Natural Products on Deck: Keeping Joints in the Game

Many patients with osteoarthritis (OA) turn to complementary and alternative medicine, either as an adjunct to prescription therapy or to avoid side effects associated with prescription drugs. As medication experts, pharmacists can counsel patients on the potential risks a benefits of supplements marketed for OA.

Osteoarthritis (OA) is the most common form of arthritis, affecting an estimated 27 million adults in 2005.¹ Patients who are obese; participate in certain sports such as football, wrestling, boxing, and baseball pitching; have a history of joint trauma; experience repetitive occupational stress to joints, such as carpenters, agricultural workers, and those who have to bend or squat for prolonged periods of time; and those who are genetically predisposed are all considered to be at risk for OA.^2,3

Pathophysiology of OA

The molecular mechanism of how OA occurs is rather complex. Trauma or injury to the articular cartilage, overloading a joint due to obesity, or damage to the joint leading to problems with loading often begins the cascade of events that leads to cartilage destruction and bone overgrowth. The activity of chondrocytes, the only cells in cartilage, is greatly enhanced following some type of damage to the cartilage. As a result, a hypertrophic phase occurs in which there is an increase in the production of constituents of the cartilage matrix, leading to swelling.

Rather than repairing the problem, however, this actually contributes to the condition. Further damage occurs following this hypertrophic phase, and chondrocytes in the damaged cartilage undergo apoptosis (ie, cell death), reducing the number of cells available to make cartilage components. The net product of this complex series of events is cartilage and chondrocyte loss, with subsequent joint space narrowing and potentially deformed joints.² Osteophytes, or new bone growths, may also develop near sites of cartilage destruction as the disease progresses.³

Reducing pain, improving quality of life, and maintaining the function of the impaired joint are treatment goals for patients with OA. ^2,3 Many of the current treatment modalities are aimed at relieving pain. However, given some of the untoward side effects associated with various prescription therapies, as well as patient preference, some patients experiencing OA will turn to complementary alternative medicine (CAM). In fact, a study from 2009 suggested that 80% to 90% of survey responders had attempted at least 1 CAM for arthritis symptoms.⁴

Glucosamine/Chondroitin

Two of the most commonly seen supplements marketed for OA include glucosamine and chondroitin, which are usually marketed together in the same product. Glucosamine is an endogenous amino sugar that is required for the synthesis of glycoproteins and glycosaminoglycans, molecules found in cartilage and other tissues. It also distributes into cartilage and other connective tissue, which becomes degraded in OA.^5,6 Once in cartilage, glucosamine stimulates the metabolism of chondrocytes, whose activity increases in OA. The typical daily dosage is 1500 mg divided 3 times daily.⁵

Glucosamine is sold as either the sulfate or hydrochloride (HCl) salt.^5,6 Many of the studies conducted have used glucosamine sulfate in their methods, and have mostly focused on OA of the knee.

Glucosamine is generally well tolerated with the only complaints being mild gastrointestinal (GI) symptoms.⁵ There are some concerns that glucosamine may worsen glycemic control and cause greater insulin resistance in patients with diabetes. Clinical trials have found that glucosamine does not significantly increase blood glucose or A1C levels in patients with type 2 diabetes.^6-8 In addition, because glucosamine is derived from the exoskeleton of shellfish, there is concern that glucosamine may cause reactions in individuals who are allergic to shellfish. However, shellfish allergies are caused by antigens in the meat of the shellfish (not the shell), and there have been no reports of reactions in persons with shellfish allergies who take glucosamine.⁶

Patients with a sulfa allergy should avoid glucosamine sulfate.⁵ Some drugs that may interact with glucosamine include antihyperglycemic medications and warfarin. Concomitant use of glucosamine and antihyperglycemic drugs may cause reduced efficacy of the latter. Using glucosamine with warfarin may increase a patient’s risk of bleeding.⁵

Chondroitin is usually promoted in conjunction with glucosamine. However, it is important to note that current research is inconsistent on whether combining chondroitin with any formulation of glucosamine is more effective than glucosamine sulfate alone.⁶ Also of note, there is much less research available about chondroitin compared with glucosamine sulfate. It is one of the primary glycosaminoglycans, which is a class of large molecules found in cartilage.⁵ Chondroitin sulfate may inhibit synovial enzymes that are thought to contribute to cartilage destruction and limit joint function in OA. The typical dose of chondroitin sulfate for OA is 200 to 400 mg taken 2 to 3 times daily.⁵

The main benefit from taking chondroitin appears to be pain relief. Older studies showed that taking chondroitin with an analgesic had a greater effect in relieving pain than taking an analgesic alone. ^6,9 Some evidence also suggests that chondroitin may slow OA progression by reducing joint space narrowing.^6,10 Chondroitin is very well tolerated, with the only safety concerns being diarrhea, nausea, and abdominal pain. In addition, as with glucosamine, chondroitin should be used cautiously in patients with bleeding disorders and those taking anticoagulant drugs, especially warfarin, due to an increased risk of bleeding. ⁵ In general, patients with anticoagulation disorders should avoid glucosamine/chondroitin supplements.

The largest study that looked at glucosamine and chondroitin for knee OA is the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT). ¹¹ The purpose of this study was to measure the efficacy of glucosamine HCl and chondroitin sulfate alone and in combination against 2 control groups (celecoxib and placebo) for 6 months. The trial found that glucosamine HCl did not significantly reduce symptoms of knee OA when used alone or in combination with chondroitin, although a subgroup analysis did find that patients with severe symptoms experienced a reduction in pain.

