Фитохимические вещества и растительные экстракты

Avocado/soybean unsaponifiables

Four double-blind placebo-controlled RCTs (Table ​(Table4)4) and one systematic review evaluated ASUs on knee and hip OA [24-28]. In two 3-month RCTs, one on knee and hip OA [24] and one solely on knee OA [25], 300 mg once a day decreased NSAID intake. No statistical difference in any primary or secondary endpoints was detected between 300 and 600 mg once a day [25]. In a 6-month RCT on knee and hip OA, 300 mg once a day resulted in an improved LFI compared with placebo [26]. ASUs had a 2-month delayed onset of action as well as residual symptomatic effects 2 months after the end of treatment. In a 2-year RCT on hip OA, 300 mg once a day did not slow down narrowing of joint space width [27]. In addition, none of the secondary endpoints (LFI, VAS of pain, NSAID intake, and patients' and investigators' global assessments) was statistically different from placebo after 1 year. However, a post hoc analysis suggested that ASUs might decrease narrowing of joint space width in patients with the most severe hip OA. In summary, although ASUs might display medium-term (several months') symptom-modifying effects on knee and hip OA, their symptom-modifying effects in the long term (>1 year) have not been confirmed. ASUs might slow down narrowing of joint space width in patients with severe hip OA, but this requires confirmation. Based on our best-evidence synthesis, good evidence is provided by ASUs for symptom-modifying effects in knee and hip OA but at the same time, there is some evidence of absence of structure-modifying effects (Table ​(Table3).3). A recent systematic review on ASUs recommended further investigation because three of the four rigorous RCTs suggest that ASUs is an effective symptomatic treatment, but the long-term study is largely negative [28]. However, the fact that this long-term study was primarily aiming at demonstrating structure-modifying and not symptom-modifying effects might explain why no symptomatic effects from ASUs were detected in the long-term study. Indeed, symptoms and structural damage are known to mildly correlate in OA, and the most appropriate patients to demonstrate a structure-modifying effect might not be the most appropriate to demonstrate a symptom-modifying effect. As for safety, none of the four RCTs reported significant differences in adverse effects between ASUs and placebo.

In sheep with lateral meniscectomy, 900 mg once a day for 6 months reduced the loss of toluidine blue stain in cartilage and prevented subchondral sclerosis in the inner zone of the lateral tibial plateau but not focal cartilage lesions [29].

In vitro, ASUs display anabolic, anticatabolic, and anti-inflammatory effects on chondrocytes. ASUs increased collagen synthesis [30] and inhibited the spontaneous and interleukin (IL)-1β-induced collagenase activity [23,31]. They increased the basal synthesis of aggrecan and reversed the IL1β-induced reduction in aggrecan synthesis [32]. ASUs were also shown to reduce the spontaneous and IL1β-induced production of matrix metalloproteinase (MMP)-3, IL-6, IL-8, and prostaglandin E2 (PGE2) while weakly reversing the IL1β-induced decrease in TIMP (tissue inhibiting metalloproteinase)-1 production [23,30,32]. One study showed that ASUs decreased the spontaneous production of nitric oxide (NO) and macrophage inflammatory protein-1β [32] while stimulating the expression of transforming growth factor-β and plasminogen activator inhibitor-1 [33]. This stimulated production of plasminogen activator inhibitor-1 could decrease MMP activation.

The effects of avocado unsaponifiables alone, of soybean unsaponifiables alone, and of three mixtures of ASUs, were compared [23,32]. The mixtures were A1S2 (Piascledine), A2S1, and A1S1, with respective ratios of ASUs of 1:2, 2:1, and 1:1. All mixtures significantly reduced the spontaneous production of IL-6, IL-8, and PGE2 and the IL1β-induced production of PGE2. A1S2 and A1S1, but not A2S1, significantly reduced the spontaneous and IL1β-induced production of MMP-3 and the IL1β-induced increase in collagenase activity, but only A1S2 inhibited the spontaneous collagenase activity. For some parameters, avocado unsaponifiables or soybean unsaponifiables alone were as potent as mixtures. In some cases, a single source of unsaponifiables seemed to be active. In other cases, both sources of unsaponifiables were active with synergistic or counteracting effects. The superiority of Piascledine over different ASU mixtures or over avocado or soybean unsaponifiables alone thus remains to be demonstrated.

