osteoarthritis ( oa ) is a chronic synovial joint disease , characterized by two main features : ( 1 ) progressive damage of articular cartilage , bone remodeling , and new bone formation ( osteophytes and subchondral bone sclerosis ) and ( 2 ) synovial inflammation and fibrosis of ligaments , tendons , menisci , and capsules .
all joints may be affected , but the most commonly involved are knees , hands , and hips ( fig .
1 ) . while chronic oa used to be regarded as a  wear and tear disease , 
researchers now believe that low - grade inflammation and growth of blood vessels and nerves from the subchondral bone into articular cartilage , as well as metabolic disorders , play a major role in disease pathology .
pharmacological interventions are mostly palliative , focusing on alleviation of symptoms or slowing disease progression until damaged hip or knee joints are eventually replaced .
differences in knee anatomy ( narrower femurs , thinner patellae , larger quadriceps angles , and differences in tibial condylar size ) , previous knee trauma , and genetic and hormonal influences may play a role .
women present for treatment in more advanced stages of oa and have more debilitating pain than men .
women also have less cartilage volume , greater cartilage wear , and overall differences in mechanical alignment .
symptomatic knee oa typically presents with narrowing of the joint space and bone spurs ( arrows ) .
( a and b ) during the development of oa , articular cartilage breaks down over time and becomes thin . as a result ,
the bone surfaces rub against each other , further damaging the cartilage and bone and causing pain .
( c and d ) joints with late - stage oa are often painful , warm to the touch , possibly red , swollen , have subchondral cysts , and notable loss of function .
pain medications currently used to treat the symptoms of oa include acetaminophen , topical capsaicin , topical and oral nonsteroidal anti - inflammatory drugs ( nsaids ; i.e. , naproxen and ibuprofen ) , and the synthetic opioids tramadol and codeine . however , each of these therapies has potential drawbacks that may limit their widespread use .
analgesics can be addictive , whereas acetaminophen can have serious side effects , such as kidney and liver damage .
treatment with nsaids , which inhibit cyclooxygenases ( cox1 and cox2 ) , thereby blocking prostaglandin synthesis , improves quality of life and decreases pro - inflammatory cytokines including interleukin-6 ( il-6 ) , vascular endothelial growth factor ( vegf ) , and tumor necrosis factor- ( tnf- ) in synovial fluid and mitogen - activated protein kinases ( mapks ) in knee oa .
however , nsaids can also cause serious side effects , including upper gastrointestinal ( gi ) toxicity ( dyspepsia , ulcers , perforation , obstructions , and bleeding ) and liver dysfunction .
as such , they are typically prescribed for the shortest possible duration at the lowest effective dose . to reduce the risk of these upper gi complications , the us
fda has approved the use of the nsaid hzt501 ( duexis ) , a drug containing 800 mg ibuprofen , in combination with 26.6 mg famotidine , a histamine h2-receptor antagonist .
alternatively the nsaid celecoxib has less risk of upper gi complications by selectively inhibiting the isoenzyme cox-2 , which is specific to inflamed tissue , versus cox-1 , which is constitutive in many tissues including the gi tract .
it should be noted that daily treatment with celecoxib is more effective in patients with normal body mass index ( bmi ) than obese patients .
intra - articular injection of corticosteroids ( gc ) is recommended to relieve inflammation and pain in oa joints .
however , gc injections are short acting , prone to adverse side effects , and have limited disease - modifying effects . for patients with knee oa , viscosupplementation with hyularonin may be used to replaces shock absorbing and lubricant material in the joint fluid , but the effects are similarly short - lived .
currently , guidelines for oa management are available from numerous organizations , including the american academy of orthopedic surgeons ( aaos ) , the american college of rheumatology ( acr ) , the american geriatrics society ( ags ) , the american pain society ( aps ) , and the osteoarthritis research society international ( oarsi ) in the united states and the european league against rheumatism ( eular ) and the united kingdom s national institute for health and clinical excellence ( nice ) in europe .
