y.
      Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.
      . Glucosamine only shows significant efficacy in Rottapharm-supported pivotal trials, of which three well conducted trials had a pooled efficacy of ES=0.27 (95% CI: 0.12–0.43)
      • Reginster J.Y.
      The efficacy of glucosamine sulfate in osteoarthritis: financial and nonfinancial conflict of interest.
      . Never the less the efficacy of glucosamine has been heavily debated, among many things because of the great heterogeneity between efficacy outcomes
      • Towheed T.E.
      • Anastassiades T.P.
      Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete.
      • Towheed T.E.
      Current status of glucosamine therapy in osteoarthritis.
      • Vlad S.C.
      • LaValley M.P.
      • McAlindon T.E.
      • Felson D.T.
      Glucosamine for pain in osteoarthritis: why do trial results differ?.
      .
      In the present analysis of R. canina hip powder, the lack of heterogeneity between studies gives credit to an efficacy. The drawback of this observation is – as with the Rottapharm product – that the same company sponsored all three studies on R. canina hip powder. Ideally, other similar products from other manufacturers should be tested to substantiate the outcome or even better, the presumed active ingredient (e.g., GOPO) should be isolated, patented, and tested in a strictly controlled clinical trial, following guidelines for Good Clinical Practice (GCP) and consolidated standards of reporting trials (CONSORT)
      • Altman D.G.
      • Schulz K.F.
      • Moher D.
      • Egger M.
      • Davidoff F.
      • Elbourne D.
      • et al.
      The revised CONSORT statement for reporting randomized trials: explanation and elaboration.
      . Such initiatives would increase the external validity of any proposed herbal therapy
      • Gagnier J.J.
      • Boon H.
      • Rochon P.
      • Moher D.
      • Barnes J.
      • Bombardier C.
      Recommendations for reporting randomized controlled trials of herbal interventions: explanation and elaboration.
      . Patients with chronic painful diseases seek complementary-alternative therapy for various reasons. Ramsey et al. has previously reported from a US cohort, that alternative medicine use is highly prevalent among those with OA (47%) and that levels of expenditure for those who do consume these services ($1,127 per year) approximate expenditures on more traditional medical care ($1,148 per year)
      • Ramsey S.D.
      • Spencer A.C.
      • Topolski T.D.
      • Belza B.
      • Patrick D.L.
      Use of alternative therapies by older adults with osteoarthritis.
      . The traditional medical approach has only been able to offer slight improvements with regard to pain
      • Towheed T.
      • Maxwell L.
      • Judd M.
      • Catton M.
      • Hochberg M.
      • Wells G.
      Acetaminophen for osteoarthritis.
      • Bjordal J.M.
      • Ljunggren A.E.
      • Klovning A.
      • Slordal L.
      Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials.
      with a definite problem of a rather frightening list of adverse events
      • Bjordal J.M.
      • Ljunggren A.E.
      • Klovning A.
      • Slordal L.
      Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials.
      • Lee C.
      • Straus W.L.
      • Balshaw R.
      • Barlas S.
      • Vogel S.
      • Schnitzer T.J.
      A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta-analysis.
      . In contrast, alternative medications are repeatedly found (i.e., report) to have almost no adverse effects; this has been shown for both glucosamine
      • Towheed T.E.
      • Maxwell L.
      • Anastassiades T.P.
      • Shea B.
      • Houpt J.
      • Robinson V.
      • et al.
      Glucosamine therapy for treating osteoarthritis.
      , chondroitin
      • Reichenbach S.
      • Sterchi R.
      • Scherer M.
      • Trelle S.
      • Burgi E.
      • Burgi U.
      • et al.
      Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
      , avocado/soybean unsaponifiables (ASU)

      Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado/soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2007 Nov 23 [Epub ahead of print].

      among many – as well as R. canina hip powder.
      We turn to the question: whether treatment of OA via prescription of anti-oxidants is dream or reality?
      • Henrotin Y.
      • Kurz B.
      Antioxidant to treat osteoarthritis: dream or reality?.
