Glucosamine supplements are available in three different salt forms: glucosamine sulfate, glucosamine hydrochloride, and N-acetyl glucosamine. The glucosamine base used in supplements has most commonly been derived from the exoskeletons of shellfish, such as shrimp, lobster, and crabs. However, glucosamine can also be created synthetically or obtained from Aspergillus or fermented corn [1].

N-acetyl glucosamine, the acetylated derivative of glucosamine, is the least common form found in supplements. This form of glucosamine has not been extensively studied in clinical research; most of the evidence around the use of glucosamine supplements is for the sulfate and hydrochloride salts [5].

Most research has focused on the use of oral glucosamine sulfate for the management of knee osteoarthritis. A very limited amount of research has been conducted in hip and spine osteoarthritis, with inconclusive findings [7].

When used for knee osteoarthritis, meta-analyses of the available research show that taking glucosamine sulfate 1,500 mg daily for up to three years modestly improves pain and function when compared with placebo. Individual studies have shown a 28% to 41% pain reduction and 21% to 46% improvement in function [3,8,9,10,11,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

Small studies comparing glucosamine sulfate with nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen 400 mg three times daily or piroxicam 20 mg daily, suggest that these treatments provide similar benefit. However, NSAIDs appear to relieve symptoms within two weeks, whereas glucosamine sulfate can take four to eight weeks [12,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

To date, the most consistent positive evidence for glucosamine sulfate has been seen with Dona, a specific crystalline glucosamine sulfate product that has been sold as a prescription in some countries and is thus often referred to as "pharmaceutical-grade." In fact, some studies with this product have shown that it can prevent joint space narrowing of greater than 0.5 mm by up to 54% when compared with placebo. Studies using other glucosamine sulfate products have yielded conflicting findings related to disease progression [1,13,15].

In contrast to the generally positive findings related to the use of glucosamine sulfate for knee osteoarthritis, glucosamine hydrochloride has shown no real benefit in clinical research.

A meta-analysis of the available research shows that taking glucosamine hydrochloride 1,500 mg daily for up to 18 months does not seem to reduce pain when compared with placebo. Research on the use of glucosamine hydrochloride in combination with chondroitin sulfate has yielded conflicting findings. Some research has found that taking this combination is non-inferior to celecoxib 200 mg daily for relieving pain, but not for improving stiffness or function. Other research has shown no benefit. It is possible that any benefit identified from this combination may be due to chondroitin sulfate [15,24,31,32,33,34].

Although the research indicates that glucosamine hydrochloride is less effective than glucosamine sulfate for the management of knee osteoarthritis, head-to-head trials comparing these two salt forms are lacking. It has been proposed that the bioavailability of glucosamine from glucosamine hydrochloride may be reduced in comparison to pharmaceutical-grade crystalline glucosamine sulfate, but more research is needed to confirm [15,24,31,32,33,34].

Chondroitin sulfate, when taken alone, has demonstrated modest benefit for reducing pain and improving function in some patients with knee osteoarthritis. Meta-analyses of the available research show that taking chondroitin sulfate 800–2,000 mg in single or divided doses daily for at least three months can modestly reduce pain and disability when compared with placebo [11,22,23,30,35,36,37,38,39,40,41,42,43,44,45,46]. Some research has suggested that the number needed to treat for one patient to experience at least a 20% reduction in pain may be as high as 16.

The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine or chondroitin products for any form of osteoarthritis. The European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade glucosamine sulfate or chondroitin sulfate products in patients with osteoarthritis. The ESCEO also provides a weak recommendation against the use of glucosamine and chondroitin in combination [52,53].

These conflicting recommendations are related to differing interpretations of the previously discussed evidence. The ACR has determined that the positive benefits identified in industry-funded studies evaluating pharmaceutical-grade products, as opposed to the conflicting findings identified with other products, indicates the introduction of industry bias [52].

The ESCEO, on the other hand, has determined that the positive benefits identified in industry-funded studies evaluating pharmaceutical-grade products is due to the higher quality and bioavailability of the products used [1,53].

Glucosamine is commonly derived from the exoskeletons of shrimp, lobster, and crabs. Thus, there is concern that the risk for hypersensitivity reactions to glucosamine may be greater in those with shellfish allergy [1].

Shellfish allergies are caused by IgE-mediated reactions to antigens found in shellfish meat, not the exoskeleton. However, it is possible that allergen contamination can occur during manufacturing. Until more is known, use glucosamine with caution in these patients [1].

Chondroitin sulfate has been evaluated extensively in clinical research, with limited reports of adverse effects. When used in a dose of up to 2,000 mg daily for up to six years, it appears to be safe for most adults [61].

The most frequently reported adverse effects include abdominal pain, bloating, constipation, diarrhea, heartburn, and nausea.