collectively , these guidelines reflect the experience of physicians across a variety of medical disciplines . whereas all generally use the same data sources ( i.e. , evidence - based research , expert opinion , patient experience , and cost - effectiveness analysis ) , they differ in focus .
for instance , the aaos and ags guidelines reflect the perspective of specialists in orthopedic surgery , geriatrics , and pain management , whereas the eular and oarsi guidelines primarily emphasize the findings of experts in rheumatology .
the nice guidelines are developed jointly by physicians and other health care professionals working in conjunction with a range of clinical researchers .
in addition , the scope varies , with some guidelines ( e.g. , aaos , acr , eular , and oarsi ) addressing specific types of oa ( i.e. , knee , hip , or hand ) and others ( e.g. , ags , aps , and nice ) addressing oa more generally . as such
, recommendations can vary widely , for instance , guidelines for use of nsaids . recommended nonpharmacologic interventions range between therapeutic exercises , patient education , transcutaneous electrical nerve stimulation , acupuncture , orthotics and insoles , heat and cryotherapy , patellar tapping , and weight control . in an effort to evaluate these varying guidelines ,
the appraisal of guidelines research and evaluation ( agree ii ) scored 17 clinical practice guidelines ( cpgs ) including eular , nice , oarsi , aaos , and acr , on six different measures : d1 , scope and purpose ; d2 , stakeholder involvement ; d3 , rigor of development ; d4 , clarity and presentation ; d5 , applicability ; and d6 , editorial independence .
the general clinical management recommendations tended to be similar among high - quality cpgs , although interventions addressed varied .
new noninvasive , disease - modifying therapies for oa are lacking and needed by millions of patients .
a number of prospective new treatments targeting pro - inflammatory mediators , cytokines , bone turnover , and angiogenic and neurogenic factors are being investigated , with varying success in clinical trials and clinical use .
interleukin-1 ( il-1 ) may prove an effective target , as il-1 induces matrix metalloproteinase ( mmp ) production , resulting in the degradation of aggrecan and other matrix constituents .
il-1 also induces high levels of cox2 and prostaglandin e2 ( pge2 ) , which may explain the pain associated with oa degeneration .
the drug diacerein , an inhibitor of il-1 , may modify both disease symptoms and disease structure in oa .
oral diacerein has proven effective in reducing pain , although evidence from clinical trials and scientific literature suggest that the effectiveness in oa is weak .
it can be used in conjunction with nsaids or viscosupplementation therapies for additive effects due to its alternative mechanism of action .
the most common side effects of diacerein are gastrointestinal , such as diarrhea , and changes in the color of urine .
meanwhile , the il-1-receptor antagonists anakinra and orthokin are reported to improve western ontario and mcmaster universities arthritis index ( womac ) scores .
gevokizumab  is in phase ii clinical trials for safety and biological activity in the treatment of hand oa .
nerve growth factor ( ngf ) has also been recognized as an important mediator of chronic pain in oa .
tanezumab , a monoclonal antibody against -ngf receptor tyrosine kinase ( trka ) , inhibits ngf action and reduces pain in patients .
two randomized phase iii clinical trials indicate that tanezumab provides superior pain relief while improving physical function and global disease assessment scores in patients with painful hip oa .
although in most cases tanezumab is well tolerated , the unexpected occurrence of rapid destructive arthropathies suggests there may be safety issues .
alternatively , using the drug adalimumab to inhibit tnf- , which upregulates -ngf , does not improve global disease assessment scores in oa of the hand .
strontium ranelate ( srra ) , an element similar to calcium , is easily taken up by the body and incorporated into bones in place of calcium .
the sekoia ( srra efficacy in knee osteoarthritis trial ) trial , a 3-year randomized , double - blind , placebo - controlled trial , evaluated the efficacy , safety , and disease - modifying effects of srra given at 1 to 2 g / day in patients with knee
magnetic resonance imaging ( mri ) data indicate that srra significantly reduced cartilage volume loss and bone marrow lesion progression .
