Knee osteoarthritis (OA) is characterized by progressive degeneration of articular cartilage and subchondral bone that manifests clinically as pain and dysfunction. It is traditionally classified as a non-inflammatory arthritis, although localized inflammatory processes are present in certain stages of the disease.1
Primary knee OA is thought to be caused by repetitive mechanical stress, which initiates and perpetuates degeneration.2 Secondary OA is initiated by prior trauma, sepsis, or inflammatory conditions with resultant joint instability, incongruity of the articular surface, and/or altered cartilage metabolism and matrix composition.3
Epidemiology including risk factors and primary prevention
OA is the leading cause of musculoskeletal debility in the world and 11th highest contributor to global disability.4 Approximately 19-28% of Americans over the age of 45 have knee OA.5 Prevalence of knee OA peaks around the age of 50, with an average of 30 years of disease burden.4,6 Since the mid-20th century, prevalence of knee OA has doubled, even when controlling for age and BMI.7
Multiple local and systemic risk factors have been identified. Advanced age is the risk factor most associated with OA, with incidence rates increasing significantly over the age of 50.8 Obesity is another strong risk factor linked to knee OA, associated with significant rates of incidence and progression.9,10 Other risk factors include female sex, hormonal status, osteoporosis, ethnicity, genetic predisposition, dietary intake, muscle weakness, altered biomechanics, joint laxity/deformity, occupational factors, certain competitive sports, and previous trauma.11
The evidence for effective primary prevention of knee OA is somewhat limited; however, risk may be reduced through weight loss, regular exercise, prevention and management of osteoporosis.6,12,13,14
Recently, predictive models have been implemented in order to identify patients at risk for TKA. These models may help the rehabilitation team understand when a surgical referral is necessary. Many predictive variables are similar to those present for the development of early-stage OA: age, sex, race, and body-mass index. Other variables include history of knee arthroscopy, frequent knee pain, current use of analgesics, current use of glucosamine, and the WOMAC pain score. The Kellgren-Lawrence grade has recently been added into this model with improved predictive performance compared to models without radiographic scores.15
Initiation and progression of knee OA is a consequence of one or more factors including loss of cartilage matrix, alteration of the extracellular matrix, and chondrocyte injury. The disease may also involve focal macroscopic chondral or subchondral injury. Cartilage edema may develop secondary to increased chondrocyte activity in response to such injury. Over time and with repetitive injury, disruption of matrix equilibrium leads to a catabolic shift; the cartilage thus begins to lose structural integrity, resulting in progressive surface fibrillations and erosions. Resultant breakdown products stimulate synovial inflammation, immune cell activity, and high levels of proinflammatory cytokines as the disease progresses. The role of inflammation in symptom and disease progression in knee OA is unclear, but evidence indicates these factors exacerbate cartilage erosion.16 Inflammatory factors such as interleukins, tumor necrosis factor, and prostaglandin E2 have been linked to further matrix-degrading enzyme reproduction, oxidation of molecules, and decreased matrix synthesis. These factors may also play a significant role in pain produced by nociceptors located throughout the joint capsule.17
OA phenotypes, or subtypes of OA that share distinct pathobiological and pain mechanisms as a result of their structural and functional consequences, is a growing area of study. Researchers are hoping to identify whether treatment efficacy may differ between OA phenotypes with goals to tailor treatment strategies to individual phenotypes rather than treating OA as a homogeneous condition.
Roemer et al proposed five structural phenotypes in their 2022 study: the inflammatory, meniscus-cartilage, subchondral bone, atrophic, and hypertrophic phenotypes. Classification systems currently consist of a variety of variables, such as biochemical markers, imaging, and pain characteristics.18
Trajerova et al also proposed OA phenotypes specific to the pattern of immune cells and proteins in knee synovial fluid. These included: activated phenotype (high T-lymphocytes, low monocyte-macrophage, low neutrophils), lymphoid progressive (high neutrophils, low lymphocytes and monocyte-macrophages), myeloid progressive (high NK and monocyte-macrophage lineage cells, low T-lymphocytes), and the aggressive phenotype (high cell lines throughout). Additional research is needed to understand the clinical significance of these phenotypes with regards to targeted therapeutic treatments.19
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Knee OA is characterized by an insidious onset of pain and dysfunction related to progressive limitations in mobility. Symptoms worsen over time, typically in a stepwise fashion. Patients often report symptoms with ambulation, transfers, and ascending stairs. Knee stiffness or “locking” secondary to the formation of loose bodies, degenerative meniscal tears, and osteophyte formation may occur.20 These can significantly increase pain severity, hinder activities of daily living, and reduce quality of life.