      In a short-term cross-over trial 1 g of calcium ascorbate for either knee or hip OA was given for 14 days, resulting in a small to moderate (statistically significant) pain reduction compared to placebo
      • Jensen N.H.
      Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebo-controlled cross-over trial in general practice.
      , which is equivalent to our results for R. canina hip powder. It is, however, noteworthy that data have been presented that the anti-inflammatory properties of R. canina hip powder is unrelated to its vitamin C content
      • Winther K.
      • Rein E.
      • Kharazmi A.
      The anti-inflammatory properties of rose-hip.
      • Kharazmi A.
      • Winther K.
      Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
      . In regard to anti-oxidants, however, a recent large-scale meta-analysis found that treatment with β-carotene, vitamin A, and vitamin E may increase mortality, while a potential role for vitamin C remains to be clarified
      • Bjelakovic G.
      • Nikolova D.
      • Gluud L.L.
      • Simonetti R.G.
      • Gluud C.
      Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
      . By consequence, large-scale trials on anti-oxidants are still relevant, and no final conclusion may be drawn regarding safety.
      Alternative therapy should be subjected to a similar scrutiny of effect vs adverse effects as ordinary medications
      • Christensen R.
      • Kristensen P.K.
      • Bartels E.M.
      • Bliddal H.
      • Astrup A.
      Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.
      • Berlin J.A.
      • Colditz G.A.
      The role of meta-analysis in the regulatory process for foods, drugs, and devices.
      . The alternative OTC market is huge
      • Ramsey S.D.
      • Spencer A.C.
      • Topolski T.D.
      • Belza B.
      • Patrick D.L.
      Use of alternative therapies by older adults with osteoarthritis.
      whether it is efficacious or not
      • Ernst E.
      Complementary or alternative therapies for osteoarthritis.
      , and with an inevitable influence on both direct and indirect costs
      • Rabenda V.
      • Manette C.
      • Lemmens R.
      • Mariani A.M.
      • Struvay N.
      • Reginster J.Y.
      Direct and indirect costs attributable to osteoarthritis in active subjects.
      . With regard to R. canina hip powder a large-scale trial is justified by the magnitude of clinical efficacy demonstrated in this meta-analysis of short-term trials – an efficacy in the area of 0.4 SMD-points. In a parallel group design this would correspond to 133 OA patients in each group in order to assess a statistically significant effect (P<0.05, two-tailed) with a proper statistical power (90%)
      • Campbell M.J.
      • Julious S.A.
      • Altman D.G.
      Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons.
      . In order to monitor the clinical efficacy applying these R. canina hip powder products, the next RCT should be of at least half a year duration, although a 1-year trial with sufficient imaging would be even better
      • Bellamy N.
      • Kirwan J.
      • Boers M.
      • Brooks P.
      • Strand V.
      • Tugwell P.
      • et al.
      Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III.
      . We emphasize the need for future studies applying empirically validated outcomes (e.g., WOMAC
      • Bellamy N.
      • Buchanan W.W.
      • Goldsmith C.H.
      • Campbell J.
      • Stitt L.W.
      Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
      , knee and osteoarthritis outcome core (KOOS)
      • Roos E.M.
      • Toksvig-Larsen S.
      Knee injury and Osteoarthritis Outcome Score (KOOS) – validation and comparison to the WOMAC in total knee replacement.
      or the Lequesne index
      • Lequesne M.G.
      • Mery C.
      • Samson M.
      • Gerard P.
      Indexes of severity for osteoarthritis of the hip and knee. Validation – value in comparison with other assessment tests.
      )
      • Dougados M.
      Monitoring osteoarthritis progression and therapy.
      , and that these studies explicitly report the number of so-called responders according to the OMERACT–OARSI response criterion
      • Dougados M.
      Monitoring osteoarthritis progression and therapy.
      • Pham T.
      • van der H.D.
      • Altman R.D.
      • Anderson J.J.
      • Bellamy N.
      • Hochberg M.
      • et al.
      OMERACT–OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited.
      . Also, a study should strictly adhere to the CONSORT statement
      • Altman D.G.
