Systematic Review
Supplementary Methods in the Nonsurgical Treatment of Osteoarthritis Marco Antônio Percope de Andrade, M.D., Ph.D., Túlio Vinícius de Oliveira Campos, M.D., and Guilherme Moreira de Abreu-e-Silva, M.D., Ms.C., Ph.D.
Purpose: This article discusses current evidence in nutraceuticals and viscosupplementation uses in osteoarthritis (OA) treatment. Methods: A search was carried out to identify systematic reviews, randomized controlled trials, review articles, and original articles (PubMed and Cochrane Database) about nutraceuticals and viscosupplementation. The keywords used were nutraceuticals, glucosamine, chondroitin, diacerein, avocado, soybean unsaponifiables, nutraceuticals, and viscosupplementation, independently or combined with the terms “review” and “randomized.” Results: Glucosamine hydrochloride has no effect on pain management, although the sulfate formulation has a moderate effect. Diacerein leads to pain relief, with a superior carryover effect when compared with placebo. Avocado and soybean unsaponifiables may have positive effects on knee and hip OA, but long-term results could not be confirmed. Despite the American Academy of Orthopaedic Surgeons’ recommendation against the use of hyaluronic acid in OA, some systematic reviews found some benefits in the knee. Conclusions: There is no evidence that nutraceuticals or viscosupplementation influences OA’s natural progression. However, some of these agents seem to reduce pain and improve function. Level of Evidence: Level IV, systematic review of studies with Level I through Level IV evidence.
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O
steoarthritis (OA) is a prevalent joint disease characterized by progressive loss of articular cartilage accompanied by bony remodeling, atrophy of periarticular muscles, and capsular contracture. Conservative treatment of OA includes analgesic and antiinflammatory drugs, lifestyle changes, and medications that may alter synovial fluid properties and reduce pain.1 The term “nutraceutical” was derived from “nutrition” and “pharmaceutical” and was originally defined as “a food that provides health benefits, including the prevention and/or treatment of a disease.”2 In general, nutraceuticals have a late onset of action and should be devoid of adverse effects. OA as a chronic disease is the From the Orthopaedic Department, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. The authors report the following potential conflict of interest or source of funding: M.A.P.d.A. receives support from Zimmer (grant CW81571). Received July 12, 2014; accepted November 13, 2014. Address correspondence to Marco Antônio Percope de Andrade, M.D., Ph.D., Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Aparelho Locomotor, Av Prof Alfredo Balena, 110, Santa Efigênia, CEP 30130-100, Belo Horizonte/MG, Brazil. E-mail: mapa.bhz@ terra.com.br Ó 2015 by the Arthroscopy Association of North America 0749-8063/14603/$36.00 http://dx.doi.org/10.1016/j.arthro.2014.11.021
perfect paradigm of a pathology whose treatment could be addressed by nutrition. In 1993 interest in intra-articular injection of hyaluronic acid (HA) emerged from a study by Balazs and Denlinger.3 Since then, numerous researchers have focused on the understanding of HA’s mechanism of action whereas clinical studies have tried to establish HA’s safety in practical use. The purpose of this article is to discuss the current evidence concerning supplementary methods used in OA treatment.
Methods We carried out a search in the literature for systematic reviews (SRs), randomized controlled trials (RCTs), review articles, and original articles in PubMed and the Cochrane Database. We reviewed the full text or abstract of articles provided by keyword search for each source. The keywords used were glucosamine, chondroitin, diacerein, avocado, soybean unsaponifiables, nutraceuticals, and viscosupplementation, independently or combined with the terms “review” and “randomized.” Articles were included if they had a single-blinded, double-blinded, or randomized controlled design. Analytic review was performed to critically understand and discuss the scientific evidence. Only recent studies
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Table 1. Inclusion Criteria of Review
Glucosamine Chondroitin HA Diacerein ASUs Total
No. of Records Identified Through Database Searching 535 486 162 208 22 1,413
No. of Records Screened 118 92 80 52 22 364
No. of Studies Included in Qualitative Synthesis 14 10 10 8 4 d
ASUs, avocado/soybean unsaponifiables; HA, hyaluronic acid.
(published within the past 10 years) in the English language were included. For this review, 1,413 articles were identified through our database search. According to the inclusion criteria, 364 articles were selected for detailed analysis, and of these, only 44 fulfilled all criteria for inclusion in our qualitative synthesis (Table 1). The level of evidence and results of the main studies are summarized in Table 2.
Results Glucosamine Glucosamine is an aminosaccharide naturally occurring in the body; it is the principal substrate in the biosynthesis of proteoglycan, which is essential for maintaining cartilage integrity.1,28 Glucosamine is the most commonly used supplement by patients with OA. The recommended dose is 1,500 mg once a day. On the basis of the essential role that aggrecans play by giving the cartilage its hydrophilicity, compounds enhancing synthesis of aggrecans may be beneficial in cases of OA.28 Advantages of the use of glucosamine are the possible clinical improvement with minimal side effects. However, in the past few years, questions regarding its efficacy have been raised. Many RCTs evaluating glucosamine in the treatment of OA are currently available with divergent results among them. Vlad et al.4 questioned why trial results are so different, wondering whether their heterogeneity is because of the difference among forms of glucosamine, quality of study, and industry sponsorships. In North America glucosamine is not considered a conventional prescription drug; rather, it is considered a dietary supplement, which is widely available as an over-the-counter preparation.5 Glucosamine hydrochloride has a summary effect size statistically indistinguishable from the null, with no effect on pain. On the other hand, trials using glucosamine sulfate have shown a moderate summary effect size and marked heterogeneity. Trials not funded by industry had null results.4 In a meta-analysis comparing glucosamine, chondroitin, and placebo in patients with hip or knee OA, Wandel et al.6 studied 3,803 patients (10 studies),
