Treatment options for patients with advanced osteoarthritis who decline knee surgery

Abstract

Total knee arthroplasty is the treatment of choice for end-stage knee osteoarthritis (OA). However, only one-third of patients with knee OA are initially willing to undergo surgery. This narrative review aims to provide clinicians with a concise overview of the current non-surgical treatment options for knee OA based on clinical guidelines and research on novel medications and procedures. The international guidelines reviewed included those of the American Academy of Orthopedic Surgeons, American College of Rheumatology, European Alliance of Associations for Rheumatology, European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, United Kingdom National Institute for Health and Care Excellence, and Osteoarthritis Research Society International. Recommended nonsurgical treatment methods broadly encompass weight reduction strategies, oral and topical pharmaceutical treatments, intra-articular injections, bracing, and supplementation. This review also deals with research on novel nonsurgical knee OA treatment options that have not yet been universally addressed by guidelines, including minimally invasive therapies such as radiofrequency nerve ablation and genicular artery embolization, as well as pharmacological treatments such as glucagon-like peptide-1 receptor agonists, cannabinoids, and gabapentinoids, all of which clinicians can currently begin to apply in practice.

Key Words: Knee osteoarthritis; Osteoarthritis; Conservative treatment; Practice guidelines; Non-surgical treatment

Core Tip: Among the reviewed guidelines, there is agreement on first-line therapies, specifically weight loss, exercise, and topical non-steroidal anti-inflammatory drugs (NSAIDs). Secondary treatment options, such as oral NSAIDs, intra-articular corticosteroids, and acetaminophen, are recommended but with varying support. Beyond these therapies, the guidelines provide substantially varied recommendations. Emerging therapies that are not covered by current guidelines, such as minimally invasive interventions and novel pharmacological agents, offer promising alternative strategies.

INTRODUCTION

Osteoarthritis (OA) affects over 7% of the population, with knee OA being the most prevalent, representing 69% of cases[1]. Patients with advanced knee OA experience persistent pain that significantly impairs their functionality and quality of life[2]. Among individuals aged over 70 years, OA is the 7^th leading cause of disability worldwide, and the economic cost of early onset OA is estimated to be over 106 billion USD[1]. Its prevalence is the highest in economically developed countries and is projected to continue to increase along with obesity rates. OA is a source of a very large individual and societal economic burden, with estimates pointing to an economic burden of 1%-2.5% of the gross domestic product of high-income countries[3] and surgical interventions often constitute the greatest direct cost[4]. Furthermore, evidence suggests that OA increases the risk of mortality, possibly because of physical inactivity and chronic treatment with non-steroidal anti-inflammatory drugs (NSAIDs)[4]. In 2021, OA was ranked 14^th in the percentage of all-cause years lived with disability[5].

The pathogenesis of OA is thought to result from a complex interplay of mechanical forces and inflammatory factors, although the precise mechanisms remain uncertain[3]. Conservative treatment options are usually recommended for patients with early OA, whereas surgery, such as joint-preserving procedures, partial knee replacement, or total knee arthroplasty (TKA), is recommended for most patients with more advanced OA[6]. Despite the existing recommendations, many patients are unwilling or unable to undergo surgical treatment; indeed, only 33.5% may be willing to consider TKA[7]. Furthermore, in a cohort study of over 30000 patients, 35% of patients with knee OA who were initially willing to undergo surgery became unwilling after 12 months of first-line intervention[8]. Patient willingness to undergo surgery is correlated with the pain they experience. Reducing pain by 1 point on a 0-10 scale may decrease the willingness to consider surgery by up to 60%-80%[8]. Therefore, nonsurgical treatments have a significant effect on the well-being of patients, highlighting the importance of exploring effective treatment options other than surgery. Moreover, combining various treatment approaches results in greater improvements than administering each treatment individually[9]. Hence, by combining these guidelines with recent research on novel treatment methods, a comprehensive overview can inform clinicians.

The severity of knee OA is commonly assessed by using radiographic grading systems. Kellgren-Lawrence (K-L) radiographic grading, the most commonly used method, ranges from grade 0 (no radiological evidence of OA) to grade 4 (severe OA marked by narrowing of the joint space, large osteophytes, severe sclerosis, and bone end deformity)[10]. It is believed that half of the symptomatic cases of knee OA are advanced (K-L grade 3-4)[11].

