Vitamin C

In prospective studies examining micronutrient intakes, the Framingham study identified a protective association between higher intake of vitamin C and the progression of radiographic knee OA⁽ Reference McAlindon, Jacques and Zhang ^{14 )} and a higher vitamin C intake was also associated with lower risk of knee pain⁽ Reference McAlindon, Jacques and Zhang ^{14 ,} Reference McAlindon ^{15 )}. However, a longitudinal study showed no protective effect of vitamin C supplements on the progression of knee OA, although in multivariate analyses vitamin C supplements were beneficial in preventing the development of knee OA⁽ Reference Peregoy and Wilder ^{16 )}. In healthy subjects, vitamin C intake has been associated with reduced risk of bone marrow lesions on MRI⁽ Reference Wang, Hodge and Wluka ^{17 )}. In these publications, vitamin C has been viewed simply as an antioxidant, but it should not be forgotten that vitamin C is a co-factor enabling the proline and lysine hydroxylation essential for correct collagen biosynthesis. It also has effects on regulating the expression and translation of collagen, a major component of many connective tissues including cartilage and bone⁽ Reference Clark, Rohrbaugh and Otterness ^{18 )}. Animal model data (all from the guinea pig) are conflicting. Early studies showed that dietary ascorbate decreased pathology in surgically induced OA⁽ Reference Schwartz, Oh and Leveille ^{19 )}. In a further study, additional ascorbate in the drinking water showed a protective effect on spontaneous cartilage lesions, but no effect on pathology post-surgery⁽ Reference Meacock, Bodmer and Billingham ^{20 )}. Most recently, ascorbate supplementation increased disease severity in spontaneous OA⁽ Reference Kraus, Huebner and Stabler ^{21 )}.

Vitamin E

The Framingham study identified a weak protective association between higher intake of vitamin E and the progression of radiographic knee OA⁽ Reference McAlindon, Jacques and Zhang ^{14 )}. A study examining tocopherol isoforms and radiographic knee OA suggested complex associations⁽ Reference Jordan, De Roos and Renner ^{22 )} and intervention trials of vitamin E have to date been contradictory⁽ Reference Canter, Wider and Ernst ^{23 )}. In vitro data in chondrocytes are sparse, but a recent study suggests that vitamin E protects against hydrogen peroxide-induced changes in extracellular matrix gene expression⁽ Reference Bhatti, Mehmood and Wajid ^{24 )}.

Vitamin D

Vitamin D has multiple functions in the musculoskeletal system, particularly in bone health and pathologies⁽ Reference Wolff, Jones and Hansen ^{25 )}. Many studies have explored the association between vitamin D levels and OA. Recent systematic review suggests that low serum concentrations of 25-hydroxyvitamin D are associated with increased radiographic progression of OA, but associations are weaker with symptoms of disease⁽ Reference Cao, Winzenberg and Nguo ^{26 )}. A recent longitudinal study demonstrated the converse, that moderate vitamin D deficiency predicts both knee and hip pain, independent of structural change⁽ Reference Laslett, Quinn and Burgess ^{27 )}. However, a recent 2-year intervention trial showed no decrease in knee pain or structural change in patients with knee OA, with knee function significantly worse following vitamin D intervention⁽ Reference McAlindon, LaValley and Schneider ^{28 )}. Further intervention trials are ongoing⁽ Reference Cao, Jones and Cicuttini ^{29 )}. Vitamin D supplementation in a rat post-surgical model of OA showed a protective effect during the early phase of the disease, but not during the later phase⁽ Reference Castillo, Hernandez-Cueto and Vega-Lopez ^{30 )}. However, this was scored using condyle width, an unusual method. Interestingly vitamin D receptor-deficient mice showed aggravated inflammation and cartilage damage when crossed into a TNF transgenic model⁽ Reference Zwerina, Baum and Axmann ^{31 )}.