showing that industry-independent trials showed smaller effects than commercially funded trials. They concluded that compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain and have no impact on joint space narrowing. A Cochrane SR studying 4,926 patients in 25 randomized and quasi-randomized clinical trials concluded that glucosamine improved pain when compared with placebo (relative risk, 0.47 [95% confidence interval, 0.23 to 0.72]).5 However, analysis restricted to those studies with adequate allocation concealment did not show any superiority of glucosamine over placebo for pain. In a recent review, the Osteoarthritis Research Society International (OARSI) made some recommendations regarding nonsurgical treatment of OA.7 On the basis of SRs and RCTs analyzed by expert board members, the degree of recommendation for glucosamine use for symptom relief was “uncertain” and that for disease modification was “not appropriate.” The estimated effect size for pain relief ranged from 0.17 to 0.47, with a good evidence level. The American Academy of Orthopaedic Surgeons (AAOS) released 2 guidelines that concluded that there is no clear benefit in using glucosamine (isolated or combined with chondroitin) in the treatment of knee OA, advising against its use in clinical practice.8,9 The most important RCT, that is, the GAIT study (Glucosamine/Chondroitin Arthritis Intervention Trial), enrolled 1,583 patients with OA and failed to show significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score for glucosamine hydrochloride, chondroitin sulfate, or their combination.10 Only the subgroup in which the WOMAC score was classified as moderate to severe showed pain improvement when treated by a combination of glucosamine and chondroitin. Moreover, the placebo response rate in this trial was high: Approximately 60% of patients in the placebo group had a 20% decrease in the WOMAC score. It would be difficult for a treatment to surpass this effect, which may also explain the negative findings of this trial. Concerning glucosamine safety, a 2011 review found that long-term use of glucosamine was not associated with cardiovascular risks.29 Two more SRs found no increase in overall adverse events when compared with placebo.5,6 Scroggie et al.,30 in an RCT evaluating glucosamine hydrochloride side effects, concluded that oral glucosamine supplementation did not adversely affect glycemic control when administered to patients with type 2 diabetes mellitus. Simon et al.31 argued that glucosamine has no effect on fasting blood glucose levels, glucose metabolism, or insulin sensitivity at any oral dose level in healthy subjects, individuals with diabetes, or patients with impaired glucose tolerance. However, an SR studying glucosamine side effects
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Table 2. Inclusion Criteria and Level of Evidence of Studies Article Fransen et al.,1 2014
No. of Patients 605
Study Design Double blind, placebo controlled
Follow-up 2 yr
Level of Evidence I
Vlad et al.,4 2007
15 studies, 24630 patients
Systematic review
4-156 wk
IV
Towheed et al.,5 2005 Wandel et al.,6 2010
2,570
Systematic review
NR
IV
3,803
Systematic review
NR
IV
McAlindon et al.,7 2014
NR
Panel of experts
NR
IV
Richmond et al.,8 2009 Jevsevar,9 2013
NR
Panel of experts
NR
IV
NR
Panel of experts
NR
IV
Clegg et al.,10 2006
1,583
Randomized, multicenter, double blind, placebo and celecoxib controlled
24 wk
I
Reichenbach et al.,11 2007 Pavelka et al.,12 2007
3,846
Meta-analysis
NR
I
168
20 wk
I
Bartels et al.,13 2010
1,533
Randomized, multicenter, double blind, placebo controlled Meta-analysis
NR
I
Sharma et al.,14 2008
7,923
Open label, postmarketing
13 wk
III
Louthrenoo et al.,15 2007
150
Double blind, randomized, piroxicam controlled
16 wk
III
Dougados et al.,16 2001
507
3 yr
I
Rintelen et al.,17 2006
NR
Randomized, double blind, placebo controlled Meta-analysis
NR
I
Conclusion The combination of glucosamine and chondroitin resulted in a statistically significant reduction in joint space narrowing at 2 yr. All groups showed reduced knee pain. None of the treatment groups showed significant symptomatic benefit above placebo. There was high heterogeneity among trials. Glucosamine hydrochloride was not effective. Among trials with industry involvement, ESs were consistently higher. There was no difference with glucosamine in comparison with placebo using WOMAC scores. Compared with placebo, glucosamine, chondroitin, and their combination did not reduce joint pain or have an impact on joint space narrowing. ASUs, chondroitin, diacerein, glucosamine, and intra-articular HA treatments should be considered of uncertain appropriateness for OA. The authors do not recommend glucosamine and/ or chondroitin and HA. The authors cannot recommend using glucosamine and chondroitin for patients with symptomatic OA of the knee. They are unable to recommend for or against the use of intra-articular corticosteroids for patients with symptomatic OA of the knee. They indicate that a strong recommendation should be followed unless a clear and compelling rationale for an alternative approach is present. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with OA of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate to severe knee pain. Symptomatic benefit of chondroitin is minimal or nonexistent. Diacerein is safe and effective for the treatment of knee OA and has a long carryover effect.
Diacerein may be an alternative therapy for OA in patients who cannot take acetaminophen (paracetamol) or NSAIDs because of adverse effects or lack of benefit. However, it is associated with increased risk of diarrhea. Therapy with diacerein was well tolerated, and only 5.44% of the patients had an adverse event after treatment. Over the 12-wk study period, diacerein provided a significant and sustained reduction in VAS pain scores. Diacerein was as effective as piroxicam in reducing pain and improving function but, unlike piroxicam, displayed a carryover effect and a better safety profile. Treatment with diacerein for 3 yr has a significant structure-modifying effect as compared with placebo. There is evidence of the symptomatic efficacy of diacerein in the treatment of knee and hip OA. (continued)
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Table 2. Continued No. of Patients 2,210
Study Design Meta-analysis
Follow-up NR
Level of Evidence I
Ernst,19 2003
NR
Systematic review
NR
IV
Pavelka et al.,20 2010 Maheu et al.,21 2014
364
Comparative study
8 mo
III
399
3 yr
I
Aggarwal and Sempowski,22 2004
13 randomized controlled trials
Prospective, randomized, double blind, parallel group, placebo controlled Review
NR
IV
Bannuru et al.,23 2011
7,545
Meta-analysis
NR
I
Wang et al.,24 2004
NR
Meta-analysis
NR
II
Rutjes et al.,25 2012
12,667
Meta-analysis
NR
I
Miller and Block,26 2013
4,866
Meta-analysis
NR
I
Bellamy et al.,27 2006
NR
Systematic review
NR
IV
Article Fidelix et al.,18 2014
Conclusion Symptomatic benefit provided by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip. Most rigorous trial data available to date suggest that ASUs are effective for the symptomatic treatment of OA. The first direct comparison between ASUs and chondroitin sulfate showed no difference. ASUs reduce the percentage of joint space narrowing, indicating a potential structuremodifying effect in hip OA Viscosupplementation with highemolecular weight HA is an effective treatment for patients with knee OA who have ongoing pain or are unable to tolerate conservative treatment or joint replacement. HA is efficacious by 4 wk, reaches its peak effectiveness at 8 wk, and exerts a residual detectable effect at 24 wk. On the other hand, the peak ES (0.46; 95% CI, 0.28 to 0.65) is greater than published effects from other OA analgesics (acetaminophen [ES, 0.13; 95% CI, 0.04 to 0.22]; NSAIDs [ES, 0.29; 95% CI, 0.22 to 0.35]; and COX-2 inhibitors [ES, 0.44; 95% CI, 0.33 to 0.55]). The therapeutic efficacy and safety of intraarticular injection of HA for the treatment of OA of the knee were confirmed. In OA, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk of serious adverse events. Intra-articular injection of United Stateseapproved HA products is safe and efficacious in patients with symptomatic knee OA. Viscosupplementation is an effective treatment for OA of the knee with beneficial effects on pain, function, and patient global assessment, especially at 5 to 13 wk.