      • Schulz K.F.
      • Moher D.
      • Egger M.
      • Davidoff F.
      • Elbourne D.
      • et al.
      The revised CONSORT statement for reporting randomized trials: explanation and elaboration.
      • Gagnier J.J.
      • Boon H.
      • Rochon P.
      • Moher D.
      • Barnes J.
      • Bombardier C.
      Recommendations for reporting randomized controlled trials of herbal interventions: explanation and elaboration.
      • Moher D.
      • Schulz K.F.
      • Altman D.
      The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.
      , and be subjected to central registration (e.g., http://www.clinicaltrials.gov).
      In conclusion, the dry powder of R. canina L. fruit (i.e., R. canina hip powder) seems to have a consistent, small to moderate efficacy on pain in OA patients; however, an efficacy only observed in short-term clinical trials (3–4 months). The adverse events were similar to placebo in the available literature, and it seems safe to apply this herbal remedy, though long-term safety remains to be tested. The results of the present meta-analysis – that R. canina hip powder does reduce pain – should be further substantiated in a large-scale (i.e., phase III) trial.

      Conflicts of interest

      RC is statistical editor in the Cochrane Musculoskeletal Group (CMSG, Australian editorial base); the present meta-analysis is not a Cochrane review. The funding agencies (The Danish Rheumatism Association and The Oak Foundation) had no role in study design, data collection, data synthesis, data interpretation, writing the report, or the decision to submit the manuscript for publication. None of the authors is affiliated with or funded by any manufacturer of a R. canina hip powder agent.

      Acknowledgements

      This study was supported by grants from the Oak Foundation, The Danish Rheumatism Association, and Frederiksberg Hospital. We acknowledge the personal and scientific supports of Professor Bente Danneskiold-Samsøe, M.D., Head of the Parker Institute. We thank Mette Gad, M.A., for linguistic support.

      References

        • Dieppe P.A.
        • Lohmander L.S.
        Pathogenesis and management of pain in osteoarthritis.
        Lancet. 2005; 365: 965-973
        • Altman R.D.
        Criteria for classification of clinical osteoarthritis.
        J Rheumatol Suppl. 1991; 27: 10-12
        • Altman R.
        • Asch E.
        • Bloch D.
        • Bole G.
        • Borenstein D.
        • Brandt K.
        • et al.
        Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association.
        Arthritis Rheum. 1986; 29: 1039-1049
        • Abramson S.B.
        Inflammation in osteoarthritis.
        J Rheumatol Suppl. 2004; 70: 70-76
        • Spector T.D.
        • Hart D.J.
        • Nandra D.
        • Doyle D.V.
        • Mackillop N.
        • Gallimore J.R.
        • et al.
        Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease.
        Arthritis Rheum. 1997; 40: 723-727
        • Jordan K.M.
        • Arden N.K.
        • Doherty M.
        • Bannwarth B.
        • Bijlsma J.W.
        • Dieppe P.
        • et al.
        EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
        Ann Rheum Dis. 2003; 62: 1145-1155
        • Zhang W.
        • Doherty M.
        • Arden N.
        • Bannwarth B.
        • Bijlsma J.
        • Gunther K.P.
        • et al.
        EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
        Ann Rheum Dis. 2005; 64: 669-681
        • Abadie E.
        • Ethgen D.
        • Avouac B.
        • Bouvenot G.
        • Branco J.
        • Bruyere O.
        • et al.
        Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis.
        Osteoarthritis Cartilage. 2004; 12: 263-268
        • Bellamy N.
        • Kirwan J.
        • Boers M.
        • Brooks P.
        • Strand V.
        • Tugwell P.
        • et al.
        Recommendations for a core set of outcome measures for future phase III clinical trials in knee, hip, and hand osteoarthritis. Consensus development at OMERACT III.
        J Rheumatol. 1997; 24: 799-802
        • Tugwell P.
        • Shea B.
        • Boers M.
        • Brooks P.
        • Simon L.S.
        • Strand V.
        • et al.
