Sage Journals: Discover world-class research

Abstract

Osteoarthritis (OA) is a prevalent condition that affects nearly 528 million people worldwide, including 23% of the global population aged ⩾40, and is characterized by progressive damage to articular cartilage, which often leads to substantial pain, stiffness, and reduced mobility for affected patients. Pain related to OA is a barrier to maintaining physical activity and a leading cause of disability, accounting for 2.4% of all years lived with disability globally, reducing the ability to work in 66% of US patients with OA and increasing absenteeism in 21% of US patients with OA. The joint most commonly involved in OA is the knee, which is affected in about 60%–85% of all OA cases. The aging population and longer life expectancy, coupled with earlier and younger diagnoses, translate into a growing cohort of symptomatic patients in need of alternatives to surgery. Despite the large number of patients with knee OA (OAK) worldwide, the high degree of variability in patient presentation can lead to challenges in diagnosis and treatment. Multiple society guidelines recommend therapies for OAK, but departures from guidelines by healthcare professionals in clinical settings reflect a discordance between evidence-based treatment algorithms and routine clinical practice. Furthermore, disease-modifying pharmacotherapies are limited, and treatment for OAK often focuses solely on symptom relief, rather than underlying causes. In this narrative review, we summarize the patient journey, analyze current disease burden and nonsurgical therapy recommendations for OAK, and highlight emerging and promising therapies—such as cryoneurolysis, long-acting corticosteroids, and gene therapies—for this debilitating condition.

Keywords

emerging therapies guidelines intraarticular injections NSAIDs osteoarthritis

Introduction

Osteoarthritis (OA) is a degenerative disorder of synovial joints characterized by progressive articular cartilage damage; structural alterations of subchondral bone, menisci, ligaments, joint capsule, and periarticular muscles; and degrees of synovial proliferation, resulting in substantial joint pain, stiffness, and functional limitations.^1–3 Clinical presentation of knee OA (OAK) and etiologies can be highly variable,³ with inflammatory, metabolic, mechanical, and environmental factors including mechanical stress, limb overuse, injury, age, genetic disorders, and metabolic syndromes contributing to disease onset and progression.^2–4 Direct costs of OA account for 1%–2.5% of gross national product in the United States, United Kingdom, Canada, and Australia; total direct medical costs in the United States are approximately $72 billion.⁵ Rates of disability associated with OA will likely increase given an earlier onset of disease, an aging population with longer life expectancy, and growing obesity rates.^6,7

Racial and social factors (e.g., socioeconomic status) can impact disease prevalence, radiographic features, healthcare resource accessibility, and disease severity.⁸ Osteoarthritis Research Society International (OARSI) grading, based on cartilage histopathology, defines mild OA (grades 1–3) as lacking erosion of collagen matrix, while more severe disease (grades 4–6) is typified by partial to complete erosion of the cartilage matrix and deformation of joint surfaces.⁹ Although objective findings (e.g., physical examination, X-ray analyses) are necessary for diagnosis, pain is the key presenting symptom and clinical measure of severity, which guides treatment.^10,11

Currently, there are no office-based/nonsurgical curative or disease-modifying agents for OA.^3,12,13 Nonsurgical options are the first line of treatment for patients with OA,¹⁴ yet there is often a disconnect between treatment guidelines and clinical practice.¹⁵ As there is robust literature describing surgical management of OAK,^16–19 this narrative review will focus on nonsurgical management, providing an overview of disease burden, current guidelines, standard treatments, and evidence for emerging therapies. We end with suggested clinical scenarios for various treatment approaches.

Epidemiology of OAK

OA affects millions of people worldwide, with the highest prevalence observed in the United States (9961 per 100,000 people),²⁰ where the overall lifetime risk of symptomatic OA is between 41% and 45%.²¹ The joint most commonly affected by OA is the knee, accounting for 60%–85% of total OA cases.^20,22,23 Incidence of OAK is 1.39 times higher in women than men (95% confidence interval (CI), 1.24–1.56; p < 0.00).²² Prevalence of OAK in women is 1.69 times higher than it is among men (95% CI, 1.59–1.80; p < 0.00).²² Prevalence of OAK in the United States has been increasing in tandem with an aging population and a growing obesity epidemic.^7,24,25 The incidence of OAK in the United States is approximately 240 people per 100,000 each year¹ and is highest among patients aged 55–64 years.⁷ However, OA is also being diagnosed in an increasingly younger population.⁷ As the face of OA becomes younger and life expectancy increases, patients are anticipated to be symptomatic for a greater proportion of their lives.

Risk factors vary across age and gender; they are often studied in older populations with accumulated OA symptoms.^26,27 Factors that increase OAK risk in adults aged ⩾50 years include overweight/obesity, previous knee injury, female sex, older age, presence of hand OA, family history of OA, and exposure to physical exertion at work.^26,28 Increased age and physical activity in men, and increased body mass index (BMI) and alcohol intake in women, are associated with an elevated risk of OA.²⁷ In addition, both bilateral thumb OA and upper limb disability increase the risk of OAK among women.²⁷ Studies have identified 90 genetic risk loci for OA.²⁹ Gene single-nucleotide polymorphisms linked to increased OA risk or increased disease progression are associated with proinflammatory mediators, including interleukin-1 (IL-1) family cytokines; factors in skeletal development, including tumor growth factor-beta; and collagen components, including COL2.^29–32

OA patient journey

Diagnosis and presentation

Patients often avoid seeking healthcare until they experience burdensome symptoms; therefore, healthcare providers (HCPs) may not see patients with OA until they become symptomatic with severe pain, stiffness, and functional limitations—often with concomitant advanced joint degeneration.^1,33,34 A survey of HCPs and patients with OAK noted the absence of persistent pain, difficulty in scheduling medical appointments, slow progression of OA, and optimism about OA getting better without intervention as reasons for the delay in seeking treatment.³⁴ Furthermore, imaging modalities used to diagnose OAK may not correlate with physical signs and symptoms as the presence of cartilage defects is estimated at 43% in adults ⩾40 years old; this prevalence may be impacted by different magnetic resonance imaging (MRI) techniques, including field strength and the type of MRI sequences used.^35,36

Upon presentation to a physician with symptoms consistent with OA, established guidelines may aid in OA diagnosis. The American College of Rheumatology (ACR) clinical classification criteria outline idiopathic OA as knee pain with ⩾3 of the following characteristics: age >50 years, morning stiffness <30 min in duration, crepitus, bony tenderness, bony enlargement, and no palpable warmth.³⁷ A heterogeneous condition, OAK can be further defined using patients’ radiographic severity, comorbidity status (Charlson Comorbidity Index), pain, joint sensitivity, and psychological factors to give an overall OA phenotype.^38,39 Patient phenotypes can be broadly categorized into four groups: (1) age-related and systemic phenotypes driven by metabolic diseases, aging, and endocrine diseases; (2) extra-articular phenotypes involving ligament and tendon laxity, sarcopenia, and varus and valgus malalignment; (3) intraarticular (IA) phenotypes including alterations in articular cartilage, subchondral bone, and meniscus, as well as the presence of synovitis; and (4) secondary phenotypes capturing OA driven by development of crystals, traumatic injury, previous autoimmune arthritis, and occupational injuries.⁴⁰ However, the phenotype may neither predict symptoms nor inform specific treatment and management strategy,^40,41 and not all patient types fit neatly within these four phenotypes (e.g., a young athlete with a sports injury or a patient with generalized pain such as fibromyalgia). Pain at presentation can vary significantly and may be affected by neuroinflammation, joint inflammation (synovitis), OA-triggering joint trauma severity, compromised endogenous joint-repair processes, structural changes (bone marrow lesions, subchondral bone remodeling, and osteophyte formation), and peripheral and central sensitization.^41–43 In addition, patient symptoms may not align with structural changes observed on X-ray or MRI.^44,45 Structural changes precede disease development, diagnosis, and chronic pain,³³ and MRI imaging can often detect changes in soft tissues, such as meniscus changes or articular cartilage degeneration, better than radiographic imaging.⁴⁶ However, MRI is often not used if radiographic OA is present—unless mechanical symptoms or unusual pain suggestive of an alternative diagnosis are observed—given high cost, limited availability, generally long scanning times, and lack of standardization in MRI acquisition and interpretation.^46,47

Disease progression and monitoring

Loss of articular cartilage, combined with cellular changes and biomechanical stress, can cause subchondral bone remodeling; osteophyte formation; development of bone marrow lesions; changes in the synovium, joint capsule, ligaments, and periarticular muscles; and meniscal tears and extrusion.⁴⁸ Disease progression is determined by assessing cartilage volume, thickness, and defects; presence and severity of bone marrow lesions via imaging; signs of inflammation (i.e., synovitis); and presence of meniscal alterations.⁴⁹ Chondrocyte hypertrophy and endochondral ossification are key indicators of OA progression.³¹ However, key factors in determining the clinical significance of disease progression are worsening pain and persistent symptoms.

Multiple methods have been used to assess OA severity. The Kellgren–Lawrence (K–L) scale, the most common, grades the radiographic extent of disease overall between 0 (no OA) and 4 (severe; Figure 1).⁵⁰ Risk for medical progression to surgical treatment increases considerably as the K–L grade increases.⁵¹ In addition, the OARSI system grades changes to the subchondral bone and articular cartilage on a scale between grade 0 (normal cartilage) and grade 6 (articular cartilage and subchondral bone changes present).⁹

Figure 1.

Disease Severity Ranking Scales for osteoarthritis.^9,50,52

Biomarkers in bodily fluids that indicate type 2 collagen degradation may allow for further characterization of disease progression.⁵³ This disease’s impact on patients and symptomatic treatments can be evaluated via patient-reported assessments, such as the Knee Injury and Osteoarthritis Outcomes Score and its multiple subscales, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and its subscales, and the Patient-Reported Outcomes Measurement Information System.^54,55 Minimum clinically important difference (MCID) thresholds have been characterized for OAK assessments, though a recent meta-analysis found that proposed MCID values differed across pain assessment publications.⁵⁵

Ultimately, despite an improved understanding of diagnosis and patient phenotypes, responsiveness to treatment based on phenotypes, MRI, or other radiographic presentations, symptomatic classification systems remain unpredictable.