ASUs, avocado/soybean unsaponifiables; CI, confidence interval; COX-2, cyclooxygenase 2; ES, effect size; HA, hyaluronic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
showed that it was not possible to confirm the safety of glucosamine mainly in patients with impaired glucose tolerance or insulin resistance and indicated that more studies would be necessary to establish its safety.32 Glucosamine is derived from the exoskeleton of shellfish. There is concern about reactions in persons allergic to shellfish. However, seafood allergies are caused by antigens in its meat (not the shell), and there have been no reports of reactions in persons with shellfish allergies who take glucosamine.33 Chondroitin Chondroitin sulfate is a major component of aggrecan, which is part of the cartilage ultrastructure.34 It is
often derived from animal sources, such as shark cartilage (chondroitin 4-sulfate) and porcine cartilage (chondroitin 6-sulfate).35 It may be ingested in isolation or combined with glucosamine sulfate. As is the case for glucosamine, understanding of the mechanism of action of chondroitin is incomplete; however, in vitro studies have shown anti-inflammatory, anticatabolic, antiapoptotic, and antioxidant effects.34,35 Animal studies suggest that the combination of glucosamine and chondroitin is better than glucosamine alone.36 However, there is no evidence that the same occurs in humans.10 The literature shows a great divergence in results regarding the clinical benefit of chondroitin sulfate.7 A
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high degree of heterogeneity in addition to the small number and poor quality of the included trials in 1 meta-analysis made a definitive assessment difficult.11 Reichenbach et al.11 showed a small effect size for pain relief (i.e., 0.01 [95% CI, 0.07 to 0.13]). The OARSI consensus classified chondroitin sulfate use as “uncertain” in clinical practice and as “not appropriate” for disease modification.7 The latest AAOS guideline recommends against chondroitin use in clinical terms.9 Diacerein Diacerein is a disease-modifying drug for the treatment of OA with interleukin (IL) 1 inhibitory properties. Boileau et al.37 investigated the effects of diacerein on degenerated subchondral bone and concluded that diacerein reduced, in a dose-dependent manner, the IL1einduced matrix metalloproteinase (MMP) 13 production. Diacerein belongs to the anthraquinone chemical class and may be taken orally twice daily as 50-mg tablets. It has a half-life of 7 to 8 hours and renal elimination.12 Bartels et al.,13 in an SR with 1,533 patients, found a significant improvement in function but noted a questionable clinical effect in trials with follow-up periods longer than 6 months. Sharma et al.14 evaluated 7,923 patients with knee OA in an open-label, multicenter postmarketing surveillance study and showed that after 12 weeks’ follow-up, 85.5% of cases treated by diacerein were rated as good or very good. Therapy with diacerein was reported to be well tolerated, and only 5.44% of the patients had adverse events after treatment, the most common being diarrhea (2.3%). Pavelka et al.12 reported the superiority of diacerein over placebo regarding WOMAC scores (P < .0001) at month 5 (2 months after the end of treatment), showing the drug carryover effect. Favorable outcomes in pain scores (P ¼ .001) and WOMAC scores (P ¼ .0021) were already evident in month 2 and month 1, respectively. Louthrenoo et al.15 carried out an RCT, piroxicam controlled, in which 161 patients were evaluated for 24 weeks (16 weeks of treatment with diacerein, 100 mg/d, or piroxicam, 20 mg/d, followed by 8 weeks of observation). Pain decreased to a similar level in both groups at week 16. Pain increased in the piroxicam group at weeks 20 and 24, whereas improvements persisted in the diacerein group, showing the carryover effects of the drug. The ECHODIAH (Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip) study evaluated the structure-modifying effects of diacerein in patients with primary hip OA with a 3-year follow-up.16 The percentage of patients with radiographic progression was significantly lower in the group taking diacerein compared with the placebo group.
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Rintelen et al.17 in an SR reported that diacerein and nonsteroidal anti-inflammatory drugs (NSAIDs) were superior to placebo during treatment. However, diacerein but not NSAIDs showed a carryover effect, persisting up to 3 months after treatment, with a significant analgesic-sparing effect during the follow-up period. A Cochrane SR pointed out low-quality evidence in 6 trials (1,283 participants), indicating that diacerein had a small effect on overall pain (visual analog scale) at 3 to 36 months.18 No difference in physical function (4 studies, 1,006 participants) was perceived between the diacerein and placebo groups. Two trials with lowquality evidence (616 participants) analyzed knee or hip joint space narrowing. The results favored diacerein over placebo when both joints were studied together but not when the knee was studied alone (1 study, 170 participants). Seven trials with low-quality evidence comparing diacerein with placebo showed more adverse events, mostly diarrhea, in the diacerein group after 2 to 36 months. There was no difference in dropout rates because of adverse events between the groups. Avocado/Soybean Unsaponifiables Avocado/soybean unsaponifiables (ASUs) display anabolic, anticatabolic, and anti-inflammatory effects on chondrocytes; increase collagen synthesis; and inhibit spontaneous and IL-1beinduced collagenase activity.19 They also increase aggrecan synthesis and reverse the IL-1b effect.19 Apparently, ASUs reduce the spontaneous and IL-1beinduced production of MMP-3, IL-6, IL-8, and prostaglandin E2 (PGE2). Four RCTs and 1 SR evaluated the effect of ASUs on knee and hip OA. ASUs (300 mg once a day) decreased NSAID intake in 3 trials after 3 months of follow-up. No difference in primary or secondary endpoints was perceived with a 300- versus 600-mg dosage. In a 6month trial, ASUs resulted in more symptom relief than placebo. ASUs had a 2-month delayed onset of action and a carryover effect after 2 months of treatment.38 An SR did not show a long-term (>1 year) symptom-modifying effect of ASUs on knee and hip OA.19 One study showed that ASUs decreased the spontaneous production of nitric oxide and macrophage inflammatory protein 1b and stimulated the expression of transforming growth factor b and plasminogen activator inhibitor 1, which could diminish MMP activation.19 Henrotin et al.39 compared the effects of avocado unsaponifiables (A), soybean unsaponifiables (S), and 3 mixtures of ASUs (A1S2 [Piascledine, Laboratoires Expanscience, Epernon, France], A2S1, and A1S1, with respective ratios of 1:2, 2:1, and 1:1). All mixtures reduced spontaneous production of IL-6e, IL-8e, PGE2e, and IL-1beinduced production of PGE2. A1S2 and A1S1 reduced IL-1beinduced production of
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MMP-3 and collagenase activity. Only Piascledine inhibited collagenase activity. Pavelka et al.20 compared ASUs and chondroitin sulfate in knee OA. Three hundred sixty-one patients were enrolled, and there was no difference between the groups after a 6-month follow-up period. The study by Maheu et al.21 enrolled 399 patients with symptomatic hip OA. After 3 years, ASUs decreased joint space narrowing in the treated group, indicating a potential structure-modifying effect of ASUs on hip OA. Viscosupplementation HA is a polysaccharide composed of glucosamine and glucuronic acid, which exists in the normal synovial fluid.40 It was first used in ophthalmology for cataract surgery in the 1970s.22 Since the 1980s, its intraarticular use gained popularity in Europe and, afterward, in the United States.22 In osteoarthritic joints, the synovial fluid becomes less viscous and less concentrated with a lower molecular weight, which leads to less shock absorption, lubrication, and protection of joints.40,41 HA’s suggested mechanisms of action are inhibiting inflammatory mediators, decreasing cartilage degradation, and promoting cartilage matrix synthesis.41 Other possible mechanisms of action include control of synovial permeability, blockade of inflammation by scavenging oxygen free radicals, and inhibition of MMP.41 In an SR about HA’s effect in knee OA, 49 trials (6,962 patients) were included in the meta-analysis for pain-related outcomes.23 The effect size favored HA by week 4 (0.31; 95% CI, 0.17 to 0.45), reaching a peak at week 8 (0.46; 95% CI, 0.28 to 0.65), and then trended downward, with a residual detectable effect at week 24 (0.21; 95% CI, 0.10 to 0.31). Sixteen trials (2,571 patients) were included in the meta-analysis for functionrelated outcomes, favoring HA with an effect size of 0.31 (95% CI, 0.11 to 0.51) but with great heterogeneity among trials. Regarding joint stiffness, 15 trials (2,488 patients) were included in the meta-analysis, showing an effect size of 0.31 favoring HA (95% CI, 0.12 to 0.49). In another SR, HA treatment was effective except in patients with severe or complete loss of knee joint space.24 Rutjes et al.25 studied HA’s effect on knee OA in 89 trials with 12,667 patients. After exclusion of studies with methodologic flaws, they showed minimal effects on pain relief or on functional improvement in patients treated by HA. Considering the OARSI guideline, they estimated that the effect size for pain relief ranged from 0.37 to 0.46 and that for functional improvement ranged from 0.31 to 0.33. Indeed, the degree of recommendation for HA was considered “uncertain” for knee OA and “not appropriate” for multiple-joint OA.25 The first AAOS guideline did not define the role of intra-articular HA for patients with mild to moderate
