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Guideline for the management of knee and hip osteoarthritis

Recommendations

Nutraceuticals

Guideline for the management of knee and hip osteoarthritis
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  3. Figures and tables
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Last revised: 01 Jul 2018

Herbal therapies, supplements and nutraceuticals

Nutraceuticals


 

Glucosamine – Knee and/or hip

Recommendation

We suggest not offering glucosamine for people with knee and/or hip osteoarthritis (OA).

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low (knee)
Low (hip)

What is it? 

Glucosamine is a naturally produced sugar by the body, and one of the building blocks of cartilage. It comes in two forms – glucosamine sulfate and hydrochloride, and the usual dose is 1500 mg daily. Glucosamine supplements are usually made from crab, lobster or shrimp shells, although some supplements are made from a plant form of glucosamine. These are available as tablets or liquid, and often in combination with chondroitin. 

Rationale 

Overall, there is very low-quality evidence from a large number of randomised controlled trials (RCTs) that found that glucosamine provides some benefits to pain in the short term, but no apparent benefits to function, quality of life or joint space narrowing. When the studies are restricted to higher quality trials, no benefit is demonstrated. There is only one RCT on the effect on hip OA, which failed to demonstrate a benefit. 

The working group discussed the concerns in the literature of publication bias, effects being driven by small industry-sponsored trials, and the overall poor quality of the positive trials. Larger publicly funded trials generally demonstrate no effect over placebo. In the context of high-quality trial data that suggest no effect, the working group decided on a conditional against recommendation to increase awareness of the unlikely benefit of glucosamine and chondroitin. This discussion occurred in the context of the costs associated with ongoing supplement use, competing treatment priorities where this might be prioritised over more effective interventions, and the possible influence of direct-to-consumer marketing of supplements. If someone who is taking glucosamine or chondroitin is feeling marked symptomatic benefit as a consequence of its consumption, it is appropriate not to discourage whatever placebo effects may come from use of these supplements. 

Harms 

Overall, there was a low risk of adverse effects reported in the trials. Shellfish allergy and interactions with warfarin and diabetes are of concern, and trials are likely to have excluded participants with those conditions more carefully than usual practice (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document).

Chondroitin – Knee and/or hip

Recommendation

We suggest not offering chondroitin for people with knee and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low

What is it? 

Chondroitin is a component of connective tissues and bone, which is believed to help draw water and nutrients into the cartilage, keeping it spongy and healthy. Chondroitin is available as chondroitin sulfate supplements, which are made from bovine (cow) or shark cartilage. The usual dose is 800–1200 mg daily as a tablet, capsule or powder. 

Rationale 

There are a large number of trials on the use of chondroitin (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document), where at least seven are industry sponsored. When all 16 studies are pooled, there is a clinically and statistically significant effect on pain and function in the short term (up to three months), which lessens to clinically not significant by six to 12 months, and no effect is demonstrated at 24 months. However, when the analysis is restricted to studies of higher quality or free of industry sponsorship, no benefit is demonstrated.

There are some moderate-term to long-term (12–24 months) benefits on joint space narrowing, but these are not clinically meaningful (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The studies are all on participants with knee OA, so extrapolation to OA of hip or other joints requires further caution. 

The working group discussed the concerns in the literature of publication bias, effects being driven by small industry-sponsored trials, and the overall poor quality of the positive trials. In the context of high-quality trial data that suggest no effect, the working group decided on a conditional against recommendation to increase awareness of the unlikely benefit of widespread use of glucosamine and chondroitin. This discussion occurred in the context of the costs associated with ongoing supplement use, competing treatment priorities where this might be prioritised over more effective interventions, and current use as a consequence of direct-to-consumer marketing that may be inconsistent with the scientific evidence. If someone who is taking glucosamine or chondroitin is feeling marked symptomatic benefit as a consequence of its consumption, it is appropriate not to discourage whatever placebo effects may come from use of these supplements.