Patient burden

As OA is the leading cause of disability among US adults,⁵⁶ and OA-related pain is a barrier to physical activity,⁵⁷ OAK symptoms can cause considerable functional limitations.^1,57–59 Disability can range from minimal to severe, with severe disability involving chronic pain and reduced function.⁵⁷ Patients with OAK lost an average of 0.55 quality-adjusted life-years (QALYs) per person because of inactivity, with Black Hispanic women having the highest per-person QALY loss of 0.76.⁶⁰ Factors influencing the degree of disability and loss of function include female sex, lower education levels, and social disadvantages.⁵⁷ Disability associated with OA most substantially impacts patients whose careers or daily activities require weight-bearing exercise or positions that involve walking or knee bending.⁵⁷ Specific changes in physical abilities, such as gait alterations, can alter load distribution at the knee and have been associated with the risk of OAK, disease severity, and progression.^58,59

Patients with OA reported significant pain interference with activities outside the home, including work, relative to those without OA (p < 0.0001).⁶¹ Those with OA missed more work days and had higher odds of experiencing OA-related limitations than those without (3.68; p = 0.000).⁶² Workers employed as manual laborers may be more affected by OA-related disability because of the activity level their jobs require.⁶³ Patients with higher disease severity are more likely to be unemployed and, if employed, are more likely to experience impairment while working.^61,64 The economic burden of OA can be summarized in annual per-patient costs (primarily indirect costs due to lost productivity) ranging from $9801 for mild disease to $22,111 for severe disease,^61,64 which is comparable to heart failure ($17,000–$30,000) and cancer ($2160–$31,176).^65,66

Pain and functional limitations vary in intensity and over time.^{1,57–59,67,68} In a study of 719 participants, 23%–32% reported substantial pain variability over time.⁶⁷ Another study reported significant variation in pain intensity by age, particularly between age groups of 20–39 and 40–59 years (mean difference, −3.68; p = 0.01) and 60–79 years (mean difference, −3.23; p = 0.04), with higher pain intensity in the 40–59 years group.⁶⁸ In addition, significant variation in physical function was observed between age groups of 60–79 and 20–39 years (mean difference, −20.85; p = 0.02) and 40–59 years (mean difference, −10.70; p = 0.03), with greater function in the 20–39 years group. Increased pain and decreased function in the 40–59 age group could reduce employment capacity and increase the economic burden of OAK.

Decreased ability to participate in physical exercise can increase obesity among patients with OA.⁵⁷ In the United States, adults with obesity and OA were 44% more likely to be physically inactive than adults with obesity who did not have OA.⁶⁹ Comorbidities with common risk factors (i.e., age and obesity), such as diabetes mellitus (DM) and hypertension, are increased in patients with OA.⁵⁷ The prevalence of diabetes among patients with knee or hip OA is between 9.7% and 33%, and patients with OA have a relative risk of 1.32 of developing diabetes over 12 years.⁵⁷ Approximately 52% of patients with DM also suffer from some form of arthritis.⁷⁰ Furthermore, US patients with OA and diabetes experience more inactivity (29.8%) than those with OA or diabetes alone (17.3% and 21.0%, respectively). This is a particularly difficult cohort of patients to treat, as some effective treatment modalities, such as IA corticosteroid injections, may adversely impact glucose control.⁷¹ Between 32% and 81% of patients with OA also have hypertension, and the combination of OA and hypertension is the most common combination of comorbidities, impacting more than 24% of adults over 65 years.⁵⁷ Metabolic syndrome—the combination of obesity, diabetes, hypertension, and dyslipidemia—affects 59% of patients with OA compared with 23% of those without; physical and mental burdens of OA may limit the ability to self-manage comorbidities.⁵⁷ Overall, comorbidities associated with OA and their consequences may worsen the clinical impact of OA, and OA may contribute to the development and/or exacerbation of comorbidities, which creates a negative feedback loop, impacting physical function and treatment decisions.

The cumulative impact of all these associations may explain why OA is also an independent risk factor for all-cause mortality. Patients with symptomatic or radiographic OAK have greater mortality (15.7 or 14.1 deaths per 1000 person-years, respectively) than patients with neither OAK nor knee pain (9.4 deaths per 1000 person-years), mediated in part by the impact of OA on either disability or physical component scores of quality of life assessments.⁷² Of particular importance are activity restrictions; increases in physical activity, such as brisk walking, are associated with decreased all-cause mortality, but symptomatic OAK may preclude any vigorous activity.⁷³ As OA is prevalent among older patients, additional comorbidities increase the likelihood of polypharmacy, increasing the risk for frailty, falls, hospitalizations, and cognitive and physical impairment.^74–76

Treatment selection

As noted previously, patients with symptomatic OAK present with different phenotypes, and with variable symptom severity. Therefore, therapeutic decisions must be individualized, focused on reducing pain and improving function, slowing disease progression, improving patient mobility and well-being, and ultimately reducing healthcare resource utilization.⁷⁷ Parameters such as patient age, comorbidities, presence of inflammation, disease severity, and patient preferences and expectations should be considered when determining patient-specific treatment plans.^78,79 Initiation of both nonpharmacological and pharmacological interventions is standard, and therapies progress from noninvasive treatment to more advanced, potent pharmaceuticals.⁷⁷ Total knee arthroplasty (TKA) may be required if a patient does not respond to interventions or is experiencing severe symptoms and poor quality of life.⁷⁷

The decision to move forward with surgical intervention in the form of knee replacement when nonsurgical management has failed is almost entirely subjective. In addition, TKA outcomes are not always predictable and can be impacted by patient age, gender, activity level, expectations, comorbidities, surgeon and institutional volume and expertise, and many other patient- and surgeon-specific determinants.^80–82 In addition, some patients are either unready or cannot medically tolerate the intervention of knee replacement and rehabilitation that follows; conversely, some surgical practices delay or deny TKA procedures for patients who are above a certain BMI or who have other modifiable risk factors such as diabetes control and smoking.^83–85 Other individuals may be at risk for catastrophic complications, including fracture, infection, and poor functional outcomes.⁸⁶ Recent data suggest that roughly 10%–20% of patients are not fully satisfied with their pain and functional outcomes,^87,88 and 31%–54% of patients have residual symptoms.⁸⁹ Finally, although the longevity and durability of TKA are outstanding, with 82.3% of TKAs lasting 25 years,⁹⁰ need for revision due to aseptic loosening, infection, or other mechanical complications increases over time⁹¹; furthermore, revision knee arthroplasty is typically less durable than the primary procedure.⁹² Younger patients with symptomatic OA, particularly those under 55 years, are at increased risk for revision,^93–95 primarily because of surface wear and biological responses to wear debris; new implant designs are not effectively reducing residual symptoms or revision risks among this population.^96,97 In addition, patients under 50 who undergo a knee revision are more likely to require re-revision than older patients.⁹⁸ Given the challenges with TKA in younger patients, it is crucial to understand and incorporate nonsurgical management options into the management paradigm of symptomatic OAK for patients who want to or for whom it is medically advisable to delay TKA. The remainder of this manuscript is devoted to reviewing current therapeutic guidelines established to support clinicians in identifying current and emerging nonsurgical therapies for patients with OA.

Nonsurgical treatment options for OA

Several guidelines for nonsurgical OAK treatment recommend weight loss, exercise, and pharmacologic interventions (Table 1).^{1,41,78,99–101} Treatment selection should be based on patient-specific factors, such as disease duration, pain intensity, and presence of comorbid conditions.^78,102 Current OA therapies generally focus on reducing pain and improving function, and many therapies and technologies are under investigation to further improve disease outcomes. As of May 2023, there are 109 active interventional phase II or phase III studies for OAK (including 42 phase III studies).^103,104

Table 1.

Pharmacologic treatment guidelines for osteoarthritis.^{1,41,78,99–101}

Treatment	AAOS	ACR	NICE	OARSI^a	EULAR^b	ASPN
Topical NSAID	Strong recommendation	Strongly recommender	Recommended	Level 1A recommendation	Level A recommendation	Strong recommendation
Oral NSAID	Strong recommendation	Strongly recommender	Recommended	Level 1B recommendation	Level A recommendation	Strong recommendation
Oral acetaminophen	Strong recommendation	Conditionally recommender	Recommended	Conditionally not recommended	Level 1B recommendation	No recommendation
Oral narcotics	Strong recommendation	No recommendation	Recommended	No recommendation	No recommendation	Strongly against
Hyaluronic acid	Moderate recommendation	Conditionally against	Not recommended	Level 1B recommendation	Level B recommendation	Strong recommendation
Intraarticular corticosteroids	Moderate recommendation	Strongly recommender	Recommended	Level 1B recommendation	Level A recommendation	Moderate recommendation
Platelet-rich plasma	Limited recommendation	Strongly against	No recommendation	Strongly against	No recommendation	Strong recommendation

Level 1A: ⩾75% of panelists in favor of recommendation and >50% in favor of strong recommendation; Level 1B: ⩾75% of panelists in favor of recommendation and >50% in favor of conditional recommendation.

Level A: directly based on category 1 evidence (meta-analysis of randomized controlled trials or ⩾1 randomized controlled trial); Level B: directly based on category 2 evidence (⩾1 controlled study without randomization or ⩾1 type of quasi-experimental study) or extrapolated from category 1 evidence.

AAOS, American Academy of Orthopaedic Surgeons; ACR, American College of Rheumatology; ASPN, American Society of Pain and Neuroscience; EULAR, European Alliance of Associations for Rheumatology; NICE, National Institute for Health and Care Excellence; NSAID, nonsteroidal anti-inflammatory drug; OARSI, Osteoarthritis Research Society International.

Nonpharmacologic interventions

The AAOS guidelines for OAK recommend manual therapy delivered by a therapist in conjunction with an exercise program.¹ Supervised or unsupervised exercise (land or aquatic) to strengthen muscles is recommended by AAOS, NICE, OARSI, and ACR.^1,41,99,101 To reduce the burden on and increase the function of the affected joint, guidelines also recommend self-management (i.e., patient-driven therapy and exercise programs), mobility aids, braces, heat and cold therapies, neuromuscular training, and weight loss.^1,105 Weight loss reduces joint loads, decreases joint pain, and has been associated with improved long-term prognoses and adherence to subsequent therapies.¹⁰⁶ Despite known health benefits, weight loss is difficult to achieve and has a high recidivism rate¹⁰⁶ because of dietary habits, sedentary behaviors, and difficulties with exercise—including temporary soreness or increase in knee pain.¹⁰⁶ In addition, dyslipidemia in patients with obesity, specifically elevations in proinflammatory adipokines and reduced high-density lipoproteins, is associated with bone lesions and increased inflammation, both systemically and within the joint.^107,108 Recent advances in treatment for type 2 diabetes, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide, liraglutide, and dulaglutide, are potentially disease-modifying therapies for OAK.¹⁰⁹ An observational study of 1807 patients with OAK showed clinically relevant (>5%) weight reductions in 57.9% of patients treated with GLP-1RA (135/233).¹⁰⁹ Significant differences from baseline were observed in WOMAC total scores (p = 0.038) and pain subscores (p = 0.007) for patients treated with GLP-1RA compared with those who were not, as well as lower incidence of TKA (p = 0.014) and IA steroid use (p < 0.001).¹⁰⁹ Cartilage-loss velocity was significantly lower in patients with predominantly lateral OA who were treated with GLP-1RA compared with those who were not (p = 0.026).¹⁰⁹ Importantly, changes were not consistently found to be mediated by weight reduction and HbA1c change,¹⁰⁹ so further research is needed to understand the impact of GLP-1RAs on OAK.

