Effectiveness and Safety of Glucosamine in the Treatment of Osteoarthritis
Rana Makhous
Department of Pharmacology, College of Pharmacy, Al-Andalus University. Syria.
*Corresponding Author E-mail: ranamakhous@gmail.com
ABSTRACT:
There is a lot of controversy about the effect of glucosamine in the treatment of osteoarthritis and prevention of its progression, and there are always questions: is glucosamine effective in treatment and prevention of osteoarthritis?, what is the best duration of treatment to give the best efficacy?, Is glucosamine safe?, and is its combination with chondroitin more effective than administration of glucosamine alone?. To perform a systematic review to answer the questions above, we searched the online database, including PUBMED and Google Scholar until data inception February 2017. We found that there are conflicting results about the efficacy of glucosamine, but most of studies showed that it is safe and effective in treatment and prevention of osteoarthritis progression, but it often needs long period to be effective especially for prevention of the progression of the disease (2 years). Several studies found that glucosamine sulfate may is more effective than glucosamine hydrochloride, and its combination with chondroitin is more effective than administration of glucosamine alone especially in improvement of joint function.
KEYWORDS: glucosamine, osteoarthritis, efficacy, treatment, prevention and safety.
INTRODUCTION:
Osteoarthritis (OA) is extremely common and poses tremendous personal, societal, and economic costs. It's a result of both mechanical and biologic events that destabilize the normal coupling of degradation and synthesis of articular cartilage, and subchondral bone1. Key players in the degradation are the matrix metalloproteinases (MMPs) in response to inflammatory mediators present in OA (mainly interleukin-1 and tumor necrosis factor α) . Chondrocytes in OA cartilage undergo apoptosis, likely as a result of induction of nitric oxide and they are hyporesponsive to the anabolic stimulus transforming growth factor β. The net result of all of these processes is that there is a progressive cycle of cartilage destruction and loss of chondrocytes1.
Drugs use in OA are divided into 2 subgroups:
· rapid-acting drugs : analgesics (acetaminophen), nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoids and opioids.
· slow-acting drugs or SYSADOA (Symptomatic Slow Acting Drugs for Osteoarthritis): cartilaginous matrix precursors (glucosamine, chondroitin, and hyaluronic acid) and cytokine modulators (diacerein and metalloprotease inhibitors)2.
SYSADOA offer a slow onset of relief—approximately 2 weeks—and their effects may remain active for as long as 2 months after their omission.
The European Medicines Agency has suggested that at least 6 months of treatment are required for the evaluation of SYSADOA effectiveness for articular pain and 2 years are necessary to assess modifications of articular structures2.
The most commonly used SYSADOA treatment for osteoarthritis is glucosamine, but there is a lot of controversy about its effect in treatment and prevention of osteoarthritis, and we will focus in this review on this compound.
METHODS:
To perform a systematic review, we searched the online database, including PUBMED and Google Scholar until data inception February 2017.
The search term included “glucosamine”, “osteoarthritis”, “efficacy”, “treatment”, “prevention” and “safety”.
Glucosamine:
Glucosamine is precursor molecule which is incorporated by chondrocytes into the components of glycosaminoglycan chains in the cartilage and stimulates the synthesis of physiologic proteoglycans2. Their integrity is important to maintain the strength and elasticity of articular cartilage which confers resistance to mechanical stress2. We can explain the therapeutic effects of glucosamine too by its anti-inflammatory effects, particularly its effects on interlukin-1 (IL-1), by inhibiting its intracellular signaling cascade, and other inflammatory markers like COX-2, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α and IL-6. It inhibits matrix degradation factors, such as metalloproteinase, and inhibits the gene expression of NF-kB. It has pro-anabolic effect, and it promots osteoblast proliferation2,3,4. The main compounds including glucosamine are glucosamine hydrochloride(GH), and glucosamine sulfate (GS)2.
Is glucosamine effective in the treatment of osteoarthritis and prevention of its progression?
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for management of knee osteoarthritis recommends the chronic use of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), in particular prescription glucosamine sulfate(GS) and chondroitin sulfate (CS), as a first-line pharmacological treatment for slow- onset medium to long term control of symptoms5. The 2014 Osteoarthritis Research Society International (OARSI) guideline update gives SYSADOAs an “uncertain” status for pain control6.