symptoms also improved in terms of pain and physical function after 6 and 12 months , respectively , although treatment was deemed safe and well tolerated .
these data indicate that srra could be a promising new symptom and disease - modifying treatment for oa .
additionally , there is a need for further investigations to establish the optimal dosage and to better clarify the mechanism of action of srra in oa .
several clinical studies have investigated the effects of anti - resorptive therapies such as bisphosphonates on oa symptoms . a study by carbone et al .
found that alendronate ( aln ) use in oa patients decreased bone abnormalities and attenuated knee pain , yet cartilage degeneration was still present in the mri scans of treated patients .
determined that risedronate use led to significant improvements in womac scores and preservation of knee joint space compared with placebo in a 1-year randomized control trial involving patients with moderate oa .
however , a 2-year randomized control trial of risedronate treatment revealed contradictory results , with no significant improvement of womac score or joint space retention in the knee . similarly , nishii et al . observed no inhibition of oa progression in treated hip oa patients after 2 years of aln treatment
therefore , in spite of the growing body of clinical work investigating the subject , no definitive conclusion can be reached on the practicality of using bisphosphonates to treat patients with oa .
antidepressants have shown promising preliminary results for treatment of pain associated with oa by increasing serotonin levels in the brain .
serotonin - norepinephrine reuptake inhibitors duloxetine ( cymbalta ) and milnacipran significantly improve pain in oa .
an open - label trial also suggested analgesic effectiveness of methotrexate , an anti - inflammatory drug that acts by inhibiting the metabolism of folic acid , demonstrating that up to 20 mg / week for 6 months achieved oarsi responder criteria in knee oa and warranted a randomized controlled trial .
the small molecule kartogenin was identified in an image - based high - throughput screen to promote chondrocyte differentiation .
it shows chondroprotective effects in vitro and is efficacious in two animal models of oa .
kartogenin induces chondrogenesis by disrupting the interaction between filamin a and the transcription factor core - binding factor b subunit ( cbf ) , thereby altering cbf-runx1 and possibly runx2 transcriptional programs .
autologous injection of platelet - rich plasma ( prp ) has been used to stimulate cartilage repair and healing in oa patients , but the presence of other growth factors in prp may be problematic .
furthermore , bone morphogenic protein 7 ( bmp7 ) , fgf-8 , and botulium toxin a ( bont - a ) are used in the treatment of knee oa .
bont - a has an analgesic effect by temporarily suppressing acetylcholine secretion at presynaptic nueuromuscular junctions and appears to be effective and safe for the management of advanced knee oa .
however , these results can not be generalized to patients with mild knee joint pain or nonspecific soft tissue pain in the knee joint region .
further research is necessary to investigate possible complications such as aggravation of infection , effect on muscle strength , and neuropathic joint degeneration .
recently , a phase i trial was reported in which chondrocytes were modified via intra - articular dna injection to produce tgf-1 in patients with advanced knee
intra - articular injection of adipose - derived stem cell ( adsc ) therapy in a new european program is also under investigation .
adsc induced the release of trophic factors that exerted anti - inflammatory effects on both synoviocytes and chondrocytes , with no mmp1 , mmp3 , or mmp13 production , suggesting safe and effective use of adscs for clinical applications . however , both treatments need proof - of - concept studies in larger patient populations .
alternatively , intra - articular injection of human mesenchymal stem cells can lead to articular cartilage protection through the sdf-1/cxcr4 axis .
natural products can be safer than prescription medications with less undesirable side effects . dietary supplements including avocado soybean unsaponifiables ( asu ) , chondroitin sulfate , hyaluronan , and glucosamine sulfate
they are used to treat mild to moderate pain and alleviate symptoms to reduce the consumption of nsaids .
several trials for chondroitin sulfate , glucosamine sulfate , and hyaluronan ( c14h21no11 ) are in process .