Specific secondary or associated conditions or complications
OA has been linked to deformities of the knee joint, most often a varus deformity.21 Secondary altered biomechanics during functional tasks may lead to the development of pes anserine and/or trochanteric bursitis. Knee OA has also been associated with greater prevalence and increased risk of developing frailty in the elderly.22 Knee OA may alter gait patterns by aberrantly loading the contralateral joint during ambulation, which may result in secondary OA in the opposite hip and knee. Associated health effects such as weight gain and reduced cardiovascular health may arise from decreased activity levels.23,24 Increasing evidence has found that knee OA with pain – especially in females, Caucasians, age < 65 years, and BMI > 30 – is associated with a significant increase in premature all-cause mortality.10
Essentials of Assessment
The most common presenting symptoms include pain and dysfunctional movement due to stiffness, decreased range of motion, and subjective joint instability. Onset is gradual and typically occurs in males age >40 years and females in perimenopause or older. Individuals may report involvement of one or both knees. Pain is often described as dull and may be localized or involve the whole knee. Initial pain occurs with standing or walking but may become persistent at rest with disease progression. It is important to note that pain may fluctuate over time, and it is not uncommon to have prolonged periods without pain followed by exacerbations lasting weeks to months.1,25
Inspection: Erythema, warmth, and swelling are mild if present. Assessment of stance and gait may demonstrate contralateral asymmetry in the setting of joint hypertrophy.
Palpation: Tenderness to palpation is often present at the at joint line (most commonly medial) or patellofemoral articulation. An effusion may be palpable at the suprapatellar bursa with associated ballottement of the patella. Bony enlargement may also be present.
Range of motion (ROM): Active and passive movement may elicit pain and crepitus. Flexion may be reduced in early disease, with limitations in extension typically occurring in later stages.
Strength: Manual muscle testing may be limited secondary to pain. Muscle atrophy and weakness may be seen over time secondary to avoidance of painful activities. Weakness is most prominent in the quadriceps (specifically the distal vastus medialus obliqus) and associated hip musculature but may also involve the hamstrings.26
Special Tests: Instability may be noted on valgus/varus stress testing. Dynamic functional assessments such as the single leg squat may demonstrate misalignment of the kinetic chain and/or altered patellar tracking.1,25
Clinical functional assessment
Performance-based tests and patient-reported outcomes measures (PROMs) have been utilized to evaluate pain and function in individuals with knee OA. The Osteoarthritis Research Society International (OARSI) recommends a set of five performance-based tests:
- 30s Chair Stand Test
- 40m Fast-paced Walk Test
- Stair Climb Test
- Timed up & Go Test
- 6 Minute Walk Test
Evidence supports the use of these assessments as clinically significant predictors of future health. A description of the tests, copies of scoring sheets, and clinimetric data can be accessed via the ORSI website.27
PROMs have also been developed and validated to assess severity and treatment outcomes specific to knee OA. The following measures are most commonly used27
- Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) – a 24-item assessment of pain, stiffness, and physical function in knee OA
- Knee injury and Osteoarthritis Outcome Score (KOOS) – a 42-item assessment of pain, symptoms, function in daily living, function in sports/recreation, and knee-related quality of life
- Visual Analog Scale (VAS) – a single-item measure of pain severity that can be used for OA in any joint