symptomatic OA of the knee.8 This recommendation was based on 6 SRs and 1 RCT. The conclusion was that viscosupplementation showed positive effects but these results could have been influenced by trial quality, potential publication bias, and unclear clinical significance. However, the latest guideline of the AAOS recommended against routine use of HA for knee OA.9 A recent SR questioned the latest AAOS recommendation, arguing that the inclusion criteria of the RCT were not fully demonstrated, only 14 RCTs were included, and the definition of the efficacy criteria was not clear.26 Moreover, a 2006 Cochrane SR (updated in 2014) showed that HA is an effective treatment for knee OA regarding pain, joint function, and patient global assessment.27 Clinical improvement was more evident between week 5 and week 13. Compared with intra-articular corticosteroid or placebo treatments, HA provided better results regarding expected effect duration. Concerns about HA adverse events were raised recently, mainly by 1 RCT, in which the authors described serious adverse events in the gastrointestinal, cardiovascular, and musculoskeletal systems, besides cancer.25 However, bias regarding the study selection criteria in the former SR must be mentioned.42 In another SR the risk of moderate or serious adverse events was not higher in the HA group when compared with the sham group.26 Adverse side effects tended to be minor, such as injection-site pain and swelling; systemic reactions were rare.43
Discussion Nutraceuticals and viscosupplementation have been extensively used in conservative treatment of OA. This may be because of the low incidence of adverse effects and the chronic course of the disease. OARSI recommendations for OA treatment have established that the effect size for pain relief from HA, glucosamine sulfate, chondroitin sulfate, and ASUs diminished during treatment even though there was heterogeneity of outcomes and evidence of publication bias.44 They also reported a progressive reduction of clinical effects with time that may be due to worsening of OA and external factors, such as noncompliance and medication interruption. Literature concerning glucosamine and chondroitin in OA management states that glucosamine hydrochloride has no effect on pain. The sulfate formulation has a moderate effect size, but studies about this subject have had marked heterogeneity. Moreover, trials not funded by industry have had null results. The AAOS guideline does not recommend these drugs in OA treatment. Animal studies suggest that the combination of glucosamine and chondroitin is better than glucosamine alone, but there is no clinical study that confirms such an assertion.
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The literature considers that diacerein leads to pain relief, with a superior carryover effect when compared with placebo.16,18 One study showed slowing of radiographic progression in hip OA, but similar results were not presented in knee OA.16 ASUs are supposed to modify the effects on knee and hip OA, but as is the case for the other nutraceuticals, their effects in the long-term (>1 year) have not been confirmed.19 The role of viscosupplementation in OA treatment is difficult to interpret because of heterogeneity in clinical trials. Despite the latest recommendation of the AAOS against the use of HA, some SRs showed that patients with knee OA could benefit from HA use.7,24,27,44 Limitations The limitations of our study were as follows: heterogeneity of trials, sponsorship bias, short follow-up, and subjective factors inherent to the primary outcome tested (pain). As a result, different SRs came to divergent conclusions on the same subject, impairing a final and clear conclusion regarding the safety and efficacy of nutraceuticals. Further nutraceutical and viscosupplementation RCTs must address those limitations.
Conclusions On the basis of the available data, there is no evidence that nutraceuticals or viscosupplementation influences OA’s natural progression. However, some of these agents seem to interfere in pain relief and function.
References 1. Fransen M, Agaliotis M, Nairn L, et al. Glucosamine and chondroitin for knee osteoarthritis: A double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis in press, available online 6 January, 2014. doi:10.1136/ annrheumdis-2013-203954. 2. Kalra EK. NutraceuticaldDefinition and introduction. AAPS PharmSci 2003;5:E25. 3. Balazs EA, Denlinger JL. Viscosupplementation: A new concept in the treatment of osteoarthritis. J Rheumatol Suppl 1993;39:3-9. 4. Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: Why do trial results differ? Arthritis Rheum 2007;56:2267-2277. 5. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005:CD002946. 6. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: Network meta-analysis. BMJ 2010;341: c4675. 7. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363-388. 8. Richmond J, Hunter D, Irrgang J, et al. Treatment of osteoarthritis of the knee (nonarthroplasty). J Am Acad Orthop Surg 2009;17:591-600.
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9. Jevsevar DS. Treatment of osteoarthritis of the knee: Evidence-based guideline, 2nd edition. J Am Acad Orthop Surg 2013;21:571-576. 10. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354: 795-808. 11. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: Chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580-590. 12. Pavelka K, Trc T, Karpas K, et al. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: A randomized, multicenter, double-blind, placebocontrolled study with primary end points at two months after the end of a three-month treatment period. Arthritis Rheum 2007;56:4055-4064. 13. Bartels EM, Bliddal H, Schøndorff PK, Altman RD, Zhang W, Christensen R. Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: A metaanalysis of randomized placebo-controlled trials. Osteoarthritis Cartilage 2010;18:289-296. 14. Sharma A, Rathod R, Baliga VP. An open prospective study on postmarketing evaluation of the efficacy and tolerability of diacerein in osteo-arthritis of the knee (DOK). J Indian Med Assoc 2008;106:54-56:58. 15. Louthrenoo W, Nilganuwong S, Aksaranugraha S, Asavatanabodee P, Saengnipanthkul S, Group TS. The efficacy, safety and carry-over effect of diacerein in the treatment of painful knee osteoarthritis: A randomised, double-blind, NSAID-controlled study. Osteoarthritis Cartilage 2007;15:605-614. 16. Dougados M, Nguyen M, Berdah L, et al. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the chondromodulating effect of diacerein in OA of the hip. Arthritis Rheum 2001;44: 2539-2547. 17. Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med 2006;166:1899-1906. 18. Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V. Diacerein for osteoarthritis. Cochrane Database Syst Rev 2014;2:CD005117. 19. Ernst E. Avocado-soybean unsaponifiables (ASU) for osteoarthritisdA systematic review. Clin Rheumatol 2003;22:285-288. 20. Pavelka K, Coste P, Géher P, Krejci G. Efficacy and safety of piascledine 300 versus chondroitin sulfate in a 6 months treatment plus 2 months observation in patients with osteoarthritis of the knee. Clin Rheumatol 2010;29: 659-670. 21. Maheu E, Cadet C, Marty M, et al. Randomised, controlled trial of avocado-soybean unsaponifiable (Piascledine) effect on structure modification in hip osteoarthritis: The ERADIAS study. Ann Rheum Dis 2014;73: 376-384. 22. Aggarwal A, Sempowski IP. Hyaluronic acid injections for knee osteoarthritis. Systematic review of the literature. Can Fam Physician 2004;50:249-256. 23. Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE. Therapeutic trajectory following
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32.
33.