The recommendations given by the American College of Rheumatology conditionally do not advocate the use of glucosamine and chondroitin in the treatment of knee OA7. We need to review experimental and clinical studies about efficacy of glucosamine.
Experimental studies:
Wen ZH., et al found that treatment with oral glucosamine sulfate in a rat OA model attenuates the development of OA, reduces nociception, and modulates chondrocyte metabolism8. Naito K, et al found that glucosamine has a potential to exert a chondroprotective action on OA by inhibiting type II collagen degradation and enhancing type II collagen synthesis in the articular cartilage in an experimental OA model induced in the knee joint by anterior cruciate ligament transection9. long-term oral administration of glucosamine inhibited OA progression in a model of spontaneous osteoarthritis (OA) in Hartley guinea pigs10.
chondroitin sulfate plus glucosamine protected against cartilage degradation and reduced the levels of inflammatory mediators such as interleukin-1β and tumor necrosis factor-α in the affected knee in a mouse model of OA induced by anterior cruciate ligament transaction11.
chondroitin and glucosamine sulfate in a rabit model of OA induced by anterior cruciate ligament transection and partial meniscectomy prevented cartilage swelling, but had no effect on cartilage surface, synovial membrane or subchondral bone12.
Roman-Blas JA., et al found that therapies of chondroitin sulfate plus glucosamine sulfate or chondroitin sulfate plus glucosamine hydrochloride failed to improve structural damage or to ameliorate the inflammatory profile of joint tissues during experimental osteoarthritis13. Treatment with glucosamine alone seemed to have no effect in the progression of cartilage pathology in a rabit model of OA induced by anterior cruciate ligament transection and partial medial meniscectom14.
Clinical studies:
There are several clinical studies that compare the efficacy of GH vs GS and the efficacy of glucosamine alone vs its combination with chondroitin Qiu GX., et al found in a multi-central, randomized, parallel-controlled clinical trial of GH vs GS performed in patients suffering from knee OA for 6 weeks a considerable improvement in OA symptoms and a reduce of total Lequesne's score after 4-week treatment. There were no significant differences in efficacy and safety between GH and GS15.
However, several studies have reported that when comparing both formulations, glucosamine sulfate exhibits more favorable results, especially in its crystalline form2. Altman RD found that only prescription patented crystalline glucosamine sulfate pCGS once-daily dose (1500 mg) is with a documented pharmacological effect16.
Wu D., et al found in a meta analysis of randomised, double-blind, placebo-controlled trials that GH is ineffective for pain reduction in patients with knee OA, and GS may have function-modifying effects in patients with knee OA when administered for more than 6 months. However, it showed no pain-reduction benefits after 6 months of therapy17.
The poor bio- availability obtained with GH may help to understand the negative results obtained with this formulation18 .
Studies in osteoarthritic cartilage found that glucosamine sulfate is a stronger inhibitor of gene expression than glucosamine hydrochloride: sufficient sulfur is essential for the synthesis of proteoglycans and other S-containing metabolic intermediates (e.g. coenzyme A, glutathione, etc.) that are important for chondrocyte metabolism2.
Zhang W., et al found that glucosamine sulphate has a similar effect to placebo for pain19.
J. Runhaar., et al found in a study of a total of 407 overweight women with no diagnosis of knee OA but at risk of developing it that glucosamine sulfate1500 mg once daily decreased the risk of developing radiographic knee OA over 2.5 years20.
Towheed TE., et al found that glucosamine sulphate is providing a greater benefit than placebo in the treatment of pain and functional impairment resulting from symptomatic OA21.
In a study comparing the effects of intra-articular injection hyaluronic acid (IAHA) with oral glucosamine sulphate ( GS) for 12 weeks on pain and stiffness and physical function. Both HA and GS significantly reduce pain and stiffness and physical function compared with placebo group22.
Glucosamine plus chondroitin :
Fransen M., et al found a statistically significant reduction in joint space narrowing after two years for a glucosamine/chondroitin combination compared to placebo. However, no statistical difference was found with individual treatment alone23.