Knee OA is a clinical diagnosis established by a thorough history and physical examination, therefore there are no diagnostic blood or urine tests. Joint aspiration is not routinely indicated, however fluid obtained from the joint may be useful in distinguishing OA from other causes of joint pain, such as rheumatoid arthritis.25 Synovial fluid analysis consistent with OA should have <2000 leukocytes and lymphocytic predominance.1
The European Alliance of Associations for Rheumatology (EULAR) and the American College of Radiology (ACR) have released recommendations for clinical indications of imaging in knee OA. Plain radiography is first-line due to its fast acquisition, widespread availability, and low cost. Furthermore, radiography allows optimal visualization of characteristic OA findings including osteophytes, subchondral sclerosis and cysts, and joint space narrowing (JSN). Imaging can be obtained in non-weight-bearing (NWB) or weight-bearing (WB), and in full extension or semiflexion views. WB and semiflexion anteroposterior (AP) views have been shown to more accurately reflect OA-related structural damage and better correlate with arthroscopic findings.28
The Kellgren-Lawrence (KL) system is accepted as the standard by the World Health Organization and is most commonly used. Radiographic images are graded as follows28
- Grade 0 (No OA): No radiographic findings of OA
- Grade 1 (Doubtful OA): Doubtful JSN and possible osteophytic lipping
- Grade 2 (Mild OA): Definite osteophytes and possible JSN
- Grade 3 (Moderate OA): Moderate multiple osteophytes, definite JSN, some sclerosis, and possible deformity of bony contour
- Grade 4 (Severe OA): Large osteophytes, marked JSN, severe sclerosis, and definite deformity of bony contour
When considering the role of imaging in the diagnosis and management of knee OA, it is important to recognize that radiographic evidence of structural damage does not imply clinical disease.25
Supplemental assessment tools
Computed tomography (CT) and Magnetic Resonance Imaging (MRI) can be used as second-line imaging for knee OA. CT has a higher sensitivity for osteophytes, subchondral cysts, and tricompartmental disease than radiographs, however its utility is limited by radiation exposure, expense, and NWB positioning. MRI avoids exposure to radiation while allowing for superior characterization of soft tissues. In comparison to radiographs, MRI allows improved detection of early structural changes in OA, however there is an associated risk of overdiagnosis given the high prevalence of MRI findings in asymptomatic individuals.28
In recent years, there has been growing support for the use of Ultrasound (US) in OA assessment. US is more accessible and cost-effective in comparison to MRI, while providing detailed imaging of the soft tissues surrounding the joint (including meniscus, ligament/tendon, cartilage, synovium, and fluid collections). Furthermore, US has emerged as a valuable interventional tool for improving targeted precision and avoiding neurovascular structures during procedures such as intra-articular injections.29
Early predictions of outcomes
Baseline rates of incidence and progression of knee OA have been estimated to be 2.5% and 3.6% per year, respectively.9 Predictors of disease progression include age, obesity, the presence of OA in other joints, previous knee injury, history of regular sports progression, and varus deformity of the knee.9,30 Radiographic features of disease, including Kellgren-Lawrence scale severity, presence of chondrocalcinosis, and osteophyte score, are also predictive of progression.30 Increased physical activity (of any intensity level) and increased quadriceps muscle strength are associated with decreased progression of disability in adults with knee OA.31,32
Aquatic access to resistance exercise equipment and safe walking routes or treadmills can help patients maintain active lifestyles. Aquatic exercise is a viable option for those patients experiencing significant pain with land-based exercise.32-34 Ground floor habitation or living in elevator buildings can help improve accessibility and further promote patient mobility.