Omega-3 PUFAs

The articular cartilage content of arachidonic acid, a n-6 precursor of the pro-inflammatory eicosanoid PGE2, correlates with OA severity [37]. n-3 and n-6 are metabolised by cyclo-oxygenases (COXs) and lipo-oxygenases (LOXs) into distinct eicosanoids. The n-6-derived eicosanoids tend to be pro-inflammatory, whereas the n-3-derived eicosanoids tend to be anti-inflammatory. Hence, a high proportion of n-3 is supposed to lead to a relative deficiency in pro-inflammatory n-6 metabolites [34]. Dietary lipid interventions in animals modified the PUFA composition of articular cartilage [38], suggesting that high n-3 intake could have a beneficial effect on cartilage metabolism. In addition to eicosanoids, the anti-inflammatory effect of n-3 could also be mediated by their newly discovered oxygenated derivatives called resolvins, which through their binding to G protein-coupled receptors act as potent antagonists of inflammation [39].

The in vitro effects of 10 to 100 μg/ml of n-3 (linolenic, eicosapentaenoic, and docosahexaenoic acids) on chondrocytes have been investigated [40-42]. n-3 did not affect the spontaneous or the IL1-induced decrease in glycosaminoglycan (GAG) synthesis, but dose-dependently inhibited the IL1-induced GAG degradation. n-3 dose-dependently decreased the IL1-induced aggrecanase activity and basal aggrecanase and collagenase activity, whereas, in contrast, n-6 stimulated the basal aggrecanase and collagenase activity. n-3 also decreased the IL1-induced mRNA expression of ADAMTS-4 (aggrecanase), COX-2, 5-LOX, FLAP (5-LOX-activating protein), IL1α, and tumour necrosis factor (TNF) α and the basal mRNA levels of these genes. Finally, n-3 decreased the basal and IL1β-induced mRNA and protein levels of MMP-3 and MMP-13. All these parameters were unaffected by n-6 PUFAs. Taken together, these results indicate that n-3 PUFAs have anticatabolic and anti-inflammatory properties. Nevertheless, too low of an n-6/n-3 ratio can be detrimental. A diet with very low levels of n-6 PUFAs induced occasional surface irregularities and localised proteoglycan depletion in cartilages in rats [38].

Lipid extract from New Zealand green-lipped mussel (Perna canaliculus)

In a 6-week double-blind placebo-controlled RCT in dogs, 1 g per day of a green-lipped mussel powder sprinkled on the food or on semi-moist treats or directly incorporated as 0.3% in a dry diet significantly improved total arthritic score, joint pain, and joint swelling [44,49]. More than 50% of the dogs demonstrated a 30% or greater reduction in total arthritic score. However, it is unclear whether these dogs suffered from OA specifically, and the disease severity was not described.

Cetyl myristoleate

Vitamins and minerals

The effects of vitamins C, E, and B on OA have been formally investigated in RCTs (see below). One obvious candidate not yet evaluated is vitamin D (vit D). Pathophysiological changes in OA affect periarticular bone, and normal bone metabolism requires vit D. Hence, suboptimal levels of vit D may impair bone metabolism and predispose to OA. In addition, the expression of vit D receptors is upregulated in human OA chondrocytes [54]. The Framingham study found a threefold increase in risk of OA progression for patients in the middle and lowest tertiles of serum levels of 25-vit D [55]. Low serum levels of vit D also predicted loss of joint space and osteophyte growth. The Study of Osteoporotic Fractures in women found that the risk of incident hip OA defined by joint space narrowing was increased for patients in the middle and lowest tertiles of serum levels of 25-vit D₃ [56]. Based on these data, an RCT testing the efficacy of vit D may be required.