Other micronutrients

In a Japanese population (Research on Osteoarthritis Against Disability), low habitual vitamin K intake was the only dietary factor associated with the increased prevalence of radiographic knee OA in a cross-sectional study⁽ Reference Oka, Akune and Muraki ^{32 )}. This supports data from US cohorts where low vitamin K was associated with OA in the hand and knee⁽ Reference Misra, Booth and Tolstykh ^{33 ,} Reference Neogi, Booth and Zhang ^{34 )}. However, a further study, using minimum joint space width and osteophytosis as variables showed an association of vitamins K, B₁, B₂, B₆ and C with the former and vitamins E, K, B₁, B₂, niacin (B₃) and B₆ with the latter, both in women only⁽ Reference Muraki, Akune and En-Yo ^{35 )}. Vitamin K is an essential co-factor for the formation of γ-carboxyglutamic acid (Gla) residues, and Gla-containing proteins include osteocalcin and matrix Gla protein, both expressed in the skeleton. Vitamin K regulates mineralisation in both bone and cartilage⁽ Reference Krueger, Westenfeld and Schurgers ^{36 )}. Polymorphisms in the matrix Gla protein gene have been associated with hand OA⁽ Reference Misra, Booth and Crosier ^{37 )}, and serum levels of undercarboxylated osteocalcin may be associated with synovitis in knee OA⁽ Reference Naito, Watari and Obayashi ^{38 )}. Niacinamide, a form of vitamin B₃, has been examined in a pilot scale clinical study of OA and reported to show improvements at 12 weeks⁽ Reference Jonas, Rapoza and Blair ^{39 )}.

An association between dietary magnesium intake and knee OA was demonstrated in the Johnston County Osteoarthritis Project, but this varied with ethnicity⁽ Reference Qin, Shi and Samai ^{40 )}. This is supported by data from the Twins UK registry where discordant twin pair analysis showed a decrease in magnesium in co-twins with OA⁽ Reference Hunter, Hart and Snieder ^{41 )}. Selenium has been implicated the osteoarthropathy of Kashin–Beck disease; meta-analysis of supplementation studies supports the benefit of supplementation in children, but highlights the low quality of methodology⁽ Reference Zou, Liu and Wu ^{42 )}.

Lipid metabolism

Recent studies have suggested that OA may be part of metabolic syndrome⁽ Reference Zhuo, Yang and Chen ^{43 )}. Alterations in lipid metabolism may be key to this, with population-based studies suggesting that serum cholesterol is a risk factor for OA (reviewed in⁽ Reference Gkretsi, Simopoulou and Tsezou ^{44 )}). Population studies also suggest that statin use is associated with a reduction in OA incidence and/or progression⁽ Reference Clockaerts, Van Osch and Bastiaansen-Jenniskens ^{45 ,} Reference Kadam, Blagojevic and Belcher ^{46 )}, but studies of pain and function in patients with OA have shown no association⁽ Reference Riddle, Moxley and Dumenci ^{47 )}. This area therefore remains controversial. It has been reported that high levels of fat and fatty acids are found in osteoarthritic joint tissues and that this is associated with pathology⁽ Reference Lippiello, Walsh and Fienhold ^{48 ,} Reference Plumb and Aspden ^{49 )}. n-3 PUFA, but not n-6 PUFA were found to be associated with the specific loss of cartilage in the Multicenter Osteoarthritis Study population of people at risk of OA⁽ Reference Baker, Matthan and Lichtenstein ^{50 )}. In healthy individuals, consumption of SFA or n-6 PUFA (but not n-3 PUFA) was associated with an increased risk of bone marrow lesions⁽ Reference Wang, Davies-Tuck and Wluka ^{51 ,} Reference Wang, Wluka and Hodge ^{52 )}. In animal models, a high-fat diet accelerated progression of OA⁽ Reference Mooney, Sampson and Lerea ^{53 )}, while n-3 PUFA reduced disease⁽ Reference Knott, Avery and Hollander ^{54 )}. Studies in isolated chondrocytes showed that n-3 PUFA inhibited IL-1-induced MMP3, MMP13, ADAMTS4, ADAMTS5 and COX2 (matrix metalloproteinase (MMP); a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS); cyclooxygenase (COX)) expression, while n-6 PUFA had no effect⁽ Reference Hurst, Rees and Randerson ^{55 ,} Reference Zainal, Longman and Hurst ^{56 )}. A small improvement in OA in dogs was seen with fish oil supplementation⁽ Reference Hielm-Bjorkman, Roine and Elo ^{57 ,} Reference Roush, Dodd and Fritsch ^{58 )}. Interestingly, a supplement rich in fish oil, Phytalgic, was shown to improve function and pain in OA patients⁽ Reference Jacquet, Girodet and Pariente ^{59 )}, although the design of this trial has been criticised⁽ Reference Christensen and Bliddal ^{60 )}.