chondroitin sulfate , glucosamine sulfate , and hyaluronan are building blocks for proteoglycan synthesis , and major constituents of the extracellular matrix in cartilage and synovial fluid .
hyaluronan and hyaluronic acid ( hyalgan hylan - gf20/synvisc ) can be injected into the knee joint of patients with oa who can not tolerate nsaids or are awaiting joint surgery .
a recent report indicates that viscosupplementation with hylan - gf20 slows type ii collagen degradation and joint inflammation in patients with oa .
however , hylan - gf20 was not present in granulomas , an indicator of inflammation , raising the question of clinical significance in pain reduction .
also , viscosupplementation with hyaluronic acid itself does not significantly improve disease outcome , and little is known about long - term effects .
the efficacy of glucosamine and/or chondroitin in treating knee oa pain was evaluated in the glucosamine / chondroitin arthritis intervention trial , funded by the national center for complementary and alternative medicine and the national institute of arthritis and musculoskeletal and skin diseases .
patients were treated daily for 24 weeks with glucosamine alone ( 1,500 mg ) , chondroitin sulfate alone ( 1,200 mg ) , glucosamine and chondroitin sulfate combined ( same doses ) , a placebo , or celecoxib ( 200 mg ) , which served as a positive control .
although there were no statistically significant differences between any of the experimental treatments and the placebo overall , patients with moderate - to - severe pain given both glucosamine and chondroitin sulfate did show improvement ( 79% experienced pain reduction vs. 54% for placebo ) .
because of the small size of this subgroup , these findings should be considered preliminary and need to be confirmed in further studies .
glucosamine does not appear to slow arthritis progression over the long term and has many potential complications .
the most common adverse effects are epigastric pain or tenderness , heartburn , diarrhea , and nausea .
glucosamine also may cause allergic reactions in patients with seafood allergies , as a product of lobster , crab , and shrimp shells .
glucosamine may interact with various pharmaceuticals , such as warfarin ( coumadin ) and diabetes medications , dangerously modifying their efficacy .
similarly , chondroitin sulfate appears not to provide meaningful benefit for patients with oa , and their combination has not proven effective for either pain management or functional improvement .
oarsi and nice no longer recommend the use of glucosamine or chondroitin sulfate alone , or in combination , if no effects are observed after 6 months or radiographic changes are marginal . a network meta - analysis of 10 trials in 3,803 patients by juni and collaborators in 2012 found no clinically significant improvements in oa pain alleviation or jsn parameters with glucosamine , chondroitin , or combined treatment compared with placebo . despite these results ,
many patients believe otherwise , potentially due to the natural course of disease , regression to the mean , or the placebo effect .
the authors conclude that such patients should be permitted to use these supplements if they cover the cost themselves , since neither of these preparations was found to be dangerous .
sierrasil is a dietary supplement marketed for joint pain relief that is derived from the mineral - rich clay found in the high sierra mountains in the united states .
clinical trial testing short - term efficacy of sierrasil at doses of 2 and 3 g per day failed to show sustained benefits over placebo , and iron toxicity has been reported .
some oa patients experience pain relief from topical creams containing capsaicin , the active component of chili peppers .
however , use of these creams may introduce side effects such as burning , stinging , and redness of the skin and eyes .
avocado / soybean unsaponifiables are natural vegetable extracts made from avocado and soybean oils , consisting of the leftover fraction ( approximately 1% ) that can not be made into soap after saponification .
asu is composed of one third avocado and two thirds soybean unsaponifiables ( a1s2u ) .
the major components of asu are phytosterols -sitosterol , campesterol , and stigmasterol , which are rapidly incorporated into cells .
asu is a complex mixture of many compounds including fat - soluble vitamins , sterols , triterpene alcohols , and possibly furan fatty acids .
the sterol contents of asu preparations are the primary contributors to biological activity in articular chondrocytes .
preclinical in vitro and in vivo studies have demonstrated that asus have beneficial effects on oa .