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intra-articular hyaluronic acid injection in knee osteoarthritisdMeta-analysis. Osteoarthritis Cartilage 2011;19: 611-619. Wang CT, Lin J, Chang CJ, Lin YT, Hou SM. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 2004;86:538-545. Rutjes AW, Jüni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: A systematic review and meta-analysis. Ann Intern Med 2012;157:180-191. Miller LE, Block JE. US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: Systematic review and metaanalysis of randomized, saline-controlled trials. Clin Med Insights Arthritis Musculoskelet Disord 2013;6:57-63. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006: CD005321. Reginster JY, Bruyere O, Fraikin G, Henrotin Y. Current concepts in the therapeutic management of osteoarthritis with glucosamine. Bull Hosp Jt Dis 2005;63:31-36. Palma Dos Reis R, Giacovelli G, Girolami F, André R, Bonazzi A, Rovati LC. Crystalline glucosamine sulfate in the treatment of osteoarthritis: Evidence of long-term cardiovascular safety from clinical trials. Open Rheumatol J 2011;5:69-77. Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: A placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-1590. Simon RR, Marks V, Leeds AR, Anderson JW. A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. Diabetes Metab Res Rev 2011;27:14-27. Dostrovsky NR, Towheed TE, Hudson RW, Anastassiades TP. The effect of glucosamine on glucose metabolism in humans: A systematic review of the literature. Osteoarthritis Cartilage 2011;19:375-380. Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy? J Allergy Clin Immunol 2004;114:459-460.
34. Chou MM, Vergnolle N, McDougall JJ, et al. Effects of chondroitin and glucosamine sulfate in a dietary bar formulation on inflammation, interleukin-1beta, matrix metalloprotease-9, and cartilage damage in arthritis. Exp Biol Med (Maywood) 2005;230:255-262. 35. Henrotin Y, Lambert C. Chondroitin and glucosamine in the management of osteoarthritis: An update. Curr Rheumatol Rep 2013;15:361. 36. Gupta RC, Canerdy TD, Skaggs P, et al. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Ther 2009;32:577-584. 37. Boileau C, Tat SK, Pelletier JP, Cheng S, Martel-Pelletier J. Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: A possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Res Ther 2008;10:R71. 38. Ameye LG, Chee WS. Osteoarthritis and nutrition. From nutraceuticals to functional foods: A systematic review of the scientific evidence. Arthritis Res Ther 2006;8:R127. 39. Henrotin YE, Labasse AH, Jaspar JM, et al. Effects of three avocado/soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes. Clin Rheumatol 1998;17: 31-39. 40. Pagnano M, Westrich G. Successful nonoperative management of chronic osteoarthritis pain of the knee: Safety and efficacy of retreatment with intra-articular hyaluronans. Osteoarthritis Cartilage 2005;13:751-761. 41. Neustadt DH. Intra-articular injections for osteoarthritis of the knee. Cleve Clin J Med 2006;73:897-898:901-904, 906-911. 42. McAlindon TE, Bannuru RR. Osteoarthritis: Is viscosupplementation really so unsafe for knee OA? Nat Rev Rheumatol 2012;8:635-636. 43. Webber TA, Webber AE, Matzkin E. Rate of adverse reactions to more than 1 series of viscosupplementation. Orthopedics 2012;35:e514-e519. 44. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16: 137-162.
Supplementary Methods in the Nonsurgical Treatment of Osteoarthritis Marco Antônio Percope de Andrade, M.D., Ph.D., Túlio Vinícius de Oliveira Campos, M.D., and Guilherme Moreira de Abreu-e-Silva, M.D., Ms.C., Ph.D.
Purpose: This article discusses current evidence in nutraceuticals and viscosupplementation uses in osteoarthritis (OA) treatment. Methods: A search was carried out to identify systematic reviews, randomized controlled trials, review articles, and original articles (PubMed and Cochrane Database) about nutraceuticals and viscosupplementation. The keywords used were nutraceuticals, glucosamine, chondroitin, diacerein, avocado, soybean unsaponifiables, nutraceuticals, and viscosupplementation, independently or combined with the terms “review” and “randomized.” Results: Glucosamine hydrochloride has no effect on pain management, although the sulfate formulation has a moderate effect. Diacerein leads to pain relief, with a superior carryover effect when compared with placebo. Avocado and soybean unsaponifiables may have positive effects on knee and hip OA, but long-term results could not be confirmed. Despite the American Academy of Orthopaedic Surgeons’ recommendation against the use of hyaluronic acid in OA, some systematic reviews found some benefits in the knee. Conclusions: There is no evidence that nutraceuticals or viscosupplementation influences OA’s natural progression. However, some of these agents seem to reduce pain and improve function. Level of Evidence: Level IV, systematic review of studies with Level I through Level IV evidence.
See commentary on page 793
O
steoarthritis (OA) is a prevalent joint disease characterized by progressive loss of articular cartilage accompanied by bony remodeling, atrophy of periarticular muscles, and capsular contracture. Conservative treatment of OA includes analgesic and antiinflammatory drugs, lifestyle changes, and medications that may alter synovial fluid properties and reduce pain.1 The term “nutraceutical” was derived from “nutrition” and “pharmaceutical” and was originally defined as “a food that provides health benefits, including the prevention and/or treatment of a disease.”2 In general, nutraceuticals have a late onset of action and should be devoid of adverse effects. OA as a chronic disease is the From the Orthopaedic Department, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. The authors report the following potential conflict of interest or source of funding: M.A.P.d.A. receives support from Zimmer (grant CW81571). Received July 12, 2014; accepted November 13, 2014. Address correspondence to Marco Antônio Percope de Andrade, M.D., Ph.D., Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Aparelho Locomotor, Av Prof Alfredo Balena, 110, Santa Efigênia, CEP 30130-100, Belo Horizonte/MG, Brazil. E-mail: mapa.bhz@ terra.com.br Ó 2015 by the Arthroscopy Association of North America 0749-8063/14603/$36.00 http://dx.doi.org/10.1016/j.arthro.2014.11.021
perfect paradigm of a pathology whose treatment could be addressed by nutrition. In 1993 interest in intra-articular injection of hyaluronic acid (HA) emerged from a study by Balazs and Denlinger.3 Since then, numerous researchers have focused on the understanding of HA’s mechanism of action whereas clinical studies have tried to establish HA’s safety in practical use. The purpose of this article is to discuss the current evidence concerning supplementary methods used in OA treatment.
Methods We carried out a search in the literature for systematic reviews (SRs), randomized controlled trials (RCTs), review articles, and original articles in PubMed and the Cochrane Database. We reviewed the full text or abstract of articles provided by keyword search for each source. The keywords used were glucosamine, chondroitin, diacerein, avocado, soybean unsaponifiables, nutraceuticals, and viscosupplementation, independently or combined with the terms “review” and “randomized.” Articles were included if they had a single-blinded, double-blinded, or randomized controlled design. Analytic review was performed to critically understand and discuss the scientific evidence. Only recent studies
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Table 1. Inclusion Criteria of Review
Glucosamine Chondroitin HA Diacerein ASUs Total
No. of Records Identified Through Database Searching 535 486 162 208 22 1,413
No. of Records Screened 118 92 80 52 22 364
No. of Studies Included in Qualitative Synthesis 14 10 10 8 4 d
ASUs, avocado/soybean unsaponifiables; HA, hyaluronic acid.