Diet-derived bioactives

Typically, foods contain multiple bioactive compounds and these can impact upon many biological pathways⁽ Reference Ameye and Chee ^{61 )}. Diet-derived bioactives can be classified into several groups, e.g. flavonoids (and related compounds), carotenoids, plant sterols, glucosinolates and others⁽ Reference Denny and Buttriss ^{62 )}.

Flavonoids

Flavonoids are polyphenols and include flavan-3-ols, flavonols, flavones, isoflavones, flavanones and anthocyanins. More than 6000 different flavonoids have been found and they are widely distributed in plants, with several hundred found in edible plants⁽ Reference Falcone Ferreyra, Rius and Casati ^{63 ,} Reference Manach, Scalbert and Morand ^{64 )}.

Flavonols

Flavonols are found in many foods and are exemplified by quercetin, myricetin and kaempferol⁽ Reference Manach, Scalbert and Morand ^{64 )}. Quercetin and kaempferol showed no activity against IL-1-induced MMP13 levels in SW1353 chondrosarcoma cells⁽ Reference Lim, Park and Kim ^{65 )}. However, Lay et al. report that quercetin is able to block aggrecan loss from articular cartilage potentially via inhibition of ADAMTS4 and ADAMTS5⁽ Reference Lay, Samiric and Handley ^{66 )} and Lee et al. show that myricetin can inhibit IL-1 induction of MMP1 from a synovial cell line⁽ Reference Lee and Choi ^{67 )}.

Flavones

In fruit and vegetables, flavones are found in celery and parsley, mainly luteolin and apigenin. In the skin of citrus fruit, polymethoxylated flavones are also found, e.g. tangeretin, nobiletin and sinensetin⁽ Reference Manach, Scalbert and Morand ^{64 )}. Luteolin and nobiletin have been shown to inhibit aggrecanases ADAMTS4 and ADAMTS5, both in vitro ⁽ Reference Imada, Lin and Liu ^{68 ,} Reference Moncada-Pazos, Obaya and Viloria ^{69 )} and in vivo ⁽ Reference Imada, Lin and Liu ^{68 )}. Luteolin appears to be selective as a better ADAMTS than MMP inhibitor⁽ Reference Moncada-Pazos, Obaya and Viloria ^{69 )}, it also has anti-inflammatory activity, which could play a role in chondroprotection⁽ Reference Lopez-Lazaro ^{70 )}. Nobiletin, tangeretin and sinensetin all repress the IL-1 induction of MMP9 in synovial cells, with nobiletin also active in chondrocytes⁽ Reference Ishiwa, Sato and Mimaki ^{71 )}. Apigenin was shown to be a potent inhibitor of IL-1-induced MMP13 expression in SW1353 chondrosarcoma cells, potentially via activator protein 1 and the JAK/STAT (Janus kinase (JAK) and signal transducer and activator of transcription (STAT)) pathway, with no activity against NF-κB⁽ Reference Lim, Park and Kim ^{65 )}. It has also been shown to block IL-1-induced glycosaminoglycan release⁽ Reference Lim, Park and Kim ^{65 )} and hyaluronan release⁽ Reference Durigova, Roughley and Mort ^{72 )} from cartilage explants in vitro.