Topical therapies

For OA-related pain, guidelines recommend topical nonsteroidal anti-inflammatory drugs (NSAIDs) and topical capsaicin.^1,100,110 A meta-analysis evaluated topical NSAIDs—including diclofenac, ketoprofen, piroxicam, eltenac, felbinac, flurbiprofen, piketoprofen, nimesulide, flufenamate, indomethacin, and ibuprofen—applied as solutions, gels, or patches, and found topical NSAIDs, particularly diclofenac, to be as effective as oral NSAIDs in OAK.¹¹¹ In addition, topical NSAID therapy was well tolerated in patients ⩾65 years of age and patients with multiple comorbidities, including hypertension, type 2 DM, and cardiovascular disease.¹¹² While studies on long-term use of topical NSAIDs are scarce, consistent improvement was seen in pain, stiffness, and physical function after 12 months of consistent treatment with topical diclofenac sodium 1% gel.¹¹³ In addition, the most common adverse events (AEs) reported with long-term use of topical NSAIDs were headache, arthralgia, back pain, and application-site dry skin or dermatitis.^113,114 Topical capsaicin provides comparable pain control to topical NSAIDs but has limited evidence in OA.¹¹⁵ Though topical treatments limit the amount of medication absorbed systemically,¹¹⁶ a comprehensive evaluation found topical NSAIDs not clinically important for the treatment of OAK.¹¹⁷ Furthermore, topical treatments can cause skin reactions, including dry skin, rash, and dermatitis,¹¹⁸ but reactions are generally mild and transient.¹¹¹

Systemic therapies

Systemic, oral therapies recommended for OA pain management include oral NSAIDs (nonselective and COX-2 selective, with/without proton pump inhibitor), oral acetaminophen, and oral tramadol,^1,100,110 but chronic treatment with systemic therapies includes substantial risks. For example, acetaminophen is an adjunctive therapy that should be used with caution given risks of liver toxicity with excessive dosing,^1,119 and NSAIDs are contraindicated in patients taking some antihypertensives or with a history of hypertension.¹²⁰ In addition, narcotics should be avoided except in extreme cases given the high risk of AEs.¹

In 2007, the Food and Drug Administration released a medication guide for oral NSAIDs.¹²¹ This guide details associated AEs, including serious AEs (e.g., heart attack, stroke, intestinal bleeding, and kidney failure) and less-threatening AEs (e.g., stomach pain, constipation, and heartburn).¹²¹ The guide specifies that NSAIDs should be taken at the lowest dose possible for the shortest time needed.¹²¹ However, >111 million prescriptions for NSAIDs are written in the United States annually.¹²² Chronic use of NSAIDs increases with age, so even low percentages of AEs can add up to a large number of affected patients. Most NSAIDs are used as needed, and whereas NSAIDs such as ibuprofen have a short half-life and are absorbed quickly for immediate relief, NSAIDs with a longer half-life—such as naproxen or celecoxib—may be more beneficial for the persistent chronic OAK-associated pain.¹²² Compared with the efficacy of opioids for musculoskeletal conditions such as OA, NSAIDs have been shown to comparably reduce pain intensity, with some studies showing significantly lower rates of AEs.¹²³ Similarly, compared with acetaminophen, NSAIDs are associated with improved pain control and a better safety profile.¹²⁴ Though a recent meta-analysis of symptom relief and AEs with oral NSAIDs for treatment of OA found that all NSAIDs were associated with an increased probability of gastrointestinal (GI) AEs and minor cardiovascular events relative to placebo, this cardiovascular risk was lower with increased COX-2 selectivity.¹²⁵ Furthermore, the absolute risk of serious GI and cardiovascular complications such as GI bleeding and heart failure-related mortality increases with age among patients taking nonselective NSAIDs, particularly those with prior bleeding complications, hospitalizations for heart failure, and concomitant use of anticoagulants.¹²⁶ These collective safety issues with NSAIDs suggest alternatives should be explored for long-term OA pain management.

Novel systemic treatments under investigation to target specific pain-signaling channels may improve OA-related pain treatment by avoiding off-target effects that may lead to AEs (PF05089771 for Na_v1.7 sodium channels, capsaicin for transient receptor potential cation channel subfamily V member 1).^127,128 In addition, treatments developed for osteoporosis, including strontium ranelate and denosumab, have shown potential as disease-modifying therapies in OA, with significant improvements in radiological changes, as well as function and pain.^129,130 For example, in patients with OAK, daily treatment with 2 g strontium ranelate significantly improved versus placebo in joint space width (−0.27 vs −0.37 mm, respectively; p = 0.018), WOMAC total score (−51.9/300 vs −40.7/300 mm; p = 0.045), and WOMAC pain subscore (−19.1/100 vs −14.7/100 mm; p = 0.028).¹²⁹

Local injection therapies

Locally delivered therapies, such as IA injections, can more directly address OA symptoms. In general, guidelines recommend IA-CS injections and do not recommend other IA injections, although AAOS gives IA platelet-rich plasma (IA-PRP) a limited recommendation (discussed in “Emerging Treatments”).¹ Injections of IA-CS can provide effective relief of OAK pain for up to 3 months.¹³¹ While IA-CS injections are recommended for short-term OAK relief,¹ a comparison of short-acting IA-CS with other injectables found no difference in pain level for all injections; however, other injectables led to greater improvements in function than IA-CS injectables at and beyond 3 months following treatment.¹³² In addition, a review of nonoperative treatments for OAK found that IA injections of hyaluronic acid (IA-HA) demonstrated clinical efficacy at molecular weights between ⩾1500 to <6000 and ⩾6000 kDa,¹¹⁷ though they are not generally recommended by guidelines.^{1,41,78,99–101} In 54 trials that used IA-HA injections to treat OAK pain, function, and stiffness, IA-HA was efficacious at 4 weeks, reached peak effectiveness at 8 weeks, and had a residual effect at 24 weeks after treatment.¹³³ Across 74 trials, IA-HA products were well tolerated, with AE rates similar to those of placebo.¹³⁴ In a systematic review and meta-analysis of 50 years of data regarding viscosupplementation with IA-HA—which reviewed 24 placebo-controlled trials (N = 8997) for pain outcomes, 19 placebo-controlled trials (N = 6307) for function, and 15 placebo-controlled trials (N = 6462) for serious AEs—viscosupplementation demonstrated greater reductions in pain intensity than those of placebo, but the incidence of serious AEs was higher in the treatment group and pain reductions were below the MCID.¹³⁵ Many randomized controlled trials of viscosupplementation with IA-HA exhibited similar or worse treatment outcomes compared with placebo, though these results were never published.¹³⁵ The implications of these findings for ongoing and future use of viscosupplementation are yet to be determined.

The AAOS cautions that short-acting IA injections carry a potential risk of accelerating OA,¹ yet some evidence for this is based on populations not representative of typical OA patients and derived from studies with notable limitations. Two observational studies published in 2019 investigated OA progression to TKA following IA-CS.¹³⁶ One found an increased risk of TKA with IA-CS treatment compared with those treated without IA-CS (22.3% vs 5.4%), but the authors also acknowledged that only one patient in the IA-CS group had TKA due to worsening K/L assessment.^136,137 The other study found no increased 5-year risk in patients treated with IA-CS compared with patients treated with IA-HA.^136,138 Another questionnaire-based study identified a possible increase in risk for TKA in professional soccer players; results for this study were limited to survey respondents, and information gathered from professional athletes is not directly translatable to the general arthritic patient.^136,139 Despite these concerns, a trial of 140 patients with OAK injected with IA triamcinolone or placebo every 3 months found that cartilage thickness loss was not statistically different between groups (p = 0.14) among study completers.¹⁴⁰ The reported worst-case scenario of cartilage loss with IA triamcinolone (~0.055 mm/year over 2 years)¹⁴⁰ is unlikely to be clinically meaningful, particularly if the steroid provides symptomatic relief.

A significant challenge of IA-CS, which contributes to its short-term clinical impact, is that small-molecule drugs such as triamcinolone acetonide (TA) are not retained in the joint space, leading to rapid egress from the joint into plasma circulation and waning analgesic effects.¹⁴¹ Formulation of these drugs with compounds that allow longer joint residence should enable longer treatment periods without increased toxicity.¹⁴² An extended-release formulation of TA (TA-ER) has been developed that embeds TA within poly(lactic-co-glycolic acid) microspheres.¹⁴¹ These microspheres reside within the synovium of the joint and slowly degrade to release bioactive TA.¹⁴³ The microspheres, which degrade to carbon dioxide and water, reside in the joint for at least 3 months—this corresponds with clinically relevant detectable levels of TA within the joint at 3 months in contrast to standard TA, which is gone from the joint by 6 weeks.^143,144 The low IA concentration leads to a low diffusion gradient and an 18 times lower peak plasma concentration of TA.¹⁴⁴ This lower plasma concentration has demonstrated no adrenal suppression and minimal impact on blood glucose in diabetic patients.^144–147 Initial phase II studies demonstrated significant pain reduction with TA-ER relative to saline placebo.^141,148 A subsequent three-arm, phase III study comparing placebo, crystalline-suspension formulation of TA (TA-CS), and TA-ER demonstrated an approximately 50% reduction in pain from baseline with TA-ER at 12 weeks (average daily pain (ADP) intensity scores from baseline to week 12 of −3.12 compared with −2.86 with TA-CS (p = 0.2964) and −2.14 with placebo (p < 0.0001)), with a statistically and clinically meaningful reduction in pain compared with placebo (least squares mean (LSM) difference −0.37; p < 0.0001) and TA-CS (LSM difference −0.17; p = 0.0475) at 12 weeks, and rescue medication use was also significantly reduced with TA-ER versus placebo (LSM difference −0.50; p = 0.0006).¹⁴⁹ Subsequent post hoc analysis of these same data also demonstrated statistically significant improvement using TA-ER versus TA-CS in ADP intensity scores from weeks 4 to 21 (p < 0.05) and WOMAC-A scores at weeks 4, 8, 12, and 24 (p < 0.05) in patients with unilateral OAK and those who at baseline had consistent concordant pain reporting utilizing both ADP and WOMAC-A.^150,151 Furthermore, in a phase IIIb real-world study, 92% of participants opted for a repeat injection based on efficacy of the first injection.¹⁵² The clinical response of the second injection was comparable in duration and magnitude to the first injection, with a median time for redosing of 16.6 weeks.¹⁵² At 52 weeks, there were no radiographic signals to suggest progression of disease with no change in joint space narrowing, subchondral bone changes, insufficiency fracture, and osteonecrosis.¹⁵² Other than a slight increase in arthralgia, the second dose of TA-ER did not increase incidence of AEs, and the increase in arthralgia was attributed to disease pathology or progression of OA.¹⁵² Extended-release intraarticular corticosteroids (IA-CS) are included in the AAOS guidelines with a moderate recommendation to improve patient outcomes over immediate-release corticosteroids.¹