(published within the past 10 years) in the English language were included. For this review, 1,413 articles were identified through our database search. According to the inclusion criteria, 364 articles were selected for detailed analysis, and of these, only 44 fulfilled all criteria for inclusion in our qualitative synthesis (Table 1). The level of evidence and results of the main studies are summarized in Table 2.
Results Glucosamine Glucosamine is an aminosaccharide naturally occurring in the body; it is the principal substrate in the biosynthesis of proteoglycan, which is essential for maintaining cartilage integrity.1,28 Glucosamine is the most commonly used supplement by patients with OA. The recommended dose is 1,500 mg once a day. On the basis of the essential role that aggrecans play by giving the cartilage its hydrophilicity, compounds enhancing synthesis of aggrecans may be beneficial in cases of OA.28 Advantages of the use of glucosamine are the possible clinical improvement with minimal side effects. However, in the past few years, questions regarding its efficacy have been raised. Many RCTs evaluating glucosamine in the treatment of OA are currently available with divergent results among them. Vlad et al.4 questioned why trial results are so different, wondering whether their heterogeneity is because of the difference among forms of glucosamine, quality of study, and industry sponsorships. In North America glucosamine is not considered a conventional prescription drug; rather, it is considered a dietary supplement, which is widely available as an over-the-counter preparation.5 Glucosamine hydrochloride has a summary effect size statistically indistinguishable from the null, with no effect on pain. On the other hand, trials using glucosamine sulfate have shown a moderate summary effect size and marked heterogeneity. Trials not funded by industry had null results.4 In a meta-analysis comparing glucosamine, chondroitin, and placebo in patients with hip or knee OA, Wandel et al.6 studied 3,803 patients (10 studies),
showing that industry-independent trials showed smaller effects than commercially funded trials. They concluded that compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain and have no impact on joint space narrowing. A Cochrane SR studying 4,926 patients in 25 randomized and quasi-randomized clinical trials concluded that glucosamine improved pain when compared with placebo (relative risk, 0.47 [95% confidence interval, 0.23 to 0.72]).5 However, analysis restricted to those studies with adequate allocation concealment did not show any superiority of glucosamine over placebo for pain. In a recent review, the Osteoarthritis Research Society International (OARSI) made some recommendations regarding nonsurgical treatment of OA.7 On the basis of SRs and RCTs analyzed by expert board members, the degree of recommendation for glucosamine use for symptom relief was “uncertain” and that for disease modification was “not appropriate.” The estimated effect size for pain relief ranged from 0.17 to 0.47, with a good evidence level. The American Academy of Orthopaedic Surgeons (AAOS) released 2 guidelines that concluded that there is no clear benefit in using glucosamine (isolated or combined with chondroitin) in the treatment of knee OA, advising against its use in clinical practice.8,9 The most important RCT, that is, the GAIT study (Glucosamine/Chondroitin Arthritis Intervention Trial), enrolled 1,583 patients with OA and failed to show significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score for glucosamine hydrochloride, chondroitin sulfate, or their combination.10 Only the subgroup in which the WOMAC score was classified as moderate to severe showed pain improvement when treated by a combination of glucosamine and chondroitin. Moreover, the placebo response rate in this trial was high: Approximately 60% of patients in the placebo group had a 20% decrease in the WOMAC score. It would be difficult for a treatment to surpass this effect, which may also explain the negative findings of this trial. Concerning glucosamine safety, a 2011 review found that long-term use of glucosamine was not associated with cardiovascular risks.29 Two more SRs found no increase in overall adverse events when compared with placebo.5,6 Scroggie et al.,30 in an RCT evaluating glucosamine hydrochloride side effects, concluded that oral glucosamine supplementation did not adversely affect glycemic control when administered to patients with type 2 diabetes mellitus. Simon et al.31 argued that glucosamine has no effect on fasting blood glucose levels, glucose metabolism, or insulin sensitivity at any oral dose level in healthy subjects, individuals with diabetes, or patients with impaired glucose tolerance. However, an SR studying glucosamine side effects
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Table 2. Inclusion Criteria and Level of Evidence of Studies Article Fransen et al.,1 2014
No. of Patients 605
Study Design Double blind, placebo controlled
Follow-up 2 yr
Level of Evidence I
Vlad et al.,4 2007
15 studies, 24630 patients
Systematic review
4-156 wk
IV
Towheed et al.,5 2005 Wandel et al.,6 2010
2,570
Systematic review
NR
IV
3,803
Systematic review
NR
IV
McAlindon et al.,7 2014
NR
Panel of experts
NR
IV
Richmond et al.,8 2009 Jevsevar,9 2013
NR
Panel of experts
NR
IV
NR
Panel of experts
NR
IV
Clegg et al.,10 2006
1,583
Randomized, multicenter, double blind, placebo and celecoxib controlled
24 wk
I
Reichenbach et al.,11 2007 Pavelka et al.,12 2007
3,846
Meta-analysis
NR
I
168
20 wk
I
Bartels et al.,13 2010
1,533
Randomized, multicenter, double blind, placebo controlled Meta-analysis
NR
I
Sharma et al.,14 2008
7,923
Open label, postmarketing
13 wk
III
Louthrenoo et al.,15 2007
150
Double blind, randomized, piroxicam controlled
16 wk
III
Dougados et al.,16 2001
507
3 yr
I
Rintelen et al.,17 2006
NR
Randomized, double blind, placebo controlled Meta-analysis
NR
I
Conclusion The combination of glucosamine and chondroitin resulted in a statistically significant reduction in joint space narrowing at 2 yr. All groups showed reduced knee pain. None of the treatment groups showed significant symptomatic benefit above placebo. There was high heterogeneity among trials. Glucosamine hydrochloride was not effective. Among trials with industry involvement, ESs were consistently higher. There was no difference with glucosamine in comparison with placebo using WOMAC scores. Compared with placebo, glucosamine, chondroitin, and their combination did not reduce joint pain or have an impact on joint space narrowing. ASUs, chondroitin, diacerein, glucosamine, and intra-articular HA treatments should be considered of uncertain appropriateness for OA. The authors do not recommend glucosamine and/ or chondroitin and HA. The authors cannot recommend using glucosamine and chondroitin for patients with symptomatic OA of the knee. They are unable to recommend for or against the use of intra-articular corticosteroids for patients with symptomatic OA of the knee. They indicate that a strong recommendation should be followed unless a clear and compelling rationale for an alternative approach is present. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with OA of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate to severe knee pain. Symptomatic benefit of chondroitin is minimal or nonexistent. Diacerein is safe and effective for the treatment of knee OA and has a long carryover effect.