Flavan-3-ols

These exist as both monomer (catechins) and polymer (proanthocyanidins) forms⁽ Reference Manach, Scalbert and Morand ^{64 )}. Green tea polyphenols were shown to be effective in a model of inflammatory arthritis⁽ Reference Haqqi, Anthony and Gupta ^{73 )}. Catechins from green tea (and also present in other foods including dark chocolate) can inhibit cartilage degradation in vitro, particularly those containing a gallate ester⁽ Reference Adcocks, Collin and Buttle ^{74 )}. Epigallocatechin gallate and epicatechin gallate have been shown to be effective (submicromolar) inhibitors of ADAMTS4 and ADAMTS5 aggrecanase activity, indeed significantly more than their ability to inhibit MMP1 and MMP13 collagenase activity⁽ Reference Vankemmelbeke, Jones and Fowles ^{75 )}. Other anti-inflammatory activities have been described (e.g.⁽ Reference Akhtar and Haqqi ^{76 )}) that suggests promise in OA (reviewed in⁽ Reference Ahmed ^{77 )}), but no human clinical trials have been performed to date.

While not a diet-derived bioactive, Flavocoxid, a mixture of baicalin (a flavone) from Scutellaria baicalensis and catechins from Acacia catechu, is marketed as Limbrel, a ‘medical food’ which inhibits COX2 and 5-lipoxygenase⁽ Reference Burnett, Jia and Zhao ^{78 )}. An assessment of the major catechins from A. catechu suggests that they are predominantly those described earlier found in green tea⁽ Reference Shen, Wu and Wang ^{79 )}. Small clinical trials have suggested that Limbrel shows efficacy in OA (e.g.⁽ Reference Levy, Khokhlov and Kopenkin ^{80 )}), but recently severe liver toxicity has been described in some patients⁽ Reference Chalasani, Vuppalanchi and Navarro ^{81 )}.

A grape seed proanthocyanidin extract is protective in the monosodium iodoacetate model of OA in the rat, showing chondroprotection and decreased pain⁽ Reference Woo, Joo and Jung ^{82 )}. Specifically, procyanidin B3 abrogates cartilage destruction and heterotopic cartilage formation in a surgical model of OA in the mouse⁽ Reference Aini, Ochi and Iwata ^{83 )}. It was shown to block IL-1 repression of matrix gene expression in vitro and also decrease inducible nitric oxide synthase in vitro and in vivo ⁽ Reference Aini, Ochi and Iwata ^{83 )}.

Another mixture not derived from the diet, Pycnogenol is a pine bark extract rich in procyanidins⁽ Reference D'Andrea ^{84 )}. It has been reported to inhibit NF-κB activation and the activity of some MMP⁽ Reference Grimm, Chovanova and Muchova ^{85 ,} Reference Grimm, Schafer and Hogger ^{86 )}. Three small clinical trials have been performed in OA with positive outcomes reported (e.g.⁽ Reference Belcaro, Cesarone and Errichi ^{87 ,} Reference Cisar, Jany and Waczulikova ^{88 )}). However, a Cochrane review of Pycnogenol in chronic diseases (including OA) stated that it was not possible to reach definite conclusions on either efficacy or safety of Pycnogenol⁽ Reference Schoonees, Visser and Musekiwa ^{89 )}.