Other liposomal or extended-release formulations of corticosteroids have been investigated for OAK. In a preliminary phase I study, extended-release fluticasone propionate (FP-ER) was well tolerated with a trend toward improved pain relative to placebo between 8 and 12 weeks, although significance was not reached.¹⁵³ In addition, TLC599, a liposome-delivered extended-release formulation of dexamethasone sodium phosphate, was evaluated in a phase IIa study in 75 patients with OAK.¹⁵⁴ One 12-mg dose significantly improved patient pain compared with placebo (p = 0.0027) and showed sustained pain control through week 24.¹⁵⁴ A phase III trial of TLC599 has been completed, but results have not yet been released [ClinicalTrials.gov identifier: NCT04123561]. In addition, nano products—such as micelles, exosomes, and cell-based nanotherapies—for targeted and sustained delivery of therapies are under investigation.¹⁵⁵ Emerging treatments also include potential disease-modifying therapies that would prevent further joint destruction and improve function (e.g., IL-1 receptor antagonist IA injection, gene therapy such as PCRX201, cell-based therapies including ELIXCYTE and TissueGene-C, and inhibitors of Wnt signaling pathway (lorecivivint)).^{142,156–159}

PRP products concentrate platelets, white blood cells, and platelet-derived growth factors from a patient’s centrifuged blood.¹⁶⁰ IA-PRP receives a limited recommendation in the AAOS guidelines¹ but is not recommended in the ACR guidelines.¹⁰¹ In a meta-analysis of randomized clinical trials of IA-PRP compared with IA-HA, ozone, and IA-CS, significant differences for IA-PRP over the control group were demonstrated in total WOMAC scores and WOMAC physical function subscores at 3, 6, and 12 months.¹⁶¹ Similarly, significant improvements in total WOMAC scores and International Knee Documentation Committee Subjective Knee Evaluation Form scores at 24 weeks were noted in a systematic review and analyses of four randomized clinical trials and two prospective cohort studies comparing IA-PRP with IA-HA or placebo.¹⁶² Significant improvement in radiographic parameters, including patellofemoral cartilage volume and synovitis, was observed 8 months after IA-PRP treatment compared with placebo (p = 0.001 and p = 0.026, respectively) in a 2020 randomized clinical trial.¹⁶³ Hypertension and proteinuria have been noted by AAOS as treatment-related AEs for IA-PRP,¹ but a meta-analysis found that all AEs—including pain, stiffness, syncope, dizziness, headache, nausea, gastritis, sweating, and tachycardia—were neither specific nor severe and resolved within days.¹⁶¹ Although the European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) consensus group found enough evidence to support the use of PRP in OAK,¹⁶⁴ AAOS guidelines note that additional evidence over a 2-to-5-year period is needed to determine whether IA-PRP is cartilage sparing compared with IA-CS.¹ Given the heterogeneity of preparation and variable concentrations of blood products (e.g., platelets, leukocytes), investigators have also called for increased consistency in reporting PRP preparation steps and composition of the PRP delivered in clinical studies,¹⁶⁵ as available data lack sufficient detail to interpret results or enable trial replication.¹⁶⁶ Furthermore, current studies lack knee function or structural change data, limiting analysis of long-term efficacy.¹⁶⁷

Other formulations of human plasma are under investigation for localized pain management. A combination of human plasma containing clonidine and HA, JTA-004, was designed for injectable pain control.¹⁶⁸ Although improvements were seen in the WOMAC pain subscale, physical function subscale, and total scores at all time points, the initial dosing study for JTA-004 did not show a significant difference from a reference treatment.¹⁶⁸

Denervation therapies

Cryoneurolysis is a form of thermal neurolysis in which a cryoprobe cooled from −20°C to −100°C (−88°C with nitrous oxide as a coolant) is used to freeze peripheral sensory nerves at or near the source of pain.^169,170 The mechanism of action is to locally freeze the nerve, which results in Wallerian degeneration of the axon and myelin distal to the injury, but preservation of the nerve sheath. Over time, the nerve regenerates at 1–2 mm per day along the intact nerve sheath to its target innervation.^169,171 In a study including 180 patients with OAK, the application of cryoneurolysis to the infrapatellar branch of the saphenous nerve in patients with OA-related knee pain was well tolerated, with most commonly reported AEs (bruising, numbness, redness, tenderness upon palpation, and swelling) resolving within 30 days.¹⁷² Cryoneurolysis significantly decreased knee pain (visual analog scale score) compared with sham treatment through 150 days (least-squares mean difference, −14.6; p = 0.0010).¹⁷² A parallel-group randomized controlled trial currently recruiting in KOA [ClinicalTrials.gov identifier: NCT03774121] will allocate participants 1:1 to cryoneurolysis or sham treatment in combination with exercise and education¹⁷³.

Another form of thermal denervation is radiofrequency ablation (RFA).^174,175 In contrast to cryoneurolysis, cooled RFA delivers radiofrequency energy to degrade nerve structures through ionic heating at a high thermal temperature of 60°C to disrupt or destroy neurons.^176,177 The temperature is cooled locally during treatment, but high temperatures still may cause injury to surrounding tissues or permanent nerve injury.^176,178 In a randomized study of 38 patients with severe OAK pain lasting over 3 months, RFA (n = 19) significantly reduced visual analog scale (VAS) pain scores from baseline after 1 week compared with a sham-treated control group (n = 19).¹⁷⁹ Among patients treated with RFA, 59% achieved 50% pain reduction after 12 weeks, with no patients in the control group showing a similar reduction. In a direct comparison between RFA (n = 37) and IA-delivered analgesics (morphine and betamethasone; n = 36), patients treated with RFA saw significant reductions in VAS-pain, WOMAC total scores, and WOMAC-physical function after 1 month and VAS-pain and WOMAC stiffness after 3 months compared with those treated with IA.¹⁸⁰ Similar results were observed in comparisons of RFA with oral analgesics.¹⁸¹ Patients treated with RFA showed sustained pain control, with a 67% improvement in pain from baseline at 3 months post-RFA and a 95% improvement at 6 months post-RFA,¹⁸² and improvements in physical function and general health perceptions were seen post-RFA treatment.¹⁶¹ Although AAOS guidelines suggest that denervation therapy may reduce pain and improve function, the number of studies is too limited for a full recommendation.¹ Data on long-term outcomes are limited for denervation therapies, and there is additional research, which is warranted regarding the potential complications of treating a neuropathic joint.

Framework to guide clinical decision-making

Although guidelines have been established for OAK treatment, real-world treatment decisions vary greatly based on patient phenotype and may differ from guideline recommendations.¹⁵ Although guidelines outline general recommendations for clinical management of OA, they are based on evidence from clinical trials and meta-analyses, which may not reflect patient outcomes in clinical practice.¹⁸³ In addition, clinical trials rarely include stacked therapy of multiple modalities, which is frequently utilized in clinical practice. For example, clinical trials have a limited duration of patient follow-up, whereas an HCP may see patients for a decade or more and thus develop a different perspective on safety and effectiveness, particularly for therapies continued over many years.¹⁸³ Likewise, efficacy thresholds set in clinical trials and incorporated into meta-analyses may not adequately reflect the chronicity of OA.¹⁸³ One study compared treatment effect sizes and thresholds of statistical significance and clinical importance to illustrate that 19 interventions, including commonplace treatments such as acetaminophen and topical NSAIDs, did not meet the standards of clinical importance.¹¹⁷ Continuous ultrasound, lateral wedge insole, pulsed ultrasound, transcutaneous electrical nerve stimulation, and valgus bracing demonstrated possible clinical importance in this analysis.¹¹⁷ To address the clinical complexity in the treatment of real-world OA patient populations, step-wise treatment algorithms have been utilized alongside published guidelines, as well as algorithms that monitor for suboptimal therapy and increased morbidity from AEs.¹⁸⁴

With the development of technologies such as microspheres for targeted steroid release, denervation therapies, and gene therapy, it is appropriate to tailor treatment options to specific patients at specific times in their OA journey. To this end, the authors propose the following principles for consideration for treatment selection. Nonpharmacologic therapies, including bracing, therapy, and exercise, should be utilized throughout a patient’s treatment plan. Depending on the level of pain at presentation, topical NSAIDs can be an initial choice for pain management to limit systemic exposure, followed by over-the-counter analgesics, such as oral NSAIDs and acetaminophen, if topical treatments are ineffective. These first-line anti-inflammatory adjuncts are important, but managing a 45-year-old male manual labor worker with severe bone-on-bone arthritis with ibuprofen for 10 years would not be an ideal treatment choice and could lead to a multitude of deleterious health consequences. In addition, a 50-year-old female account executive who wants to ski and ride horseback would likely be more amenable to targeted and local anti-inflammatory technologies versus oral medication that has significant systemic deleterious effects. For chronic treatment in patients with risk factors or comorbidities for AEs associated with systemic, pharmacologic agents, repeat treatment with TA-ER, cryoneurolysis, or emerging injectables may provide a local treatment option with minimal risk for systemic AEs.