Vitamin C

The Framingham epidemiological study found a threefold reduction in risk of OA progression for both the middle and highest tertiles of vit C intake and an inverse association between vit C intake and cartilage loss [57]. No association was found between vit C intake and osteophyte growth or rate of apparition of the disease. In this study, vit C intake was assessed using a food frequency questionnaire, which can induce errors and bias. In a 14-day double-blind crossover RCT on knee and hip OA, 1 g twice a day of calcium ascorbate was more efficient than placebo in decreasing VAS of pain [58] (Table ​(Table4).4). Although the quality of the RCT was high (Table ​(Table3),3), the measured effect was small (a 4.6-mm decrease from a starting basal level of 50 mm) and obtained with a dose equal to the upper tolerable intake level for adults (that is, the highest level of daily intake from food, water, and supplements which is likely to pose no risk of adverse health effects for almost all individuals in the general population), well above the current recommended daily allowances (RDAs) of 60 to 200 mg per day. The long-term safety of such high doses of vit C in elderly patients with OA needs to be evaluated, and efficacy needs to be confirmed by longer RCTs.

Guinea pigs, like humans, possess a nonfunctional gene for L-gulono-γ-lactone oxidase, which makes them unable to synthesise ascorbic acid and dependent on dietary ascorbic acid to prevent scurvy. In guinea pigs, a 'megadose' of 150 mg per day of ascorbic acid decreased the severity of surgically induced knee OA [59,60] but increased severity of spontaneous OA [61], despite the ability of ascorbic acid to increase cartilage collagen content. A third guinea pig trial stated, on the contrary, without providing any details, that a fivefold increase of ascorbic acid to the drinking water (equivalent to 1 g per liter) had a slight chondroprotective effect on the development of spontaneous lesions but not on surgically induced OA [62]. In view of these conflicting results and in the absence of strong evidence of efficacy in humans, it was recommended that vit C intakes for OA not exceed the current RDA [61].

Articular cartilage accumulates ascorbic acid [63]. In chondrocytes, ascorbic acid and dehydroascorbate are transported, respectively, through the sodium-dependent vit C transporter (SVCT)-2 [64] and the glucose transporter GLUT 1 [65]. In OA, the majority of vit C is expected to be transported through SVCT-2 [65]. Ascorbic acid serves as a cofactor for prolyl and lysyl hydroxylases, enzymes crucial in collagen synthesis. In vitro, ascorbate and ascorbic acid increased protein and proteoglycan synthesis by articular chondrocytes [64,66,67] and increased the mRNA levels of type I and II collagen [64,68] and aggrecan and α-prolyl 4-hydroxylase [64]. It decreased the lipopolysaccharide (LPS)-induced GAG release [69]. It also affected the activities of lysosomal enzymes, decreasing the activities of arylsulfatase A and arysulfatase B, an N-acetylgalactosaminidase-4-sulfatase, but increasing the activity of acid phosphatase in normal and OA chondrocytes [66].

Ascorbic acid can cross-link collagen and other proteins by non-enzymatic glycation, leading to the formation of advanced glycation endproducts (AGEs). Threose, a metabolite of ascorbic acid, increases the AGE content of articular cartilage in vitro [70]. These cross-links increase the stiffness of the collagen network, which is hypothesised to increase cartilage susceptibility to OA. High in vitro levels of ascorbic acid (756 μM) also increased protein carbonylation, one type of oxidative damage [64]. However, when guinea pigs were fed with diets containing different levels of ascorbic acid, no changes in the AGE content of articular cartilage were detected [61].

Vitamin E

Five RCTs have tested the natural form of vit E or α-tocopherylacetate. Two trials concluded that vit E was more efficient than placebo in decreasing pain. In a small 10-day single-blind crossover RCT on mainly spondylosis, 600 mg of vit E per day was superior to placebo as assessed by a patient questionnaire [71], whereas in a 6-week double-blind RCT on OA, 400 IU of α-tocopherylacetate once a day was superior to placebo as assessed by a joined patients' and doctors' global assessment of pain [72]. One trial suggested that vit E was no less efficient than diclofenac in decreasing pain. In a 3-week double-blind RCT on OA, no significant difference was found between 544 mg of α-tocopherylacetate three times a day and 50 mg diclofenac three times a day on VAS of pain [73]. However, the two most recent trials failed to show any benefit over placebo on knee OA. In a 6-month double-blind RCT, 500 IU of vit E a day showed no symptomatic benefit over placebo as assessed by WOMAC [74], whereas in a 2-year double-blind RCT, 500 IU of vit E a day showed no symptomatic or structure-modifying benefit over placebo as assessed by magnetic resonance imaging or WOMAC, respectively [75]. Although three out of the five RCTs concluded that vit E decreased pain, the two longest, largest, and highest-quality trials (Table ​(Table3)3) failed to detect any symptomatic or structural effects in knee OA. This suggested that, at least for knee OA, vit E alone has no medium-term beneficial effect. According to the best-evidence synthesis (Table ​(Table3),3), there is no evidence of symptom-modifying efficacy for vit E and some evidence of inefficacy regarding structure-modifying effects. No significant adverse event was reported.