A literature search was conducted to identify major guidelines for knee OA. To provide additional context for the recommendations set by the guidelines and to evaluate the impact of knee OA severity on treatment effectiveness, findings from various types of studies, ranging from systematic reviews to prospective studies, were included. To identify these studies, a literature search was conducted in MEDLINE and ScienceDirect using key terms related to advanced knee OA, including pharmacological and minimally invasive treatment options. The search terms included NSAIDs, acetaminophen, opioids, intra-articular injections corticosteroids, platelet-rich plasma (PRP), and hyaluronic acid (HA), gabapentinoids, duloxetine, supplements, exercise, radiofrequency ablation (RFA), genicular artery embolization (GAE), glucagon-like peptide-1 receptor agonists, bracing, and weight loss. Additionally, the reference lists of the retrieved articles were reviewed to identify relevant articles.

COMPARATIVE SUMMARY OF KNEE OA

This search identified studies on various non-surgical treatment methods for knee OA, including intra-articular injections, oral and topical pharmaceutical treatments, weight reduction strategies, and emerging minimally invasive therapies. We also reviewed international guidelines for the non-surgical management of OA including the American Academy of Orthopedic Surgeons (AAOS), American College of Rheumatology (ACR), European Alliance of Associations for Rheumatology (EULAR), European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), the United Kingdom’s National Institute for Health and Care Excellence (NICE), and Osteoarthritis Research Society International (OARSI). Table 1 provides a comparative summary of the key guidelines established by the organizations, and Table 2 presents valuable points for clinicians. Figure 1 shows the possible non-surgical intervention strategies involving a guideline-supported core and potential adjuncts[9,12-16].

Figure 1 An overview of non-surgical treatment strategies for knee osteoarthritis in patients unwilling or unable to undergo surgery, highlighting the link between including guideline-recommended treatments, and emerging interventions available to clinicians. OA: Osteoarthritis; NSAIDs: Nonsteroidal anti-inflammatory drugs; RFA: Radiofrequency ablation; GAE: Genicular artery embolization; GLP-1RA: Glucagon-like peptide-1 receptor agonist; K-L: Kellgren-Lawrence.

Table 1 International guidelines comparison for non-surgical knee osteoarthritis treatment.

Domain	EULAR/ESCEO	ACR	OARSI	AAOS	NICE
Exercise	+++	+++	+++	+++	+++
Weight management	+++	+++	+++	++	+++
Topical NSAIDs	+++	+++	+++	+++	+++
Oral NSAIDs	+++	+++	++	+++	++
Acetaminophen	+	++	-	+++	+
Intra-articular corticosteroids	+	+++	++	++	++
Intra-articular hyaluronic acid	+	-	++	-	-
Opioids1	+	++	--	--	+
Duloxetine	+	++	+	ND	ND
Supplementation	++	--	-	+	--
Bracing	+	++	-	+	+

¹Among opioids guidelines often make a distinction between tramadol and other opioids. If this distinction is made the recommendation for tramadol is applied.

+++: Strong recommendation; ++: Conditional recommendation; +: Weak recommendation, -: Conditional recommendation against; --: Strongly recommended against; ND: Not defined; EULAR: European Alliance of Associations for Rheumatology; ESCEO: Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; ACR: American College of Rheumatology; OARSI: Osteoarthritis Research Society International; AAOS: American Academy of Orthopedic Surgeons; NICE: United Kingdom’s National Institute for Health and Care Excellence; NSAID: Non-steroidal anti-inflammatory drugs.

Table 2 Most important differences and take-away points from clinical guidelines.

Domain	Key points or differences: EULAR/ESCEO, ACR, OARSI, AAOS, NICE
Exercise	Optimal exercise protocols have not been identified; hence, exercise should be tailored to a patient’s needs and accessibility. ACR and OARSI endorse Tai Chi/Yoga
Weight management	Weight loss for overweight or obese patients is generally strongly recommended
Topical NSAIDs	The use of topical NSAIDs is a core recommendation
Oral NSAIDs	Generally, a strong recommendation but some point to the fact that they should be used after topical
Acetaminophen	OARSI discourages acetaminophen while AAOS has the best outlook. Other guidelines suggest its use during flare ups
Intra-articular corticosteroids	Guidelines recommend intra-articular corticosteroids for short-term relief, but repeated use is discouraged
Intra-articular hyaluronic acid	OARSI has the best outlook on HA, suggesting HA may have longer lasting effects and a good safety profile. ESCEO points to use when patients have contraindications to NSAIDs. ACR, AAOS, and NICE recommend clinicians against frequent use
Opioids	AAOS and OARSI strongly discourage opioids due to risks. Otherwise, tramadol could be used conditionally, for example, in severe cases
Duloxetine	Duloxetine could be used to help patients with widespread pain and as an alternative to opioids, but AAOS and NICE have not made a recommendation
Supplementation	If recommended its use is rather limited to early cases
Bracing	Insoles are generally not recommended but braces and walking aids may be recommended with emphasis on increasing participation in physical activity. OARSI recommends against bracing of the knee but conditionally recommends walking aids

EULAR: European Alliance of Associations for Rheumatology; ESCEO: Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; ACR: American College of Rheumatology; OARSI: Osteoarthritis Research Society International; AAOS: American Academy of Orthopedic Surgeons; NICE: United Kingdom’s National Institute for Health and Care Excellence; NSAID: Non-steroidal anti-inflammatory drugs; HA: Hyaluronic acid.

Weight loss and glucagon-like peptide 1 receptor agonists

Overweight and obesity significantly increased the risk of knee OA, with odds ratios of 2.45 and 4.55, respectively[17]. Furthermore, for every 5 kg/m² increase in body mass index, the risk of knee OA increases by 35%[17]. Messier et al[18] found a dose-dependent relationship between weight loss and improvements in health outcomes in patients with knee OA. Those who lost at least 10% of their body weight experienced significant reductions in pain and improved function, while the ≥ 20% weight loss group had the greatest benefits. Consequently, all guidelines recommend weight loss in overweight and obese patients with knee OA[9,12-16]. The NICE suggests that clinicians should explain to their patients that any amount of weight loss is likely to benefit them, but losing 10% of their body mass is likely to be better than losing 5%[12]. Before delving further into this topic, it is important to note that clinical trials investigating this matter often do not include patients in the most advanced stages, where structural joint damage predominates and improvements may be marginal. Moreover, challenges such as long-term weight loss maintenance and potential muscle loss highlight the need for cautious and individualized approaches[19,20].

Glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide, liraglutide) used to treat obesity and diabetes also show promise for knee OA through weight loss and possible direct joint protection[21-24]. For instance, a prospective study of more 40000 participants with knee OA and comorbid type 2 diabetes mellitus found that patients treated with GLP-1R agonists experienced greater weight loss, reduced cartilage damage, and improved pain and function, which led to a reduction in the use of medications and a lower incidence of knee surgery (1.7% vs 5.9%)[22]. Moreover, beyond their role in metabolic health and weight loss, GLP-1R agonists may directly induce a chondroprotective effect through decreasing inflammation and reducing the activity of metalloproteinases (MMPs)[25]. Although these findings are preliminary, they suggest that GLP-1R therapies may offer benefits in OA beyond weight loss[25].

Exercise therapy

Exercise therapy is strongly recommended as a conservative treatment according to all guidelines, even in advanced cases[9,12-16]. A recent Cochrane systematic review confirmed significant improvements in pain and function compared to no exercise[26]. Furthermore, Holden et al[27] found that exercise led to the greatest improvement in patients with severe knee OA. Moreover, one study found that physical therapy (manual therapy and exercise) was more effective than intra-articular corticosteroids (IACs) in improving pain and function[28]. However, manual therapy alone is less supported and recommended only in addition to exercise[12,13,15]. Although exercise is a core treatment option, the optimal protocol has not been identified, and there is agreement that the dosage and intensity should be tailored to the patient’s physical function and available options[9,13,15,16]. According to EULAR, there is some evidence that exercise protocols following recommendations from the American College of Sports Medicine provide better improvement in pain than those that do not[9,29,30].

Oral/topical medications

OA pain is a major clinical challenge, as existing pharmacological treatments often fail to provide satisfactory relief[31]. Mainline OA pharmacological treatments involve NSAIDs, acetaminophen, opioids, and sometimes antidepressants[32].

Topical NSAIDs are widely recommended as first-line therapy because of their strong efficacy and low systemic risk[12-16,33]. Oral NSAIDs are effective, but carry higher risks, including gastrointestinal, cardiovascular, and renal issues. Therefore, cyclooxygenase 2 inhibitors and NSAIDs with proton pump inhibitors may be recommended for patients at risk of gastrointestinal complications[16]. A large meta-analysis reported etoricoxib 60 mg/day and diclofenac 150 mg/day as the most effective treatment of pain caused by OA[34].

However, the use of acetaminophen has been debated. The AAOS strongly recommends it, while others recommend against routine use and suggest limiting its use to an NSAID alternative during flare-ups[12-16]. Acetaminophen has a more favorable safety profile than NSAIDs; however, studies have suggested that acetaminophen provides limited pain relief for OA, particularly in advanced cases and long-term therapy[31,33].

There are considerable differences among the different guidelines regarding the recommendations for opioids. ESCEO and NICE weakly recommend the use of weak opioids, such as tramadol, for patients with severe knee OA who cannot undergo surgery[12,14]. ACR conditionally recommends tramadol[13]. In contrast, AAOS and OARSI strongly discourage opioids, including tramadol, because of their limited effectiveness and side effects, including addiction[15,16,31]. Among opioids, tramadol is associated with the highest efficacy, but is still less effective than NSAIDs[34], and its long-term use is questionable[31].

Analgesic properties of duloxetine have been reported in knee OA[35]. ACR, OARSI, and ESCEO conditionally recommend the use of duloxetine for chronic or widespread pain in patients with depression[13,14,16]. ESCEO highlights its use as an alternative to opioids in advanced cases[14].

Furthermore, ACR notes that, while various centrally acting agents have been used to manage chronic pain, duloxetine is the only agent to date with sufficient evidence to support a recommendation for OA. Nevertheless, pregabalin and gabapentin are recognized as promising candidates for future research[13]. A trial comparing gabapentin, duloxetine, and acetaminophen found the first two to be more effective, with duloxetine’s effect appearing early and gabapentin’s effects becoming more prominent after three months of treatment[36]. Although pregabalin has not been widely investigated, studies have indicated its therapeutic potential[37,38].

Topical capsaicin provides only modest relief and it is conditionally recommended by ACR. On the other hand, the latest OARSI guidelines have degraded capsaicin to a recommendation against, owing to inadequate efficacy[1,13,16].

According to a survey study of patients with arthritis using cannabinoids (CBD), 83% reported pain relief, 66% reported improvement in function and sleep quality, and 60.5% reported reducing or stopping other medications, such as NSAIDs, acetaminophen, and opioids, suggesting that CBD may play a role in reducing reliance on other medications[39]. However, one randomized controlled trial (RCT) found that combining CBD with acetaminophen did not lead to statistically significant reductions in pain compared with adding a placebo[40].

Intra-articular injections

The most common intra-articular treatments include IACs, which are valued for their fast action and lower cost; HA, a widely used but controversial option; and PRP, an alternative with growing interest but mixed evidence[11].

OARSI, AAOS, ESCEO, and NICE conditionally recommend IACs for knee OA, noting that they may provide short-term pain relief[12,14-16]. ACR strongly recommends the use of IACs, acknowledging that their efficacy may be limited to the short term, but emphasizes that IACs have the highest quality evidence in support of them among all intra-articular treatments[13]. IACs was the most frequently prescribed initial treatment for patients with newly diagnosed knee OA (26%)[41].

A Cochrane review demonstrated that IACs relieved pain and improved function; however, these benefits diminished over time and became statistically insignificant for pain by week 26 and function by week 13[42]. There is no consensus that IACs are less effective in advanced OA[43,44]. However, IACs should not be used as standalone long-term treatments because of the potential side effects of repeated injections[42,45]. Clinicians should be aware of the possibility of cartilage damage associated with the use of IACs[11,46,47]. Moreover, IACs have systemic effects, such as increased blood pressure and blood glucose[11,48]. This is particularly important because diabetes is one of the most common comorbidities in patients with knee OA[41]. Therefore, patients with diabetes should have their blood glucose levels monitored after treatment[49,50]. EULAR recommendations for intra-articular treatments advocate a general limit of 3-4 IACs injections per joint annually, although they acknowledge that this consensus is not based on research evidence[49].

Intra-articular HA is considered controversial; however, it is used relatively often and appears to improve functionality and pain[51]. In fact, 17.6% of patients with newly diagnosed knee OA were prescribed HA[41]. Guidelines are rather unsupportive of the use of HA, but also acknowledge that its use may be appropriate in individual cases[12-15]. For example, ACR conditionally recommends against its use, claiming that HA does not show favorable outcomes in studies with a low risk of bias[13]. Nevertheless, the ACR acknowledges that for clinicians, HA might be a better alternative than no intervention for patients who do not respond to other treatments[13]. Among the guidelines reviewed, OARSI offers the most favorable stance toward HA, conditionally recommending its use owing to its potential longer-lasting effects and a more favorable long-term safety profile compared to repeated IACs[16].

Pereira et al[52] analyzed placebo-controlled trials with 8997 participants and found that HA provided only a small, clinically irrelevant reduction compared with placebo, discouraging its broad use. In contrast, Strand et al[53] found that HA is safe and effective for up to 26 weeks. Their subgroup analysis found differences in effectiveness between patients with less severe (K-L grade < 3) and more severe (with K-L grade ≥ 3) knee OA, but these differences were statistically insignificant[53]. Nicholls et al[54] further explored the effect of OA severity, showing statistically significant pain relief from HA in studies recruiting patients with K-L grade ≤ 3 knees, but not in those that recruited patients with K-L grade 4 knees. A survey of North American clinicians found that despite 90.6% of respondents acknowledging uncertainty regarding HA efficacy, 85.2% used HA annually, with 57.4% prescribing it even for late-stage knee OA[55].

PRP treatment is strongly recommended against by ACR and OARSI owing to the lack of standardization in formulations and study designs[11,13,16]. AAOS recognizes PRP as a potential therapy to reduce pain and improve function, but its support is limited[15].

RCTs have reported mixed outcomes[56]. Some studies have reported superior effects of PRP over other intra-articular treatments and placebo, whereas others, such as the RCT by Bennel et al[57] with 288 patients, demonstrated no statistically significant differences between PRP and placebo after 12 months. In terms of its effectiveness across different severities, Vilchez-Cavazos et al[58] demonstrated PRP improved pain and function, and a subgroup analysis found these improvements to not be statistically different across severities. Despite promising findings, the efficacy of PRP remains inconsistent, likely because of variability in preparation methods, patient selection, and study design[11,56,59]. Researchers have suggested that a high dose of 10 billion platelets is crucial for clinical efficacy[60]. To date, PRP is an experimental treatment, and further high-quality research is required[61].

Bracing

Guidelines such as EULAR, AAOS, and ACR conditionally recommend the use of braces, but not lateral wedges or other insoles[9,13,15]. Braces may be used in patients who cannot participate in therapeutic exercises without stabilization[12]. A Cochrane review analyzed the effects of braces (e.g., valgus knee braces) and orthoses (e.g., lateral wedge insoles) on knee OA and found minimal improvement with braces[62]. To evaluate treatment effectiveness in severe knee OA, one can refer to the prospective randomized trial by Chughtai et al[63], which included only patients with K-L grades 3-4. This study compared pneumatic unloader braces and conventional treatment with conventional treatment alone. The results showed a lower rate of TKA (18% vs 36%), longer time to TKA (482 days vs 389 days), and fewer pain-relieving injections (46% vs 83%) in the brace group. However, that study did not assess pain or functionality; hence, drawing definitive conclusions remains difficult[63].

RFA

RFA works by delivering targeted thermal damage to nerve tissue. There are various RFA treatment modalities, including conventional (thermal monopolar) RFA, cooled RFA, bipolar RFA, and pulsed RFA[64]. Overall, RFA has not yet been widely included in OA management guidelines, but the ACR and AAOS conditionally recommend RFA for knee OA[13,15]. This recommendation remains conditional owing to the variety of methods used and the lack of long-term safety data[13].

A systematic review demonstrated that fluoroscopically guided genicular nerve RFA led to a ≥ 50% reduction in pain at 6 months in 49% to 74% of patients, making it 4.5 times more likely to succeed than IACs[65]. RFA may be superior to IACs and NSAIDs, owing to longer-lasting effects and fewer safety concerns[66]. Soetjahjo et al[67] showed that both cooled and pulsed RFA led to significantly reduced knee OA pain after 12 months of treatment. Furthermore, a study of 120 patients with exclusively K-L grade 3-4 showed that ultrasound-guided RFA significantly reduced pain throughout a follow-up course of 6 months, proving that RFA is effective in treating end-stage knee OA[68].

GAE

GAE is a novel treatment for knee OA. It works through the selective catheterization and embolization of abnormal blood vessels linked to areas of pain during angiography[69]. By reducing blood flow to the synovial lining, GAE may relieve pain associated with inflammation, neovascularity, and neoinnervation[69]. A systematic review and meta-analysis by Taslakian et al[69] found that GAE was effective in relieving pain, and meta-regression analyses showed that patients with higher baseline pain responded better. Furthermore, the study reported that GAE had few complications, with a 99.7% technical success rate. Considering the minimally invasive nature of GAE, its low complication rate, and high efficacy in severe cases, it may become a frequently used method in the treatment of knee OA. Further studies are required[69].

Supplementation

Supplementary regimens involving glucosamine, chondroitin, and curcumin have demonstrated statistically significant improvements in pain, stiffness, and function in patients with OA, although heterogeneity in study designs and inconsistent results limit generalizability[70-72]. Prescription of crystalline glucosamine sulfate and chondroitin sulfate is recommended separately by ESCEO for the early background treatment of knee OA, while other non-pharmacological formulations are not advised[14]. AAOS also recognizes these supplements as useful for mild-to-moderate OA[15]. In contrast, ACR strongly recommends against the use of glucosamine or chondroitin, indicating possible publication bias[13].

Emerging medications

Currently, there is a lack of approved disease-modifying drugs, but ongoing research has explored biological agents, inhibitors of nerve growth factor (NGF) and tropomyosin receptor kinase A (TrkA), and ion channel modulators[31]. Anti-NGF antibodies significantly reduce pain in patients with moderate-to-severe knee OA. However, the use of anti-NGF antibodies has raised safety concerns owing to their association with rapidly progressive joint damage, leading to a temporary suspension of clinical trials. Since then, trials have resumed. However, further research is essential to clarify how NGF inhibition contributes to joint deterioration[31]. According to OARSI and ACR, anti-NGF treatments, though not yet approved and strongly discouraged, could continue to be a target for further research[13,16]. Furthermore, the oral TrkA inhibitor ASP7962 was ineffective, but intra-articular administration of GZ389988A reduced pain[31].

MMP inhibitors are another area of research. Currently, synthetic inhibitors, ghrelin (an anti-inflammatory neuropeptide with possible MMP-inhibiting properties), and approaches targeting upregulated miRNAs and long non-coding RNAs are under investigation. However, these approaches are still in the experimental stage[73].

DISCUSSION ON OA TREATMENT

Conservative management of knee OA is a frequent focus of the literature, with recent reviews documenting exercise, weight loss, pharmacological therapy, and injections as effective treatment modalities[74,75]. Through this review, the goal is to provide clinicians with a view of where major guidelines converge and where they do not, and then map potential ways to fill these gaps for patients with advanced disease who decline surgery. In other words, we anchor care in consensus measures while indicating where selected options beyond the scope of recent guidelines may plausibly help when core care is insufficient.

Managing advanced knee OA without surgery requires an individualized strategy that balances the efficacy, safety, and patient preferences. In this subgroup of patients, clinicians must consider all available modalities and often combine therapies for maximal relief, as the goal shifts from curing structural disease to optimizing pain, function, and quality of life.

Current clinical guidelines converge on several core nonsurgical treatments for knee OA. Weight loss and exercise therapy are universally recommended first-line interventions. Obesity is a well-established, modifiable risk factor for knee OA, and its management remains central to symptom control. Despite being educated about the importance of weight reduction, many patients struggle to achieve or maintain significant weight loss through lifestyle changes alone.

The emergence of GLP-1R agonists has created new opportunities to support metabolic health and reduce joint load. Hence, rather than viewing weight loss drugs as outside the traditional scope of orthopedic treatment, clinicians should consider GLP-1R agonists as part of a holistic OA management plan. Furthermore, although still under investigation, GLP-1R agonists may target the metabolic components of knee OA both locally within the joint and systemically. Thus, future treatment algorithms may position GLP-1R agonists or other incretin-based metabolic agents currently in development, alongside diet and exercise, as first-line options for patients with obesity. This approach could help delay disease progression and reduce the reliance on analgesics.

