Research
The Journal of Bone and Joint Surgery, Inc.
Therapeutic Effects Of Hyaluronic Acid On Osteoarthritis Of The Knee
A Meta-Analysis of Randomized Controlled Trials
Chen-Ti Wang, MD1, Jinn Lin, MD, PhD1, Chee-Jen Chang, PhD1, Yu-Tsan Lin, MD1 and Sheng-Mou Hou, MD, PhD,
MPH1
1 Department of Orthopedics (C.-T.W., J.L., and S.-M.H.), Department of Medical Research (C.-J.C.), and
Department of Pediatrics (Y.-T.L.), National Taiwan University Hospital and National Taiwan University
College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan. E-mail address for S.-M. Hou: shengmou@ha.mc.ntu.edu.tw
Investigation performed at the National Taiwan University Hospital and National Taiwan University
College of Medicine, Taipei, Taiwan
In support of their research or preparation of this manuscript, one or more of the authors received a grant
(DOH89-NH-058) from the Bureau of National Health Insurance, Taiwan. None of the authors received payments
or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No
commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund,
foundation, educational institution, or other charitable or nonprofit organization with which the authors
are affiliated or associated.
A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org)
and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).
Background: The magnitude of the therapeutic effects of intra-articular injection of hyaluronic acid on
osteoarthritis of the knee is still in question. The aim of this meta-analysis was to elucidate the
therapeutic efficacy and safety of intra-articular injection of hyaluronic acid for osteoarthritis of the
knee.
Methods: We conducted a meta-analysis of twenty blinded randomized controlled trials that compared the
therapeutic effect of intra-articular injection of hyaluronic acid with that of intra-articular injection
of a placebo to treat osteoarthritis of the knee. The outcome end points were classified into three
categories: pain with activities, pain without activities, and function. The outcome measures of the
efficacy of hyaluronic acid were the mean differences in the efficacy scores between the hyaluronic acid
and placebo groups. The outcome measure of the safety of hyaluronic acid was the relative risk of adverse
events.
Results: Intra-articular injection of hyaluronic acid can decrease symptoms of osteoarthritis of the knee.
We found significant improvements in pain and functional outcomes with few adverse events. However, there was significant between-study heterogeneity in the estimates of the efficacy of hyaluronic acid. Subgroup analysis and meta-regression analysis showed that lower methodological quality such as a single-blind or single-center design resulted in higher estimates of hyaluronic acid efficacy, that introduction of acetaminophen as an escape analgesic in the trial resulted in lower estimates of hyaluronic acid efficacy, and that patients older than sixty-five years of age and those with the most advanced radiographic stage of osteoarthritis (complete loss of the joint space) were less likely to benefit from intra-articular injection of hyaluronic acid.
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 clinical situations and patient populations.
Level of Evidence: Therapeutic study, Level II-3b (systematic review; nonhomogeneous Level-I studies).
See Instructions to Authors for a complete description of levels of evidence.
The Journal of Bone and Joint Surgery (American). 2006;88:295-302.
The Journal of Bone and Joint Surgery, Inc.
Sodium Hyaluronate In The Treatment Of Osteoarthritis Of The Ankle: A Controlled, Randomized, Double-Blind
Pilot Study
Robert S. Salk, DPM1, Thomas J. Chang, DPM1, Walter F. D''Costa, DPM2, David J. Soomekh, DPM3 and Kirk A.
Grogan, DPM1
Investigation performed at the Northern California Foot and Ankle Center, San Francisco and Santa Rosa,
California
A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and
on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).
Note: The authors thank Sara Dahle, MPH, and Huong Le, MPH, for their assistance in statistical analysis. In support of their research for or preparation of this manuscript, one or more of the authors received
grants or outside funding from Sanofi-Aventis, Inc. None of the authors received payments or other benefits
or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid
or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational
institution, or other charitable or nonprofit organization with which the authors are affiliated or
associated.
Background: Intra-articular injections of hyaluronans have been shown to be safe and effective for the
treatment of pain associated with osteoarthritis of the knee. This pilot study was undertaken to gather
preliminary data on the efficacy and safety of five weekly intra-articular injections of Hyalgan (sodium
hyaluronate; molecular weight, 500 to 730 kDa) as compared with saline solution for the treatment of pain
associated with osteoarthritis of the ankle.