it inhibits the breakdown of cartilage and promotes cartilage repair by inhibiting a number of molecules and pathways implicated in oa ( tables 1 and 2 ) .
asu stimulates the synthesis of collagen and aggrecan by inhibiting inflammatory cytokines such as il-1 , il-6 , il-8 , tnf , and pge2 through modulation of nf - kappab .
the combination of asu and epigallocatechin gallate ( egcg ; a major component of green tea catechins ) affects an array of inflammatory molecules including expression of cox-2 and production of pge2 in chondrocytes .
cox-2 regulates the production of pge2 ; both are mediators involved in the process of cartilage breakdown .
asu also inhibits the release and activity of collagenase ( mmp2 ) and stromelysin 1 ( mmp3 ) in cultured chondrocytes , increases tissue inhibitors of metalloproteinases ( timp-1 ) , and inhibits il1-induced erk but not p38 or jnk in chondrocytes in vitro .
stimulatory effects of avocado soybean unsaponifiable on anti - inflammatory , anabolic mediators that protect against osteoarthritis .
inhibitory effects of avocado soybean unsaponifiable on inflammatory and catabolic mediators of osteoarthritis . in vitro studies show that asu inhibits fibrinolysis by stimulating the expression of plasminogen activator inhibitor ( pai-1 ) .
pai-1 inhibits tissue plasminogen activator and urokinase ( upa ) , thereby blocking plasminogen activation and inhibiting fibrinolysis ( the physiological breakdown of blood clots )
. this fibrinolytic and tissue destructive proteinase cascade may play a role in oa joint inflammation via altered expression of upa receptors .
asus alter growth factor levels implicated in oa pathogenesis , increasing tgf-1 and tgf-2 in the canine knee joint fluid , to repair cartilage and decreasing vegf , which is markedly elevated in synovial fluid of patients . in a study of implant osseointegration in rat tibiae , asu administration improved markers of bone growth , including bone morphogenic protein 2 ( bmp-2 ) and transforming growth factor beta 1 ( tgf-1 ) , though histomorphometric analysis of implant osseointegration was only slightly improved .
sixty percent of patients with oa exhibit high levels of oxidized low - density lipoproteins ( oldl ) in serum , which mediates reactive oxygen species ( ros ) activity in chondrocytes and oa pathology . treating patients with a daily dose of 300 mg asu for 3 months decreased oldl levels . at the clinical level
, asu reduces pain and stiffness while improving function in joints , resulting in decreased dependence on analgesics . asu efficacy and safety during and after treatment
have been assessed in various randomized , double - blind , multicenter trials in patients with symptomatic knee or hip oa .
two studies conducted over a 3-month period report that standard treatment with 300 mg / day of asu improved indices of pain , stiffness , and physical function , as measured by womac , and decreased analgesic drug demanded in patients with oa .
a third trial conducted over 6 months reports similarly improved function compared with placebo , measured by the lequense functional index , with persistent effects after termination of treatment . in a 6-month trial on patients with femorotibial gonarthrosis , asu was as effective as 400 mg of chondroitin sulfate three times per day , as measured by womac .
most recently , a 3-year randomized trial on patients with hip oa , performed under the acr criteria ( minimum of 1 - 4 mm hip jsw on the pelvic radiographs ) , reports excellent safety , but no significant reduction in the mean rate of jsn after 1 year .
however , analyzing the results under different parameters reveals a significant 20% reduction in the rate of progression in patients with severe hip oa ( p = 0.04 ) , indicating a potential structure modifying effect of asu , as confirmed in the eradias study . in a clinical trial of patients with hip oa
, the effects of asu treatment over 3 years were evaluated by radiography to identify joint pathology and disease progression on the structural level . although jsn was not statistically significant between asu and placebo treatment , secondary analysis of disease progression , measured by jsn ( 0.5 mm ) or total hip replacements , indicated 20% improvement with asu ( 42.2% vs. 51.4% of placebo group , p = 0.054 ) .
