(BEING CONTINUED FROM 3/06/18)
The most thoroughly investigated lipid mixture is Piascledine (Pharmascience, Inc., Montreal, Quebec, Canada). Piascledine is composed of one third avocado and two thirds soybean unsaponifiables (ASUs), the oily fractions that, after hydrolysis, do not produce soap .
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  and one solely on knee OA , 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 . In a 6-month RCT on knee and hip OA, 300 mg once a day resulted in an improved LFI compared with placebo . 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 . 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 . 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.
ASU = avocado soybean unsaponifiable; BMI = body mass index; DJW = Duhuo Jisheng Wan; F = female; Glu = glucosamine; ht = height; ITT = intention-to-treat; LFI = Lequesne functional index; M = male; MSM = methylsulfonyl methane; N = total sample size; NS = not significant; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; PP = per protocol; SKI = SKI 306X; VAS = visual analog scale; Vit = vitamin; WOMAC = Western Ontario and McMaster universities [index]; wt = weight.
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 .
In vitro, ASUs display anabolic, anticatabolic, and anti-inflammatory effects on chondrocytes. ASUs increased collagen synthesis  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 . 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  while stimulating the expression of transforming growth factor-β and plasminogen activator inhibitor-1 . 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.
PUFAs are classified as n-3, n-6, or n-9 depending on the position of the last double bond along the fatty acid chain. In n-3, this last double bond is located between the third and fourth carbon atom from the methyl end of the fatty acid chain. The main dietary PUFAs are n-3 (such as linolenic acid and eicosapentenoic acid) and n-6 (such as linoleic acid and arachidonic acid). Omega-3 is found in soybean and canola oils, flaxseeds, walnuts, and fish oils, whereas n-6 is found in safflower, corn, soybean, and sunflower oils as well as in meat. The modern Western diet is relatively low in n-3 PUFAs and relatively high in n-6 compared with the diet in Western pre-industrialised societies or with the modern Eastern diet. The n-6/n-3 ratio is 25:1 in the modern Western diet compared with 2:1 in Western pre-industrialised societies. A high n-3 intake correlates with a low incidence of cardiovascular and inflammatory diseases [34,35]. The utility of n-3 for OA remains to be shown. In a 24-week double-blind placebo-controlled RCT, 10 ml of cod liver oil per day containing 786 mg of eicosapentaenoic acid, in addition to treatment with NSAIDs, did not decrease the VAS of pain or disability .
The articular cartilage content of arachidonic acid, a n-6 precursor of the pro-inflammatory eicosanoid PGE2, correlates with OA severity . 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 . Dietary lipid interventions in animals modified the PUFA composition of articular cartilage , 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 .
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 .
(TO BE CONTINUED)
Laurent G Ameye and Winnie SS Chee
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