literature review on osteoarthritis

• Open access
• Published: 18 February 2023

Osteoarthritis: a narrative review of molecular approaches to disease management

• Loay A. Salman 1 , 2 ,
• Ghalib Ahmed 2 ,
• Stephanie G. Dakin 1 ,
• Benjamin Kendrick 1 &
• Andrew Price 1  

Arthritis Research & Therapy volume  25 , Article number:  27 ( 2023 ) Cite this article

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Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and synovium. While it is still believed to be a mechanically driven disease, the role of underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated. Post-traumatic osteoarthritis (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults and is widely used in pre-clinical models to help understand OA in general. There is an urgent need to develop new treatments as the global burden is considerable and expanding. In this review, we focus on the recent pharmacological advances in the treatment of OA and summarize the most significant promising agents based on their molecular effects. Those are classified here into broad categories: anti-inflammatory, modulation of the activity of matrix metalloproteases, anabolic, and unconventional pleiotropic agents. We provide a comprehensive analysis of the pharmacological advances in each of these areas and highlight future insights and directions in the OA field.

Introduction

Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and the synovium [ 1 ]. OA was earlier considered as a wear and tear mechanical disease that causes cartilage degeneration; however, it is now understood that the cross-talk between various joint structures and local inflammation is a central aspect of the underlying pathophysiology [ 2 ].

The stratification of OA into various phenotypes is becoming widely accepted. Post-traumatic OA (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults such as fractures or injury to the soft tissues, such as chondral surfaces, ligaments, tendons, and menisci or even surgical intervention to the joint [ 3 , 4 , 5 , 6 ]. PTOA accounts for approximately 12% of all cases of symptomatic OA [ 7 ]. While it can potentially affect any injured joint, it is most prevalent in the ankle and knee [ 3 , 7 ], PTOA accounts for up to 78%, 10%, 8%, and 2% of all ankle, knee, shoulder, and hip OA cases, respectively [ 3 , 7 , 8 , 9 ].

PTOA shares many clinical, radiological, and genetic similarities with non-traumatic OA [ 10 ]. What differentiates PTOA is that it has a clear starting point, providing an excellent opportunity for intervention and treatment as early as the time of injury [ 10 , 11 , 12 , 13 ]. Therefore, post-injury laboratory and animal models have been widely adopted to investigate the association between injury and OA and help exploit the intracellular processes seen in these same injured tissues to advance our understanding of OA pathways as a whole. Several injury induced-models have been utilized to study OA including surgical transection models of the meniscus or anterior cruciate ligament (ACL), controlled external loading such as ACL rupture (ACLr), or destabilization of the medial meniscus (DMM) models [ 10 , 14 , 15 ].

Over the past 20 years, remarkable progress has been made in osteoarthritis research; however, many questions remain unanswered due to the complexity of OA pathophysiology. It is still believed to be a mechanically driven disease; however, the role of the underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated [ 10 ]. A complete understanding of the pathophysiology of OA would enable identification of potential therapeutic targets.

Numerous therapeutic agents have been suggested for OA [ 16 , 17 , 18 ]; however, there is still no definitive treatment. This review will focus on the recent pharmacological advances in the treatment of OA and summarize the most promising therapeutic agents (Table 1 ), based on their molecular effects, which are broadly classified into anti-inflammatory, modulators of the matrix metalloproteases activity, anabolic, and unconventional pleiotropic agents. We will highlight the complex pathophysiology of OA with an overview of the biomechanics, inflammation, and other OA associated factors. Finally, we will discuss the evolving concepts and future directions in this field.