computerized image analysis also showed significant histological differences not detectable by traditional scoring methods . in sheep ,
asu treatment following cartilage insult improved articular integrity , as measured by toluidine blue staining , after 6 months compared with untreated animals .
these improvements were the result of decreased catabolism and increased anabolism of cartilage by asu .
indeed , asu reduces inflammation - mediated cartilage degradation by reducing il-1 , pge2 , and mmp-3 production , while also inducing proteoglycan , noncollagenous protein ( ncp ) , and collagen synthesis within 72 hours of administration to bovine cells in culture . a recent study in patients with nonspecific dorsalgia demonstrated analgesic effect of piascledine with positive outcome after 1 month
however , a randomized , double - blind , placebo - controlled clinical trial carried out in 14 obese adult volunteers over 3 months reports no significant effect on these parameters , as measured by hyperglycemic 
four double - blind placebo - controlled randomized human clinical trials ( rcts ) evaluate asu s impact on knee and hip oa .
another found that asu improves lfi compared with placebo over the course of 6 months , and also that improvements took 2 months to take effect , and subside after treatment ended .
alternatively , a long - term study indicated no significant difference in jsn , or other parameters of disease , after 2 years of asu treatment , indicating that the beneficial impact of asu on oa may be limited to short - term effects .
however , this study also focused on identifying structure - modifying effects , versus symptom - modifying effects ; although these two different measures of oa severity often correlate , asu may affect each uniquely .
evidence for symptom - modifying effects of asu is much stronger , and thus an alternative explanation for these contradictory findings is that while asu does not improve structural damage of oa , as measured in this study , it does improve symptoms such as pain and mobility , as measured in previous studies . in a study of chronic nonspecific back
pain , treatment with asu ( piascledine ) combined with the nsaid artrosiline ( 320 mg / day ) showed significant analgesic effect over nsaid treatment alone .
, the eradias trial determined whether asu expanscience treatment slowed the radiological progression of hip oa .
as for safety , none of the four rcts reported significant differences in adverse effects between asu and placebo .
factors like bmi , severity of disease , and activity level may influence the effect of asu , as these conditions exacerbate inflammatory conditions and mechanical stresses that contribute to oa .
adipose tissue plays an important role by producing metabolic factors with catabolic and pro - inflammatory properties , including cytokines , chemokines , and adipokines ( il-6 and tnf- , il-8 , ifn- ) , which orchestrate pathophysiological processes in oa .
soluble mediators produced by adipocytes may also modulate chondrocyte metabolism and contribute to cartilage degradation .
asu may counteract these inflammatory processes by inhibiting the translocation of the transcription factor nf-b from the cytoplasm to the nucleus , which controls transcription of many pro - inflammatory factors ( table 2 ) .
as such , asu acts as an anabolic agent in vitro , reducing the production of pro - inflammatory mediators , including il-1 , il-6 , il-8 , macrophage inflammatory protein-1 , no , mmp-13 , tnf- , and cox2/pge2 from various cell types ( table 1 ) . in mice , asu decreases pro - inflammatory interferon- ( ifn- ) and il-4 production , in the context of parasitic diseases .
although more studies need to be conducted to show the effects of asu in patients with varying bmi , the anti - inflammatory effects of asu are likely to protect cartilage from obesity - associated inflammatory degradation and improve oa symptoms . indeed , asu significantly decreased the rate of oa progression to 40% compared with 50% in the placebo group in one study .
however , this study showed that asu did not influence the rate of oa progression in the obese subset of patients with mean symptom duration 4 and bmi of 27 kg / m .
however , excessive inflammation associated with obesity may also impede efficacy , as it does with celecoxib ( nsaid ) treatment , which is not as effective in obese patients ( bmi in excess of 30 kg / m ) .
the influence of obesity , and how it influences asu efficacy , may also depend on the parameters used to measure and define disease . in a study examining the relationship between bmi and oa in patients scheduled to undergo hip replacement , increasing bmi
was associated with increasing levels of pain and functional disability , but not radiographic joint damage .