An interesting finding of GAIT was the high response rate in the placebo group. About 60% of patients given the placebo reported a decrease of 20% in the pain index. ¹¹ It has been suggested that this may have contributed to the negative findings of this trial. ⁶ GAIT trial investigators also conducted a 2-year extension of the original study, which found that glucosamine and chondroitin sulfate, in combination or alone, did not fare any better than the placebo group in the progression of OA (cartilage deterioration). ¹²

Methylsulfonylmethane

Methylsulfonylmethane (MSM) is another supplement that is marketed to patients with OA. It is commonly found in products with glucosamine/chondroitin. A lack of evidence exists to show a significant benefit to taking all 3 together.⁵ MSM is found naturally in some green plants, vegetables, and fruits. It also is found in the human adrenal glands and is believed to have anti-inflammatory and analgesic effects.^5,6 Typical doses used for OA range from 500 mg 3 times daily to 3 g taken twice daily.⁵

Very little evidence is available to support the use of MSM for OA, and the few clinical trials that have taken place were short in duration (<12 weeks).⁶ Based on research in animals, MSM is thought to reduce the degenerative process in the joint that occurs in OA.⁵ The proposed mechanisms of action, based on the animal studies, include perhaps stabilizing cell membranes, slowing/stopping leakage from injured cells, and scavenging hydroxyl free radicals that trigger inflammation. Results from studies show that MSM may moderately reduce pain and swelling, but has little/no effect in reducing joint stiffness.^6,13 Based on short-term data, MSM appears to have no major side effects or drug interactions.⁶

S-adenosylmethionine

The synthesis of S-adenosylmethionine (SAMe) occurs naturally in the liver from the metabolism of methionine.^6,14 Proposed mechanisms of action in the treatment of OA include stimulating the growth, thickness, and repair of articular cartilage, reducing cytokine-induced damage to the chondrocytes, and increasing chondrocyte proteoglycan synthesis.^6,15,16 It is believed to exert both analgesic and anti-inflammatory effects and is comparable in efficacy to nonsteroidal anti-inflammatory drugs.^6,14 However, it may take longer (~2 weeks) to derive benefit from SAMe treatment.^6,14 A recent review concluded that consistent evidence supports the use of SAMe for symptoms of OA.¹⁷

The suggested dose for SAMe for the treatment of OA is 200 mg 3 times daily. The most common adverse affects are GI effects, such as nausea, vomiting, and diarrhea. Given that SAMe effects some neurotransmitters in the body and is used in some patients to treat symptoms of depression, side effects such as insomnia, anxiety, headache, nervousness, and dizziness may occur. Hypomania and mania have been reported in some patients. Thus, SAMe should be used cautiously or avoided in patients with bipolar disorder.^6,14 Concomitant use of SAMe with drugs that have serotonergic effects, such as antidepressants, tramadol, and mepiridine, increase the patient’s risk for serotonin syndrome and should be avoided.^6,14

Dr. Brown is assistant dean for academics and associate professor of pharmacy practice at Palm Beach Atlantic University’s Lloyd L. Gregory School of Pharmacy in West Palm Beach, Florida. Mr. Roth is a fourth-year PharmD candidate at the Lloyd L. Gregory School of Pharmacy at Palm Beach Atlantic University.

References

1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008;58:26-35.

2. Buys LM, Elliott ME. Osteoarthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw Hill; 2008:1519-1537.

3. Hinton R, Moody RL, Davis AW, Thomas SF. Osteoarthritis: diagnosis and therapeutic considerations. Am Fam Physician. 2002;65:841-848.

4. Callahan LF, Wiley-Exley EK, Mielenz TJ, et al. Use of complementary and alternative medicine among patients with arthritis. Prev Chronic Dis. 2009;6:1-23.

5. Natural Medicines Comprehensive Database. 8th ed. Stockton, CA: Therapeutic Research Faculty; 2006. www.naturaldatabase.com. Accessed March 27, 2011.

6. Gregory PJ, Sperry M, Wilson AF. Dietary supplements for osteoarthritis. Am Fam Physician. 2008;77:177-184.

7. 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(13):1587-1590.

8. Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care. 2003;26(6):1941-1942.

9. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA. 2000;283(11):1469-1475.

10. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one-year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cartilage. 2004;12(4):269-276.

11. 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(8):795-808.

12. Sawitzke AD, Shi H, Finco MF, et al. Clinical efficacy and safety of glucosamine, chondroitin sulfate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis. 2010;69:1459-1464.

13. Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage. 2006;14(3):286-294.

14. Fetrow CW, Avila JR. Efficacy of the dietary supplement S-adenosyl-L-methionine. Ann Pharmacother. 2001;35:1414-1425.

15. Bottiglieri T. S-adenosyl-L-methionine (SAMe): from the bench to the bedside — molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76:1151S-1157S.

16. di Padova C. S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies. Am J Med. 1987;83:60-65.

17. De Silva V, El-Metwally A, Ernst E, et al. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review [published online ahead of print December 17, 2010]. Rheumatology (Oxford). http://rheumatology.oxfordjournals.org/content/early/2010/12/17/rheumatology.keq379.long. Accessed March 23, 2011.