A thorough literature review was performed using PubMed/MIDLINE, Web of Science, and Google Scholars databases and searched from inception till June 2022 with the following search terms: “Pathophysiology,” “Epidemiology,” “Inflammation”, “Biomechanics,” “Treatment,” “Therapy,” “Pharmacological,” “Intervention,” and “Osteoarthritis.” This yielded a total of 560 articles which were screened based on title/abstract to identify original research work and review articles written in English within the past 10 years. No restrictions were placed on the types of study design. Inclusion was limited to relevant references, mainly related to the pharmacological treatment of OA. Articles focusing on other perspectives of OA and inaccessible full texts were excluded. We also included several references not identified by the search criteria which were known to the author or were manually selected from the reference lists contained within the screened articles. Selected references were then reviewed and finalized by two authors independently. As a result, 66 articles met the eligibility criteria and were included in this review. Additionally, this narrative review was conducted in line with the Scale for the Assessment of Narrative Review Articles (SANRA) quality assessment tool [ 19 ].

Pathophysiology: biomechanics and inflammation

PTOA pathogenesis occurs from the point of injury to the time of presentation of OA symptoms (Fig. 1 ). Following a traumatic injury, a state of mechanical imbalance and overload occurs, which triggers several inflammatory signaling pathways, such as the nuclear factor kappa B (NF-kB), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and poly adenosine diphosphate (ADP)-ribose pathways in the synoviocytes [ 13 , 20 ]. The activation of these inflammatory cascades along with the continuous mechanical disturbance increases the levels of inflammatory mediators and other matrix destructive enzymes, resulting in chondrocyte apoptosis, matrix degradation, leukocyte recruitment, and other structural and molecular changes associated with OA [ 10 , 11 ]. The acute inflammatory phase either progresses to OA or resolves spontaneously, depending on the presence of aggravating factors. The risk factors that stimulate the disease’s progression are similar to that described for OA [ 10 ] (Fig. 1 ).

PTOA pathogenesis. Risk factors aggravating the process. Potential therapeutic targeting points are pointed out with red X

A complete understanding of the fundamental biological pathways and mediators involved in OA (Table 2 ) would enable creating target-based, effective therapies. Pharmacological interventions have been vigorously investigated [ 17 ]; however, they are yet to be applied clinically. The current strategies in OA management is mainly conservative, with analgesics and physiotherapy in the early stages and reconstructive or replacement surgeries at advanced stages [ 13 ]. Anatomical reconstructive procedures have advanced in terms of techniques and improved outcomes; however, evidence supporting their role in preventing OA is still insufficient [ 13 ]. Anterior cruciate ligament (ACL) injury renders the knee joint mechanically unstable and expedites osteoarthritic changes [ 18 ]. It was believed that ACL reconstruction restored the joint’s stability and prevented the development of OA; however, a large meta-analysis of 38 studies demonstrated that OA occurs even after ACL reconstruction and restoration of joint stability [ 21 ]. Therefore, apart from mechanical factors, it is critical to address the molecular pathways involved in the development of OA. This necessitates an early and robust intervention, through two possible strategies: Early, preventive interventions that target the disease process at the onset, or approaches that modify the disease prognosis (Fig. 1 ).

Anti-inflammatory agents for the treatment of OA

The pathogenic role of proinflammatory mediators, such as cytokines and chemokines, is well understood [ 11 , 12 ]. Various cytokines, such as IL-1, IL-6, IL-17, and TNF-α, are involved in the acute inflammatory phase post-joint injury, with prominent crosstalk occurring between the articular cartilage and the synovium. Therefore, inhibition of these cytokines is a promising therapeutic strategy. An imbalance between the levels of pro-inflammatory (high levels of IL-1, IL6, and IL8) and anti-inflammatory (low levels of IL-1Ra, IL-4, and IL-10) cytokines is characteristic of the acute inflammatory phase [ 11 , 12 ]. The most promising cytokine targeting therapy is the inhibition of IL-1 using IL-1Ra, currently in clinical trials [ 17 , 22 ]. Inhibition of IL-1 was therapeutically effective in alleviating the progression of OA in animal models [ 23 ]. Early intervention with a single, small intraarticular dose of the human recombinant IL-1Ra, Anakinra, significantly alleviated the arthritic changes, reducing articular degeneration and synovitis in C57BL/6 mice with tibial plateau articular fracture [ 24 ]. The continuous systemic administration of IL-1Ra, however, yielded no therapeutic effect and, interestingly, led to a greater joint deterioration. IL-1Ra was proved safe in a multicenter randomized clinical trial (RCT) in patients with knee osteoarthritis [ 25 ]. IL-Ra (a single 150 mg dose) substantially improved the functional knee outcome measures, with reduced knee pain at 2 weeks, in a pilot trial for the treatment of acute (less than a month since injury) ACL injuries [ 22 ].