Raynauld JP., et al examined the long-term (6-year) effect of combined glucosamine (Glu) and chondroitin sulfate (CS) treatment on cartilage volume loss in knee osteoarthritis. treatment with Glu/CS significantly reduced the cartilage volume loss in the global knee, and the extent of the treatment's positive effect was related to exposure time to treatment, the protective effect at 6 years being significant in participants exposed to ≥2 years of treatment24. Zeng C., et al found in a total of 54 studies that glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing25.
Roman-Blas JA., et al found in a randomized, double-blinded, placebo-controlled study performed in 164 patients with knee OA and moderate to severe pain who receive either CS (1200 mg) plus GS (1500 mg) or placebo in a single oral daily dose for 6 months that CS+GS failed to demonstrate superiority over placebo in reducing pain and function impairment in patients with symptomatic KOA at 6 months26.
Adverse effects from the exogenous administration of glucosamine sulfate are observed in less than 5% of the patients, with the most frequent being: gastrointestinal disturbances (discomfort/epigastric pain, bloating, cramps, diarrhea, constipation, nausea, and dyspepsia), somnolence, cutaneous reactions (erythema, pruritus, or skin rash) and headache1,2,4.
Glucosamine should not be used in patients with shellfish allergies1. Comparative studies with traditional NSAIDs have shown that crystalline glucosamine sulfate has a significantly better tolerability especially at the gastrointestinal level2,27.
There were concerns regarding glucosamine-induced hyperglycemia, but most studies showed 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 those with impaired glucose tolerance1,28. But other few studies showed that caution might be advisable when treating patients with impaired glucose tolerance, and monitoring of blood glucose levels may be necessary in diabetics at the start or end of therapy2,29.
Herrero-Beaumont G., et al found that there were no change in mean systolic and diastolic blood pressure with average high-normal values, as well as in a subgroup of patients with hypertension, and no changes compared with placebo in blood glucose levels after 6 months of glucosamine treatment even in hyperglycemic patients30. In a case report glucosamine was shown to cause renal toxicity31. Cases of hypercholesterolemia were reported29, but Reginster., et al found that total and low density lipoprotein cholesterol did not increase after 3 years of treatment with glucosamine32. It has a good long-term safety on cardiovascular and metabolic parameters 33.
Glucosamine supplement therapy for 3 months causes statistically significant rise of intraocular pressure, which is more pronounced in elderly patients34.
It causes elevation in transaminase values with no associated symptoms, but there are increasing reports of hepatotoxicity with supplements of GS+CS35.
Glucosamine sulfate has a low potential for drug–drug interactions and it does not inhibit or induce any enzymes of the CYP450 system36. Nevertheless, cases of increased effects of coumarinic anticoagulants have been reported and may merit attention2.
Cost/effectiveness of glucosamine productions:
cost/effectiveness of glucosamine productions is dependent on its efficacy because this can lead to reduction in other drugs use and delay the need for joint replacement and reduction of costs of physiotherapy. Treatment with glucosamine sulphate for at least 12 months significantly delayed the need for total joint replacement surgery18,37.
Several studies showed that glucosamine achieved a significant reduction in NSAID use18, 38,39,40 . The cost/effectiveness of the oral chondroitin sulphate plus glucosamine sulphate therapy derives from the reduction of costs for physiotherapy, and for gastroprotective and non-steroidal drugs41.
CONCLUSION:
There are conflicting results about the efficacy of glucosamine, but most of studies showed that it is safe and effective in treatment and prevention of osteoarthritis progression, but it needs long period to be effective especially for prevention of the progression of the disease (2 years).
several studies have reported when comparing the efficacy of GH vs GS and the efficacy of glucosamine alone vs its combination with chondroitin sulfate , that GS exhibits more favorable results than GH, and its combination with chondroitin sulfate exhibits more favorable results than glucosamine alone. In the other hand there are few studies showed that glucosamine either alone or in combination with chondroitin failed to be effective.
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Received on 02.02.2017 Modified on 09.04.2017
Accepted on 14.05.2017 © RJPT All right reserved
Research J. Pharm. and Tech 2018; 11(2): 489-493.
DOI: 10.5958/0974-360X.2018.00089.6