As described previously, OAK is a chronic condition with significant negative effects on life and work, in addition to potential comorbid contributions from various treatment options. Newer technologies appear to be safer, more effective, and possibly more economically feasible in younger patients who are not candidates for joint arthroplasty. Though evidence for chondrotoxicity from IA injections is sparse and poor, in younger patients, consideration might be given to HA or biologic injections given their generally anecdotal improved safety profile over IA steroids; meanwhile, patients with diabetes may be good candidates for targeted IA technologies that are long-acting and slowly elute steroid to modulate IA inflammation with minimal systemic absorption. Emerging technologies may be even more beneficial in patients of advanced age who are no longer candidates for surgical replacement. Denervation therapy in conjunction with long-acting IA steroids has not only been shown to be effective and safe, but they have also demonstrated improved mobility and fall reduction in the authors’ experience (e-mail, M.L., 25 March 2023). As patients approach the need for TKA, injections should be avoided within 3 months of planned surgery, and cryoneurolysis becomes an attractive extra-articular option without increasing perioperative risk or morbidity. Currently, there are no guidelines regarding which therapeutic interventions or treatment sequences are recommended for any given phenotype. Future expert consensus and additional studies will hopefully delineate this important clinical information; however, the current choice and sequence of therapeutic agents are empiric.

Areas for future research

Multiple therapies are under clinical development for OAK, with some highlighted in Table 2. Although research has been conducted into real-world treatment patterns in OAK, additional information on how extant and emerging therapies are used in clinical settings is needed. Expanded randomized clinical trials that distinguish between patient phenotypes and incorporate more long-term data, along with additional information from registries and real-world studies, will give a more thorough picture of how novel therapies impact the heterogeneous population of patients with OA. In addition, standardized time points and measurement scales would allow for more direct comparisons between current and novel therapies. Further health economics and outcomes research is also needed to better understand the financial impact of OA on the community and individuals. One real-world registry for OA is the Innovations in Genicular Outcomes Registry, which is prospectively collecting real-world data from patients undergoing treatments for OAK [ClinicalTrials.gov identifier: NCT05495334]. Clinical effectiveness, safety, health-related quality of life, and economic burden are being assessed through patient-reported outcome measures and clinical, reimbursement, and healthcare resource utilization data [ClinicalTrials.gov identifier: NCT05495334].

Table 2.

Select therapies in development for OAK^a.

Therapy	Current clinical development stage^b	Mechanism of action	Route of administration
Ion channel targeting
PF05089771¹²⁷	Preclinical	Selective intracellular blockade of Na_v1.7 sodium channels	IA
Capsaicin¹²⁸	Phase IIb TRIUMPH study (ClinicalTrials.gov identifier: NCT02558439)	Transient receptor potential cation channel subfamily V member 1 agonist	IA
OLP-1002¹⁸⁵	Phase II [ClinicalTrials.gov identifier: NCT05216341]	PNA-based drug; inhibits expression of Na_v1.7 sodium channels	SC
RTX¹⁸⁶	Phase II [ClinicalTrials.gov identifier: NCT04885972]	TRPV1 calcium channel agonist	IA
Cartilage formation promoter
Strontium ranelate¹²⁹	Phase III SEKOIA study (ISRCTN1323372)	Stimulates cartilage matrix formation and inhibits subchondral bone resorption	PO
Anti-inflammatories
Denosumab¹³⁰	Phase II (EUDRACT CT 2015-003223-53)	Receptor activator of NF-κB ligand inhibitor	NR
ER fluticasone propionate¹⁵³	Phase I (ClinicalTrials.gov identifier: NCT02609126)	Corticosteroid; anti-inflammatory	IA
TLC599 (ER dexamethasone sodium phosphate)¹⁵⁴	Phase IIa (ClinicalTrials.gov identifier: NCT03005873) and Phase III [ClinicalTrials.gov identifier: NCT04123561]	Glucocorticoid; anti-inflammatory	IA
JTA-004¹⁶⁸	Phase II/III (ClinicalTrials.gov identifier: NCT02740231)	Antihypertensive and hyaluronic acid; anti-inflammatory and analgesic	IA
Gene therapies
PCRX201¹⁵⁶	Phase I (ClinicalTrials.gov identifier: NCT04119687)	Gene therapy; IL-1R antagonist triggered by an NF-κB promoter	IA
ICM-203¹⁸⁷	Phase I/II [ClinicalTrials.gov identifiers: NCT05454566, NCT04875754]	Gene therapy; enhance NKx3.2 expression	IA
XT-150¹⁸⁸	Phase II [ClinicalTrials.gov identifier: NCT04124042]	Gene therapy; induce IL-10 expression	IA
Cell-based therapies
ELIXCYTE¹⁵⁷	Phase I/II (ClinicalTrials.gov identifier: NCT02784964)	MSCs; immunomodulator, also targets chondrocytes and cartilage	IA
TissueGene-C¹⁵⁹	Phase III (ClinicalTrials.gov identifier: NCT02072070)	Cell-based expression of TGF-β; cartilage restoration	IA
XSTEM	Phase I/II [ClinicalTrials.gov identifier: NCT05344157]	Allogenic MSCs selected for integrin α10β1	IA
SMUP-IA-01¹⁸⁹	Phase II [ClinicalTrials.gov identifier: NCT05182034]	UBC-derived MSCs producing anti-inflammatory PTX-3	IA
Amnion-based therapy
Amniotic suspension allograft¹⁹⁰	Phase III [ClinicalTrials.gov identifier: NCT04636229]	Amniotic membrane particulate and amniotic fluid cells	IA

This table includes representative therapies from each category and is not intended to be an exhaustive list.

As of January 2024.

ER, extended release; IA, intraarticular; IL-1R, interleukin-1 receptor; IL-10, interleukin 10; MSC, mesenchymal stem cell; NF-κB, nuclear factor kappa B; NKx3.2, NK3 homeobox 2; NR, not reported; OAK, knee OA; PNA, peptide nucleic acid; PO, by mouth; PTX-3, pentraxin 3; RTX, Resiniferatoxin; TGF-β, tumor growth factor-beta; SC, subcutaneous; TRPV1, transient receptor potential cation channel subfamily V member 1; UBC, umbilical cord; Wnt, Wingless-related integration site.

Conclusion

OAK is a prevalent condition with variable disease presentation and trajectory that leads to a large humanistic and economic burden. While disease modification therapies have not yet been identified, several nonsurgical options have been characterized. Nevertheless, there is an unmet need for therapies that can meaningfully improve pain and functional outcomes. Recently emerging treatment options present opportunities to manage pain and increase mobility more effectively. While treatment guidelines provide a scaffold for determining the appropriate treatment path, each patient presents with a unique set of needs which, along with emerging treatment options, should be incorporated into an individualized approach to OAK management.

Footnotes

Acknowledgements

Writing and editorial assistance was provided under the direction of the authors by Jenny Johnson, PhD, ELS, MedThink SciCom, and funded by Pacira BioSciences. All authors have authorized MedThink SciCom to submit this approved manuscript on their behalf.

Declarations

ORCID iDs

Michael Langworthy

Vinod Dasa

References

American Academy of Orthopaedic Surgeons. Management of osteoarthritis of the knee (nonarthroplasty) evidence-based clinical practice guideline, https://www.aaos.org/oak3cpg (2021, accessed 24 April 2024).

Whittaker

Runhaar

Bierma-Zeinstra

, et al. A lifespan approach to osteoarthritis prevention. Osteoarthritis Cartilage 2021; 29: 1638–1653.

Grassel

Muschter

. Recent advances in the treatment of osteoarthritis. F1000Research 2020; 9: F1000 Faculty Rev-1325.

Sakalauskiene

Jauniskiene

. Osteoarthritis: etiology, epidemiology, impact on the individual and society and the main principles of management. Medicina (Kaunas) 2010; 46: 790–797.

Leifer

Katz

Losina

. The burden of OA-health services and economics. Osteoarthritis Cartilage 2022; 30: 10–16.

Hunter

March

Chew

. Osteoarthritis in 2020 and beyond: a lancet commission. Lancet 2020; 396: 1711–1712.

Deshpande

Katz

Solomon

, et al. Number of persons with symptomatic knee osteoarthritis in the US: impact of race and ethnicity, age, sex, and obesity. Arthritis Care Res (Hoboken) 2016; 68: 1743–1750.

Callahan

Cleveland

Allen

, et al. Racial/ethnic, socioeconomic, and geographic disparities in the epidemiology of knee and hip osteoarthritis. Rheum Dis Clin North Am 2021; 47: 1–20.

Pritzker

Gay

Jimenez

, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 2006; 14: 13–29.

10.

Astephen Wilson

Deluzio

Dunbar

, et al. The association between knee joint biomechanics and neuromuscular control and moderate knee osteoarthritis radiographic and pain severity. Osteoarthritis Cartilage 2011; 19: 186–193.

11.

Silva

NCdOVE

Dos Anjos

Santana

MMC

, et al. Discordance between radiographic findings, pain, and superficial temperature in knee osteoarthritis. Reumatologia 2020; 58: 375–380.

12.

Van Spil

Kubassova

Boesen

, et al. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol 2019; 165: 41–48.

13.

Jang

Lee

. Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. Int J Mol Sci 2021; 22: 2619.

14.

Kan

Chan

Chiu

, et al. Non-surgical treatment of knee osteoarthritis. Hong Kong Med J 2019; 25: 127–133.

15.

Dysart

Utkina

Stong

, et al. Insights from real-world analysis of treatment patterns in patients with newly diagnosed knee osteoarthritis. Am Health Drug Benefits 2021; 14: 56–62.

16.

Peng

Huang

, et al. Osteotomy around the knee: the surgical treatment of osteoarthritis. Orthop Surg 2021; 13: 1465–1473.

17.

Ronn

Reischl

Gautier

, et al. Current surgical treatment of knee osteoarthritis. Arthritis 2011; 2011: 454873.

18.

Quinn

Murray

Pezold

, et al. Surgical management of osteoarthritis of the knee. J Am Acad Orthop Surg 2018; 26: e191–e193.

19.

American Academy of Orthopaedic Surgeons. Surgical management of osteoarthritis of the knee: evidence-based clinical practice guideline, https://www.aaos.org/quality/quality-programs/lower-extremity-programs/surgical-management-of-osteoarthritis-of-the-knee/ (accessed 24 April 2024).

20.

Long

Liu

Yin

, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: findings from the global burden of disease study 2019. Arthritis Rheumatol 2022; 74: 1172–1183.

21.

Murphy

Schwartz

Helmick

, et al. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum 2008; 59: 1207–1213.

22.

Cui

Wang

, et al. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine 2020; 29–30: 100587.

23.

GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388: 1545–1602.

24.

Liu

Jin

Yao

, et al. Disease burden of osteoarthritis of the knee and hip due to a high body mass index in China and the USA: 1990–2019 findings from the global burden of disease study 2019. BMC Musculoskelet Disord 2022; 23: 63.

25.