Anthocyanins

Anthocyanins are responsible for the red/blue pigmentation in fruits and vegetables⁽ Reference Manach, Scalbert and Morand ^{64 )}. To date most studies have been performed using fruit juices or extracts that are rich in anthocyanins. A recent clinical trial examined tart cherry juice in patients with knee OA⁽ Reference Schumacher, Pullman-Mooar and Gupta ^{90 )}. No difference in disease scores compared with placebo was uncovered, but high-sensitivity C-reactive protein was significantly lowered and this was associated with decreased score⁽ Reference Schumacher, Pullman-Mooar and Gupta ^{90 )}. Pomegranate juice or extracts, which have been reported to contain anthocyanins and many other flavonoids including flavanols, have been shown to inhibit IL-1-induced MMP expression in chondrocytes via inhibition of MAP kinases and NF-κB⁽ Reference Ahmed, Wang and Hafeez ^{91 –} Reference Jean-Gilles, Li and Vaidyanathan ^{93 )}. Such extracts also show efficacy in the monosodium iodoacetate model of OA in mice⁽ Reference Hadipour-Jahromy and Mozaffari-Kermani ^{94 )}. Raspberry extract⁽ Reference Jean-Gilles, Li and Ma ^{95 )} and red orange extract⁽ Reference Frasca, Panico and Bonina ^{96 )} have also been reported to have some efficacy in vitro and in vivo.

Isoflavones

Isoflavones are diphenolic compounds with structural similarity to oestrogens, and are consequently referred to as phytoestrogens. They are found mainly in legumes and soya is a major source of isoflavones in the diet⁽ Reference Manach, Scalbert and Morand ^{64 )}. Data in chondrocytes show that one isoflavone, genistein, reduces the production of inflammatory molecules such as COX2 and nitric oxide⁽ Reference Hooshmand, Soung do and Lucas ^{97 )}. Extracellular matrix synthesis in cartilage may increase or decrease, potentially with increasing dose⁽ Reference Claassen, Briese and Manapov ^{98 ,} Reference Yu, Xing and Dong ^{99 )}. In the rat inflammatory collagen-induced arthritis model, soya protein appears to be protective⁽ Reference Mohammad Shahi, Rashidi and Mahboob ^{100 )}, however, no significant effect of soya intake was measurable on OA severity in Cynomolgus monkeys⁽ Reference Ham, Loeser and Lindgren ^{101 )}. One human study suggested beneficial effects of soya protein supplementation on function, symptoms and biochemical markers of OA, particularly in men⁽ Reference Arjmandi, Khalil and Lucas ^{102 )}.

Flavanones

Flavanones are present in the diet at high concentrations only in citrus fruits including naringenin from grapefruit, hesperetin from oranges and eriodictyol from lemons⁽ Reference Manach, Scalbert and Morand ^{64 )}. No effect was seen for naringenin on IL-1-induced MMP13 production in SW1353 chondrosarcoma cells⁽ Reference Lim, Park and Kim ^{65 )}. However, hesperetin, its glycoside hesperidin or its derivatives, show efficacy in inflammatory models of arthritis⁽ Reference Choi and Lee ^{103 –} Reference Umar, Kumar and Sajad ^{105 )}. Red orange juice extract showed repression of inflammatory molecules in chondrocytes as mentioned earlier⁽ Reference Frasca, Panico and Bonina ^{96 )}.

Carotenoids

β-Carotene is the most widely known carotenoid and is a precursor to vitamin A⁽ Reference Maiani, Caston and Catasta ^{106 )}. Vitamin A and its derivatives, retinoids, are known to have profound effects on cartilage and the skeleton and may contribute to OA⁽ Reference Davies, Ribeiro and Downey-Jones ^{107 )}. The Framingham study identified a weak protective association between intake of β-carotene and the progression of radiographic knee OA⁽ Reference McAlindon, Jacques and Zhang ^{14 )}. A case–control study in the Johnston Couny Osteoarthritis Project examined the association between serum levels of several carotenoids (lutein, zeaxanthin, β-cryptoxanthin, lycopene, α-carotene and β-carotene) and OA⁽ Reference De Roos, Arab and Renner ^{108 )}. People with high levels of lutein or β-cryptoxanthin were less likely to have knee OA, while those with high levels of trans-β-carotene or zeaxanthin were more likely to have knee OA. Similarly, a cross-sectional study in a Japanese population with radiographic knee OA examined the association between serum levels of several carotenoids (lutein, zeaxanthin, cantaxanthin, cryptoxanthin, lycopene, α-carotene and β-carotene) and OA, but found nothing significant⁽ Reference Seki, Hasegawa and Yamaguchi ^{109 )}. It is worth noting that there is evidence that β-cryptoxanthin is associated with a decreased risk of inflammatory arthritis (e.g.⁽ Reference Pattison, Symmons and Lunt ^{110 )}). In healthy, middle-aged people, lutein and zeaxanthin intake were associated with decreased risk of cartilage defects on MRI and β-cryptoxanthin intake was inversely associated with tibial plateau bone area⁽ Reference Wang, Hodge and Wluka ^{17 )}.