Only a few papers investigated the in vitro effects of vit E on chondrocytes. Tiku et al. [76] showed that when chondrocytes were submitted to an oxidative burst, vit E reduced the catabolism of collagen by preventing the protein oxidation mediated by aldehydic downproducts of lipid peroxidation. Vit E strongly increased the sulfate incorporation while slightly reducing the glucosamine incorporation [77], suggesting that it increased GAG sulfatation or that it increased GAG synthesis while reducing glycoproteins or glycolipids synthesis. Like vit C, vit E affected the activities of lysosomal enzymes: it decreased the activities of arylsulfatase A and of acid phosphatase in cultures of human articular chondrocytes [77]. However, vit E did not affect the LPS-induced catabolism of GAGs [69] and did not prevent synoviocyte apoptosis induced by superoxide anions [78].

Vitamins B

A 2-month double-blind crossover RCT in hand OA comparing 6,400 μg of folate with or without 20 μg of cobalamin (vitamin B₁₂) daily, to placebo, had no significant effects on mean hand grip values [81].

Cocktail of vitamins and selenium

Two cocktails of vitamins with added selenium, a component of the antioxidative enzyme glutathione peroxidase, have been investigated. In a small pilot 6-month double-blind placebo-controlled RCT, a mixture of vitamins A, C, and E (in undisclosed amounts) and 144 μg of selenium per day had no effect on VAS of pain or stiffness [82]. Vitamins A, C, E, B2, and B6 and selenium decreased OA incidence and severity in STR/1N mice, possibly through an antioxidant effect because the expression of two antioxidative enzymes, glutathione peroxidase and superoxide dismutase, was increased in cartilage [83].

Boron

Femoral OA bone contains less boron, a nonmetallic trivalent chemical element, than does normal bone [84], suggesting that boron might have a beneficial effect in OA. A small 8-week double-blind placebo-controlled RCT suggested that 6 mg/day, taken as sodium tetraborate decahydrate, was more efficient than placebo in reducing a patients' assessment scale of symptoms [85] (Table ​(Table4).4). This RCT, however, is of low quality (Table ​(Table3);3); hence, longer and higher-quality RCTs are required to evaluate thoroughly the benefits of boron for OA.

Cocktail of minerals

Sierrasil, a cocktail of 36 minerals from the Sierra Mountains in the U.S., was tested at two doses (2 or 3 g/day) and at a dose of 2 g/day with a cat's claw extract (100 mg/day) in an 8-week double-blind placebo-controlled RCT on knee OA [86]. None of these treatments was more effective at relieving symptoms than placebo as assessed by WOMAC or VAS of pain.

Phytochemicals and plant extracts

Bromelain

Bromelain is a crude, aqueous extract obtained from both the stems and immature fruits of the pineapple plant (Ananas comosus Merr, mainly var Cayenne from the family of bromeliaceae), which contains a number of proteolytic enzymes. Bromelain was suggested to have anti-inflammatory, analgesic, antioedematous, antithrombic, and fibrinolytic effects, although many of the studies describing these properties were of poor quality ([87], and reviewed in [88]). Three different preparations containing bromelain mixed with diverse enzymes have been tested in nine trials on knee OA ([87,89,90] for a review and references therein). Bromelain was taken in tablets coated to resist stomach digestion at a daily dose ranging from 270 to 1,890 mg. All trials might have been insufficiently powered, were of short duration (3 to 6 weeks), and enrolled OA patients with flare-up episodes. Most used the LFI as a primary endpoint. Although bromelain was as effective or more effective effective than 100 to 150 mg of diclofenac per day in seven trials, it was also not more efficient than placebo in two other trials. This absence of efficacy over placebo, coupled with the fact that in some diclofenac-controlled trials the LFI or other functional endpoints continued to decrease in both groups even 4 weeks after the end of treatment [91,92], suggested a possible spontaneous resolution of the flare-up episode rather than a real efficacy of the treatment. Longer trials of higher quality were advocated to confirm the efficacy of bromelain [87]. The best-evidence synthesis indicates a limited evidence of efficacy based on five trials (Tables ​(Tables33 and ​and4).4). Lack of sufficiently detailed data prevented the inclusion of the four other trials.