Wallace

Worthington

Felson

, et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc Natl Acad Sci U S A 2017; 114: 9332–9336.

26.

van Tunen

JAC

Peat

Bricca

, et al. Association of osteoarthritis risk factors with knee and hip pain in a population-based sample of 29–59 year olds in Denmark: a cross-sectional analysis. BMC Musculoskelet Disord 2018; 19: 300.

27.

Szilagyi

Waarsing

Schiphof

, et al. Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females. Rheumatology (Oxford) 2022; 61: 648–657.

28.

Silverwood

Blagojevic-Bucknall

Jinks

, et al. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2015; 23: 507–515.

29.

Reynard

Barter

. Osteoarthritis year in review 2019: genetics, genomics and epigenetics. Osteoarthritis Cartilage 2020; 28: 275–284.

30.

Loughlin

. Genetic contribution to osteoarthritis development: current state of evidence. Curr Opin Rheumatol 2015; 27: 284–288.

31.

Park

Bello

Arai

, et al. Functional duality of chondrocyte hypertrophy and biomedical application trends in osteoarthritis. Pharmaceutics 2021; 13: 1139.

32.

Budhiparama

Lumban-Gaol

Sudoyo

, et al. Interleukin-1 genetic polymorphisms in knee osteoarthritis: what do we know? A meta-analysis and systematic review. J Orthop Surg (Hong Kong) 2022; 30: 23094990221076652.

33.

Felson

Hodgson

. Identifying and treating preclinical and early osteoarthritis. Rheum Dis Clin North Am 2014; 40: 699–710.

34.

Prasanna

Korner-Bitensky

Ahmed

. Why do people delay accessing health care for knee osteoarthritis? Exploring beliefs of health professionals and lay people. Physiother Can 2013; 65: 56–63.

35.

Culvenor

Oiestad

Hart

, et al. Prevalence of knee osteoarthritis features on magnetic resonance imaging in asymptomatic uninjured adults: a systematic review and meta-analysis. Br J Sports Med 2019; 53: 1268–1278.

36.

Crema

Roemer

Marra

, et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics 2011; 31: 37–61.

37.

Altman

Asch

Bloch

, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 1986; 29: 1039–1049.

38.

Kittelson

Schmiege

Maluf

, et al. Determination of pain phenotypes in knee osteoarthritis using latent profile analysis. Pain Med 2021; 22: 653–662.

39.

Kittelson

Stevens-Lapsley

Schmiege

. Determination of pain phenotypes in knee osteoarthritis: a latent class analysis using data from the osteoarthritis initiative. Arthritis Care Res (Hoboken) 2016; 68: 612–620.

40.

Mobasheri

Saarakkala

Finnila

, et al. Recent advances in understanding the phenotypes of osteoarthritis. F1000Research 2019; 8: F1000 Faculty Rev-2091.

41.

National Institute for Health and Care Excellence. Osteoarthritis: care and management. London: National Institute for Health and Care Excellence, 2020.

42.

Bjurstrom

Bodelsson

Montgomery

, et al. Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype. Pain 2020; 161: 2142–2154.

43.

Robbins

McDougall

. Osteoarthritis: the genesis of pain. Rheumatology (Oxford) 2018; 57: iv43–iv50.

44.

Martel-Pelletier

Barr

Cicuttini

, et al. Osteoarthritis. Nat Rev Dis Primers 2016; 2: 16072.

45.

Bedson

Croft

. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord 2008; 9: 116.

46.

Lee

Chan

Fung

, et al. Imaging of knee osteoarthritis: a review of current evidence and clinical guidelines. Musculoskeletal Care 2021; 19: 363–374.

47.

Sherman

Gulbrandsen

Lewis

, et al. Overuse of magnetic resonance imaging in the diagnosis and treatment of moderate to severe osteoarthritis. Iowa Orthop J 2018; 38: 33–37.

48.

Man

Mologhianu

. Osteoarthritis pathogenesis—a complex process that involves the entire joint. J Med Life 2014; 7: 37–41.

49.

Raynauld

Martel-Pelletier

Berthiaume

, et al. Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes. Arthritis Res Ther 2006; 8: R21.

50.

Kellgren

Lawrence

. Radiological assessment of osteoarthrosis. Ann Rheum Dis 1957; 16: 494–502.

51.

Cerejo

Dunlop

Cahue

, et al. The influence of alignment on risk of knee osteoarthritis progression according to baseline stage of disease. Arthritis Rheum 2002; 46: 2632–2636.

52.

Schiphof

Identifying knee osteoarthritis: classification, early recognition and imaging, https://repub.eur.nl/pub/31136/120201_Schiphof,%20Dieuwke%20-%20Identifying%20Knee%20Osteoarthritis_%20Classification,%20early%20recognition%20and%20imaging.pdf (2012, accessed 25 April 2024).

53.

Bay-Jensen

Andersen

Charni-Ben Tabassi

, et al. Biochemical markers of type II collagen breakdown and synthesis are positioned at specific sites in human osteoarthritic knee cartilage. Osteoarthritis Cartilage 2008; 16: 615–623.

54.

Concoff

Rosen

, et al. A comparison of treatment effects for nonsurgical therapies and the minimum clinically important difference in knee osteoarthritis: a systematic review. JBJS Rev 2019; 7: e5.

55.

Molino

Harrington

Racine-Avila

, et al. Deconstructing the minimum clinically important difference (MCID). Orthop Res Rev 2022; 14: 35–42.

56.

Weber

Jevsevar

McGrory

. AAOS clinical practice guideline: surgical management of osteoarthritis of the knee: evidence-based guideline. J Am Acad Orthop Surg 2016; 24: e94–e96.

57.

Osteoarthritis Research Society International. Osteoarthritis: a serious disease. Mount Laurel, NJ: Osteoarthritis Research Society International, 2016.

58.

Favre

Jolles

. Gait analysis of patients with knee osteoarthritis highlights a pathological mechanical pathway and provides a basis for therapeutic interventions. EFORT Open Rev 2016; 1: 368–374.

59.

Segal

Nevitt

Gross

, et al. The Multicenter Osteoarthritis Study (MOST): opportunities for rehabilitation research. PM R 2013; 5: 647–654.

60.

Losina

Silva

Smith

, et al. Quality-adjusted life-years lost due to physical inactivity in a US population with osteoarthritis. Arthritis Care Res (Hoboken) 2020; 72: 1349–1357.

61.

Dibonaventura

Gupta

McDonald

, et al. Impact of self-rated osteoarthritis severity in an employed population: cross-sectional analysis of data from the National Health and Wellness Survey. Health Qual Life Outcomes 2012; 10: 30.

62.

Menon

. Osteoarthritis related absenteeism and activity limitations. Osteoarthritis Cartilage 2015; 23(Suppl. 2): A343.

63.

Holte

Tambs

Bjerkedal

. Manual work as predictor for disability pensioning with osteoarthritis among the employed in Norway 1971–1990. Int J Epidemiol 2000; 29: 487–494.

64.

Sadosky

Bushmakin

Cappelleri

, et al. Relationship between patient-reported disease severity in osteoarthritis and self-reported pain, function and work productivity. Arthritis Res Ther 2010; 12: R162.

65.

Hessel

. Overview of the socio-economic consequences of heart failure. Cardiovasc Diagn Ther 2021; 11: 254–262.

66.

Iragorri

de Oliveira

Fitzgerald

, et al. The out-of-pocket cost burden of cancer care—a systematic literature review. Curr Oncol 2021; 28: 1216–1248.

67.

Parry

Ogollah

Peat

. Significant pain variability in persons with, or at high risk of, knee osteoarthritis: preliminary investigation based on secondary analysis of cohort data. BMC Musculoskelet Disord 2017; 18: 80.

68.

Ekediegwu

Ekechukwu

Odole

. Variations in chronic pain intensity and physical function by age and sex for patients with knee osteoarthritis. J Musculoskelet Disord Treat 2022; 8: 108.

69.

Centers for Disease Control and Prevention. Arthritis as a potential barrier to physical activity among adults with heart disease—United States, 2005 and 2007. MMWR Morb Mortal Wkly Rep 2009; 58: 165–169.

70.

Centers for Disease Control and Prevention. Arthritis as a potential barrier to physical activity among adults with diabetes—United States, 2005 and 2007. MMWR Morb Mortal Wkly Rep 2008; 57: 486–489.

71.

Habib

Khazin

Sakas

, et al. The impact of intra-articular injection of diprospan at the knee joint on blood glucose levels in diabetic patients. Eur J Rheumatol 2018; 5: 96–99.

72.

Wang

Nguyen

UDT

Lane

, et al. Knee osteoarthritis, potential mediators, and risk of all-cause mortality: data from the osteoarthritis initiative. Arthritis Care Res (Hoboken) 2021; 73: 566–573.

73.

Kraus

Sprow

Powell

, et al. Effects of physical activity in knee and hip osteoarthritis: a systematic umbrella review. Med Sci Sports Exerc 2019; 51: 1324–1339.

74.

Pazan

Wehling

. Polypharmacy in older adults: a narrative review of definitions, epidemiology and consequences. Eur Geriatr Med 2021; 12: 443–452.

75.

Salaffi

Di Carlo

Carotti

, et al. Frailty prevalence according to the Survey of Health, Ageing and Retirement in Europe-Frailty Instrument (SHARE-FI) definition, and its variables associated, in patients with symptomatic knee osteoarthritis: findings from a cross-sectional study. Aging Clin Exp Res 2021; 33: 1519–1527.

76.

Betancourt

Marchi

Machado

, et al. Detection of possible problematic polypharmacy in patients with osteoarthritis and associated factors. Osteoarthritis Cartilage 2022; 30: S195–S196.

77.

Bruyère

Honvo

Veronese

, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum 2019; 49: 337–350.

78.

Pendleton

Arden

Dougados

, et al. EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2000; 59: 936–944.

79.

Johnson

. A personalized shared decision-making tool for osteoarthritis management of the knee. Orthop Nurs 2021; 40: 64–70.

80.

Patel

Gronbeck

Chambers

, et al. Gender and total joint arthroplasty: variable outcomes by procedure type. Arthroplast Today 2020; 6: 517–520.

81.

Olsen

Lindberg

Rose

, et al. Factors correlated with physical function 1 year after total knee arthroplasty in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA Netw Open 2022; 5: e2219636.

82.

Rankin

Alarcon

Chang

, et al. NIH consensus statement on total knee replacement December 8–10, 2003. J Bone Joint Surg 2004; 86: 1328.

83.