Diacerein may be an alternative therapy for OA in patients who cannot take acetaminophen (paracetamol) or NSAIDs because of adverse effects or lack of benefit. However, it is associated with increased risk of diarrhea. Therapy with diacerein was well tolerated, and only 5.44% of the patients had an adverse event after treatment. Over the 12-wk study period, diacerein provided a significant and sustained reduction in VAS pain scores. Diacerein was as effective as piroxicam in reducing pain and improving function but, unlike piroxicam, displayed a carryover effect and a better safety profile. Treatment with diacerein for 3 yr has a significant structure-modifying effect as compared with placebo. There is evidence of the symptomatic efficacy of diacerein in the treatment of knee and hip OA. (continued)
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Table 2. Continued No. of Patients 2,210
Study Design Meta-analysis
Follow-up NR
Level of Evidence I
Ernst,19 2003
NR
Systematic review
NR
IV
Pavelka et al.,20 2010 Maheu et al.,21 2014
364
Comparative study
8 mo
III
399
3 yr
I
Aggarwal and Sempowski,22 2004
13 randomized controlled trials
Prospective, randomized, double blind, parallel group, placebo controlled Review
NR
IV
Bannuru et al.,23 2011
7,545
Meta-analysis
NR
I
Wang et al.,24 2004
NR
Meta-analysis
NR
II
Rutjes et al.,25 2012
12,667
Meta-analysis
NR
I
Miller and Block,26 2013
4,866
Meta-analysis
NR
I
Bellamy et al.,27 2006
NR
Systematic review
NR
IV
Article Fidelix et al.,18 2014
Conclusion Symptomatic benefit provided by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip. Most rigorous trial data available to date suggest that ASUs are effective for the symptomatic treatment of OA. The first direct comparison between ASUs and chondroitin sulfate showed no difference. ASUs reduce the percentage of joint space narrowing, indicating a potential structuremodifying effect in hip OA Viscosupplementation with highemolecular weight HA is an effective treatment for patients with knee OA who have ongoing pain or are unable to tolerate conservative treatment or joint replacement. HA is efficacious by 4 wk, reaches its peak effectiveness at 8 wk, and exerts a residual detectable effect at 24 wk. On the other hand, the peak ES (0.46; 95% CI, 0.28 to 0.65) is greater than published effects from other OA analgesics (acetaminophen [ES, 0.13; 95% CI, 0.04 to 0.22]; NSAIDs [ES, 0.29; 95% CI, 0.22 to 0.35]; and COX-2 inhibitors [ES, 0.44; 95% CI, 0.33 to 0.55]). The therapeutic efficacy and safety of intraarticular injection of HA for the treatment of OA of the knee were confirmed. In OA, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk of serious adverse events. Intra-articular injection of United Stateseapproved HA products is safe and efficacious in patients with symptomatic knee OA. Viscosupplementation is an effective treatment for OA of the knee with beneficial effects on pain, function, and patient global assessment, especially at 5 to 13 wk.
ASUs, avocado/soybean unsaponifiables; CI, confidence interval; COX-2, cyclooxygenase 2; ES, effect size; HA, hyaluronic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
showed that it was not possible to confirm the safety of glucosamine mainly in patients with impaired glucose tolerance or insulin resistance and indicated that more studies would be necessary to establish its safety.32 Glucosamine is derived from the exoskeleton of shellfish. There is concern about reactions in persons allergic to shellfish. However, seafood allergies are caused by antigens in its meat (not the shell), and there have been no reports of reactions in persons with shellfish allergies who take glucosamine.33 Chondroitin Chondroitin sulfate is a major component of aggrecan, which is part of the cartilage ultrastructure.34 It is
often derived from animal sources, such as shark cartilage (chondroitin 4-sulfate) and porcine cartilage (chondroitin 6-sulfate).35 It may be ingested in isolation or combined with glucosamine sulfate. As is the case for glucosamine, understanding of the mechanism of action of chondroitin is incomplete; however, in vitro studies have shown anti-inflammatory, anticatabolic, antiapoptotic, and antioxidant effects.34,35 Animal studies suggest that the combination of glucosamine and chondroitin is better than glucosamine alone.36 However, there is no evidence that the same occurs in humans.10 The literature shows a great divergence in results regarding the clinical benefit of chondroitin sulfate.7 A
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high degree of heterogeneity in addition to the small number and poor quality of the included trials in 1 meta-analysis made a definitive assessment difficult.11 Reichenbach et al.11 showed a small effect size for pain relief (i.e., 0.01 [95% CI, 0.07 to 0.13]). The OARSI consensus classified chondroitin sulfate use as “uncertain” in clinical practice and as “not appropriate” for disease modification.7 The latest AAOS guideline recommends against chondroitin use in clinical terms.9 Diacerein Diacerein is a disease-modifying drug for the treatment of OA with interleukin (IL) 1 inhibitory properties. Boileau et al.37 investigated the effects of diacerein on degenerated subchondral bone and concluded that diacerein reduced, in a dose-dependent manner, the IL1einduced matrix metalloproteinase (MMP) 13 production. Diacerein belongs to the anthraquinone chemical class and may be taken orally twice daily as 50-mg tablets. It has a half-life of 7 to 8 hours and renal elimination.12 Bartels et al.,13 in an SR with 1,533 patients, found a significant improvement in function but noted a questionable clinical effect in trials with follow-up periods longer than 6 months. Sharma et al.14 evaluated 7,923 patients with knee OA in an open-label, multicenter postmarketing surveillance study and showed that after 12 weeks’ follow-up, 85.5% of cases treated by diacerein were rated as good or very good. Therapy with diacerein was reported to be well tolerated, and only 5.44% of the patients had adverse events after treatment, the most common being diarrhea (2.3%). Pavelka et al.12 reported the superiority of diacerein over placebo regarding WOMAC scores (P < .0001) at month 5 (2 months after the end of treatment), showing the drug carryover effect. Favorable outcomes in pain scores (P ¼ .001) and WOMAC scores (P ¼ .0021) were already evident in month 2 and month 1, respectively. Louthrenoo et al.15 carried out an RCT, piroxicam controlled, in which 161 patients were evaluated for 24 weeks (16 weeks of treatment with diacerein, 100 mg/d, or piroxicam, 20 mg/d, followed by 8 weeks of observation). Pain decreased to a similar level in both groups at week 16. Pain increased in the piroxicam group at weeks 20 and 24, whereas improvements persisted in the diacerein group, showing the carryover effects of the drug. The ECHODIAH (Evaluation of the Chondromodulating Effect of Diacerein in Osteoarthritis of the Hip) study evaluated the structure-modifying effects of diacerein in patients with primary hip OA with a 3-year follow-up.16 The percentage of patients with radiographic progression was significantly lower in the group taking diacerein compared with the placebo group.