Plant sterols

As discussed earlier, there is a positive association between serum cholesterol and OA, with statin use appearing to show efficacy in disease incidence and/or progression. Intake of plant phytosterols/stanols significantly reduce LDL cholesterol and total cholesterol in intervention trials⁽ Reference Kamal-Eldin and Moazzami ^{111 ,} Reference Wu, Fu and Yang ^{112 )} and of the three phytosterols tested, (stigmasterol, sitosterol and campesterol), stigmasterol bound best to chondrocyte membranes⁽ Reference Gabay, Sanchez and Salvat ^{113 )}. It inhibited IL-1-induced MMP and ADAMTS4 expression, although had no effect on ADAMTS5, potentially via its ability to inhibit NF-κB activation⁽ Reference Gabay, Sanchez and Salvat ^{113 )}. Intra-articular injection of stigmasterol was shown to suppress MMP expression and reduce cartilage degradation in a rabbit anterior cruciate ligament transection model of OA⁽ Reference Chen, Yu and Hu ^{114 )}.

Glucosinolates

Glucosinolates are found in cruciferous vegetables and are the precursors of isothiocyanates. Broccoli is rich in glucoraphanin, and when the vegetable is chopped or chewed, it is exposed to the action of an enzyme myrosinase to yield sulforaphane, the isothiocyanate. In chondrocytes, sulforaphane was initially shown to decrease shear stress-induced apoptosis⁽ Reference Healy, Lee and Gao ^{115 )}. More recently, it has been shown to exhibit pro-survival and anti-apoptotic activities when cell death is induced by a variety of stimuli⁽ Reference Facchini, Stanic and Cetrullo ^{116 )}. Sulforaphane has been shown to block IL-1 and TNFα induction of MMP1 and MMP13 expression, as well as PGE2 and nitric oxide in chondrocytes⁽ Reference Kim, Yeo and Kim ^{117 )} and inhibit cartilage degradation in vitro ⁽ Reference Kim, Yeo and Jung ^{118 )}. Later work showed that it was effective in inhibiting expression of ADAMTS4 and ADAMTS5, and abrogating cartilage destruction in the ‘destabilisation of the medial meniscus’ model of OA in the mouse, acting as a direct inhibitor of NF-κB⁽ Reference Davidson, Jupp and de Ferrars ^{119 )}.

Resveratrol

Resveratrol is a plant-derived phenol of the stilbenoid class, found at high concentrations in the skin of red grapes and in red wine. It has come to the fore as an activator of the histone deacetylase Sirt1, which has important roles in cell survival and as a mimic of caloric restriction that extends lifespan in many models⁽ Reference Lam, Peterson and Ravussin ^{120 )}. Sirt1 is intimately involved in OA with deletion of Sirt1 in mice causing more rapid development of OA in a post-surgical model⁽ Reference Matsuzaki, Matsushita and Takayama ^{121 )}. Resveratrol decreases OA score when directly injected intraarticularly in the rabbit anterior cruciate ligament transection model of OA⁽ Reference Elmali, Esenkaya and Harma ^{122 ,} Reference Wang, Gao and Chen ^{123 )}. It is an NF-κB inhibitor in chondrocytes and blocks inflammation and apoptosis⁽ Reference Csaki, Keshishzadeh and Fischer ^{124 –} Reference Shakibaei, Csaki and Nebrich ^{126 )}. It has also been shown to decrease proteolysis (e.g. MMP and ADAMTS) and enhance extracellular matrix synthesis⁽ Reference Im, Li and Chen ^{127 )}.