Social role and support system
It is important to determine if stiffness, pain, or decreased ROM is interfering with an individual’s ability for self-care. Having someone who can provide assistance, or regular positive social interaction (be it a family member or paid caregiver), can ultimately affect patient outcomes.35 In patient with knee OA, there has been evidence that normal mood at baseline (characterized by self-efficacy with pain and improved satisfaction with life) predicts improved function. In contrast, increased pain catastrophizing and fear of movement (kinesiophobia) predicts poor function.37
Therapists and care teams can provide psychosocial support to patients by helping them understand that OA-related pain can be managed effectively. This is crucial in helping individuals overcome the associated kinesiophobia. This may promote patient engagement in safe exercise, even in the presence of pain. Ultimately, this can lead to improved muscle strength and reduction in pain severity.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Guidelines for the management of knee OA have been published by the American College of Rheumatology/Arthritis Foundation (ACR/AF), the American Academy of Orthopedic Surgeons (AAOS), and the Osteoarthritis Research Society International (OARSI). While some differences exist across these organizations, there is a general consensus supporting the following nonpharmacologic treatment modalities1,38,39
- Self-management programs and education
- Weight loss (if overweight)
- Low-impact aerobic exercise (aquatic and/or land based)
- Physical Therapy
- Neuromuscular training (e.g., balance)
Regarding pharmacologic management, several treatments exist however there are differing levels of support across organizations1,38,39
|Topical NSAIDs||strongly recommended||strongly recommended||strong recommendation|
|Acetaminophen||conditionally not recommended||recommended for short-term use||strong recommendation|
|Oral NSAIDs||conditionally recommended||strongly recommended when no contraindication||strong recommendation|
|Tramadol||uncertain||conditionally recommended||strongly recommend against|
|Hyaluronic Acid||conditionally recommended||conditionally not recommended||moderate recommendation|
|Intra-articular Corticosteroids||conditionally recommended||recommended||moderate recommendation|
Additionally, several braces (e.g., off-loader braces), orthotics (e.g., medial and lateral wedges), and assistive devices (e.g., canes) have been used in the treatment of knee OA. These items received inconsistent levels of review among the three societies with differing levels of recommendation when discussed by more than one society.
At different disease stages
Early management of OA should focus on decreasing pain level, increasing function, and attempting to slow disease progression. Structured weight-loss programs should be implemented in patients who are overweight or obese in order to decrease mechanical forces across the knee.40 Physical therapy incorporating low-impact land-based exercise, aquatic exercise, strength training, and neuromuscular education should be considered as the foundation of the treatment plan for any stage of OA. Strength training should focus on improving quadriceps, hamstrings, calf, and hip girdle strength. Stretching exercises can be incorporated as a useful adjunct to therapy exercises for functional progress.41 Oral analgesics, intra-articular injections, therapeutic modalities, and bracing/orthotics are additional treatment options that should be considered within the context of an individual patient and their co-morbidities.
Injectable therapies are generally trialed next, particularly when initial conservative therapies are ineffective or minimally effective. Corticosteroid injections (CSI), hyaluronic acid (HA), platelet rich plasma (PRP), prolotherapy, and mesenchymal stem cells (MSCs) derived from adipose tissue and bone marrow aspirate concentrate (BMAC) can be delivered to the intra-articular space. Generally, this is performed with ultrasound guidance, although many physicians still perform anatomic landmark-guided CSI.42
Intra-articular corticosteroid injections may be helpful in patients who have moderate to severe OA of the knee to target decreasing inflammation for reducing pain. Multiple types of corticosteroids have been used, including prednisolone, methylprednisolone, betamethasone, and triamcinolone. Typically, local anesthetics are combined with CSI for both diagnostic and therapeutic purposes.42 However, repeated use of intra-articular corticosteroids could potentially cause thinning of cartilage.38 Similar to CSI, many different formulations of hyaluronic acid are being used. These treatments can be categorized as native versus crosslinked, low-molecular weight versus high-molecular weight, and single injection versus series of three injection options. Commonly employed forms include sodium hyaluronate, hyaluronan, and Hylan G-F-20.43