Methods: Twenty patients at two test sites were randomized with use of a double-blind (blinded observer),
saline solution-controlled, parallel experimental design. Patients were randomized to receive five weekly
intra-articular injections of either 1 mL of sodium hyaluronate (10 mg/mL) or 1 mL of phosphate-buffered
saline solution into the ankle joint. The primary outcome measurement was the ankle osteoarthritis score.
Several secondary outcome measures also were assessed.
Results: Significant improvement in the mean ankle osteoarthritis score from baseline was seen at all
follow-up visits from one to six months in both the sodium hyaluronate group and the saline solution group
(p < 0.0001). In addition, five of nine patients in the sodium hyaluronate group had >30 mm of improvement
in this score, compared with one of eight patients in the control group. No withdrawals were directly attributable to the injections of sodium hyaluronate or saline solution, and no severe medication-related adverse events were observed.
Conclusions: The present study suggests that five weekly intra-articular injections of sodium hyaluronate
(molecular weight, 500 to 730 kDa) are well tolerated, can provide sustained relief of pain, and can improve function in patients with osteoarthritis of the ankle. These findings are consistent with those of previously published studies involving intra-articular injections of sodium hyaluronate in other joints, but they require confirmation in a large, randomized, saline solution-controlled study.
Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of
evidence.
Research article
Inhibition of antithrombin by hyaluronic acid may be involved in the pathogenesis of rheumatoid arthritis
Xiaotian Chang1 , Ryo Yamada1 and Kazuhiko Yamamoto1, 2
1Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan
2Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Arthritis Res Ther 2005, 7:R268-R273 doi:10.1186/ar1487
Published 11 January 2005
Abstract
Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis, proinflammatory processes,
and proliferation of fibroblast-like cells. Abnormalities in these processes are primary features of
rheumatoid arthritis (RA) in synovial tissues. Tissue destruction in joints causes the accumulation of
large quantities of free hyaluronic acid (HA) in RA synovial fluid. The present study was conducted to
investigate the effects of HA and several other glycosaminoglycans on antithrombin, a plasma inhibitor of
thrombin. Various glycosaminoglycans, including HA, chondroitin sulfate, keratan sulfate, heparin, and
heparan, were incubated with human antithrombin III in vitro. The residual activity of antithrombin was
determined using a thrombin-specific chromogenic assay. HA concentrations ranging from 250 to 1000 μg/ml
significantly blocked the ability of antithrombin to inhibit thrombin in the presence of Ca2+ or Fe3+, and
chondroitin A, B and C also reduced this ability under the same conditions but to a lesser extent. Our study
suggests that the high concentration of free HA in RA synovium may block antithrombin locally, thereby
deregulating thrombin activity to drive the pathogenic process of RA under physiological conditions. The
study also helps to explain why RA occurs and develops in joint tissue, because the inflamed RA synovium is
uniquely rich in free HA along with extracellular matrix degeneration. Our findings are consistent with those of others regarding increased coagulation activity in RA synovium.
Effects of Different Hyaluronic Acid Products on Synovial Fluid Levels of Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1 in Knee Osteoarthritis
Saliha Karatay1, Ahmet Kiziltunc2, Kadir Yildirim1, Rabia Cerrah Karanfil1 and Kazim Senel1
1 Department of Physical Medicine and Rehabilitation and 2 Department of Biochemistry, Medical Faculty, Atatürk University, Erzurum, Turkey
Address correspondence to Dr. Saliha Karatay, Atatürk Üniversitesi, Tip Fakültesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dali, 25240 Erzurum, Turkey; tel 90 442 236 1212/ 1625; fax 90 442 236 1301; e-mail: skaratay73@hotmail.com
Abstract
The aim of this study was to evaluate the effects of different hyaluronic acid (HA) forms on synovial fluid levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) during the treatment of patients with knee osteoarthritis (OA). Forty patients were randomly assigned to 2 groups that were treated with native sodium hyaluronate (group I) or cross-linked hylan G-F 20 (group II). Clinical evaluations and synovial fluid aspirations were performed before the 1st injection (baseline), the 2nd injection (week 1), the 3rd injection (week 2), and at 1 week after the 3rd injection (week 3). Synovial fluid levels of both ICAM-1 and VCAM-1 were significantly reduced at weeks 1 to 3, compared to the baseline values. The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index was used for clinical evaluations; the WOMAC pain score and physical function score were progressively improved at weeks 1 to 3 in both groups; the WOMAC stiffness score was significantly improved at week 3 in both groups. No significant differences were noted between the 2 treatment groups in respect to ICAM-1 levels, VCAM-1 levels, WOMAC pain score, stiffness score, or physical function score at any time. The decreased ICAM-1 and VCAM-1 levels after intra-articular HA injection may help to explain the anti-inflammatory effects of HA therapy in knee OA.
J Biomech. 2005 Mar;38(3):503-7.
Hyaluronic Acid Diminishes The Resistance To Excursion After Flexor Tendon Repair: An In Vitro Biomechanical Study
Akasaka T, Nishida J, Araki S, Shimamura T, Amadio PC, An KN.
Department of Orthopaedic Surgery, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka
020-8585, Japan.
Adhesion between the tendon and tendon sheath after primary flexor tendon repair is seen frequently, and
postoperative finger function is occasionally unsatisfactory. A reduction of the friction may facilitate
tendon mobilization, which in turn may reduce the risk of the adhesion and restriction of range of motion. We considered the possibility of utilizing the hyaluronic acid (HA) as a lubricant.
To evaluate the effect of HA, the gliding resistance between the canine flexor digitorum profundus tendon
repaired by a modified Kessler suture technique with running epitendinous suture and the annular pulley located on the proximal phalanx (corresponding to the A2 pulley in humans) was evaluated and compared before and after administration of HA. The HA solution measurement groups were identified as follows; intact tendon as a control; repaired tendon; tendon soaked in 0.1, 1, and 10mg/ml HA. The resistance increased after repairing, then it decreased after soaking in 10mg/ml HA solution. The results of this study revealed that HA diminishes the excursion resistance after flexor tendon repair. We believe that some style of administration of the HA might reduce the excursion resistance and prevent adhesion until the synovial surface is fully developed.
PMID: 15652548 [PubMed - in process]
Dermatol Surg. 2003; 29(6):588-95 (ISSN: 1076-0512)
A Randomized, Double-Blind, Multicenter Comparison Of The Efficacy And Tolerability Of Restylane Versus Zyplast For The Correction Of Nasolabial Folds.
Narins RS; Brandt F; Leyden J; Lorenc ZP; Rubin M; Smith S
Dermatology and Laser Center, White Plains, New York, USA. rsnmd@worldnet.att.net
BACKGROUND: Bovine collagen is extensively used for facial soft tissue augmentation but provides only temporary correction and can cause hypersensitivity reactions. Hyaluronic acid derivatives potentially offer improved longevity of correction and a reduced risk of immunogenicity and hypersensitivity.
OBJECTIVE: To compare the efficacy and safety of nonanimal stabilized hyaluronic acid gel (Restylane; Q-Med, Uppsala, Sweden) with that of bovine collagen (Zyplast) for treatment of nasolabial folds.
METHODS: One hundred thirty-eight patients with prominent nasolabial folds were randomized to treatment with hyaluronic acid gel and bovine collagen on contralateral sides of the face. Treatments were repeated at 2-week intervals, as required, to achieve "optimal cosmetic result" (baseline). Outcomes were evaluated by a blinded investigator at 2, 4, and 6 months after baseline. RESULTS: Less injection volume was required for "optimal cosmetic result" with hyaluronic acid gel than with bovine collagen, and patients and investigators judged hyaluronic acid gel to be more effective in maintaining cosmetic correction. The investigator-based Wrinkle Severity Rating Scale and Global Aesthetic Improvement Scale assessments at 6 months after baseline indicated that hyaluronic acid gel was superior in 56.9% and 62.0% of patients, respectively, whereas bovine collagen was superior in 9.5% and 8.0% of patients, respectively. The frequency, intensity, and duration of local injection-site reactions were similar for the two products.
CONCLUSION: Nonanimal stabilized hyaluronic acid provides a more durable aesthetic improvement than bovine collagen and is well tolerated.
nOsteoarthritis Cartilage. 2006 Mar;14(3):286-94. Epub 2005 Nov 23.
Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial.
Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF.
Southwest College Research Institute, Southwest College of Naturopathic Medicine and Health Sciences, Tempe, AZ 85282, USA. l.kim@scnm.edu
OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the second most common cause of long-term disability among middle-aged and older adults in the United States. Methylsulfonylmethane (MSM) is a popular dietary supplement used as a single agent and in combination with other nutrients, and purported to be beneficial for arthritis. However, there is paucity of evidence to support the use of MSM.
METHODS: A randomized, double-blind, placebo-controlled trial was conducted. Fifty men and women, 40-76 years of age with knee OA pain were enrolled in an outpatient medical center. Intervention was MSM 3g or placebo twice a day for 12 weeks (6g/day total). Outcomes included the Western Ontario and McMaster University Osteoarthritis Index visual analogue scale (WOMAC), patient and physician global assessments (disease status, response to therapy), and SF-36 (overall health-related quality of life).
RESULTS: Compared to placebo, MSM produced significant decreases in WOMAC pain and physical function impairment (P<0.05). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM also produced improvement in performing activities of daily living when compared to placebo on the SF-36 evaluation (P<0.05).
CONCLUSION: MSM (3g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed.
PMID: 16309928 [PubMed - indexed for MEDLINE]
1: Yakugaku Zasshi. 2006 Apr;126(4):297-300.
[Effect Of Orally Administered Chondrosine On Uptake Of 35S Sulfate Into Rat Cartilage]
[Article in Japanese]
Kusano S, Igarashi N, Sakai S, Toida T.
Fuji-Sangyou Co., Ltd., Marugame City, Japan.
Chondroitin sulfate is widely distributed in animal tissues and possibly plays an important role in different types of metabolic reactions as well as protecting joints, the internal wall of blood vessels, skin, bone, etc. In cartilage, glycosaminoglycans have a protective function; in particular, chondroitin sulfate stabilizes fibrous and cellular elements of the connective tissue and, at the same time, lubricates and protects the membranes in joints. Recently, chondroitin sulfate has been used as a nutraceutical for the treatment of joint diseases such as osteoarthritis, although acidic and large molecules such as chondroitin sulfate might not be able to be absorbed through digestive apparatus such as the intestine. In this study, we investigated the effects of orally administered chondrosine derived from shark chondroitin sulfate on the uptake of inorganic (35)S sulfate into rat cartilage and found that chondrosine stimulates the incorporation of (35)S sulfate into cartilage compared with intact chondroitin sulfate.
PMID: 16596020 [PubMed - indexed for MEDLINE]
1: Am J Physiol Cell Physiol. 2006 Aug 9; [Epub ahead of print]
Glucosamine protects neonatal cardiomyocytes from ischemia-reperfusion injury via increased protein-associated O-GlcNAc.
Champattanachai V, Marchase RB, Chatham JC.
Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States.
Increased levels of protein O-linked-N-acetylglucosamine (O-GlcNAc) have been shown to increase cell survival following stress. Therefore, the goal of this study was to determine whether in isolated neonatal rat ventricular myocytes (NRVMs) an increase in protein O-GlcNAcylation resulted in improved survival and viability following ischemia/reperfusion (I/R). NRVMs were exposed to 4 hours ischemia and 16 hours of reperfusion and cell viability, necrosis, apoptosis and O-GlcNAc levels assessed. Treatment of cells with glucosamine, hyperglycemia or O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc), an inhibitor of O-GlcNAcase, significantly increased O-GlcNAc levels and improved cell viability following I/R; glucosamine and hyperglycemia also reduced both necrosis and apoptosis compared to untreated cells following I/R. Alloxan, an inhibitor of O-GlcNAc transferase, markedly reduced O-GlcNAc levels and exacerbated I/R injury. The improved survival with hyperglycemia was attenuated by azaserine, which inhibits glucose metabolism via the hexosamine biosynthesis pathway. Reperfusion in the absence of glucose reduced O-GlcNAc levels on reperfusion compared to normal glucose conditions and decreased cell viability. O-GlcNAc levels significantly correlated with cell viability during reperfusion. The effects of glucosamine and PUGNAc on cellular viability were associated with reduced calcineurin activation as measured by nuclear NFAT translocation suggesting that increased O-GlcNAc levels may attenuate I/R induced increase in cytosolic Ca(2+). These data support the concept that, activation of metabolic pathways leading to an increase O-GlcNAc levels is an endogenous stress activated response, and that augmentation of this response improves cell survival. Thus, strategies designed to activate these pathways may represent novel interventions for inducing cardioprotection.
PMID: 16899550 [PubMed - as supplied by publisher]
Prolonged vitamin C supplementation and recovery from demanding exercise.
Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, Powell JR., UK, 268. Int J Sport Nutr Exerc Metab. 2001 Dec;11(4):466-81.
In this study 16 males were given either a placebo or vitamin C twice/day for 2 weeks. After 14 days of supplements, the subjects performed a 90-minute exercise test. Those taking supplementation had less muscle soreness and better muscle function after unaccustomed exercise.