Notably, exercise remains beneficial even in patients with advanced OA, although clinicians must recognize the limitations imposed by the advanced disease. Addressing the metabolic component and reducing joint loading through weight loss can make physical activity more feasible, and physical activity helps preserve muscle mass during weight loss. Thus, weight management and exercise are complementary. In addition, braces, particularly pneumatic tibiofemoral unloaders, may help patients with advanced knee OA increase their mobility. Because of the large number of brace types and heterogeneity in protocols and outcomes, guidelines have not consistently issued strong recommendations. Nevertheless, in advanced knee OA, braces, such as tibiofemoral pneumatic unloader braces, may play a role in improving function and delaying surgery.

All major guidelines strongly agree on the importance of weight loss and exercise and converge on topical and oral NSAIDs. This is the core of what is considered reliable. Undoubtedly, these recommendations rely on a large, consistent evidence base and remain central to nonsurgical care. However, even in combination, they often provide insufficient relief for patients with advanced knee OA who refuse surgery. Simply moving down the guideline “efficacy ladder” is rarely the right answer in this subgroup. Acetaminophen remains a safe option for short-term flares; however, it provides limited leverage against progression to surgery in patients with advanced knee OA. IACs can deliver short-term relief but are not a feasible long-term strategy given the durability of their effects and potential downsides with repeated use. Similarly, intra-articular HA, for which the guideline positions vary, is unlikely to offer clinically relevant results in advanced cases. Altogether, these realities warrant the pursuit of additional approaches rather than relying solely on progressively trying second-line guideline options.

If symptoms persist despite first- and second-line care, stronger analgesics are often administered. However, the guidelines diverge: AAOS and OARSI, for example, strongly discourage opioids in knee OA, given their limited benefit and potential harm. This reality further argues for looking beyond the core of the guidelines toward alternative pharmacological strategies. Among centrally acting agents, duloxetine is acknowledged by most guidelines but typically with a weak recommendation. Duloxetine may assume a larger role in advanced knee OA, particularly when central pain or fibromyalgia is present. Furthermore, gabapentinoids, although still under investigation for their use in OA, represent another beyond-guideline route in the presence of neuroplastic or neuropathic features. CBD may also play a selective role in controlling chronic pain associated with advanced knee OA. Taken together, these alternative strategies may offer a way to reduce opioid exposure.

Guideline conservatism, appropriate for evidence standards, can leave promising options in the gray zone, especially for end-stage disease. For instance, genicular RFA has only received a conditional recommendation in recent ACR/AAOS updates. Most guidelines focus on early-to-moderate OA and then refer to surgery for end-stage OA, so clinicians often must rely on emerging evidence to help patients who fall outside the “average” scenario contemplated by guidelines. Accordingly, once core guideline-based therapies are exhausted, it is more sensible to steer patients toward newer interventions such as RFA or GAE, rather than moving linearly down the ladder of lower-yield options.

For patients with advanced knee OA who refuse surgery, RFA and GAE offer minimally invasive options with month-long relief in appropriately selected patients. The evidence is currently stronger for RFA, but both modalities would benefit from standardized protocols, longer follow-up periods, and head-to-head comparisons. In practice, layering one of these procedures onto optimized core care represents a realistic way to improve pain and function while avoiding surgery.

CONCLUSION

Knee OA still lacks disease-modifying therapies, and substantial progress across biological targets may take considerable time. For patients with advanced knee OA who refuse surgery, care should begin with optimized and guideline-endorsed measures, including structured exercise, weight reduction, and topical NSAIDs. When weight loss is indicated but difficult to achieve, GLP-1R agonist-based therapy may support lifestyle interventions, whereas resistance training helps to preserve lean mass. Centrally acting agents such as duloxetine and gabapentinoids can reduce the symptom burden and help limit opioid exposure. Minimally invasive options merit consideration when pain persists despite these steps. Although not new, genicular RFA and GAE are relatively recent approaches whose durable effects make them promising for managing knee OA pain in patients refusing surgery. Genicular RFA can address persistent nociceptive knee pain, particularly when the symptoms are localized. When signs of active synovium persist despite topical NSAIDs and short courses of IAC for flares, GAE is a reasonable option. Clinicians should be aware of these minimally invasive procedures, even though universal recommendations have not yet been issued.