Interestingly, resveratrol has been shown to display synergistic effects on chondrocyte phenotype and apoptosis with curcumin (see later)⁽ Reference Csaki, Mobasheri and Shakibaei ^{128 ,} Reference Shakibaei, Mobasheri and Buhrmann ^{129 )}. These compounds both inhibit NF-κB, but are known to act via different mechanisms.

Curcumin

Curcumin is the major curcuminoid found in the spice, turmeric. It has been shown to be an NF-κB inhibitor⁽ Reference Singh and Aggarwal ^{130 )}, and used in chondrocytes as an inhibitor of oncostatin M-, IL-1- and TNFα-induced signalling⁽ Reference Li, Dehnade and Zafarullah ^{131 –} Reference Liacini, Sylvester and Li ^{133 )}. Here it was shown to inhibit c-Jun N-terminal kinase, activator protein 1, STAT and mitogen-activated protein kinase signalling, to inhibit expression of key MMP in cartilage and proposed to have potential clinical utility. Innes et al. used a turmeric extract in a clinical trial of OA in the dog, with clinical assessments showing significant improvement⁽ Reference Innes, Fuller and Grover ^{134 )}. The anti-catabolic effects of curcumin in human articular chondrocytes were confirmed⁽ Reference Schulze-Tanzil, Mobasheri and Sendzik ^{135 )} and its impact extended to include anti-apoptotic activity⁽ Reference Shakibaei, Schulze-Tanzil and John ^{136 )}, pro-anabolic effects on matrix expression⁽ Reference Lay, Samiric and Handley ^{66 ,} Reference Shakibaei, Schulze-Tanzil and John ^{136 )}, inhibition of COX2 expression and other inflammatory mediators⁽ Reference Mathy-Hartert, Jacquemond-Collet and Priem ^{137 ,} Reference Shakibaei, John and Schulze-Tanzil ^{138 )}. Efficacy was also shown in cartilage explants⁽ Reference Lay, Samiric and Handley ^{66 ,} Reference Clutterbuck, Mobasheri and Shakibaei ^{139 )} and murine models of inflammatory arthritis⁽ Reference Mun, Kim and Kim ^{140 )}, although not yet OA. Curcumin itself has poor solubility and bioavailability⁽ Reference Henrotin, Clutterbuck and Allaway ^{141 )}, but a curcumin–phophatidylcholine complex (Meriva), designed to overcome this, has shown some efficacy in small-scale clinical trials⁽ Reference Belcaro, Cesarone and Dugall ^{142 ,} Reference Belcaro, Cesarone and Dugall ^{143 )}. As discussed earlier, a thorough understanding of mechanism of action has led to experiments showing synergy between curcumin and resveratrol⁽ Reference Csaki, Mobasheri and Shakibaei ^{128 ,} Reference Shakibaei, Mobasheri and Buhrmann ^{129 )}.

