Osteoarthritis (OA) is a prevalent cause of chronic pain and disability and a major public health concern.1 NPs and PAs must be aware of the clinical signs and symptoms associated with OA, as well as the range of available treatments. This article focuses on viscosupplementation (VS), or the replacement of hyaluronan, a major component of synovial fluid, for the treatment of knee OA.
Description of OA
OA is a chronic, progressive and intermittently painful joint disease. It is the most common form of arthritis in the United States, affecting more than 27 million people.1 OA typically occurs during the second half of life and produces impairment of joint function in the hands, knees and hips.1 Risk factors include age older than 45, female gender, previous joint injury (especially to the knee), increasing body mass index (especially at an early age), higher bone mass, malalignment, prior meniscal surgery, manual labor, construction work, lifting more than 10 kg 10 times a week, climbing more than 15 flights of stairs daily, squatting, and side knee-bending.1,2 Patients with OA experience gradually increasing difficulty with daily activities, employment and quality of life, and incur higher medical costs for the treatment of both OA and associated comorbid conditions.1
Despite the higher risk with increasing age, OA is not simply a normal process of "wear and tear."3 OA is an inflammatory disease associated with structural changes to the entire joint, including degeneration and loss of cartilage as well as bone hypertrophy.3 Further damage manifests as synovial inflammation, degeneration of ligaments and menisci, swelling of the joint capsule, and changes to muscles and nerves.3 Hyaline cartilage lacks nerve endings and blood vessels, and adult cartilage cells (chondrocytes) are normally quiescent. In OA, chondrocytes become activated with increased matrix-degrading enzyme production, leading to chondrocyte hypertrophy and cartilage calcification, and the formation of blood vessels and sensory nerves, all of which can contribute to pain.3,4
Because no cure for OA exists, treatments are intended to relieve pain, improve function and quality of life, and delay disease progression.5,6 Treatment may begin with nonpharmacologic strategies such as exercise, weight loss and physical therapy, and progress to medications including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, tramadol and opioids.5 Intra-articular glucocorticoid injections are usually considered next, and total joint replacement (TJR) is a last resort.5 Viscosupplementation by hyaluronic acid (HA) injection is another intra-articular option.4 Administration of HA is intended to restore metabolic homeostasis in the joint while decreasing enzymatic cartilage destruction.4
Figure 1: This x-ray shows mild to moderate medial joint space narrowing with osteophyte formation on the tibial plateau and faint chondrocalcinosis in the medial compartment. Foreign body appearance in lateral compartment not seen in joint on lateral view (not shown). Courtesy the author
Figure 2: Lateral flexed knee injection approach for a seated patient. Courtesy the author
Figure 3: Superior lateral extended knee injection approach. Courtesy the author
Figure 4: Medial extended knee injection approach. Courtesy the author
Figure 5: Injection location (black dot) at the midpoint of the patellofemoral joint. P = patella; F = femur; T = tibia; FP = fat pad. Redrawn with permission from reference 6.
