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Hyaluronate Injections for Knee OA

A 56-year-old woman presents with a 2-year history of right knee pain that she rates as moderate in intensity. Initially, the patient fell at work and developed pain in her hip, knee and foot. In addition, she aggravated a chronic back condition with associated radicular symptoms. Prior to her clinic visit, she had been evaluated and was receiving chiropractic and physical therapy treatments with gradual improvement of her symptoms, particularly her back, hip and foot. Unfortunately, her knee did not respond as favorably.

She had tried various over-the-counter anti-inflammatories and acetaminophen with little success. The pain had worsened and was affecting her activities of daily life, including ambulation, stair climbing and descending, squatting and kneeling. Her knee pain was limiting her exercise capacity. Furthermore, she noted stiffness, especially in the early morning and with prolonged sitting and driving. She had no mechanical symptoms, such as locking or catching, and no history of any prior knee injuries or surgeries. The patient’s medical history included coronary artery disease and angioplasty with stent placement 2 years earlier.

On exam, the patient had a body mass index (BMI) of 33.7 kg/m2. She walked with a limp. The right knee examination demonstrated range of motion from 0 to 125 degrees with pain on extreme flexion. No erythema, warmth or swelling was apparent. Crepitus was noted, but no effusion was present. All ligamentous and meniscal stress tests were negative. Patella facet and medial joint-line tenderness to palpation were evident. Hip and ankle examinations were normal. Her back had a good range of motion with some mild pain on hyperextension. Neurologic evaluation was normal.


An MRI study was performed a month prior to the patient’s visit and revealed a popliteal cyst, as well as mild-moderate patellofemoral and medial compartment cartilage loss, but no ligamentous pathology. A degenerative posterior horn medial meniscus tear was identified. Based on her clinical examination and radiographic studies, a diagnosis of knee osteoarthritis (OA) was made, and the patient was educated about her condition. Subsequently, additional conservative treatment options were discussed, including a weight-loss program, activity modification (e.g., low-impact activities), topical agents and additional pain medications (e.g., tramadol). However, given her pain intensity at the time of presentation, a corticosteroid injection was performed.


The patient presented 6 weeks later with 50% improvement in her knee symptoms. Once again, additional counseling was provided about OA. She subsequently lost 7 pounds with dieting and exercise. She was able to get back to full duty at work and perform most of her daily activities with little, if any, pain. She was advised to continue her current course of conservative OA management.

The patient did extremely well for 4 to 6 months before her symptoms began to recur. She once again developed difficulty with her daily activities, including ambulation, standing, sitting, driving, and climbing and descending stairs. No mechanical locking or catching was reported. Since her OA symptoms had worsened and were not responsive to previously recommended conservative OA options alone, a course of intra-articular hyaluronic acid injections was recommended. A complete series was provided with excellent relief of her symptoms for several months. At follow-up over the next 2 years, the patient’s knee OA symptoms remained reasonably well-controlled.


Hyaluronic acid (HA) injections have been used along with other knee OA treatments, including steroid injections, since 1997, when they were approved by the FDA for use in humans as a medical device, not as a drug. However, only fairly recently have these injections truly caught on as a viable option for treating patients with knee OA.

HA injections can provide significant pain relief for some patients who have not improved with other knee OA treatments. Meta-analysis of 76 trials that evaluated the efficacy of HA suggested that pain relief is typically demonstrable 5 to 13 weeks after injection.1-4 The magnitude of relief ranged from 28% to 54% for pain and 9% to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted compared with intraarticular corticosteroids. Steroid injections tended to work more effectively for immediate, short-term relief of knee OA pain.

The basis of recommending HA injections stems from the role played in the joint by healthy synovial fluid, which facilitates joint movement, acts as a transport medium for nutrients and waste products, and helps protect and cushion the joint from trauma. HA is a major component of normal synovial fluid and likely provides viscoelastic properties that aid in the proper functioning of the joint. HA may facilitate load absorption (i.e., elasticity) during rapid movements and provide lubrication (i.e., viscosity) during slow movements.5

Furthermore, the properties of synovial fluid change in patients with knee OA. Thus, the notion that injecting HA into the joint might have benefit is intuitively appealing.