        Evidence-Based Rheumatology.
        1st edn. BMJ Books, London2004
        • Dougados M.
        Monitoring osteoarthritis progression and therapy.
        Osteoarthritis Cartilage. 2004; 12: S55-S60
        • Chrubasik C.
        • Duke R.K.
        • Chrubasik S.
        The evidence for clinical efficacy of rose hip and seed: a systematic review.
        Phytother Res. 2006; 20: 1-3
        • Ameye L.G.
        • Chee W.S.
        Osteoarthritis and nutrition. From nutraceuticals to functional foods: a systematic review of the scientific evidence.
        Arthritis Res Ther. 2006; 8: R127
        • Winther K.
        • Rein E.
        • Kharazmi A.
        The anti-inflammatory properties of rose-hip.
        Inflammopharmacology. 1999; 7: 63-68
        • Kharazmi A.
        • Winther K.
        Rose hip inhibits chemotaxis and chemiluminescence of human peripheral blood neutrophils in vitro and reduces certain inflammatory parameters in vivo.
        Inflammopharmacology. 1999; 7: 377-386
        • Larsen E.
        • Kharazmi A.
        • Christensen L.P.
        • Christensen S.B.
        An antiinflammatory galactolipid from rose hip (Rosa canina) that inhibits chemotaxis of human peripheral blood neutrophils in vitro.
        J Nat Prod. 2003; 66: 994-995
        • Orhan D.D.
        • Hartevioglu A.
        • Küpeli E.
        • Yesilada E.
        In vivo anti-inflammatory and antinociceptive activity of the crude extract and fractions from Rosa canina L. fruits.
        J Ethnopharmacol. 2007; 112: 394-400
        • Jager A.K.
        • Eldeen I.M.
        • van S.J.
        COX-1 and -2 activity of rose hip.
        Phytother Res. 2007 Dec; 21: 1251-1252
        • Winther K.
        • Apel K.
        • Thamsborg G.
        A powder made from seeds and shells of a rose-hip subspecies (Rosa canina) reduces symptoms of knee and hip osteoarthritis: a randomized, double-blind, placebo-controlled clinical trial.
        Scand J Rheumatol. 2005; 34: 302-308
        • Moher D.
        • Cook D.J.
        • Eastwood S.
        • Olkin I.
        • Rennie D.
        • Stroup D.F.
        Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses.
        Lancet. 1999; 354: 1896-1900
        • Jadad A.R.
        • Moore R.A.
        • Carroll D.
        • Jenkinson C.
        • Reynolds D.J.
        • Gavaghan D.J.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Control Clin Trials. 1996; 17: 1-12
        • Huskisson E.C.
        Measurement of pain.
        J Rheumatol. 1982; 9: 768-769
        • Christensen R.
        • Sørensen L.B.
        • Bartels E.M.
        • Astrup A.
        • Bliddal H.
        Rose-hip in osteoarthritis (OA): a meta-analysis.
        Ann Rheum Dis. 2007; 66 (Abstract): 495
        • Elbourne D.R.
        • Altman D.G.
        • Higgins J.P.
        • Curtin F.
        • Worthington H.V.
        • Vail A.
        Meta-analyses involving cross-over trials: methodological issues.
        Int J Epidemiol. 2002; 31: 140-149
        • Curtin F.
        • Elbourne D.
        • Altman D.G.
        Meta-analysis combining parallel and cross-over clinical trials. III: the issue of carry-over.
        Stat Med. 2002; 21: 2161-2173
      1. Deeks J.J. Higgins J.P.T. Altman D.G. Higgins J.P.T. Green S. Analysing and Presenting Results. 4.2.5. edn. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. John Wiley & Sons, Ltd, Chichester, UK2005: 97-166 (Updated May 2005)
        • Altman D.G.
        • Bland J.M.
        Interaction revisited: the difference between two estimates.
        BMJ. 2003; 326: 219
        • Normand S.L.
        Meta-analysis: formulating, evaluating, combining, and reporting.
        Stat Med. 1999; 18: 321-359
        • Cohen J.