In one trial, a high dose of bromelain (945 mg/day) induced a higher incidence of adverse effects and dropouts compared with diclofenac [92], whereas in another trial, a lower dose (270 mg/day) induced a higher dropout rate due to adverse effects than diclofenac [90]. Together, these two reports question the safety and tolerability of bromelain.

Rosa canina

A standardised rose-hip powder made from the seeds and husks of the fruits from a subtype of R. canina (Hyben Vital™ produced by Hyben Vital International, Langeland, Denmark), the common wild-briar rose of English hedgerows, was evaluated in three RCTs. In a 4-month double-blind RCT on hip and knee OA, 2,500 mg of this powder twice a day did not improve active or passive mobility (joint rotation, flexion, and extension) more than placebo, except for passive hip flexion [93]. In a 3-month crossover double-blind RCT, 2,500 mg of Rosa powder twice a day decreased pain (as measured by a categorical scale) more efficiently than placebo when placebo was given first but not when it was given second [94]. No pain difference was found when the two groups were compared before crossover either. This RCT, which enrolled patients with OA in various joints, did not include any washout period. In a 3-month crossover double-blind RCT on knee and hip OA which included a 3-week washout period, 2,500 mg of Rosa powder twice a day was more effective than placebo in decreasing WOMAC pain after 3 weeks of treatment but not after 3 months [95]. The lack of significance after 3 months could have been due to the decreased paracetamol consumption observed when patients were under active treatment. At 3 months, the Rosa treatment decreased the WOMAC function and stiffness subscales (secondary endpoints) more efficiently than placebo. According to the best-evidence synthesis, there is a lack of scientific evidence for R. canina extracts. However, the last RCT suggests that R. canina powder might have some efficacy. Hence, further research on this extract is required before making any conclusion about its efficacy or lack of efficacy. No major side effects were reported in these three RCTs.

Daily intake of 45 g of rose hip powder reduced chemotaxis of peripheral blood neutrophils and serum creatinine and C-reactive protein (CRP) levels in healthy and OA subjects [96,97].

Harpagophytum procumbens (devil's claw)

H. procumbens, also called devil's claw, is a South African plant that grows in regions bordering the Kalahari. Secondary tuberous roots are used to prepare powders or extracts, which were tested in several RCTs (reviewed in [98]). Product standardisation is based on the content of harpagoside, the principal compound found in the raw material. In all RCTs, the harpagoside content was similar and greater than 50 mg/day.

In a 2-month double-blind RCT on spine and knee OA, 670 mg of powder three times a day was more efficient than placebo in reducing VAS of pain [99] (Table ​(Table4).4). In a 4-month double-blind diacerhein-controlled RCT on hip and knee OA with flare-up episodes at inclusion, 2.6 g of powder/day was no less efficient than 200 mg of diacerhein per day in improving VAS of pain [100,101]. Devil's claw was also better tolerated than diacerhein. A systematic review of the efficacy of Harpagophytum for OA concluded that there is limited evidence of efficacy for ethanolic extract when providing less than 30 mg of harpagoside per day in the treatment of knee and hip OA and moderate evidence of efficacy for the use of powder when providing 60 mg of harpagoside daily in the treatment of spine, hip, and knee OA [102]. The best-evidence synthesis used here (Table ​(Table3)3) indicates a limited evidence of efficacy. Whether the efficacy differs between patients with flare-up episodes or without is currently not clear. The need for larger, better designed RCTs with higher doses has been advocated before making categorical recommendations for Harpagophytum [98]. No safety concerns appeared from the 4,300 patients, who received Harpagophytum products. In an uncontrolled surveillance study, 0.8 g of an aqueous extract three times a day reduced blood sedimentation time and CRP levels [103]. An extract reduced the IL1β-induced production of MMP-1, MMP-3, and MMP-9 proteins by chondrocytes [104].