Ighani Arani

Wretenberg

W-Dahl

. Information and BMI limits for patients with obesity eligible for knee arthroplasty: the Swedish surgeons’ perspective from a nationwide cross-sectional study. J Orthop Surg Res 2022; 17: 550.

84.

Royal College of Surgeons of England. Smokers and overweight patients: soft targets for NHS savings? London: Royal College of Surgeons, 2016.

85.

Harris

Bowe

Gupta

, et al. Hemoglobin A1C as a marker for surgical risk in diabetic patients undergoing total joint arthroplasty. J Arthroplasty 2013; 28: 25–29.

86.

Heo

Harris

Naylor

, et al. Complications to 6 months following total hip or knee arthroplasty: observations from an Australian clinical outcomes registry. BMC Musculoskelet Disord 2020; 21: 602.

87.

DeFrance

Scuderi

. Are 20% of patients actually dissatisfied following total knee arthroplasty? A systematic review of the literature. J Arthroplasty 2023; 38: 594–599.

88.

Bourne

Chesworth

Davis

, et al. Patient satisfaction after total knee arthroplasty: who is satisfied and who is not? Clin Orthop Relat Res 2010; 468: 57–63.

89.

Parvizi

Nunley

Berend

, et al. High level of residual symptoms in young patients after total knee arthroplasty. Clin Orthop Relat Res 2014; 472: 133–137.

90.

Evans

Walker

Evans

, et al. How long does a knee replacement last? A systematic review and meta-analysis of case series and national registry reports with more than 15 years of follow-up. Lancet 2019; 393: 655–663.

91.

Lee

Song

, et al. Causes and clinical outcomes of revision total knee arthroplasty. Knee Surg Relat Res 2017; 29: 104–109.

92.

Roman

Russu

Mohor

, et al. Outcomes in revision total knee arthroplasty (review). Exp Ther Med 2022; 23: 29.

93.

Losina

Katz

. Total knee arthroplasty on the rise in younger patients: are we sure that past performance will guarantee future success? Arthritis Rheum 2012; 64: 339–341.

94.

Julin

Jamsen

Puolakka

, et al. Younger age increases the risk of early prosthesis failure following primary total knee replacement for osteoarthritis. A follow-up study of 32,019 total knee replacements in the Finnish Arthroplasty Register. Acta Orthop 2010; 81: 413–419.

95.

Charette

Sloan

DeAngelis

, et al. Higher rate of early revision following primary total knee arthroplasty in patients under age 55: a cautionary tale. J Arthroplasty 2019; 34: 2918–2924.

96.

Nunley

Nam

Berend

, et al. New total knee arthroplasty designs: do young patients notice? Clin Orthop Relat Res 2015; 473: 101–108.

97.

Keeney

. Total knee arthroplasty in the younger patient: challenges and solutions. Orthop Res Rev 2015; 7: 33–38.

98.

Chalmers

Syku

Joseph

, et al. High rate of re-revision in patients less than 55 years of age undergoing aseptic revision total knee arthroplasty. J Arthroplasty 2021; 36: 2348–2352.

99.

Bannuru

Osani

Vaysbrot

, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019; 27: 1578–1589.

100.

Hunter

Deer

Jones

, et al. Consensus guidelines on interventional therapies for knee pain (STEP guidelines) from the American Society of Pain and Neuroscience. J Pain Res 2022; 15: 2683–2745.

101.

Kolasinski

Neogi

Hochberg

, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Rheumatol 2020; 72: 220–233.

102.

Geenen

Overman

Christensen

, et al. EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis. Ann Rheum Dis 2018; 77: 797–807.

103.

ClinicalTrials.gov. Knee osteoarthritis | not yet recruiting, recruiting, active, not recruiting, enrolling by invitation studies | Phase: 2, 3 | Interventional studies https://clinicaltrials.gov/ct2/results?cond=Knee+Osteoarthritis&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=Intr&rslt=&phase=1&phase=2&Search=Apply (accessed 16 May 2023).

104.

ClinicalTrials.gov. Knee osteoarthritis | not yet recruiting, recruiting, active, not recruiting, enrolling by invitation studies | phase: 3 | interventional studies. https://clinicaltrials.gov/ct2/results?cond=Knee+Osteoarthritis&recrs=b&recrs=a&recrs=f&recrs=d&age_v=&gndr=&type=Intr&rslt=&phase=2&Search=Apply (accessed 16 May 2023).

105.

Yusuf

. Pharmacologic and non-pharmacologic treatment of osteoarthritis. Curr Treatm Opt Rheumatol 2016; 2: 111–125.

106.

Bliddal

Leeds

Christensen

. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons—a scoping review. Obes Rev 2014; 15: 578–586.

107.

Thijssen

van Caam

van der Kraan

. Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology (Oxford) 2015; 54: 588–600.

108.

Koonce

Bravman

. Obesity and osteoarthritis: more than just wear and tear. J Am Acad Orthop Surg 2013; 21: 161–169.

109.

Zhu

Zhou

Wang

, et al. Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort. Ann Rheum Dis 2023; 82: 1218–1226.

110.

Hochberg

Altman

April

, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012; 64: 465–474.

111.

Derry

Moore

Rabbie

. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2012; 9: CD007400.

112.

Peniston

Gold

Wieman

, et al. Long-term tolerability of topical diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities. Clin Interv Aging 2012; 7: 517–523.

113.

Peniston

Gold

Alwine

. An open-label, long-term safety and tolerability trial of diclofenac sodium 1% gel in patients with knee osteoarthritis. Phys Sportsmed 2011; 39: 31–38.

114.

Shainhouse

Grierson

Naseer

. A long-term, open-label study to confirm the safety of topical diclofenac solution containing dimethyl sulfoxide in the treatment of the osteoarthritic knee. Am J Ther 2010; 17: 566–576.

115.

Persson

MSM

Stocks

Walsh

, et al. The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials. Osteoarthritis Cartilage 2018; 26: 1575–1582.

116.

Rannou

Pelletier

Martel-Pelletier

. Efficacy and safety of topical NSAIDs in the management of osteoarthritis: evidence from real-life setting trials and surveys. Semin Arthritis Rheum 2016; 45: S18–S21.

117.

Vannabouathong

Bhandari

Bedi

, et al. Nonoperative treatments for knee osteoarthritis: an evaluation of treatment characteristics and the intra-articular placebo effect: a systematic review. JBJS Rev 2018; 6: e5.

118.

Makris

Kohler

Fraenkel

. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol 2010; 37: 1236–1243.

119.

Lee

. Acute liver failure. Semin Respir Crit Care Med 2012; 33: 36–45.

120.

Fanelli

Ghisi

Aprile

, et al. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Ther Adv Drug Saf 2017; 8: 173–182.

121.

US Food & Drug Administration. Medication guide for non-steroidal anti-inflammatory drugs (NSAIDs), https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018766s015MedGuide.pdf (accessed 25 April 2024).

122.

Conaghan

. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int 2012; 32: 1491–1502.

123.

Hung

Riggan

Hunt

III , et al. What’s important: a rallying call for nonsteroidal anti-inflammatory drugs in musculoskeletal pain: improving value of care while combating the opioid epidemic. J Bone Joint Surg Am 2022; 104: 659–663.

124.

Lee

Straus

Balshaw

, et al. A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: a meta-analysis. Arthritis Rheum 2004; 51: 746–754.

125.

Osani

Vaysbrot

Zhou

, et al. Duration of symptom relief and early trajectory of adverse events for oral nonsteroidal antiinflammatory drugs in knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2020; 72: 641–651.

126.

Chou

McDonagh

Nakamoto

, et al. AHRQ comparative effectiveness reviews. In: Analgesics for osteoarthritis: an update of the 2006 comparative effectiveness review. Rockville, MD: Agency for Healthcare Research and Quality (US), 2011.

127.

Reid

Cote

McDougall

. Long-term blockade of nociceptive Na(v)1.7 channels is analgesic in rat models of knee arthritis. Biomolecules 2022; 12: 1571.

128.

Stevens

Ervin

Nezzer

, et al. Randomized, double-blind, placebo-controlled trial of intraarticular trans-capsaicin for pain associated with osteoarthritis of the knee. Arthritis Rheumatol 2019; 71: 1524–1533.

129.

Reginster

Badurski

Bellamy

, et al. Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Ann Rheum Dis 2013; 72: 179–186.

130.

Wittoek

Verbruggen

Vanhaverbeke

, et al. Effect of denosumab on structure modification in erosive hand osteoarthritis: results of a 48-week, monocentric, randomized, placebo-controlled, double-blind phase 2 study and open label extension phase [abstract]. Arthritis Rheumatol 2022; 74(Suppl. 9). https://acrabstracts.org/abstract/effect-of-denosumab-on-structure-modification-in-erosive-hand-osteoarthritis-results-of-a-48-week-monocentric-randomized-placebo-controlled-double-blind-phase-2-study-and-open-label-extension-pha/

131.

Saltychev

Mattie

McCormick

, et al. The magnitude and duration of the effect of intra-articular corticosteroid injections on pain severity in knee osteoarthritis: a systematic review and meta-analysis. Am J Phys Med Rehabil 2020; 99: 617–625.

132.

Donovan

Edwards

Judge

, et al. Effects of recurrent intra-articular corticosteroid injections for osteoarthritis at 3 months and beyond: a systematic review and meta-analysis in comparison to other injectables. Osteoarthritis Cartilage 2022; 30: 1658–1669.

133.

Bannuru

Natov

Dasi

, et al. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis—meta-analysis. Osteoarthritis Cartilage 2011; 19: 611–619.

134.

Bannuru

Osani

Vaysbrot

, et al. Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthritis Cartilage 2016; 24: 2022–2041.

135.

Pereira

Juni

Saadat

, et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ 2022; 378: e069722.

136.

Samuels

Pillinger

Jevsevar

, et al. Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee. Osteoarthritis Cartilage 2021; 29: 8–16.

137.

Zeng

Lane

Hunter

, et al. Intra-articular corticosteroids and the risk of knee osteoarthritis progression: results from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2019; 27: 855–862.

138.

Latourte

Rat

Sime

, et al. Do corticosteroids or hyaluronic acid intra-articular injections impact the risk of total knee replacement? Real-life data from the Khoala cohort. Osteoarthritis Cartilage 2019; 27: S509–S510.

139.

Fernandes

Parekh

Moses

, et al. Intra-articular injection administration in UK ex-professional footballers during their playing careers and the association with post-career knee osteoarthritis. Sports Med 2020; 50: 1039–1046.

140.

McAlindon

LaValley

Harvey

, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 2017; 317: 1967–1975.

141.

Bodick

Lufkin

Willwerth

, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am 2015; 97: 877–888.