this should be taken into account when designing and assessing studies intended to examine the impact of obesity on treatment efficacy .
asu has anti - inflammatory effects in mice when administered in conjunction with the anti - parasitic drug praziquantel , reducing inflammatory cytokines ifn- and il-4 , as well as granuloma size , while increasing cidal activity .
asu also protects gingival elastic fibers from degradation by human leukocyte elastase , hypodermatitis , and ischemic damage .
a recent electronic database analysis demonstrated the benefits and harms of oral medicinal plant products in treating oa .
the authors used standard methods for trial selection and data extraction , and they assessed the quality of the body of evidence using the grade approach for major outcomes such as pain , function , radiographic joint changes , quality of life , withdrawals due to adverse events , total adverse events , and serious adverse events .
the asu product piasclidine formed a small and clinically questionable improvement in symptoms , compared with placebo after 3 to 12 months treatment .
radiographic joint changes , as change in joint space width ( jsw ) , did not differ between asu 300 mg treatment and placebo .
moderate - quality evidence from a single study confirmed possible benefits of asu 600 mg over placebo .
there is no evidence that piasclidine significantly improves joint structure , and limited evidence that it prevents joint space narrowing .
the authors suggest further investigations are required to determine optimum daily doses producing clinical benefits without adverse events .
asu is considered as drug in most countries and is therefore prescribed by physicians . however , in the united states it is classified as dietary supplement and can be purchased as over - the - counter supplements , avoca asu ( asu - nmx1000 , nutramax laboratories inc . ,
avoca asu , a combination of asu and glucosamine sulfate , has been shown to suppress tnf- , il-1 , cox2 , inos , pge2 , nf-b activation and nitrite production in articular chondrocytes and monocytes / macrophages , reducing pain and inflammation in oa patients . however ,
conflicting reports indicate the complete absence of specific asu molecules in avoca asu when compared with piascledine .
questions remain about the efficacy and safety of asus for treatment of oa ( table 4 ) .
macaigne and colleagues published a case report in 2004 describing a female with lymphatic colitis associated with piascledine treatment .
further prospective multicenter studies are warranted to investigate whether other microscopic colitis cases are observed in patients treated with piascledine .
avoca asu that contains glucosamine can induce allergic reaction in people with shellfish allergy . even in very small quantities
, these people may experience mild symptoms , such as hives or nasal congestion , or more severe , even life - threatening , symptoms . an alternative asu formulation is arthrocen ( pharmin , usa , llc , san jose , ca ) .
arthrocen is an extract from avocado and soybean oils that does not contain any ingredients of animal origin , artificial flavor , sweetener , preservative , or color .
each capsule contains 100 mg unsaponifiable persea gratissima unsaponifiable ( avocado ) and 200 mg unsaponifiable glycine max ( soybean ) extracts , silica , magnesium stearate ( e470b  manufactured from vegetable oil ) , and gelatin fines . in general
, the fda does not hold dietary supplements to the stringent standards of pharmaceutical manufacture .
if asu is to be widely used for the treatment of oa , serious consideration should be given to their current regulatory status in order to ensure potency , purity , and as well as the excipients .
many studies have demonstrated substantial variation between the content listed on the labels of these products and the actual content .
the sterols content of asu have been demonstrated to have biological activities in culture and in animal models .
2 ) . we found multiple peaks were present in the piascledine-300 ( expanscience ) mass spectrometry analysis ( agilent 7890 gc system , 7693 auto sampler , agilent vl msd with triple axis detector , brea , ca ) , compared to the arthrocen 300 mg ( pharminusa ) or asu300-avocado soy unsaponifiable with sierra 600 mg ( maximize , maximum int . ) preparations ( fig .
similar results were found for piascledine-300 , with mass spectra sterol content of c20h30o2 , c20h28o2 , sitosterol , stigmasterol , campesterol , squalene , -tocopherol , desmethyl tocopherol , oleic acid docosane , -amyrin , and cholesterol . in two letters to the editor , msika et al .