Uncaria tomentosa and Uncaria guianensis (cat's claw)

Cat's claw is a vine from the basin of the Amazon River. There are two species, U. tomentosa and U. guianensis, that are traditionally used in South America for their anti-inflammatory properties. The bark and the root are prepared as an extract in hot water. Product standardisation is based on alkaloid content, although U. guianensis extracts are more potent than U. tomentosa extracts in vitro despite a much lower alkaloid content [105]. Because numerous HPLC (high-performance liquid chromatography) fractions are biologically active in vitro, in vivo efficacy might be due to multiple compounds.

In a small 4-week double-blind RCT on knee OA, 100 mg of an extract from U. guianensis once a day was more efficient than placebo in reducing pain associated with activity but not pain at rest or at night [106] (Table ​(Table4).4). There was no statistical difference between groups in reported adverse effects in this trial, although cat's claw has been reported as nephrotoxic [107]. According to the best-evidence synthesis (Table ​(Table3),3), this low-quality RCT does not provide scientific evidence of efficacy for cat's claw. If cat's claw is proven efficacious in the future, a carefully controlled process of production will probably be required to prevent any nephrotoxicity.

Salix sp. (willow bark)

The anti-inflammatory, antipyretic, and analgesic effects of willow bark have been known since antiquity. Willow bark contains salicin, which is rapidly metabolised into salicylic acid. The acetylated derivative of salicylic acid is known as aspirin. Willow bark extracts are usually standardised based on salicin content even if salicin might not be the major active compound.

In a 2-week double-blind RCT on knee and hip OA, an amount of extract corresponding to 240 mg of salicin a day was more efficient than placebo in reducing WOMAC pain subscore, but the effect was small [108]. Another 6-week double-blind RCT comparing the effects of another willow bark extract at the same dose with placebo and diclofenac 50 mg twice a day on knee and hip OA confirmed the efficacy of diclofenac but failed to detect any significant difference between willow bark and placebo on WOMAC pain subscore [109]. In another 2-month RCT, a cocktail of five plants, which included 100 mg of willow bark, failed to conclusively demonstrate an analgesic effect [110]. Skin allergic reactions have been linked to Salix ingestion in 3% to 11% of patients [111]. The best-evidence synthesis (Table ​(Table3)3) indicates a lack of evidence of efficacy for Salix extracts.

Ginger and turmeric

The Zingiberaceae family includes gingers and turmerics. Ginger is a very popular spice with a world production of 100,000 tons a year. It is used in traditional Japanese Kampo, Ayurvedic, and Chinese medicine as an anti-inflammatory agent for musculoskeletal diseases. Three RCTs evaluated ginger extracts prepared from the rhizomes of Zingiber officinale and Alpinia galanga.

In a double-blind RCT on knee OA, after crossover at 6 months, but not at 3 months before crossover, 250 mg of an extract of Z. officinale four times a day reduced VAS of pain and handicap more efficiently than placebo [112]. In a 6-week double-blind RCT on knee OA, 255 mg of an extract of Z. officinale and A. galanga twice a day was more efficient than placebo in reducing knee pain on standing up based on the percentage of responders [113]. The RCT suffered from incomplete blinding, and the beneficial effects were small and not observed on WOMAC and quality of life [114]. Finally, a 3-month three-way crossover double-blind RCT compared the efficacy of another ginger extract with ibuprofen and placebo in knee and hip OA but failed to demonstrate a difference between placebo and ginger extract as assessed by VAS of pain and LFI [115]. The best-evidence synthesis (Table ​(Table3)3) indicates a lack of evidence of efficacy. In two RCTs, a higher number of adverse effects and higher dropout rates related to adverse effects in ginger groups [112,113] question the safety of these extracts.

In vitro, ginger extract decreased the IL1β- and LPS-induced production of NO and PGE2 by OA cartilage [116]. In synoviocytes, it decreased the IL1β- or TNF-α-induced expression of TNF-α mRNA and protein, the TNF-α-induced production of COX2, and the TNF-α-induced activation of nuclear factor (NF)-κB by reducing the protein level of the NF-κB inhibitor IκB [117].