Harms

Pooled data from six trials with more than 1000 participants found that the risk of adverse events is comparable to placebo 

Glucosamine and chondroitin in compound form – Knee and/or hip

Recommendation

We suggest not offering glucosamine and chondroitin in compound form for people with knee and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low

What is it? 

Glucosamine and chondroitin are often marketed in a combination at the same doses as individual components. There does not appear to be any beneficial drug–drug synergistic interaction. 

Rationale 

With pooling (where possible) of results from the nine available RCTs, no benefit for pain, function or joint space narrowing was demonstrated. Participants in all trials had knee OA, so extrapolation to hip OA needs additional caution (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document)

The working group discussed the concerns in the literature of publication bias, effects being driven by small industry-sponsored trials, and the overall poor quality of the positive trials. In the context of high-quality trial data that suggest no effect, the working group decided on a conditional against recommendation to increase awareness of the unlikely benefit of widespread use of glucosamine and chondroitin. This discussion occurred in the context of the costs associated with ongoing supplement use, competing treatment priorities where this might be prioritised over more effective interventions, and current use as a consequence of direct-to-consumer marketing which may be inconsistent with the scientific evidence. If someone who is taking glucosamine or chondroitin is feeling marked symptomatic benefit as a consequence of its consumption, it is appropriate not to discourage whatever placebo effects may come from use of these supplements. 

Harms 

As with the individual components, the reported rates of adverse events were similar to placebo.

Vitamin D – Knee and/or hip

Recommendation

We suggest not offering vitamin D for people with knee  and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Low (knee)
Very low (hip

What is it?

Vitamin D is a hormone that controls calcium levels in the blood, which is crucial for bone, cartilage and muscle development. Oral supplementation with vitamin D is readily available. In the studies analysed, a daily dose of 800–2000 IU, or a monthly dose of 50,000–60,000 IU, were used.

Rationale 

There were four RCTs (one to three years’ duration), all without serious risk of bias. However, there was very serious inconsistent results, leading to low-quality evidence. When combined, there is a suggestion of a favourable effect, statistically significant but not reaching what was regarded as clinical significance (standardised mean difference [SMD] >0.4). The results for function were similar to the effect estimates. There was no evidence of favourable structural effects on cartilage volume or joint space narrowing. Notably, one study in participants who were vitamin D deficient also failed to show clinically meaningful beneficial effects (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). Participants in all studies had knee OA, so extrapolation to OA of hip or other joints requires additional caution.

Harms 

Vitamin D is relatively safe; however, there is a non-statistically significant increase in hypercalciuria. There is no clinical effect or safety concern.

Omega-3 fatty acids – Knee and/or hip

Recommendation

We suggest not offering omega-3 fatty acids for people with knee and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low

What is it? 

Omega-3 polyunsaturated fatty acids are mainly produced by marine organisms (eg oil from whole fish, seal, mussels). This is widely available, and the usage is generally varied by region and disease (usual dose is 1–2 g/day). 

Rationale 

Pooled data from five RCTs (15–26 weeks) demonstrated no benefits on pain and function in people with hip and knee OA. Three studies received at least one high risk of bias. Most trials used marine oil from whole fish, but some used cod liver oil and mussel extracts. High heterogeneity was expected from pooling different sources of omega-3 fatty acids, and measures within each outcome (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The optimal type of omega-3 fatty acids could not be established in OA because only a few trials included marine oil from sources other than whole fish. There are high variations in doses of eicosapentaenoic acid (EPA; 0.01–1.7 g/day), and doses of docosahexaenoic acid (DHA; 0.01–1.10 g/day). 

A controlled trial that was not included found no additional benefit of high dose fish oil (4.5 g/day), compared with low dose fish oil (0.45 g/day). 

Harms 

Side effects are usually minor and uncommon.

Collagen – Knee and/or hip

Recommendation

We are unable to recommend either for or against the use of collagen for people with knee and/or hip OA.

Strength of recommendation

Conditional (neutral) recommendation

Quality of evidence

Low (knee)
Very low (hip)

What is it?