        Statistical Power Analysis for the Behavioral Sciences.
        2nd edn. Lawrence Earlbaum Associates, 1988
        • Hedges L.V.
        Distribution theory for Glass's estimator of effect size and related estimators.
        J Educational Statistics. 1981; 6: 107-128
        • Norman G.R.
        • Sloan J.A.
        • Wyrwich K.W.
        Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation.
        Med Care. 2003; 41: 582-592
        • Kazis L.E.
        • Anderson J.J.
        • Meenan R.F.
        Effect sizes for interpreting changes in health status.
        Med Care. 1989; 27: S178-S189
        • Zhang W.
        • Doherty M.
        • Leeb B.F.
        • Alekseeva L.
        • Arden N.K.
        • Bijlsma J.W.
        • et al.
        EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).
        Ann Rheum Dis. 2007; 66: 377-388
        • Bland J.M.
        • Altman D.G.
        Statistics notes: the odds ratio.
        BMJ. 2000; 320: 1468
        • Littell R.C.
        • Milliken G.A.
        • Stroup W.W.
        • Wolfinger R.D.
        • Schabenberger O.
        SAS for Mixed Models.
        2nd edn. SAS Institute Inc, Cary, NC2006
        • Patterson H.D.
        • Thompson R.
        Recovery of inter-block information when block sizes are unequal.
        Biometrika. 1971; 58: 545-554
        • Wang M.C.
        • Bushman B.J.
        Integrating Results through Meta-Analytic Review Using SAS Software.
        1st edn. SAS Institute Inc, Cary, NC1999
        • van Houwelingen H.C.
        • Arends L.R.
        • Stijnen T.
        Advanced methods in meta-analysis: multivariate approach and meta-regression.
        Stat Med. 2002; 21: 589-624
        • Cochran W.G.
        The combination of estimates from different experiments.
        Biometrics. 1954; 10: 101-129
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Christensen R.
        • Kristensen P.K.
        • Bartels E.M.
        • Bliddal H.
        • Astrup A.
        Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials.
        Lancet. 2007; 370: 1706-1713
        • Osiri M.
        • Suarez-Almazor M.E.
        • Wells G.A.
        • Robinson V.
        • Tugwell P.
        Number needed to treat (NNT): implication in rheumatology clinical practice.
        Ann Rheum Dis. 2003; 62: 316-321
        • Kristensen L.E.
        • Christensen R.
        • Bliddal H.
        • Geborek P.
        • Danneskiold-Samsoe B.
        • Saxne T.
        The number needed to treat for adalimumab, etanercept and infliximab based on ACR50 response in three randomized controlled trials on established rheumatoid arthritis: a systematic literature review.
        Scand J Rheumatol. 2007; 36: 411-417
        • Cates C.J.
        Simpson's paradox and calculation of number needed to treat from meta-analysis.
        BMC Med Res Methodol. 2002; 2: 1
        • Altman D.G.
        • Deeks J.J.
        Meta-analysis, Simpson's paradox, and the number needed to treat.
        BMC Med Res Methodol. 2002; 2: 3
        • Edwards A.
        • Elwyn G.
        • Mulley A.
        Explaining risks: turning numerical data into meaningful pictures.
        BMJ. 2002; 324: 827-830
        • Visual Rx
        Version 1.0–1.7. Copyright© 2000–2003.
        Christopher Cates, 2003
        • Nobaek S.
        • Johansson M.L.
        • Molin G.
        • Ahrne S.
        • Jeppsson B.
        Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome.
        Am J Gastroenterol. 2000; 95: 1231-1238
        • Rossnagel K.
        • Willich S.N.
        Value of complementary medicine exemplified by rose-hips.
        Gesundheitswesen. 2001; 63: 412-416
      2. Rein E. Hansen OT, Hansen M, Assignee. Composition and method for alleviating joint pain and stiffness. United States Patent. Patent US 6,485,752 B1. 2002 Nov 26.

        • Warholm O.
        • Skaar S.
        • Hedman E.
        • Mølmen H.M.
        • Eik L.