An extract prepared from the Indian and Javanese turmerics Curcuma domestica and Curcuma xanthorriza, was tested on hip and elbow OA in an 8-week double-blind randomised trial in dogs [118]. No significant difference on the kinetic gait analysis was found between extract and placebo.

Flavonoids

Flavonoids, a group of polyphenolic compounds widely distributed throughout the plant kingdom, are thought to contribute to the health benefits of diets rich in fruits and vegetables. The in vivo effects of several flavonoids (tea-containing catechins, soy isoflavones) have been reported in the literature.

The effect of tipi tea (Petiveria alliacea), a tea used as an antirheumatic medicine, on knee and hip OA was evaluated in a small 1-week crossover double-blind RCT against a placebo tea [119]. No significant differences as assessed in pain scores or functional assessment were found.

Regarding isoflavones, a 3-month double-blind RCT on knee OA failed to show that 40 g daily of soy protein, containing a total of 88 mg of soy isoflavones, was more efficient than a milk-based protein placebo in reducing symptoms as assessed by questionnaires on pain and quality of life [120]. Use of milk-based proteins as a placebo is confounding because milk could be effective in OA (see 'Milk and hyperimmune milk' section). Soy but not milk proteins increased serum levels of insulin-like growth factor-1, an anabolic factor for chondrocytes.

Boswellia serrata

The gummy oleoresin from the bark of B. serrata, a tree from northwest India, is used for inflammatory diseases in Ayurvedic medicine. In an 8-week double-blind crossover RCT on knee OA, 333 mg of the gum three times a day was more efficient than placebo in reducing pain, loss of movement, and swelling scores [121]. In a 3-month double-blind RCT, 500 mg three times a day of a cocktail of B. serrata and turmeric (Curcuma longa) decreased categorical scales of joint pain, tenderness, and effusion [122]. According to the best-evidence synthesis, these RCTs provide no evidence of efficacy (Table ​(Table33).

B. serrata in combination with an extract from the root of Withania somnifera, the oleoresin of C. longa, and a zinc complex was tested in a 6-month double-blind crossover RCT [123]; 650 mg twice a day of this cocktail, called Articulin-F, was more efficient than placebo in reducing pain and disability scores. According to the best-evidence synthesis, this RCT indicates a lack of evidence of efficacy (Table ​(Table33).

Cocktails of plant extracts

SKI306X is a cocktail of extracts prepared from three plants (dried roots from Clematis mandshurica and Trichosantes kirilowii and dried flower and stem from Prunella vulgaris) used for the treatment of inflammatory diseases in Far East Asia. It is clinically approved for the treatment of OA in Korea [124]. In a 4-week double-blind RCT on knee OA, 200, 400, and 600 mg three times a day were more efficient than placebo in reducing VAS of pain, with no significant difference between the three doses [125] (Table ​(Table4).4). In another 4-week double-blind RCT on knee OA, 200 mg three times a day was not less efficient than 100 mg of diclofenac (sustained release) once a day in reducing VAS of pain [126]. According to the best-evidence synthesis, these two high-quality RCTs provide moderate evidence for the efficacy of SKI306X in OA. Although generally well tolerated, three severe adverse events occurred in the SKI306X group (compared with 11 for diclofenac).

In rats, SKI306X did not cause significant gastric damage up to an oral dose of 2 g/kg and suppressed the diclofenac induced gastric damage [124]. In rabbits, 200 mg/kg per day reduced the OA-like histological changes in collagenase-injected knees [127]. In vitro, SKI306X and the T. kirilowii extract, but not the other two plant extracts, reduced the IL1α-induced GAG release [127]. Synergistic effects between the three extracts present in SKI306X are suspected because the proportion of T. kirilowii is insufficient to fully explain the product potency.

The effects of Gitadyl, an herbal formulation containing extracts from feverfew, American aspen, and milfoil, at a dose of 260 mg three times a day were compared with the effects of 400 mg of ibuprofen three times a day in a 42-day double-blind crossover RCT. Both treatments failed to significantly change pain or the patients' ability to walk as assessed by four point scales [128].

In a 4-week double-blind RCT on knee OA, 3 g three times a day of Duhuo Jisheng Wan, a traditional Chinese cocktail of 15 plants, improved the LFI and multiple VAS of pain and stiffness as efficiently as 25 mg of diclofenac three times a day [129] (Table ​(Table4).4). Duhuo Jisheng Wan had a slower onset of action than diclofenac but an equal rate of adverse events, an observation that questions its safety. According to the best-evidence synthesis, there is limited scientific evidence to support the efficacy of Duhuo Jisheng Wan (Table ​(Table33).