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Rintelen et al.17 in an SR reported that diacerein and nonsteroidal anti-inflammatory drugs (NSAIDs) were superior to placebo during treatment. However, diacerein but not NSAIDs showed a carryover effect, persisting up to 3 months after treatment, with a significant analgesic-sparing effect during the follow-up period. A Cochrane SR pointed out low-quality evidence in 6 trials (1,283 participants), indicating that diacerein had a small effect on overall pain (visual analog scale) at 3 to 36 months.18 No difference in physical function (4 studies, 1,006 participants) was perceived between the diacerein and placebo groups. Two trials with lowquality evidence (616 participants) analyzed knee or hip joint space narrowing. The results favored diacerein over placebo when both joints were studied together but not when the knee was studied alone (1 study, 170 participants). Seven trials with low-quality evidence comparing diacerein with placebo showed more adverse events, mostly diarrhea, in the diacerein group after 2 to 36 months. There was no difference in dropout rates because of adverse events between the groups. Avocado/Soybean Unsaponifiables Avocado/soybean unsaponifiables (ASUs) display anabolic, anticatabolic, and anti-inflammatory effects on chondrocytes; increase collagen synthesis; and inhibit spontaneous and IL-1beinduced collagenase activity.19 They also increase aggrecan synthesis and reverse the IL-1b effect.19 Apparently, ASUs reduce the spontaneous and IL-1beinduced production of MMP-3, IL-6, IL-8, and prostaglandin E2 (PGE2). Four RCTs and 1 SR evaluated the effect of ASUs on knee and hip OA. ASUs (300 mg once a day) decreased NSAID intake in 3 trials after 3 months of follow-up. No difference in primary or secondary endpoints was perceived with a 300- versus 600-mg dosage. In a 6month trial, ASUs resulted in more symptom relief than placebo. ASUs had a 2-month delayed onset of action and a carryover effect after 2 months of treatment.38 An SR did not show a long-term (>1 year) symptom-modifying effect of ASUs on knee and hip OA.19 One study showed that ASUs decreased the spontaneous production of nitric oxide and macrophage inflammatory protein 1b and stimulated the expression of transforming growth factor b and plasminogen activator inhibitor 1, which could diminish MMP activation.19 Henrotin et al.39 compared the effects of avocado unsaponifiables (A), soybean unsaponifiables (S), and 3 mixtures of ASUs (A1S2 [Piascledine, Laboratoires Expanscience, Epernon, France], A2S1, and A1S1, with respective ratios of 1:2, 2:1, and 1:1). All mixtures reduced spontaneous production of IL-6e, IL-8e, PGE2e, and IL-1beinduced production of PGE2. A1S2 and A1S1 reduced IL-1beinduced production of
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MMP-3 and collagenase activity. Only Piascledine inhibited collagenase activity. Pavelka et al.20 compared ASUs and chondroitin sulfate in knee OA. Three hundred sixty-one patients were enrolled, and there was no difference between the groups after a 6-month follow-up period. The study by Maheu et al.21 enrolled 399 patients with symptomatic hip OA. After 3 years, ASUs decreased joint space narrowing in the treated group, indicating a potential structure-modifying effect of ASUs on hip OA. Viscosupplementation HA is a polysaccharide composed of glucosamine and glucuronic acid, which exists in the normal synovial fluid.40 It was first used in ophthalmology for cataract surgery in the 1970s.22 Since the 1980s, its intraarticular use gained popularity in Europe and, afterward, in the United States.22 In osteoarthritic joints, the synovial fluid becomes less viscous and less concentrated with a lower molecular weight, which leads to less shock absorption, lubrication, and protection of joints.40,41 HA’s suggested mechanisms of action are inhibiting inflammatory mediators, decreasing cartilage degradation, and promoting cartilage matrix synthesis.41 Other possible mechanisms of action include control of synovial permeability, blockade of inflammation by scavenging oxygen free radicals, and inhibition of MMP.41 In an SR about HA’s effect in knee OA, 49 trials (6,962 patients) were included in the meta-analysis for pain-related outcomes.23 The effect size favored HA by week 4 (0.31; 95% CI, 0.17 to 0.45), reaching a peak at week 8 (0.46; 95% CI, 0.28 to 0.65), and then trended downward, with a residual detectable effect at week 24 (0.21; 95% CI, 0.10 to 0.31). Sixteen trials (2,571 patients) were included in the meta-analysis for functionrelated outcomes, favoring HA with an effect size of 0.31 (95% CI, 0.11 to 0.51) but with great heterogeneity among trials. Regarding joint stiffness, 15 trials (2,488 patients) were included in the meta-analysis, showing an effect size of 0.31 favoring HA (95% CI, 0.12 to 0.49). In another SR, HA treatment was effective except in patients with severe or complete loss of knee joint space.24 Rutjes et al.25 studied HA’s effect on knee OA in 89 trials with 12,667 patients. After exclusion of studies with methodologic flaws, they showed minimal effects on pain relief or on functional improvement in patients treated by HA. Considering the OARSI guideline, they estimated that the effect size for pain relief ranged from 0.37 to 0.46 and that for functional improvement ranged from 0.31 to 0.33. Indeed, the degree of recommendation for HA was considered “uncertain” for knee OA and “not appropriate” for multiple-joint OA.25 The first AAOS guideline did not define the role of intra-articular HA for patients with mild to moderate
symptomatic OA of the knee.8 This recommendation was based on 6 SRs and 1 RCT. The conclusion was that viscosupplementation showed positive effects but these results could have been influenced by trial quality, potential publication bias, and unclear clinical significance. However, the latest guideline of the AAOS recommended against routine use of HA for knee OA.9 A recent SR questioned the latest AAOS recommendation, arguing that the inclusion criteria of the RCT were not fully demonstrated, only 14 RCTs were included, and the definition of the efficacy criteria was not clear.26 Moreover, a 2006 Cochrane SR (updated in 2014) showed that HA is an effective treatment for knee OA regarding pain, joint function, and patient global assessment.27 Clinical improvement was more evident between week 5 and week 13. Compared with intra-articular corticosteroid or placebo treatments, HA provided better results regarding expected effect duration. Concerns about HA adverse events were raised recently, mainly by 1 RCT, in which the authors described serious adverse events in the gastrointestinal, cardiovascular, and musculoskeletal systems, besides cancer.25 However, bias regarding the study selection criteria in the former SR must be mentioned.42 In another SR the risk of moderate or serious adverse events was not higher in the HA group when compared with the sham group.26 Adverse side effects tended to be minor, such as injection-site pain and swelling; systemic reactions were rare.43
Discussion Nutraceuticals and viscosupplementation have been extensively used in conservative treatment of OA. This may be because of the low incidence of adverse effects and the chronic course of the disease. OARSI recommendations for OA treatment have established that the effect size for pain relief from HA, glucosamine sulfate, chondroitin sulfate, and ASUs diminished during treatment even though there was heterogeneity of outcomes and evidence of publication bias.44 They also reported a progressive reduction of clinical effects with time that may be due to worsening of OA and external factors, such as noncompliance and medication interruption. Literature concerning glucosamine and chondroitin in OA management states that glucosamine hydrochloride has no effect on pain. The sulfate formulation has a moderate effect size, but studies about this subject have had marked heterogeneity. Moreover, trials not funded by industry have had null results. The AAOS guideline does not recommend these drugs in OA treatment. Animal studies suggest that the combination of glucosamine and chondroitin is better than glucosamine alone, but there is no clinical study that confirms such an assertion.
NONSURGICAL TREATMENT OF OSTEOARTHRITIS
The literature considers that diacerein leads to pain relief, with a superior carryover effect when compared with placebo.16,18 One study showed slowing of radiographic progression in hip OA, but similar results were not presented in knee OA.16 ASUs are supposed to modify the effects on knee and hip OA, but as is the case for the other nutraceuticals, their effects in the long-term (>1 year) have not been confirmed.19 The role of viscosupplementation in OA treatment is difficult to interpret because of heterogeneity in clinical trials. Despite the latest recommendation of the AAOS against the use of HA, some SRs showed that patients with knee OA could benefit from HA use.7,24,27,44 Limitations The limitations of our study were as follows: heterogeneity of trials, sponsorship bias, short follow-up, and subjective factors inherent to the primary outcome tested (pain). As a result, different SRs came to divergent conclusions on the same subject, impairing a final and clear conclusion regarding the safety and efficacy of nutraceuticals. Further nutraceutical and viscosupplementation RCTs must address those limitations.
Conclusions On the basis of the available data, there is no evidence that nutraceuticals or viscosupplementation influences OA’s natural progression. However, some of these agents seem to interfere in pain relief and function.
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