Is there evidence supporting the use of oral diacerein and glucosamine tablets for osteoarthritis?

Evidence for Diacerein and Glucosamine in Osteoarthritis

Direct Recommendation

Do not use glucosamine or diacerein for osteoarthritis of the knee or hip—the American College of Rheumatology strongly recommends against both agents based on lack of clinically meaningful benefit over placebo. 1, 2

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Glucosamine: Strong Evidence Against Use

Current Guideline Position

• The American College of Rheumatology issues a strong recommendation against glucosamine sulphate for knee, hip, and hand osteoarthritis because contemporary analyses show no clinically meaningful benefit over placebo. 1
• This represents a significant shift from older 2007 EULAR guidelines that suggested potential benefit, but those conclusions have been superseded by more rigorous systematic reviews. 1, 2

Why the Evidence Changed

• Publication bias is the critical issue: Industry-funded trials reported efficacy, whereas publicly-funded, low-bias studies consistently failed to demonstrate benefit beyond placebo. 1, 2
• When limited to pharmaceutical-grade glucosamine preparations from low-bias trials, effect sizes are predominantly placebo-driven with no clinically relevant advantage. 1, 2
• No biologically plausible mechanism explains why different glucosamine salt formulations would have varying efficacy, undermining claims of superiority for any specific product. 1, 2

What Older Studies Showed (Now Outdated)

• A 2001 Cochrane review found glucosamine superior to placebo in 12 of 13 trials, but most evaluated only the Rotta preparation and included high-risk-of-bias, industry-sponsored studies. 3
• The 2007 EULAR guidelines suggested glucosamine sulphate was effective for knee pain relief (effect size 0.44), but this evidence is no longer considered valid. 4

Safety Profile

• Glucosamine has mild and infrequent adverse effects, making it safer than long-term NSAID therapy. 1, 2
• Some patients may experience elevations in serum glucose levels, warranting caution in individuals with diabetes or glucose metabolism disorders. 1, 2

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Diacerein: Unfavorable Benefit-Risk Profile

Current Guideline Position

• Multiple 2023 clinical practice guidelines recommend against diacerein for knee and hip osteoarthritis, citing an unfavorable benefit-to-risk profile and only modest symptomatic advantage. 1
• In patients with severe (Kellgren-Lawrence grade IV) osteoarthritis, diacerein lacks efficacy, with any potential benefit limited to mild-to-moderate disease. 1

What the Evidence Shows

• A 2006 meta-analysis of 19 randomized controlled trials found diacerein superior to placebo during active treatment (Glass score 1.50), with efficacy similar to NSAIDs and a carryover effect persisting up to 3 months after treatment cessation. 5
• However, a large multicentre RCT with 507 hip OA patients showed diacerein had no more pain relief or functional improvement than placebo over 3 years (effect size 0.00 for both outcomes). 4
• The 2007 EULAR guidelines concluded there is no direct evidence to support clinical benefits of diacerein in hip OA. 4

Adverse Effects

• Diacerein causes a significant increase in diarrhea (relative risk 3.73) and skin rash or pruritus (relative risk 2.40). 4
• Gastrointestinal disorders such as soft stools and diarrhea are common, along with mild skin reactions and uncommonly hepatobiliary disorders. 6

Combination Therapy Does Not Help

• A 2016 double-blind RCT of 148 patients found that combining diacerein with glucosamine provided no additional benefit over glucosamine alone for pain (mean difference 0.09,95% CI -0.75 to 0.94) or WOMAC scores at 24 weeks. 7

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The One Exception: Chondroitin for Hand Osteoarthritis Only

Chondroitin sulfate (800-1200 mg daily) may be conditionally recommended only for hand osteoarthritis, based on a single well-performed trial demonstrating symptomatic benefit. 1, 8

• The 2018 EULAR guidelines suggest chondroitin sulfate may be used in hand OA patients for pain relief and improvement in functioning. 4
• However, the American College of Rheumatology strongly recommends against chondroitin sulfate for knee and hip OA, as clinically meaningful effects have not been proven in these joints. 2, 8
• No placebo-controlled trials of glucosamine have been performed specifically in hand OA patients. 4, 2

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Critical Pitfalls to Avoid

Do Not Rely on Outdated Evidence

• Do not use pre-2010 systematic reviews that included high-risk-of-bias, industry-sponsored glucosamine trials when making treatment decisions. 1, 2
• The 2007 EULAR recommendations suggesting benefit have been superseded by more rigorous contemporary analysis. 1, 2

Do Not Extrapolate Across Joint Sites

• Do not extrapolate efficacy data from knee osteoarthritis studies to the hip or hand joints, as evidence for those sites is sparse and unconvincing. 1, 2
• Data specific to hip OA are particularly limited, with most trials focused on knee OA. 4

Do Not Prescribe for Disease Modification

• Do not prescribe glucosamine or diacerein with the expectation of structural improvement, because no clinically relevant disease-modifying benefit has been established. 4, 1
• The task force agreed that at this moment no drugs are available with disease-modifying properties for OA. 4

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Evidence-Based Alternatives for Osteoarthritis Pain

First-Line Pharmacologic Therapy

• Acetaminophen (≤4 g/day) is recommended as first-line pharmacologic therapy for knee and hip osteoarthritis pain, although its analgesic effect is modest. 1, 2
• Topical NSAIDs are recommended for localized pain relief as first-line approaches, particularly for hand OA. 8

Second-Line Options

• Oral NSAIDs at the lowest effective dose for the shortest duration should be used when acetaminophen provides insufficient relief, after thorough discussion of gastrointestinal, cardiovascular, and renal risks. 4, 1
• Tramadol (with or without acetaminophen) is an appropriate alternative for patients in whom NSAIDs are contraindicated. 4, 1

For Hand Osteoarthritis Specifically

• Intra-articular corticosteroid injections may be considered for painful interphalangeal joints, though they should not generally be used in thumb base OA. 4, 8
• Surgical options (arthrodesis for distal interphalangeal joints, arthroplasty for proximal interphalangeal joints) should be considered when other treatments have failed. 4, 8