and henroitin claimed that the exact ingredients and preparation of asu - expanscience was an intellectual proprietary , protected by patent .
msika further emphasized that the tocopherols , sterols , and patented specific molecules from avocado contribute to the originality of the product , different from natural avocado unsaponifiables .
in contrast , they analyzed dasuquin with msm , dasuquin , and avoca asu ( nutramax ) , and compared them with asu expanscience .
the analyses revealed content of products were significantly different from those indicated on the nutramax labels  with no citrostadienol , and brassicasterol present in asu expanscience .
contrary to that they found contents included high level of rapeseed oil and unsaponifiables products with very low tocopherol , and without respected ratio of 1:2 for avocado to soybean unsaponifiables .
the original asu piascledine 300 pills contains 100 mg of avocado unsaponifiables and 200 mg of soybean unsaponifiables .
the difference in sterol content is based on the a / s ratio and avocado - specific modified unsaponifiables obtained by a patented process .
have shown asu effects are best when the asu ratio is 2:1 . in support ,
these issues and reported adverse effects of asu ( table 4 ) raises concerns about the content and purity of asu supplements on the market , with implications for patient safety .
 mass spectrometry analysis of major sterol components of piascledine 300 , avocado 300 soy unsaponifiable with sierra 600 mg , and arthrocen 300 .
control sample exhibited characteristic peaks corresponding to 1 = dihydrocholesterol ( 5-cholestan-3-ol ; internal control ; sigma aldrich ) , 2 = brass ( brassicasterol ) , 3 = camp ( campesterol ) , 4 = stigmn ( stigmastanol ) , 5 = -sito ( -sitosterol ) , 6 = stigma ( stigmasterol ) .
improving joint function and patient activity is a central public health concern to improve quality and length of life .
the aim is not only to treat pain but also to prevent the onset of disease .
there is no cure for oa , and even symptomatic treatment options are scarce , dominated by pain management and surgical intervention .
asus may prove to be an effective treatment option for symptomatic oa , as they have been shown to possess chondroprotective , anabolic , and anticatabolic properties , as well as anti - inflammatory properties . at the clinical level , asus reduce pain and stiffness while improving joint function .
importantly , asus are a natural , slow - acting agent that do not merely address acute pain but actively prevent progression of oa symptoms .
further studies are required to determine the specific mechanisms and target molecules of asu function on oa at the cellular and metabolic level .
 osteoarthritis ( oa ) is a painful and life - altering disease that severely limits the daily activities of millions of americans , and it is one of the most common causes of disability in the world . with obesity on the rise and the world 
 s population living longer , the prevalence of oa is expected to increase dramatically in the coming decades , generating burdensome socioeconomic costs . 
 this review summarizes current pharmaceutical , nonpharmaceutical , and prospective new treatments for oa , with primary focus on the dietary supplement avocado / soybean unsaponifiables ( asu ) . 
 asu modulates oa pathogenesis by inhibiting a number of molecules and pathways implicated in oa . 
 anticatabolic properties prevent cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and increasing tissue inhibitors of these catabolic enzymes . 
 asu also inhibits fibrinolysis by stimulating the expression of plasminogen activator inhibitor . 
 anabolic properties promote cartilage repair by stimulating collagen and aggrecan synthesis via inhibition of inflammatory cytokines such as interleukin ( il)-1 , il-6 , il-8 , tumor necrosis factor , erk , and prostaglandin e2 . 
 chondroprotective effects are mediated by correcting growth factor abnormalities , increasing tgf- , and decreasing vascular endothelial growth factor ( vegf ) in synovial fluid . 
 asu also inhibits cholesterol absorption and endogenous cholesterol biosynthesis , which mediate reactive oxygen species pathology in chondrocytes . at the clinical level 
 , asu reduces pain and stiffness while improving joint function , resulting in decreased dependence on analgesics . 