        The effects of a standardized herbal remedy made from a subtype of Rosa canina in patients with osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
        Curr Ther Res Clin Exp. 2003; 64: 21-31
        • Rein E.
        • Kharazmi A.
        • Winther K.
        A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis – a double-blind, placebo-controlled, randomised trial.
        Phytomedicine. 2004; 11: 383-391
        • Ernst E.
        Complementary or alternative therapies for osteoarthritis.
        Nat Clin Pract Rheumatol. 2006; 2: 74-80
        • Chrubasik J.E.
        • Roufogalis B.D.
        • Chrubasik S.
        Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain.
        Phytother Res. 2007; 21: 675-683
        • Fan X.
        • Felsövalyi À
        • Sivo S.A.
        • Keenan S.C.
        SAS for Monte Carlo Studies: a Guide for Quantitative Researchers.
        3rd edn. SAS Institute Inc., Cary, NC, USA2001
        • Agresti A.
        A survey of exact inference for contingency tables.
        Stat Sci. 1992; 7: 131-177
        • Thomas D.G.
        Algorithm AS 36: exact confidence limits for the odds ratio in a 2×2 table.
        Appl Stat. 1971; 20: 105-110
        • Thompson S.G.
        • Pocock S.J.
        Can meta-analyses be trusted?.
        Lancet. 1991; 338: 1127-1130
        • Zhang W.
        • Moskowitz R.W.
        • Nuki G.
        • Abramson S.
        • Altman R.D.
        • Arden N.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence.
        Osteoarthritis Cartilage. 2007; 15: 981-1000
        • Tubach F.
        • Ravaud P.
        • Baron G.
        • Falissard B.
        • Logeart I.
        • Bellamy N.
        • et al.
        Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement.
        Ann Rheum Dis. 2005; 64: 29-33
        • Tubach F.
        • Ravaud P.
        • Baron G.
        • Falissard B.
        • Logeart I.
        • Bellamy N.
        • et al.
        Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: the patient acceptable symptom state.
        Ann Rheum Dis. 2005; 64: 34-37
        • Woolf A.D.
        Healthcare services for those with musculoskeletal conditions: a rheumatology service. Recommendations of the European Union of Medical Specialists Section of Rheumatology/European Board of Rheumatology 2006.
        Ann Rheum Dis. 2007; 66: 293-301
        • Chinn S.
        A simple method for converting an odds ratio to effect size for use in meta-analysis.
        Stat Med. 2000; 19: 3127-3131
        • Towheed T.
        • Maxwell L.
        • Judd M.
        • Catton M.
        • Hochberg M.
        • Wells G.
        Acetaminophen for osteoarthritis.
        Cochrane Database Syst Rev. 2006; 1 (CD004257)
        • McAlindon T.E.
        • LaValley M.P.
        • Gulin J.P.
        • Felson D.T.
        Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis.
        JAMA. 2000; : 1469-1475
        • Richy F.
        • Bruyere O.
        • Ethgen O.
        • Cucherat M.
        • Henrotin Y.
        • Reginster J.Y.
        Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis.
        Arch Intern Med. 2003; 163: 1514-1522
        • Reginster J.Y.
        The efficacy of glucosamine sulfate in osteoarthritis: financial and nonfinancial conflict of interest.
        Arthritis Rheum. 2007; 56: 2105-2110
        • Towheed T.E.
        • Anastassiades T.P.
        Glucosamine and chondroitin for treating symptoms of osteoarthritis: evidence is widely touted but incomplete.
        JAMA. 2000; 283: 1483-1484
        • Towheed T.E.
        Current status of glucosamine therapy in osteoarthritis.
        Arthritis Rheum. 2003; 49: 601-604
        • Vlad S.C.
        • LaValley M.P.
        • McAlindon T.E.
        • Felson D.T.
        Glucosamine for pain in osteoarthritis: why do trial results differ?.
        Arthritis Rheum. 2007; 56: 2267-2277
        • Altman D.G.
        • Schulz K.F.
        • Moher D.
        • Egger M.