Avocado-soyabean unsaponifiables

While not truly dietary-derived, avocado-soyabean unsaponifiables (ASU), Piascledine, has been developed by Laboratoire Expanscience and is the unsaponifiable fraction of one-third avocado oil and two-thirds soyabean oil. It is a mixture of tocopherols, plant sterols and other molecules⁽ Reference Msika, Baudouin and Saunois ^{144 )}. A recent moderate-sized trial of Piascledine in hip OA (the ERADIAS study) over 3 years showed that while there was no significant difference in mean joint space width loss between treatment and placebo, there were significantly less progressors in the treatment group. There was no difference in clinical outcomes including pain or analgesic/non-steroidal anti-inflammatory drug use⁽ Reference Maheu, Cadet and Marty ^{145 )}. This was somewhat similar to an earlier smaller study examining structural modification⁽ Reference Lequesne, Maheu and Cadet ^{146 )}, but very different from other earlier trials, where ASU demonstrated reductions in pain, functional disability or non-steroidal anti-inflammatory drug use in patients with hip or knee OA over 3–6 months⁽ Reference Appelboom, Schuermans and Verbruggen ^{147 –} Reference Maheu, Mazieres and Valat ^{149 )}. In a dog anterior cruciate ligament transection model of OA, ASU reduced disease severity and decreased MMP13 production⁽ Reference Boileau, Martel-Pelletier and Caron ^{150 )}, although in an ovine model of post-meniscectomy OA, ASU was described to have a ‘subtle, but statistically significant’ effect on cartilage⁽ Reference Cake, Read and Guillou ^{151 )}. In vitro data showed that ASU exhibit anti-catabolic (MMP expression), anti-inflammatory (PGE2, nitric oxide, COX2) and pro-anabolic (type II collagen and aggrecan synthesis) in chondrocytes. It has also been shown to inhibit NF-κB activity⁽ Reference Gabay, Gosset and Levy ^{152 –} Reference Henrotin, Sanchez and Deberg ^{154 )}. It should also be pointed out that other formulations of ASU exist and one from Nutramax has been shown to have similar in vitro activity in chondrocytes⁽ Reference Au, Al-Talib and Au ^{155 )}. Data from equine chondrocytes suggest that this ASU can act synergistically with epigallocatechin gallate⁽ Reference Heinecke, Grzanna and Au ^{156 )}. The relative merits of each preparation have been the subject of debate⁽ Reference Msika, Baudouin and Saunois ^{144 ,} Reference Frondoza ^{157 ,} Reference Henrotin ^{158 )}.

Ginger

There have been several small clinical trials exploring the efficacy of ginger extract in the treatment of OA. Trials using Zingiber officinale extract showed variable outcome and a review found that evidence for its efficacy in OA was weak⁽ Reference Leach and Kumar ^{159 )}. A mixture of extracts from Z. officinale and Alpinia galangal used in a short (6-week) study showed a significant effect in reducing clinical symptoms⁽ Reference Altman and Marcussen ^{160 )}. In vitro research suggests that ginger extract can decrease production of inflammatory mediators from chondrocytes⁽ Reference Shen, Hong and Kim ^{161 )} and synoviocytes⁽ Reference Ribel-Madsen, Bartels and Stockmarr ^{162 )}.

Sulphur-containing compounds

A cross-sectional study in twins demonstrated that consumption of both allium vegetables and also non-citrus fruits showed a protective association with hip OA⁽ Reference Williams, Skinner and Spector ^{163 )}. Furthermore, diallyl disulphide, a compound from garlic, was shown to inhibit IL-1-induced MMP1, MMP3 and MMP13 expression⁽ Reference Williams, Skinner and Spector ^{163 )}. Diallyl sulphide has also been shown to block expression of these enzymes and ameliorate cartilage destruction when administered intraarticularly in the rabbit anterior cruciate ligament transection model of OA⁽ Reference Chen, Tang and Bao ^{164 )}.

Others

Interestingly, data on the progression of knee OA, coming from the Osteoarthritis Initiative showed that frequent soft drink consumption is associated with increased disease progression in men, independent of obesity⁽ Reference Lu, Ahmad and Zhang ^{165 )}. This obviously requires replication. An extract of edible bird's nest (which is made from swiftlet saliva), has been shown to have anti-catabolic, anti-inflammatory and pro-anabolic activity on human osteoarthritic chondrocytes⁽ Reference Chua, Lee and Nagandran ^{166 )}. Sesamin, a lignan from sesame seeds has been reported to be chondroprotective in an explant assay, decreasing MMP expression and activation⁽ Reference Phitak, Pothacharoen and Settakorn ^{167 )}. An extract of a variety of mint which overexpressed rosmarinic acid inhibits lipopolysaccharide-induced glycosaminoglycan release and inflammatory mediators from porcine cartilage explants⁽ Reference Pearson, Fletcher and Kott ^{168 )}.