Recent evidence suggests that CSI, HA, and PRP can all provide short to medium term (4-12 weeks) improvement in pain and function when measured by WOMAC or VAS scores without serious adverse events. There is emerging evidence that HA may be superior to CSI in the long term (6 to 12 months). However, despite many studies illustrating the benefits of these intra-articular injections, there are still heterogeneous recommendations from two of the major academic governing societies, ACR/AF and AAOS44
|Injectate||ACR/AF (2019)||AAOS (2021)|
|Intra-articular corticosteroids||strongly recommended||moderate evidence|
|Hyaluronic Acid||conditionally recommended against||moderate evidence|
|Platelet Rich Plasma||strongly recommended against||limited evidence|
In moderate to severe OA, patients may fail conservative management and require surgical interventions. Arthroscopic debridement is generally not employed as a means of intervention in patients with a primary diagnosis of knee OA as there are very high levels of evidence that do not support its use.45 However, younger non-obese patients with symptom duration of < 6 months stemming from a primary diagnosis of meniscal tear, loose body, or other mechanical derangement with a concomitant diagnosis of incidental mild (Kellgren-Lawrence scale grade 1) OA of the knee may benefit in the event of failure of conservative measures.46 Knee preservation techniques may be used for single-compartment OA or ligamentous instability of the knee to decrease OA progression and more evenly distribute forces across the joint surface. Two common knee osteotomy procedures include high tibial osteotomy (HTO) and distal femoral osteotomy (DFO).47 Total knee arthroplasty (TKA) is generally the preferred definitive surgical treatment (cemented versus cementless TKA). Cemented TKA is currently the gold-standard, as it allows for immediate weight-bearing and may be associated with better long-term functional recovery.48
Coordination of care
OA is multifaceted and may require the input from several healthcare professionals. Direct communication among the care team members (physical therapists, physicians, and family) is important to understanding the patient’s progress and helping to achieve optimal outcomes. When treating an elderly patient, communication with the primary care provider can help address medical issues that may be a barrier to therapy or other treatments. Care may also be coordinated with the primary care provider to help an obese patient enroll in a structured weight-loss program and obtain the help of a nutritionist or a bariatric surgeon.
Patient and family education
It is important to educate patients and family members about modifiable risk factors for the development and progression of OA, so they may target specific risk factors and make appropriate lifestyle changes to reduce the disease risk and manage OA symptoms.
Measurement of treatment outcomes
Multiple survey-based and objective functional measures of mobility and function have been developed as previously described in the Clinical Functional Measures section.
Translation into practice
The use of both objective functional (e.g., 30s Chair-Stand Test, 40m Fast-Paced Walk Test) and PROMs (e.g., WOMAC, KOOS) measures have use for both tracking clinical course and response to treatments as well as providing measures of patient outcomes for quality of care reporting.
Cutting Edge/ Emerging and Unique Concepts and Practice
The field of Regenerative Medicine remains a rapidly developing area of study with growing evidence surrounding the utilization of orthobiologics for OA. The most common biologics under investigation for knee OA are platelet-rich plasma (PRP), adipose-derived MSCs, and BMAC. Two recent meta-analyses have shown that PRP injections appear to be more effective at reducing pain than placebo, hyaluronic acid injections, and corticosteroid.49,50 Controversy remains regarding which injectate is superior when comparing various biologic therapies. A meta-analysis by Tran et al showed better outcomes with bone marrow derived MSCs compared to adipose derived MSCs.51 Another study comparing BMAC and microfragmented adipose tissue showed significant improvement in pain and function from both injectates without significant difference when comparing the different tissue sources.52 Variation in injectate preparation and lack of standardization may play a role in evidence variability. Limited evidence indicates prolotherapy may be useful in improving knee pain, function, and stiffness compared to baseline.53
Investigation into the target for OA treatment is also ongoing, particularly intra-articular versus intra-osseous. Studies have shown subchondral injection of BMAC to be superior to intra-articular injection, and more effective at postponing total knee arthroplasty than intra-articular injection as well.54,55
In addition to Regenerative Medicine and orthobiologic treatments, more research is being done on a spectrum of non-traditional treatment options:
- Kinesiotaping (KT): KT is commonly utilized in sports to provide proprioceptive feedback and facilitate certain movement patterns. Some research suggests that it has additional benefits, including reducing edema, facilitating soft tissue recovery through increased blood flow and lymphatic circulation56, and mechanical support.57,58,59 Currently, it is used more as an adjunct to physical therapy as it may help reduce exercise pain when compared to therapy without KT. However, there is no current high-quality to suggest that KT enhances function.60
- High Intensity Interval Training (HIIT): Recent data suggests that HIIT may have similar effects in improving knee pain, knee function, and quality of life when compared to lower intensity strength training and therapy.61
- Phonophoresis/Ultrasound: both therapeutic ultrasound and phonophoresis (with topical corticosteroid or NSAID gels) may be beneficial adjusts for short term pain relief in knee OA.62,63
- Extracorporeal Shockwave Therapy (ESWT): ESWT utilizes mechanical sound waves in order to influence cellular migration, proliferation, differentiation, or apoptosis. This ability to influence cellular activity with external, mechanical stimuli is known as mechanotransduction. ESWT has been shown to decrease knee joint inflammation, decrease edema, improve subchondral bone architecture, and increase chondrocyte activity for cartilaginous repair.64 ESWT can improve pain and functional outcomes in knee OA with a relatively mild adverse effect profile.65
- Radiofrequency Ablation (RFA): RFA of the genicular nerves has been shown to be a safe and efficacious treatment in knee OA. Traditional (heated) RFA, cooled radiofrequency ablation (CRF), and pulsed radiofrequency ablation (PRF) have been utilized to deliver targeted, thermal damage to the genicular nerves of the knee in order to decrease the transmission of pain signals. These procedures may be done fluoroscopically or with ultrasound guidance.66
A recent systematic review with meta-analysis aimed to compare the efficacies of therapeutic ultrasound, phonophoresis, extracorporeal shockwave therapy, and vibration with placebo. Each treatment was done either in isolation or in conjunction with physical therapy. ESWT illustrated statistically significant improvement in pain when compared to placebo. Vibration, ultrasound and phonophoresis were found to be efficacious adjuncts to physical therapy, with phonophoresis illustrating superiority when compared to ultrasound.67 However, large scale randomized clinical trials are still required before establishing these modalities as mainstays of treatment in knee OA.
Gaps in the Evidence-Based Knowledge
Additional research is needed in determining factors that help predict which subgroups of patients may benefit from specific interventions. Research is also needed to provide evidence-based recommendations on lifestyle modifications for primary prevention as well as guidance on shaping public policy and population health initiatives.
- The optimal exercise prescription for OA symptom management remains unclear. A recent study illustrated that isokinetic exercises may be superior to isometric or isotonic exercises in the treatment of knee OA with respect to muscle strength measurements and femoral cartilage thickness as evaluated by ultrasound. However, further research is needed to evaluate these various exercises and their impact on knee cartilage quantity, pain, and functional outcomes.68
- Better knowledge regarding OA prevention strategies and interventions that can alter the course of OA progression, particularly in the post-traumatic injury knee, is needed.
- Additional research is needed to determine whether there are OA pain phenotypes that are better responders to specific interventions.
- Larger and higher-quality human studies of biologic therapies are needed to confirm beneficial findings from smaller studies.
- In a 2022 study by Mazor et al, it was shown that multipotent mesenchymal progenitor cells are present in adult human OA articular cartilage and that the frequency of these cells is unaffected by the severity of OA. They illustrated that in moderate OA, these MPCs illustrated the capacity to form hyaline cartilage-like tissues. Future research is needed in order to understand the clinical impacts of these findings and whether tissue engineering may allow scientists to improve intrinsic cartilage repair pathways.69
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Original Version of the Topic
Daniel C. Herman, MD, Ashley D. Zapf, MD, Heather K. Vincent, PhD, Kevin R Vincent, MD PhD. Knee Osteoarthritis. 10/6/2015.
Previous Revision(s) of the Topic
Kevin Vu, BA, William Lian, MD, Donald Kasitinon, MD, Thiru Annaswamy, MD MA. Knee Osteoarthritis. 12/8/2019.
Jaspal Singh, MD
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Zainab Shirazi, MD
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Mani Singh, MD
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Nicholas Tsitsilianos, MD
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