Osteoarthritis (OA) Is a Pain

R OBE 201 CT 1 O

Managing Osteoarthritis With Nutritional Supplements Containing Glucosamine, Chondroitin Sulfate, and Avocado/Soybean Unsaponifiables

steoarthritis (OA) is a pain- successfully recommending OJHSs treatment algorithm exists for man- ful, progressive degeneration containing a combination of glu- aging patients with OA, acetamin- O of the joint characterized by cosamine, chondroitin sulfate (CS), ophen is a first-line drug recom- progressive cartilage loss, subchon- and avocado/soybean unsaponifi- mended to help control pain and dral bone remodeling, formation of ables (ASU) for the management increase mobility. Acetaminophen periarticular osteophytes, and mild of OA. It will briefly review the is associated with both hepatic and to moderate synovitis accompanied available pharmacokinetics/phar- renal damage, particularly in patients by an increase in pro-inflammatory macodynamics and safety profile who exceed the recommended daily cytokines, chemokines, and a vari- of OJHSs containing a mixture of dose or use it in combination with ety of inflammatory mediators.1 glucosamine, CS, and ASU, outline moderate amounts of alcohol. 6 There is no cure for OA; therefore, strategies to identify appropriate Worsening pain, disease progression, once an individual is diagnosed, patients for OJHSs containing these and inefficacy of acetaminophen managing OA becomes a lifelong ingredients, and provide web-based often necessitate initiating prescrip- process. Although a physician ini- resources (TABLE 1) that will assist tion NSAIDs (such as COX-2 tially diagnoses OA, pharmacists are pharmacists in educating and coun- inhibitors), which carry the risk of the most accessible health care pro- seling patients. gastrointestinal effects (e.g., gas- fessional and play an integral role tropathy), renal toxicities, and seri- in managing each patient’s joint CURRENT RECOMMENDATIONS ous cardiovascular events. 1,6,7 discomfort by dispensing prescrip- FOR THE MEDICAL MANAGEMENT Patients unable to tolerate these tion medications (e.g., opioids, OF JOINT DISCOMFORT AND options or who do not receive selective nonsteroidal anti-inflam- CARTILAGE BREAKDOWN adequate pain relief can be prescribed matory drugs [NSAIDs], proton A multitude of treatment modalities opioids; however, pruritus, nausea, pump inhibitors); recommending exist for OA, including surgical, vomiting, constipation, and physi- nonprescription pain relievers (acet- pharmacologic, and nonpharmaco- cal dependence are problematic.7 aminophen, ibuprofen, naproxen); logic therapies.2–5 According to these and discussing adverse events (AEs) guidelines, oral and topical NSAIDs, Table 1. Web-based associated with these drugs. Another cyclooxygenase (COX)-2 inhibitors, Patient Resources important role of the pharmacist is opioids, and intra-articular injections Food and Drug Administration: counseling patients regarding the of corticosteroids or hyaluronic acid www.fda.gov/food/dietarysupplements/ use of oral joint health supplements may be prescribed as adjuncts to consumerinformation/ (OJHSs). This review will provide nonpharmacologic therapies. Nutri- ucm110567.htm relevant and timely information on tional supplements may also be Center for Disease Control and Prevention: chosen, as they are prescription www.cdc.gov/arthritis/data_statistics/ W. Steven Pray, PhD, DPh products in some countries, even arthritis_related_stats.htm Bernhardt Professor, Nonprescription Products and Devices, College of Pharmacy though they are nonprescription Arthritis Foundation: Southwestern Oklahoma State University products in the United States. www.arthritis.org/osteoarthritis.php Weatherford, Oklahoma Although no universally accepted

PHG1103 Managing Osteoarthritis With Nutritional Supplements Containing Glucosamine, Chondroitin Sulfate, and Avocado/Soybean Unsaponifiables

As a result of the AEs inherent tosamine sulfate and glucuronic amine and CS, and the superior- with the use of most OA therapies, acid that varies in molecular weight ity of the two ingredients in OJHSs have become extremely from 6000–50,000 daltons.13,14 combination has been reported.22 popular for managing joint pain Commercially available CS products One randomized, double-blind, and dysfunction. Trade sources report vary markedly in source (bovine placebo-controlled study included that yearly sales of OJHSs contain- trachea, shark cartilage, other ani- 21 men with chronic knee pain ing glucosamine and/or chondroitin mal cartilage sources), purity, con- (20 due to OA) who consumed sulfate were over $425.8 million, tent variability, contamination daily supplements of a commercial making OJHSs the most popular (other dietary supplements, trace nonprescription preparation of form of nutritional supplement.8 elements), and manufacturing pro- glucosamine (1500 mg), and CS The following section describes cedures.13 CS varies in its efficacy (1200 mg); they experienced symp- the available chemistry, pharmaco- depending on its origin, molecular tomatic relief after eight weeks.23 kinetics, and clinical data for glu- weight/chain length, and degree of In a larger study, the same com- cosamine and CS, two of the most sulfation.15 This variation in commercial product was taken by 93 popular OJHS ingredients, as well mercially available CS products patients with knee OA; a signifi- as ASU. explains why the CS selected for cant improvement in severity of inclusion in the NIH-funded Glu- OA pain was noted in patients The Role of CS, Glucosamine, cosamine/chondroitin Arthritis with mild to moderate OA.24 Sub- and ASU in Joint Health Intervention Trial (GAIT) was a jects received 1000 mg of glucos- Description, Pharmacokinetics, specific pharmaceutical grade of amine and 800 mg of CS twice and Pharmacodynamics CS rather than a non-specific com- daily for 6 months. That study 1. Glucosamine is a water- mercial source.13 Some commercially also reported a strong trend in the soluble amino monosaccharide that available OJHSs sold in the United reduction of NSAID use by patients is available as glucosamine hydro- States contain lower quality CS. receiving CS and glucosamine in chloride, glucosamine sulfate, and CS is well-absorbed following months 2 through 6 compared to N-acetyl-D-glucosamine. Both the oral administration.16 A pharmaco- those in the placebo group. The sulfate and hydrochloride forms kinetic study in 20 healthy male GAIT study found that the 72 generate glucosamine free base at volunteers reported a significant subjects with moderate to severe gastric pH. Ninety-nine percent increase in plasma CS levels 2–6 OA experienced a statistically sig- pure glucosamine hydrochloride hours after administration with the nificant improvement in pain scores generates approximately 80% glu- peak (>200% increase in levels) at (≥20%) after 24 weeks of daily cosamine free base whereas glucos- 2 hours. First-order kinetics was supplementation with 1500 mg amine sulfate only generates 50%– observed for doses up to 3000 mg, glucosamine and 1200 mg of CS.25 60% glucosamine free base. Thus, and bioavailability of oral CS ranged Four high-quality, randomized if apparently comparable supple- from 15% to 24%.17 clinical studies of ASU,26–29 one ments contain equal amounts of 3. ASU is a mixture of avocado meta-analysis,30 two systemic glucosamine, but one contains glu- and soybean unsaponifiable fractions, reviews,31,32 and one Cochrane cosamine sulfate and the other which are the oily substances that Review33 have been published sup- contains glucosamine hydrochloride, remain after hydrolysis (saponifica- porting 300 mg ASU once daily for more free glucosamine will be gen- tion) of avocado and soybean oils. the management of hip and knee erated by the product containing The major components of ASU are OA. In the first study, Blotman et the hydrochloride form.9–11 Fol- phytosterols such as beta-sitosterol, al. (1997) found that patients with lowing oral administration, glucos- campesterol, and stigmasterol, which OA experienced a reduced need for amine is rapidly absorbed and yields are considered anti-inflammatory NSAIDs after 6 weeks of supple- plasma concentrations in excess of compounds with both antioxidant mentation. Patients exhibited 30 times the baseline levels with and analgesic activities.18–21 increased function and decreased once-daily dosing (using a standard pain compared to those in the pla- dose of 1500 mg).12 Clinical Evidence cebo group. 2. CS is a sulfated, heterogeneous A number of studies have dem- In the second study, Maheu et macromolecule comprised of galac- onstrated the efficacy of glucos- al. (1998) reported improved func-

U.S. PHARMACIST OCTOBER 2011 2 Managing Osteoarthritis With Nutritional Supplements Containing Glucosamine, Chondroitin Sulfate, and Avocado/Soybean Unsaponifiables tion and decreased pain in both the randomized clinical trials cited Clinical Recommendations ASU and placebo groups; however, previously, AEs included slight to for the Use of Glucosamine, the improvement was significantly mild gastric disorders, pyrosis, nau- CS, and ASU for Joint Health greater in the ASU group. Further, sea, vomiting, febrile colitis, head- “Patient safety and a significant fewer NSAIDs were consumed in ache, drowsiness, allergy, urticaria, degree of efficacy are excellent rea- the ASU group. and pruritus. AEs were reported sons to recommend a glucosamine In a third study, Appelboom et in 26.1%, 32.6%, and 27.9% of and chondroitin sulfate product to al. (2001) also found a significant the placebo group, 300 mg ASU patients with OA pain,” wrote decrease in NSAID usage and a group, and 600 mg ASU group, Nicholas DiNubile, MD, a clinical significant increase in function in respectively (P>0.05), by Appel- assistant professor in the department the ASU group compared to the boom et al. (2001). Lequesne et of orthopedic surgery at the Uni- placebo group. al. (2002) noted that 99% and versity of Pennsylvania Hospital.38 In the final study, Lequesne et 97% of the patients rated tolerabil- More recently, DiNubile described al. (2002) found that patients ity of the treatment as either “excel- the combination of glucosamine, severely affected by hip OA who lent” or “good” in the ASU and CS, and ASU as a first-line treat- took ASU experienced significantly control groups, respectively. ment for OA for any patient who less joint space width loss, but no Glucosamine, CS, and ASU each has undergone a surgical procedure difference in joint space loss was appear to be almost completely for cartilage regeneration.34,39 noted between the ASU and placebo void of any demonstrated or hypo- Published in vitro studies dem- group patients with less severe joint thetical detrimental herb-nutrient- onstrate that the combination of space loss measured at baseline. In drug interactions. Further, a num- glucosamine, CS, and ASU exerts that study, no other clinical differ- ber of studies have shown that greater anti-inflammatory effect ences were noted between the ASU glucosamine does not alter glucose than glucosamine and/or CS alone. and placebo groups, including func- metabolism and is theoretically safe In addition, administration of tion, NSAID usage, and subjective for diabetics.35 One study reported OJHSs containing these ingredients patient assessments. no AEs in 3063 patients adminis- may reduce the need for acetamin- To date, no clinical trials assess- tered oral glucosamine for approx- ophen or NSAIDs. Data generated ing the efficacy of the combination imately 66 weeks, and AEs were from the randomized clinical trials of glucosamine, CS, and ASU have reported less frequently following described herein support the admin- been conducted; however, in vitro glucosamine administration than istration of 1500 mg glucosamine, studies summarized in a recent review either the placebo or NSAID. 36 800 mg CS, and 300 mg ASU per article suggest that anti-inflammatory This conclusion was echoed by day for individuals with OA. Using effects of the three ingredients com- Stargrove et al. (2008), who wrote, quality OJHSs that contain glu- bined may exceed those from indi- “significant interactions with either cosamine, CS, and ASU at recom- vidual administration.34 insulin or oral hypoglycemic agents mended doses as part of a multi- are improbable.” Additionally, a modal treatment protocol that Contraindications and AEs 2010 published meta-analysis by includes patient education, weight Glucosamine, CS, and ASU are Simon et al. (2010) found no effects management, and other nonphar- safe and well tolerated. In the GAIT on blood glucose levels. The authors macologic therapies appears to play trial, AEs were mild and infrequent, of that review concluded from all an integral role in successfully man- and included headache and nausea. available evidence that “Glucos- aging patients with OA by reduc- Das and Hammad (2000) reported amine has no effect on fasting blood ing pain and inflammation and an incidence of AEs of 19% in the glucose levels, glucose metabolism, improving function. placebo group and only 17% in or insulin sensitivity at any oral the treatment group (P>0.05).24 dose level in healthy subjects, indi- Recommending a Quality Product Typical AEs were transient and viduals with diabetes, or those with The FDA does not have a role in included gastrointestinal symptoms impaired glucose tolerance.”37 Only the approval process for OJHSs. (gas, indigestion, constipation), routine monitoring of glucose lev- The clinical data regarding safety fatigue, and muscle cramping. ASU els in diabetic patients taking glu- and efficacy of OJHSs discussed appears equally safe. In the four cosamine is necessary. above should be viewed in that light.

U.S. PHARMACIST OCTOBER 2011 3 Managing Osteoarthritis With Nutritional Supplements Containing Glucosamine, Chondroitin Sulfate, and Avocado/Soybean Unsaponifiables

Manufacturing of OJHSs is regulated concern. Independent testing by Table 2. The Seven-Step by the FDA; however, poor quality ConsumerLab.com found that only ACCLAIM System for Selecting products continue to slip through 16 of 21 OJHSs met quality stan- High Quality the cracks and are unknowingly dards and FDA labeling require- Nutritional Supplements purchased by consumers. Poor qual- ments. An even more sobering ity supplements include those that analysis by Adebowale et al. (2000) Does the product have the following characteristics? do not contain the type or amount reported 26 of 32 products contain- A name you recognize? of ingredient listed on the manu- ing CS failed to have even 90% of Clinical Experience. Is this product sup- facturer’s label, recommend sub- the CS amount claimed on the label, ported by published, peer-reviewed therapeutic dosages, and/or are and 17 had <40% of the label research? potentially contaminated by harm- claim.15 To lessen concerns regard- Contents clearly indicated? ful chemicals such as pesticides, ing product quality (ergo safety), Label Claims substantiated by scientific lead, or other supplement ingredi- the pharmacist might recommend studies, not testimonials? ents during the manufacturing pro- products that appear to be manu- Administration recommendations. Are they clear and easy to follow? cess. These types of supplements factured in a quality manner. The Identification of lot provided? are unlikely to be effective, delay ACCLAIM system (TABLE 2) can Manufacturer Information listed on the the use of effective supplements, are help pharmacists rapidly and con- label? economically draining for consum- fidently select quality supplements Source: Reference 34 ers, and are an important safety to recommend.

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