Currently, however, the exact mechanism by which HA produces clinical improvement remains to be elucidated. Potential mechanisms of action have been proposed, including restoring the viscoelastic properties of synovial fluid, suppressing inflammation, providing nociceptor analgesia, stimulating endogenous synoviocyte HA production, stimulating chondrocyte growth and collagen synthesis, and decreasing chondrocyte apoptosis or degradation.6-9

Understanding these potential mechanisms of action of HA injections could help explain why their clinical benefit is longer than the residence time of HA in the joint. Transit time of most HA products in the knee joint is only 1 to 2 days. How much effect the molecular weight of a particular HA injection product has on its overall efficacy is greatly debated. The uncertainty of the exact mechanism(s) of action and lack of effectiveness in some patients with advanced OA have caused some experts to question the efficacy of HA injections for knee OA treatment.


The safety profile of HA injections has been well documented compared with the long-term use of steroid injections. HA injections are considered safer than other pharmacologic therapies for knee OA. With no known drug interactions, HA is an excellent option for patients on multiple medications. Repeat cycles of HA injections have proven safe and are FDA approved for retreatment. Most patients tolerate repeat treatment cycles extremely well.

Adverse effects are rare and tend to be localized to the joint; these include local joint swelling, pain, erythema and warmth that occur in 1% to 3% of patients. Patients should be counseled about these potential side effects and to manage them with ice, NSAIDs and rest. Rarely, a pseudoseptic reaction can occur and mimic a joint infection. Typically, such reactions occur within 24 to 48 hours postinjection. These severe inflammatory reactions frequently require more aggressive treatment, including joint aspiration and steroid injection and possibly an arthroscopic lavage of the joint.

Avian-based HA products should be avoided in patients with allergies to avian proteins, feathers and egg products. Patients with a history of hypersensitivities to HA preparations need to be evaluated on a case-by-case basis before repeat injections are considered. HA injections should not be given to patients with an infection or skin disease around the injection site, and should not be used if venous or lymphatic stasis is present in the leg or if the joint is severely inflamed.11-20

Injection Technique

The technique for injecting HA products is similar to that for steroids. Injections can be performed through various portals of entry around the joint. The most accurate site for knee injection is still under debate. Arthrocentesis is typically performed using a lateral mid-patella approach. If a patient presents with an effusion, an arthrocentesis with a steroid injection prior to treating with an HA product should be considered first, since many clinicians anecdotally consider HA injections less effective in the presence of large joint effusions. Having the patient follow up in 1 to 2 weeks to begin HA injections may yield a better outcome.

Timing HA

The appropriate time to use HA injections in the treatment of knee OA is unclear. Each patient’s treatment must be individualized and considered carefully (Figure). Currently, 6 HA products are available and FDA approved for treating knee OA in the United States (Table). These products are approved only for knee OA; off-label uses for OA in other joints (e.g., shoulder or hip) are frequent and have led to numerous studies and investigations.


The American College of Rheumatology has recently released updated recommendations for the use of nonpharmacologic and pharmacologic therapies in OA of the hand, hip and knee. HA injections are conditionally recommended for treatment of knee OA in those patients who do not have a satisfactory response to initial conservative measures including a trial of full-dose acetaminophen. No recommendation was made for use of HA injections in patients with hand or hip OA secondary to lack of data from randomized controlled studies.8

In addition, the timing of HA injections for knee OA has come under scrutiny by many insurance companies, including Medicare, which has released guidelines on appropriate timing and implementation. Health care providers should familiarize themselves with these criteria. Appropriate chart documentation and coding are critical for approval and reimbursement. Many insurance companies have adopted similar policies and procedures regarding HA injections.

In the patient from the case study, HA injections were believed to be more appropriate at that time in her treatment than any type of surgery. The patient’s knee OA was not severe enough to warrant a knee arthroplasty. In addition, arthroscopy was not believed to be justified due to the lack of any significant mechanical symptoms. The potential risks of an arthroscopy worsening her condition outweighed the potential benefits of such a procedure.


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