There are many types of collagen and collagen-related derivatives, which can be extracted from chicken cartilage, pork skin and bovine bone. These are sometimes available in hydrolysed form to help absorption and distribution to joint tissues. There is insufficient research to recommend a particular dose. 

Rationale 

Pooled results from six studies found short-term (13–26 weeks) clinical benefits in pain; however, there have been very serious inconsistent results across the studies (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document).

Available data from four studies found no effect in function. All of the studies were conducted in knee OA, so extrapolation to hip or other OA requires additional caution.
The working group discussed the concerns in the literature of publication bias, effects being mostly driven by industrysponsored trials, and the overall poor quality of the positive trials. 

Harms 

Collagen use is relatively safe; however, there is a non-statistically significant increase in adverse gastrointestinal events.

Methylsulfonylmethane (MSM) – Knee and/or hip

Recommendation

We are unable to recommend either for or against the use of MSM for people with knee and/or hip OA.

Strength of recommendation

Conditional (neutral) recommendation

Quality of evidence

Very low

What is it? 

MSM is an organosulfur molecule that can be synthesised commercially from dimethylsulfoxide (DMSO). DMSO is a pungent solvent that has been used as an application for pain relief over arthritic joints. MSM has the advantage of being odourless, and can be easily taken orally in the form of a pill or a powder. The optimal dosing of MSM is not known, but 1–2 g twice a day is often offered in clinical practice.

Rationale 

There are three trials with short study durations (12–13 weeks), and pooled data found statistically and clinically significant benefits in pain. Even larger effects were found in function, but with very serious inconsistent results and high heterogeneity across studies. One trial had a high risk of bias because of inappropriate randomisation technique; while the other had potential reporting bias (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The doses in the trials ranged from 1.5–6 g/day for 12 weeks. All of the studies were conducted in knee OA, so extrapolation to hip or other OA sites requires additional caution. 

The working group discussed the concerns in the literature of publication bias, effects being mostly driven by industrysponsored trials, and the overall poor quality of the positive trials. 

Harms 

The use of MSM for OA is relatively safe. Minor side effects were recorded, including gastrointestinal adverse events, fatigue and headaches; however, these were not statistically significant compared with placebo.

Diacerein – Knee and/or hip

Recommendation

We suggest not offering diacerein for people with knee and/or hip OA.

Strength of recommendation

Conditional against recommendation

Quality of evidence

Very low

What is it?

Diacerein is purified compound with an anthraquinone structure that interferes with pro-inflammatory interleukin-1 (IL-1) and the secretion of metalloproteinases, without affecting the synthesis of prostaglandins. It is widely available on prescription in Europe, but not available in Australia. The dose used in the trials was 50 mg twice a day.

Rationale 

Five trials were included, with time durations ranging from eight weeks to 12 months, all receiving high risk of bias because of weak allocation concealment and random sequence generation. Very low-quality evidence from four trials indicated a small clinical benefit on pain reduction. Data from five trials indicated statistically significant effects on function, but this did not reach the clinically meaningful threshold. Analysis of one study demonstrated no benefit in reducing joint space narrowing (Appendix 5 of the Guideline for the management of knee and hip osteoarthritis: Technical document). The working group discussed the concerns in the literature of publication bias, effects being mostly driven by industrysponsored trials, and the overall poor quality of the positive trials.

A search of regulatory websites found a recommendation from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) that the marketing authorisation of diacerein should be suspended across Europe because of harms (particularly the risk of severe diarrhoea and potentially harmful effects on the liver) outweighing benefits. However, this guidance is not final as the PRAC recommendation will be re-examined. All of the studies were conducted in knee OA, so extrapolation to hip or other OA sites requires additional caution. 

Harms 

Adverse events were significantly increased after using diacerein, mainly diarrhoea (relative risk [RR]: 3.50; 95% confidence interval [CI]: 1.95, 6.27). There is an increase in rash, but the between-group difference was not significant.

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