Several HA preparations have been approved by the FDA. Currently available viscosupplement products are based on naturally occurring hyaluronan derived from chicken combs or bacterial cells; two formulations are synthetic modifications of hyaluronan (Table 1).7-12 The typical treatment course is one injection per week for either 3 or 5 weeks,9-12 but more recently approved therapies are given as single injections.7,8
Efficacy and Safety
HA products used for VS are approved to treat pain associated with knee OA.7-12 A Cochrane review of 76 trials of various hyaluronan or hylan preparations for knee OA found that viscosupplementation improved joint pain and function from baseline.13 Improvement ranged from 28% to 54% for pain and 9% to 32% for function at 5 to 13 weeks after injection.13 HA therapy had superior efficacy to placebo, equivalent efficacy compared with NSAIDs, and longer-lasting efficacy than intra-articular corticosteroids.13 Authors of a recent meta-analysis did not conclude that HAs were an effective knee OA treatment, although the reported class effect size met their cutoff for a clinically therapeutic effect.14
Intra-articular HA is well tolerated. The most common adverse events (AEs) are transient, mild injection-site reactions with a frequency similar to that with intra-articular injections of saline or corticosteroids.5 Rates of systemic events such as gastrointestinal and cardiovascular complications are the same or even lower for HA recipients than for controls.4,13 A comprehensive review concluded that HA caused more local reactions than other active treatments, but fewer systemic AEs and no major safety concerns.13 Serious AEs are rare.5
Pseudoseptic arthritis, defined in the medical literature as a severe acute inflammatory reaction, has been a concern with cross-linked HA.15 However, limited evidence exists that these reactions are unique to cross-linked HA. If severe reactions occur with any formulation, distinguish whether severe pain and joint effusion represent true sepsis, pseudogout, a reaction to the intra-articular injection itself, or an adverse reaction to HA.7,15 In the Cochrane review, cross-linked hyaluronan had a good safety profile compared with placebo and other treatment strategies, including corticosteroid injections, NSAIDs and routine clinical care.13 No instances of pseudoseptic arthritis were mentioned.13 True joint infections or crystalline arthropathy with cross-linked HA are rare.7
Certain patients are more appropriate than others for VS (Table 2).5 In addition, many patients with comorbid conditions cannot tolerate acetaminophen (e.g., because of gastrointestinal upset and concern over liver toxicity), NSAIDs including COX-2 inhibitors (e.g., gastrointestinal disease, renal toxicity, cardiovascular issues), or corticosteroids (e.g., preexisting joint infection, unstable diabetes, prior history of sepsis).5
Inadequate response to maximal doses of pharmacologic monotherapy or combination therapy with acetaminophen, NSAIDs, COX-2 inhibitors or steroid injections may be another indication for viscosupplementation.5,16 Intra-articular corticosteroid injections offer prompt pain relief but have a shorter duration of action than HA injection.5 In addition, possible joint infection or cartilage damage with repeated steroid treatments is a concern and may necessitate limiting this type of injection therapy to no more than four times per year.5
In addition to comorbid conditions and the previous response to therapy, age is a consideration. The odds that a patient will undergo TJR increase by 13% for each year after age 60.17 Patients younger than 60 are therefore better candidates for HA because they generally are not eligible for TJR.17 Further, early joint replacement may also necessitate the need for another TJR or revision as the replaced joint ages.18 Finally, patients may also decline TJR for many reasons, including other co-morbid conditions, the expense involved, and/or the prolonged recovery and rehabilitation process.17 In my clinical experience, I have also known patients to decline TJR because of perceived postoperative complications or stories from friends who did not tolerate the surgery well. Patients of an advanced age may simply choose not to undergo the surgery.
Viscosupplementation is also recommended as an earlier option in current OA treatment algorithms, particularly when combined with physical therapy and/or medications.19 Additionally, HAs are more effective in patients with less advanced versus more advanced OA.20,21 Complementary treatments with different modes of action are expected to improve both efficacy and safety.19 HA preparations are advantageous in this scenario because they lack any known drug-drug interactions with common OA pain medications.4,15 Because hylan G-F 20 can delay the need for TJR in patients with advanced knee OA,18 combination therapy with intra-articular HA could delay or prevent the need for surgery.5,18,19
Proper HA injection technique is important to avoid painful reactions, blockage of synovial fluid flow, and joint infection.5,6,22 Several approaches to injection technique are possible; the method used at our clinic is described here. For a demonstration, view the video posted with the online version of this article at www.advanceweb.com/NPPA. Enter "Knee Osteoarthritis" in the Search box to locate it.
An x-ray showing joint space narrowing in a patient's injected knee is shown in Figure 1. Briefly, have the patient sit on the examining table with his or her knee flexed at 90 degrees. Locate the lateral tibial plateau, the lateral femoral condyle and inferolateral aspect of the knee cap; the medial boundary will be the infrapatellar tendon. Because the joint synovium is soft, you should feel a "give" in contrast to the underlying bone of the tibial plateau. To keep the knee flexed and provide the patient with a distraction while you are performing the injection, ask the patient to help by keeping the back of his or her leg touching the examining table. I place 1 or 2 ccs of 1% lidocaine just under the skin to create a bleb and then advance the needle to the synovium while depositing a small amount of lidocaine here also. I allow 1 to 2 minutes for the lidocaine to take effect to decrease pain associated with the injection (not all practitioners use this technique). Choices for needle size include 22- or 25- gauge23 1.5-inch needle, or a 21-gauge 2-inch needle.6 My preference is a 1.5-inch 22-gauge needle.
Other approaches reported in the medical literature include variations in patient position, anatomical approach and angle of approach to the joint. For example, the patient may be in a supine position (Figure 2) and the injection may be performed from the midpatella on the medial side of the knee, or from the superiolateral approach with the knee extended (Figure 3).23 One can also accurately use the midpatellar joint line with the knee extended (Figure 4).6,23 Other options are an approach with the patient seated and the knee flexed 30 to 40 degrees.22
Regardless of approach, the injection site should be marked for accuracy and then prepped with a sterile solution.23 The injection must be intra-articular and not into the fat pad, as shown in Figure 5.6 Research suggests that the proper injection site depends on internal changes in the joint due to the severity grade of OA.24
Use of imaging techniques such as fluoroscopy or ultrasound may improve the accuracy and efficacy of injection.6,22,25 In a study of 45 patients, ultrasound-guided knee injections were significantly more successful than "blind" injections (96% vs. 77% were properly placed within the joint cavity as determined by radiography).25 Sonographic guidance helped operators avoid injection into the fat pad and allowed immediate redirection of the needle if necessary.25
The success of injection without imaging also varies by approach used. A study of anteromedial, lateral patellar and modified Waddell approaches for knee OA indicated successful intra-articular placement in 62%, 70% and 86% of cases, respectively.24 Accuracy further fluctuates depending on the treated joint; a study cited a 100% high for the knee or elbow and a 77% low for the ankle; accuracy was 82% to 97% for the shoulder, wrist and metacarpophalangeal joint.26 Despite the generally cited efficacy of blind injection, note that anatomic landmarks are difficult to distinguish in certain populations, particularly obese patients, suggesting the need for imaging confirmation of needle placement.6
Supplies needed for injection include the vial or sterile syringe of HA or hylan G-F 20, povidone-iodine solution to prep the injection site, local anesthetic such as lidocaine and/or ethyl chloride spray (if necessary, depending on needle size), and the 1.5-inch or 2-inch injection needle.23 Joint effusion should be cleared before injection and may require an 18- or 20-gauge needle; hemostat clamps can aid in stabilizing the needle to facilitate both aspiration and HA injection with the same needle and injection site.23 Some practitioners, including myself, twist the barrel of the needle off with their fingers and forego the hemostat clamp. Intra-articular placement of the needle is easy to confirm when effusion is present because aspiration will yield synovial fluid.26
The incidence of OA is expected to rise with aging of the population and increasing rates of obesity. Potential consequences for patients include both lower quality of life and increased healthcare expenditures. In general, VS is an appropriate therapy for knee OA because VS is efficacious and well tolerated in many patients. VS may be given alone or combined with other therapies, has a longer duration of effect than steroid injections, and may have a better safety profile than oral pain medications. Importantly, injection technique is a critical aspect of treatment to achieve efficacy and avoid local side effects.
1. Centers for Disease Control and Prevention. A National Public Health Agenda for Osteoarthritis. http://www.cdc.gov/arthritis/docs/oaagenda.pdf
2. NIAMS. OA risk factors workshop. http://www.niams.nih.gov/funding/Funded_Research/Osteoarthritis_Initiative/oa_risk_factors_summ.asp
3. Loeser RF, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697-1707.
4. Goldberg VM, Goldberg L. Intra-articular hyaluronans: the treatment of knee pain in osteoarthritis. J Pain Res. 2010;3:51-56.
5. Arnold W, et al. Viscosupplementation: managed care issues for osteoarthritis of the knee. J Manag Care Pharm. 2007;13(4 Suppl):3-19.
6. Jackson DW, et al. Accuracy of needle placement into the intra-articular space of the knee. J Bone Joint Surg Am. 2002;84-A(9):1522-1527.
7. Synvisc-One (hylan G-F 20) Prescribing Information. Genzyme Biosurgery.
8. Gel-One (cross-linked hyaluronate) Prescribing Information. Seikagaku Corporation.
9. Hyalgan (sodium hyaluronate) Prescribing Information. sanofi-aventis US LLC.
10. Supartz (sodium hyaluronate) Prescribing Information. Seikagaku Corporation.
11. Orthovisc (sodium hyaluronate) Prescribing Information. Anika Pharmaceuticals.
12. Euflexxa (1% sodium hyaluronate) Prescribing Information. Ferring Pharmaceuticals.
13. Bellamy N, et al. Viscosupplementation for the treatment of osteoarthritis of the knee (review). Cochrane Database Syst Rev. 2006;CD005321.
14. Rutjes AW, et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med. 2012;157(3):180-191.
15. Goldberg VM, Coutts RD. Pseudoseptic reactions to hylan viscosupplementation: diagnosis and treatment. Clin Orthop Relat Res. 2004;419:130-137.
16. McHughes M, Lipman AG. Managing osteoarthritis pain when your patient fails simple analgesics and NSAIDs and is not a candidate for surgery. Curr Rheumatol Rep. 2006;8(1):22-29.
17. Zeni JA, Jr. et al. Clinical predictors of elective total joint replacement in persons with end-stage knee osteoarthritis. BMC Musculoskelet Disord. 2010;11:86.
18. Waddell DD, Bricker DC. Total knee replacement delayed with hylan G-F 20 use in patients with grade IV osteoarthritis. J Manag Care Pharm. 2007;13(2):113-121.
19. Langworthy MJ, et al. Conservative treatment modalities and outcomes for osteoarthritis: the concomitant pyramid of treatment. Phys Sportsmed. 2010;38(2):133-145.
20. Evanich JD, et al. Efficacy of intraarticular hyaluronic acid injections in knee osteoarthritis. Clin Orthop Relat Res. 2001;390:173-181.
21. Kemper F, et al. Tolerability and short-term effectiveness of hylan G-F 20 in 4253 patients with osteoarthritis of the knee in clinical practice. Curr Med Res Opin. 2005;21(8):1261-1269.
22. Waddell D, et al. Viscosupplementation under fluoroscopic control. Am J Med Sports. 2001;4:237-241,249.
23. Wen DY. Intra-articular hyaluronic acid injections for knee osteoarthritis. Am Fam Physician. 2000;62(3):565-70, 572.
24. Toda Y, Tsukimura N. A comparison of intra-articular hyaluronan injection accuracy rates between three approaches based on radiographic severity of knee osteoarthritis. Osteoarthritis Cartilage. 2008;16(9):980-985.
25. Im SH, et al. Feasibility of sonography for intra-articular injections in the knee through a medial patellar portal. J Ultrasound Med. 2009;28(11):1465-1470.
26. Lopes RV, et al. Accuracy of intra-articular injections in peripheral joints performed blindly in patients with rheumatoid arthritis. Rheumatology (Oxford). 2008;47(12):1792-1794.
Richard Pope is a physician assistant in the Department of Rheumatology at Danbury Orthopedic Associates in Danbury, Conn., and the president-elect of the Association of Family Practice PAs (www.afppa.org). He is the founder and past president of the Society of PAs in Rheumatology (rheumpas.org). Pope is an adjunct clinical professor for the PA program at Quinnipiac University in Hamden, Conn., the University of Bridgeport Physician Assistant Institute and the New York Institute of Technology. He has completed a disclosure statement and reports that medical writing support for this article was provided by Laura Ninger, ELS, and Susan Bijur, PhD, of Precise Publications, LLC. This support was funded by Sanofi Biosurgery. Pope is a member of the speaker bureaus for Sanofi Biosurgery and Takeda Pharmaceutical Company Limited, and a member of the advisory board for Pfizer.