Others

Methylsulfonylmethane

Methylsulfonylmethane (MSM) is the oxidised form of dimethyl sulfoxide. It is found in very low amounts in fruits, corn, tomatoes, tea, coffee, and milk. Two RCTs qualified to be evaluated in this systematic review (Table ​(Table4).4). In a 12-week double-blind placebo-controlled RCT on knee OA, 500 mg of MSM three times a day, used alone or in combination with 500 mg of glucosamine HCl three times a day, significantly improved a Likert scale of pain and LFI [130]. The combination of both ingredients was not more efficacious than each ingredient used alone. In a second 12-week double-blind placebo-controlled RCT on knee OA, 3 g of MSM given twice daily was more efficient than placebo in decreasing WOMAC pain and functional scores [131]. According to the best-evidence synthesis (Table ​(Table3),3), MSM provides moderate evidence of efficacy for knee OA.

Milk and hyperimmune milk

A cross-sectional epidemiological study suggested that the frequency of symptomatic knee OA was lower in milk consumers [132] but did not take into account body mass index, an important potential confounding factor [133]. Although no trial tested regular milk, one canine and two human double-blind RCTs tested hyperimmune milk. This milk is produced by cows that are immunised with intestinal bacteria antigens. It is enriched in high-molecular weight immunoglobulins (IgG) and is claimed to contain anti-inflammatory low-molecular weight components. A concentrated form of this milk was used in the RCTs. A 6-week human RCT failed to show that 355 ml a day of a fruit-flavoured beverage fortified with hyperimmune milk, vitamins B₁₂, C, and E, and iron and zinc was more efficient than placebo in improving WOMAC [134]. In a 6-week three-arm RCT, 2 g twice a day of the milk preparation was not less efficient than 500 mg three times a day of glucosamine sulfate in improving WOMAC [135]. Unfortunately, a difference in symptomatic basal levels between treatment and placebo groups makes the placebo group of this RCT useless. Because none of these trials used regular milk as placebo, it is not known if hyperimmune milk has an effect different than regular milk. According to the best-evidence synthesis, there is a lack of scientific evidence of efficacy for hyperimmune milk.

In an 8-week RCT on dogs with musculoskeletal impairment, 1 g twice a day was more efficient than placebo in improving function as assessed by a newly developed questionnaire addressed to the pet owners [136]. Veterinarians' examination did not confirm these results. The absence of a precise diagnostic at enrolment and of any validation of the questionnaire limits the relevance of this study.

Collagen hydrolysate

Collagen hydrolysate is produced by enzymatic digestion of gelatin, which itself is produced by hydrolysis of collagen extracted from animal bones and skin.

In a 24-week multi-country double-blind placebo-controlled RCT on knee OA, 10 g/day did not improve the WOMAC index [137]. The dropout rate was high. Post hoc analysis suggested that the hydrolysate could be more efficient in severe OA. A 60-day double-blind crossover placebo-controlled RCT on knee and hip OA compared 10 g/day of collagen hydrolysate, gelatin, gelatin + glycin + CaHPO₄*2H₂O, or egg albumin [138]. The gelatin preparations were not significantly different from each other and were superior to egg albumin in reducing pain as assessed by a patient questionnaire. According to the best-evidence synthesis (Table ​(Table3),3), these two RCTs lack evidence of efficacy for collagen hydrolysate.

In vitro, type I or type II collagen hydrolysate dose-dependently increased type II collagen synthesis by chondrocytes, whereas native collagen and collagen-free hydrolysate did not [139]. The average molecular weight of collagen peptides in the hydrolysate ranges from 2 to 6 kDa. Ex vivo intestinal sac experiments suggested that peptides up to 15 kDa can be absorbed. In mice, a significant and long-lasting (>96 hours) accumulation of ¹⁴C-labeled collagen hydrolysate was observed in articular cartilage compared with ¹⁴C-labeled proline [140].

жүктеу/скачать 1.44 Mb.

Достарыңызбен бөлісу: