Treatment of Knee OA With Glucosamine and Hyaluronan - Asian Perspective

Transcription

1 Treatment of Knee OA With Glucosamine and Hyaluronan - Asian Perspective Dr. NICOLAAS C. BUDHIPARAMA Jr., SpOT., F.I.C.S. Head of Department Orthopaedic Surgery - Medistra Hospital President and Founder of Indonesian Hip and Knee Society (IHKS) Founder of ASEAN Arthroplasty Association (AAA) Vice President of Indonesian Osteoporosis Association (PEROSI)

2 Still a Controversial Topic As the most common musculoskeletal disease, OA has long been a topic of intense research and debate Symptomatic therapy with NSAIDs remains the status quo despite questionable efficacy and significant risk OSTEOARTHRITIS

3 Still a Controversial Topic Conservative or operative can only treat the symptoms of OA and not the disease itself. The possibility that Glucosamine and HA can act as disease-modifying osteoarthritis drug, should be thoroughly investigated Disease-modifying treatment options for OA has become an important aspect of orthopaedic care OSTEOARTHRITIS

4 History of Glucosamine Studies The first published study from Germany in Additional studies in Europe and Asia in the 1980 s. In late 1990s, after gaining popularity in Europe and Asia, they gained popularity in the US after the release of several lay publications. Comparison of glucosamine to NSAID - The Arthritis Cure, by Jason Theodasakis, MD, 1997 A non-permissible supplement for institutions to provide to their athletes by the NCAA. Approved as medical drug in some countries in Europe GLUCOSAMINE

5 Glucosamine Claims Treatment of knee osteoarthritis Repair and maintenance of joint cartilage Aid glycosaminoglycan (GAGs) synthesis Reduce joint pain GLUCOSAMINE

6 Glucosamine Claims Chondroitin Sulphate reduce the radiographic progression and joint space narrowing in OA patients Glucosamine Sulphate show a non-statistical trend in significant reduction of joint space narrowing Many studies supported the use of glucosamine as an effective alternative to higher risk medication such as NSAIDs and cyclooxygenase II inhibitors for OA GLUCOSAMINE

7 Drawbacks of Glucosamine Studies Many of the studies FU term are too short to make significant long term conclusions Most of the trials are manufacturer sponsored & have inadequate product concealment so they are difficult to analyze GLUCOSAMINE

8 Glucosamine A building block for articular cartilage s extracellular matrix Used to produce GAGs and proteoglycans Synthesized by chondrocytes 90% absorption by oral administration 26% available for processing by the body s tissue GLUCOSAMINE

9 Glucosamine Type of Glucosamine: Glucosamine sulfate (most common form) Glucosamine hydrochloride N-acetyl glucosamine Commonly used with; Chondroitin: a glycosaminoglycan derived from articular cartilage Methylsulfonylmethane (MSM): sulfur compound and high-temperature solvent GLUCOSAMINE

10 Glucosamine Sulfur is an essential nutrient for the stabilization of the connective tissue matrix. Glucosamine sulfate stimulates the uptake of sulfate ions indicator of GAG synthesis by chondrocytes. Glucosamine also hinders hyaluronidase (tissue damaging enzyme) Glucosamine sulfate improves the lubricant properties of synovial fluid. GLUCOSAMINE

11 Glucosamine S vs Glucosamine HCl Glucosamine Sulphate - Basic building block of connective tissues & fluids - Most common form of Glucosamine - Cost 1.5x more expensive than hydrochloride form - More research done on Sulphate form and have been proven effective - Thought to be more effective due to the sulphate part which our body needs to produce cartilage Glucosamine Hydrochloride - More concentrated & yields higher glucosamine molecules due to less sodium over effective dose - Slightly more stable form and more usable by the body - More water soluble than sulphate GLUCOSAMINE

12 GLUCOSAMINE Glucosamine S vs Glucosamine HCl Glucosamine Sulphate more popular since Glucosamine Hydrochloride which was used in GAIT Trial (Glucosamine Arthritis Intervention Trial) failed to show significant structure modifying effects after 2 years of usage and it was safe but no more effective than placebo in treating knee OA The ES pain reduction was 0.58 for GS but insignificant for GH Outcomes of trial for GH is homogenous while those for GS are very heterogenous

13 Glucosamine Source Present in meat, fish, poultry Synthesized in the body Manufactured from chitin, a substance found in shrimp, crab, and lobster shells Marine exoskeletons. Synthetic glucosamine is also available Chemically synthesized GLUCOSAMINE

14 Interactions With Drugs May increase risk of side effects Diuretics May increase risk of bleeding when taken with drugs that increase the risk of bleeding Aspirin Anticoagulants (blood thinners): warfarin or heparin Anti-platelet: clopidogrel Non-steroidal anti-inflammatory: ibuprofen or naproxen GLUCOSAMINE

15 Side Effects / Contra Indications Mild stomach upset Nausea Heartburn Diarrhea Constipation Increased blood glucose, cholesterol, triglyceride and blood pressure levels Don't use if you are allergic to shellfish GLUCOSAMINE

16 Types of Published Evidence Type of Substantiation Consensus Statement Independent expert opinions (reviews) Meta-Analyses Large, Well-Designed Human Clinical Trials Smaller, Well-Designed Human Clinical Trials Uncontrolled Human Clinical Trials Animal Intervention Studies In Vitro Studies Total Number of Publications 4 supportive 1 nonsupportive 43 supportive 14 nonsupportive 14 supportive 0 nonsupportive 12 (18) supportive 2 (3) nonsupportive 13 (13) supportive 4 (5) nonsupportive 29 supportive 4 nonsupportive 20 supportive 3 (4) nonsupportive 45 supportive 9 nonsupportive 180 (186) supportive 33 (36) nonsupportive GLUCOSAMINE

17 Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis by Clegg, D. O., et al., the New England Journal of Medicine. Feb23, 2006 Objective - Efficacy and safety as a treatment for knee pain from OA Subjects patients with symptomatic knee osteoarthritis(x-rays documented) Results - Participants used acetaminophen fewer than two 500mg tablets per day - Celecoxib: >20% reduction in 70%, 60% in placebo - Moderate-to-severe pain with G&C: 79% in G&C, 54% in placebo - Mild pain with G&C: 62.9% in G&C, 61.7% in placebo - 77 reports of mild side effects - Additional 18 months for half of the participants. GLUCOSAMINE

18 Long-term effects of glucosamine sulfate on osteoarthritis progression: a randomised, placebo-controlled crinical trial by Reginster, J.Y; et al. The Lancet; Jan27,2001;357 Objective Effect of long-term use of glucosamine to change joint structure and symptoms Results 212 patients w/ mild-moderate osteoarthritis (106 subjects each) GS (68 subjects) No average joint-space narrowing improvement of symptoms in WOMAC score (34%difference) Placebo(71 subjects) A progressive joint-space narrowing Symptoms slightly worsened Most patient reported at least 1 mild adverse event.

19 Literature - Affirms Conclusions: Treatment of knee OA with glucosamine sulphate for at least 12 months and up to 3 years may prevent TJR in an average follow-up of 5 years after drug discontinuation GLUCOSAMINE

20 The effect of oral glucosamine sulfate on insulin sensitivy in human subjects. Yu, JG., Boies, SM., Olefsky, JM. Diabetes Care. Jun2003. Objective Effect of recommended dosage of glucosamine on insulin resistance Outcome measures Comparison of fasting plasma glucose and insulin levels at baseline 4-h plasma glucose curve 4-h meal tolerance test (MTT) plasma insulin curve Results No changes in fasting plasma glucose, insulin, or lipoprotein levels Recommended dosage of glucosamine was not detrimental to glucose metabolism in humans

21 Meta Analysis In a meta-analysis published in JAMA, the researchers searched Medline and the Cochrane Controlled Trials Register and analyzed the quality of the studies as well as performing statistics on evidence Found some benefit of both compounds - more for chondroitin than glucosamine, but less effect than the manufacturer would like you to believe They also found that most studies had some financial or other ties to a manufacturer ---McAlindon et al--- GLUCOSAMINE

22 Meta Analysis Results Glucosamine Sulphate appears to be more effective than placebo and in long term use Combination with chondroitin seems to be more effective. Short term use of glucosamine may not affect insulin resistance Used it under supervision of physician GLUCOSAMINE

23 Literature - Affirms Manuscript in Preparation Does Oral Glucosamine detectably Alter Gene Expression in Car9lage and Bone? An explora9ve pilot study in pa9ents with hip OA E.J. UCerlinden M.D., H. Jahr M.D., R.M. Rozendaal M.Sc., J.L.M. Koevoet M.D., S.M.A. Bierma Zeinstra Ph.D., J.A.N. Verhaar M.D., G.J.V.M. van Osch Ph.D., H. Weinans Ph. D. Department of General Prac9ce, Erasmus MC, University Medical Center RoCerdam, The Netherlands Department of Orthopaedics, Erasmus MC, University Medical Center RoCerdam, The Netherlands Conclusion: It is possible to detect changes in gene expression of cartilage after oral use of a supposed clinically effective daily dose of glucosamine GLUCOSAMINE

24 Literature - Opposes Conclusion: Glucosamine Sulphate was not significantly better than placebo in reducing symptoms and progression of hip OA in subgroups of patients. GLUCOSAMINE

25 Literature - Opposes The 2 clinical studies from Belgium & Czech Republic were industry sponsored and had poor reproducibility and was subject to errors According to Cochrane reviews, there was no significant difference between glucosamine and placebo with respect on pain, function & ROM. Histological analysis of the alleged GLUCOSAMINE benefits of glucosamine is lacking.

26 Literature - Opposes Glucosamine is classified as a food additive or nutraceutical, therefore manufacturers do not need to comply with the same regulations that apply for quality assurance within the pharmaceutical industry. The annual cost for treating OA in USA => $86 Billion Sales of glucosamine / chondroitin => $730 Million GLUCOSAMINE

27 AAOS Guidelines & Recommendations GLUCOSAMINE

28 AAOS Guidelines & Recommendations Guidelines: - Not performing an arthroscopic lavage if a patient only displays symptoms of OA and no other problem lie loose bodies or meniscus tears Recommendations: - Patients who are overweight with BMI greater than 25 should lose a min of 5% of their body weight - Patients should be encouraged to begin or increase their participation in low-impact aerobic fitness - Against using: Glucosamine Needle Lavage Custom Made Foot Orthotics GLUCOSAMINE

29 Critics for AAOS Guidelines & Recommendations GLUCOSAMINE

30 Glucosamine induced a 28% improvement from baseline in pain & 21% improvement in function by Lequesne s index Small but significant evidence of slowing of joint space loss is found in knee OA patients but not for hip OA patients Follow up study showed that a 5 year incidence of TKR was reduced more than 50% in patients who had taken glucosamine for at least 12 months GLUCOSAMINE

31 Despite Conflicting Results of Studies, Support for Glucosamine Remains Strong Would you take a supplement containing glucosamine & chondroitin, have about 2/3 of a chance of getting signifiant relief, with some evidence that you can slow your disease progression or just numb your symptoms with acetaminophen and risk ulcers, allergies, kidney or liver damage, hypertension, heart attack & possibly death? --- Jason Theodosakis, MD --- If patients want to use glucosamine, then they should discuss this with their physician who may recommend a particular brand and manufacturer --- Marc C. Hochberg, MD --- GLUCOSAMINE

32 How about Hyaluronan? Does It Work to Prevent OA? HYALURONIC ACID

33 Hyaluronic Acid in OA Improves the inherent HA production in the knee Anti-inflammatory effect Anabolic & Anagelsic effect Chondroprotective effect HYALURONIC ACID

34 Biochemical Effects of Hyaluronan Inhibits tissue nociceptors Stimulates endogenous hyaluronan formation Has anti-inflammatory effects Inhibits MMP activity HYALURONIC ACID

35 Hyaluronan Viscosupplementation has been supported by numerous clinical trials and postmarketing studies, and the efficacy of hyaluronic acid has been supported by several meta-analyses HYALURONIC ACID

36 Clinical Effects of Hyaluronan Author Type of Study Findings Marshall et al 1996 Meta Analysis 68% with severe OA did not progress to TKA S/P Chen et al 2002 Level I Study: HA S/P scope VAS scores increased in HA patients Dai et al 2002 Level I Study: HA S/P scope VAS scores increased in control group Rolf et al 2005 Level I Study: HA v placebo Patient symptoms improved with HA & Hylan Mathies 2006 Viscoseal S/P meniscectomy Decreased effusion and pain Hempfling 2007 Level I Study: HA v control Decreased pain up to 1 year Ulucay et al 2007 Huang et al 2007 HYALURONIC ACID Level I Study: Hylan, Orthovisc, Adant, S/P scope Level I Study: HA S/P ACL repair v saline Improved pain relief Hyaluronan increased results Zietz & Selesnick 2008 Level I multi-center study Increased VAS scores S/P scope for OA

37 Literature - Affirms Conclusion: In patients who are candidates for TKR, the need for TKR can be delayed with hylan G-F 20 when used for the treatment of OA knee pain HYALURONIC ACID

38 Literature - Affirms Viscosupplementation such as injections of hyaluronan has received more attention in the media in recent years as a more natural choice to treating osteoarthritis. In effect, it improves viscosity and enhances elasticity by replacing the joint fluid that is missing in the knees of patients with OA. While reports of some patients exploring other treatment options including glucosamine and chondroitin sulfate claim to achieve some collagen growth, more studies are needed. HYALURONIC ACID

39 Literature - Affirms Cochrane Systemic Review 2006; 2; CD Viscosupplementation for the treatment of Osteoarthritis of the Knee Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G Conclusions: The 5-13 week post injection period showed the largest percent of improvement, from a baseline of 28% to 54% for pain and from 9% to 32% for function. Overall, these results support the efficacy of HA and steroids for the temporary symptomatic management of early knee OA HYALURONIC ACID

40 Literature - Affirms Conclusions: This meta-analysis confirmed the therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for the treatment of osteoarthritis of the knee. Additional well-designed randomized controlled trials with high methodological quality are needed to resolve the continued uncertainty about the therapeutic effects of different types of hyaluronic acid products on osteoarthritis of the knee in various critical situations and patient populations. HYALURONIC ACID

41 Literature - Affirms HYALURONIC ACID Conclusions: Repeat courses of the hyaluronans are safe and effective in the treatment of pain associated with OA of the knees

42 Literature - Opposes Conclusions: The currently available evidence suggests that intraarticular hyaluronic acid is not clinically effective and may be associated with increased risk of adverse events. Therefore, this type of therapy should not be used for the treatment of painful osteoarthritis until a large long term trial with clinically relevant and uniform end points has clarified the benefit-risk ratio HYALURONIC ACID

43 Hyaluronan Viscosupplementation had been accepted by the AAOS, American Pain Society, and American College of Rheumatology, as well as Medicare and private third-party payers, as a treatment for OA knee pain HYALURONIC ACID

44 AAOS Guidelines & Recommendations AAOS - December 2008 stated: We cannot recommend for or against the use of intra-articular hyaluronic acid for patients with mild to moderate symptomatic OA of the knee Inconclusive HYALURONIC ACID

45 Reduction in pain diminished with time and was no longer significant after 14 weeks Comparison between HA and Corticosteroid shows no significant difference between 4 weeks after injection but HA was shown to be more effective 5-13 weeks post injection Analyses of the results for other outcomes such as reduction stiffness and improvement in function following HA were similar. No major safety issues were detected HYALURONIC ACID

46 Intra-Articular Hyaluronan After Arthroscopic Surgery Treatment modality offered to patients with meniscal pathology with mild or moderate OA How about patients with symptomatic OA? Viscosupplementation serves a definitive role in helping to reduce symptoms of pain and improve function in a significant numbers of patients HYALURONIC ACID

47 HA Combined With Stem Cell Arthroscopy: The Journal of Athroscopic & Related Surgery, June 2010 This is a relatively simple and effective method to regenerate articular cartilage as the entire process involves only 1 single arthroscopic procedure followed by post-operative intra-articular injections of autologous PBSC combined with HA. The pre-clinical animal work has been accepted for publication. HYALURONIC ACID

48 Glucosamine & HA - The Asian Perspective Singaporean Experience - Glucosamine seems to be helpful for about 50% of mild to moderate OA but not for advanced OA - Usage and duration should be monitored by rheumatologist or orthopaedic surgeon since it s reported to have some effect causing insulin resistance and no long term safety has been established Malaysian Experience - Glucosamine does work for some patients but it has not been shown to improve cartilage - HA delays definitive surgery but the effect is limited. Some patients react quite badly to certain ones and it is very important to inject into the right area, hence requiring a rheumatologist or Orthopaedic surgeon to administer GLUCOSAMINE & HYALURONIC ACID

49 Glucosamine & HA - The Asian Perspective Thai Experience - Sales of Glucosamine & HA more than 1 Billion Baht - Some patients gain benefit - Unsupportive stand by AAOS guideline causes doctors to try to stop reimbursing them Philippines Experience - Glucosamine and HA are used as temporary fix for patients with severe OA - False hope for candidate for THR/TKR but still given as delay tactics until enough funding available - HA seems to work better against inflammation. If given in early stage, can alleviate symptoms which may delay onset of OA GLUCOSAMINE & HYALURONIC ACID

50 Glucosamine & HA - The Asian Perspective Indian Experience - Glucosamine is used liberally with MSM & Diacerin and seems to have a beneficial effect on patients with poly articular pain or problems with both knees. Clinical gains are moderate in the medium term especially on the non deformity situations - HA is effective and more patient friendly with the availability of single shot version. It is used in non deformity situations with a concentric decrease of joint space. It is not recommended if there is any varus element since the outcome seems to be very short lived or no improvement at all. It seems to work better in painful joints with mild varus with no laxity GLUCOSAMINE & HYALURONIC ACID

51 Glucosamine & HA - The Asian Perspective Taiwanese Experience - The majority of studies and publication in Asia about Glucosamine and HA are from Taiwan - Most studies confirmed the pain relief, functional improvements and safety of using intra articular Hyaluronic Acid as treatment for OA GLUCOSAMINE & HYALURONIC ACID

52 Glucosamine & HA - The Asian Perspective Asian Culture - Prescription is expected when patient visits a doctor - Taking vitamins / supplement to avoid surgery / high cost - Easily taken by advertising and word of mouth which leads to self medicating with medicine that works - Disinformation prevents full awareness or understanding the benefit vs risk of medicine My Experience - Combination of glucosamine and chondroitin sulfate for OA stage 1 & 2 (plus physical therapy) reduce NSAIDS usage - Hyaluronic IA injection are given for OA stage 2 & 3 or post arthroscopy GLUCOSAMINE & HYALURONIC ACID

53 Conclusions It Works If You Think It Works! GLUCOSAMINE & HYALURONIC ACID

54 Thank You For Your Attention