142.

Mehta

Bajpayee

. Recent advances in targeted drug delivery for treatment of osteoarthritis. Curr Opin Rheumatol 2021; 33: 94–109.

143.

Kraus

Conaghan

Aazami

, et al. Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA). Osteoarthritis Cartilage 2018; 26: 34–42.

144.

Paik

Duggan

Keam

. Triamcinolone acetonide extended-release: a review in osteoarthritis pain of the knee. Drugs 2019; 79: 455–462.

145.

Russell

Sala

Conaghan

, et al. In type 2 diabetes mellitus patients with knee osteoarthritis intra-articular injection of FX006 (Extended Release Triamcinolone) is associated with reduced blood glucose elevation vs. standard triamcinolone; a randomized, blinded, parallel group study. Diabetes 2017; 66: A289.

146.

Spitzer

Robard

Iqbal

, et al. A double-blind, randomized, parallel-group comparison of intraarticular triamcinolone acetonide extended-release versus triamcinolone acetonide immediate-release on glucose in patients with osteoarthritis of the knee and type 2 diabetes mellitus: a post hoc analysis. Paper presented at OARSI World Congress on Osteoarthritis, 17–20 March 2023, Denver, CO.

147.

Russell

Sala

Conaghan

, et al. Triamcinolone acetonide extended-release in patients with osteoarthritis and type 2 diabetes: a randomized, phase 2 study. Rheumatology (Oxford) 2018; 57: 2235–2241.

148.

Conaghan

Cohen

Berenbaum

, et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol 2018; 70: 204–211.

149.

Conaghan

Hunter

Cohen

, et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J Bone Joint Surg Am 2018; 100: 666–677.

150.

Langworthy

Conaghan

Ruane

, et al. Efficacy of triamcinolone acetonide extended-release in participants with unilateral knee osteoarthritis: a post hoc analysis. Adv Ther 2019; 36: 1398–1411.

151.

Ross

Katz

Conaghan

, et al. Improved treatment effect of triamcinolone acetonide extended-release in patients with concordant baseline pain scores on the average daily pain and Western Ontario and McMaster Universities osteoarthritis index pain scales. Pain Ther 2022; 11: 289–302.

152.

Spitzer

Richmond

Kraus

, et al. Safety and efficacy of repeat administration of triamcinolone acetonide extended-release in osteoarthritis of the knee: a phase 3b, open-label study. Rheumatol Ther 2019; 6: 109–124.

153.

Malone

Price

, et al. Safety and pharmacokinetics of EP-104IAR (sustained-release fluticasone propionate) in knee osteoarthritis: a randomized, double-blind, placebo-controlled phase 1 trial. Osteoarthr Cartil Open 2021; 3: 100213.

154.

Hunter

Chang

Wei

, et al. TLC599 in patients with osteoarthritis of the knee: a phase IIa, randomized, placebo-controlled, dose-finding study. Arthritis Res Ther 2022; 24: 52.

155.

Guo

Lou

Wang

, et al. Recent advances in nano-therapeutic strategies for osteoarthritis. Front Pharmacol 2022; 13: 924387.

156.

Cohen

Kivitz

Klassen

, et al. Safety and preliminary efficacy of PCRX201, an intra-articular gene therapy for knee osteoarthritis: a phase 1, open-label, single ascending dose study. 2023; 31(Suppl. 1): S8–S9.

157.

Chen

, et al. Treatment of knee osteoarthritis with intra-articular injection of allogeneic adipose-derived stem cells (ADSCs) ELIXCYTE(R): a phase I/II, randomized, active-control, single-blind, multiple-center clinical trial. Stem Cell Res Ther 2021; 12: 562.

158.

Yazici

McAlindon

Gibofsky

, et al. A phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis. Osteoarthritis Cartilage 2021; 29: 654–666.

159.

Kim

, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev 2018; 29: 48–59.

160.

Gato-Calvo

Magalhaes

Ruiz-Romero

, et al. Platelet-rich plasma in osteoarthritis treatment: review of current evidence. Ther Adv Chronic Dis 2019; 10: 2040622319825567.

161.

Shen

Yuan

Chen

, et al. The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials. J Orthop Surg Res 2017; 12: 16.

162.

Khoshbin

Leroux

Wasserstein

, et al. The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis. Arthroscopy 2013; 29: 2037–2048.

163.

Raeissadat

Ghorbani

Sanei Taheri

, et al. MRI changes after platelet rich plasma injection in knee osteoarthritis (randomized clinical trial). J Pain Res 2020; 13: 65–73.

164.

Laver

Filardo

Sanchez

, et al.; ESSKA-ORBIT Group. The use of injectable orthobiologics for knee osteoarthritis: A European ESSKA-ORBIT consensus. Part 1-Blood-derived products (platelet-rich plasma). Knee Surg Sports Traumatol Arthrosc 2024; 32: 783–797.

165.

Chahla

Cinque

Piuzzi

, et al. A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J Bone Joint Surg Am 2017; 99: 1769–1779.

166.

Jildeh

Vopat

, et al. Current state of platelet-rich plasma and cell-based therapies for the treatment of osteoarthritis and tendon and ligament injuries. J Bone Joint Surg Am 2022; 104: 1406–1414.

167.

American Academy of Orthopaedic Surgeons. Platelet-rich plasma (PRP) for knee osteoarthritis technology overview, https://www.aaos.org/globalassets/quality-and-practice-resources/biologics/technology-overview_prp-for-knee-oa.pdf (accessed 25 April 2024).

168.

Bettonville

Leon

Margaux

, et al. Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study. BMC Musculoskelet Disord 2021; 22: 888.

169.

Ilfeld

Preciado

Trescot

. Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves. Expert Rev Med Devices 2016; 13: 713–725.

170.

Narayanapanicker

Das

. Cryoneurolysis: is it the future of neurolysis. . .? J Recent Adv Pain 2019; 5: 78.

171.

Zhou

Kambin

Casey

, et al. Mechanism research of cryoanalgesia. Neurol Res 1995; 17: 307–311.

172.

Radnovich

Scott

Patel

, et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage 2017; 25: 1247–1256.

173.

Nygaard

Koch-Jensen

Vaegter

, et al. Cryoneurolysis for the management of chronic pain in patients with knee osteoarthritis; a double-blinded randomized controlled sham trial. BMC Musculoskelet Disord 2021; 22: 228.

174.

Cosman

Jr Cosman

Sr . Electric and thermal field effects in tissue around radiofrequency electrodes. Pain Med 2005; 6: 405–424.

175.

Jamison

Cohen

. Radiofrequency techniques to treat chronic knee pain: a comprehensive review of anatomy, effectiveness, treatment parameters, and patient selection. J Pain Res 2018; 11: 1879–1888.

176.

Chen

Khalouf

Zora

, et al. Cooled radiofrequency ablation provides extended clinical utility in the management of knee osteoarthritis: 12-month results from a prospective, multi-center, randomized, cross-over trial comparing cooled radiofrequency ablation to a single hyaluronic acid injection. BMC Musculoskelet Disord 2020; 21: 363.

177.

Ball

. The science of conventional and water-cooled monopolar lumbar radiofrequency rhizotomy: an electrical engineering point of view. Pain Physician 2014; 17: E175–E211.

178.

Pride

Poliak-Tunis

. Radiofrequency ablation and its role in treating chronic pain, https://www.asra.com/news-publications/asra-newsletter/newsletter-item/asra-news/2020/08/01/radiofrequency-ablation-and-its-role-in-treating-chronic-pain (2020, accessed 25 April 2024).

179.

Choi

Hwang

Song

, et al. Radiofrequency treatment relieves chronic knee osteoarthritis pain: a double-blind randomized controlled trial. Pain 2011; 152: 481–487.

180.

Sarı

Aydın

Turan

, et al. Which one is more effective for the clinical treatment of chronic pain in knee osteoarthritis: radiofrequency neurotomy of the genicular nerves or intra-articular injection? Int J Rheum Dis 2018; 21: 1772–1778.

181.

El-Hakeim

Elawamy

Kamel

, et al. Fluoroscopic guided radiofrequency of genicular nerves for pain alleviation in chronic knee osteoarthritis: a single-blind randomized controlled trial. Pain Physician 2018; 21: 169–177.

182.

Iannaccone

Dixon

Kaufman

. A review of long-term pain relief after genicular nerve radiofrequency ablation in chronic knee osteoarthritis. Pain Physician 2017; 20: E437–E444.

183.

Migliore

Bizzi

Herrero-Beaumont

, et al. The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! Eur Rev Med Pharmacol Sci 2015; 19: 1124–1129.

184.

Langworthy

Saad

Langworthy

. Conservative treatment modalities and outcomes for osteoarthritis: the concomitant pyramid of treatment. Phys Sportsmed 2010; 38: 133–145.

185.

Brazil

. Peptide nucleic acids promise new therapeutics and gene editing tools. ACS Cent Sci 2023; 9: 3–6.

186.

Leiman

Minkowitz

Levitt

, et al. Preliminary results from a phase 1b double-blind study to assess the safety, tolerability and efficacy of intra-articular administration of resiniferatoxin or placebo for the treatment of moderate to severe pain due to osteoarthritis of the knee. Osteoarthritis Cartilage 2020; 28: S138.

187.

Park

Collins

Lee

, et al. Semi-quantitative and quantitative cartilage improvement after intra-articular injection of ICM-203 in canine OA model. Osteoarthritis Cartilage 2022; 30: S162–S163.

188.

Grigsby

Rickam

Thewlis

, et al. XT-150—a novel immunomodulatory gene therapy for osteoarthritis pain in phase 2b development. Osteoarthritis Cartilage 2021; 29: S12.

189.

Lee

Kim

, et al. PTX-3 secreted by intra-articular-injected SMUP-cells reduces pain in an osteoarthritis rat model. Cells 2021; 10: 2420.

190.

Gomoll

Farr

Cole

, et al. Safety and efficacy of an amniotic suspension allograft injection over 12 months in a single-blinded, randomized controlled trial for symptomatic osteoarthritis of the knee. Arthroscopy 2021; 37: 2246–2257.

Knee osteoarthritis: disease burden,available treatments,and emerging options

Abstract

Keywords

Introduction

Epidemiology of OAK

OA patient journey

Diagnosis and presentation

Disease progression and monitoring

Patient burden

Treatment selection

Nonsurgical treatment options for OA

Nonpharmacologic interventions

Topical therapies

Systemic therapies

Local injection therapies

Denervation therapies

Framework to guide clinical decision-making

Areas for future research

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References