        • Davidoff F.
        • Elbourne D.
        • et al.
        The revised CONSORT statement for reporting randomized trials: explanation and elaboration.
        Ann Intern Med. 2001; 134: 663-694
        • Gagnier J.J.
        • Boon H.
        • Rochon P.
        • Moher D.
        • Barnes J.
        • Bombardier C.
        Recommendations for reporting randomized controlled trials of herbal interventions: explanation and elaboration.
        J Clin Epidemiol. 2006; 59: 1134-1149
        • Ramsey S.D.
        • Spencer A.C.
        • Topolski T.D.
        • Belza B.
        • Patrick D.L.
        Use of alternative therapies by older adults with osteoarthritis.
        Arthritis Rheum. 2001; 45: 222-227
        • Bjordal J.M.
        • Ljunggren A.E.
        • Klovning A.
        • Slordal L.
        Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials.
        BMJ. 2004; 329: 1317
        • Lee C.
        • Straus W.L.
        • Balshaw R.
        • Barlas S.
        • Vogel S.
        • Schnitzer T.J.
        A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta-analysis.
        Arthritis Rheum. 2004; 51: 746-754
        • Towheed T.E.
        • Maxwell L.
        • Anastassiades T.P.
        • Shea B.
        • Houpt J.
        • Robinson V.
        • et al.
        Glucosamine therapy for treating osteoarthritis.
        Cochrane Database Syst Rev. 2005; 2 (CD002946)
        • Reichenbach S.
        • Sterchi R.
        • Scherer M.
        • Trelle S.
        • Burgi E.
        • Burgi U.
        • et al.
        Meta-analysis: chondroitin for osteoarthritis of the knee or hip.
        Ann Intern Med. 2007; 146: 580-590
      3. Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado/soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2007 Nov 23 [Epub ahead of print].

        • Henrotin Y.
        • Kurz B.
        Antioxidant to treat osteoarthritis: dream or reality?.
        Curr Drug Targets. 2007; 8: 347-357
        • Jensen N.H.
        Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebo-controlled cross-over trial in general practice.
        Ugeskr Laeger. 2003; 165: 2563-2566
        • Bjelakovic G.
        • Nikolova D.
        • Gluud L.L.
        • Simonetti R.G.
        • Gluud C.
        Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.
        JAMA. 2007; 297: 842-857
        • Berlin J.A.
        • Colditz G.A.
        The role of meta-analysis in the regulatory process for foods, drugs, and devices.
        JAMA. 1999; 281: 830-834
        • Rabenda V.
        • Manette C.
        • Lemmens R.
        • Mariani A.M.
        • Struvay N.
        • Reginster J.Y.
        Direct and indirect costs attributable to osteoarthritis in active subjects.
        J Rheumatol. 2006; 33: 1152-1158
        • Campbell M.J.
        • Julious S.A.
        • Altman D.G.
        Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons.
        BMJ. 1995; 311: 1145-1148
        • Bellamy N.
        • Buchanan W.W.
        • Goldsmith C.H.
        • Campbell J.
        • Stitt L.W.
        Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee.
        J Rheumatol. 1988; 15: 1833-1840
        • Roos E.M.
        • Toksvig-Larsen S.
        Knee injury and Osteoarthritis Outcome Score (KOOS) – validation and comparison to the WOMAC in total knee replacement.
        Health Qual Life Outcomes. 2003; 1: 17
        • Lequesne M.G.
        • Mery C.
        • Samson M.
        • Gerard P.
        Indexes of severity for osteoarthritis of the hip and knee. Validation – value in comparison with other assessment tests.
        Scand J Rheumatol Suppl. 1987; 65: 85-89
        • Pham T.
        • van der H.D.
        • Altman R.D.
        • Anderson J.J.
        • Bellamy N.
        • Hochberg M.
        • et al.
        OMERACT–OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited.
        Osteoarthritis Cartilage. 2004; 12: 389-399
        • Moher D.
        • Schulz K.F.
        • Altman D.
        The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials.
        JAMA. 2001; 285: 1987-1991