The inhibition of other proinflammatory cytokines, such as IL-6, IL-17, and TNF-α, is expected to reduce degenerative cartilage changes, synovial inflammation, and lubrication problems [ 13 ]; however, inhibiting TNF-α is not therapeutically effective in PTOA [ 23 , 24 ].

In a rabbit PTOA model, intraarticular administration of dexamethasone immediately after surgical drill injury attenuated proinflammatory (IL-1β, IL-6, and IL-8) cytokines and OA-like histological changes [ 26 ]. Glucocorticoids exhibit anti-inflammatory effects in different tissues through the suppression of prostaglandins [ 27 ], inflammatory cytokines [ 28 ], nitric oxide [ 29 ], and other oxygen-derived radicals [ 30 ], making them an attractive therapeutic choice [ 31 ]. Low dose of dexamethasone offers significant chondroprotection, by reducing the loss of extracellular matrix (ECM) proteoglycans and collagen in an IL-1 rich environment and by reducing the loss of glycosaminoglycans (GAGs) even in the presence of inflammatory mediators, such as TNF-α, in an in vitro study in human chondrocytes [ 31 ].

Sivelestat sodium hydrate ameliorated knee PTOA in a rat model, acting via NF-kB and HMGB1; therefore, it could be potential treatment option for OA [ 32 ]. The expression of both of these factors is suppressed, indicating a potential anti-inflammatory response. The production of the pro-inflammatory cytokines, TNF-α and IL-6, is also significantly reduced. Moreover, after receiving a once-weekly dose of 10 mg/kg for four consecutive weeks, there is a dramatic reduction in cartilage degeneration.

JQ1 and flavopiridol suppressed the development of OA in vitro and in an in vivo mouse model of ACL rupture (ACLr) [ 33 ]. This was achieved via inhibiting the rate limiting enzymes of the primary response genes (PRGs), namely, bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9). In cartilage explants, they work synergistically in preventing the activation and release of IL-1β-induced inflammatory factors and glycosaminoglycan. In vivo treatment with JQ1 and flavopiridol causes a significant suppression of IL-1 and IL-6 expression, MMPs, synovial inflammation, and other joint-associated inflammatory pathways, such as iNOS and COX2.

Mitochondria-associated pathways

Disruption of mitochondrial structure and/or function is one of the earliest pathogenic mechanisms that trigger the onset of OA and its progression [ 34 ]. In the sub-acute phase following injury, chondrocyte apoptosis and articular degeneration are facilitated by mitochondrial damage, resulting in decreased respiratory function and proteoglycan content and an imbalance between the anabolic and catabolic pathways in the ECM, particularly the expression of MMP-13, as observed in a mouse DMM model [ 35 , 36 ]. The pathways downstream of the mitochondrial pathways (Fig. 2 ), such as the electron transport chain and Bax/Bak pathways, are activated, resulting in the release of oxygen radicals and caspases, respectively. Antioxidants and caspase inhibitors are used to counteract these effects [ 17 , 36 ]. The antioxidants, such as N-acetyl cysteine, Mn 3 porphyrin (a superoxide dismutase mimetic), and vitamins E and C, exhibit promising chondroprotective effects in animals and in ex vivo human studies. They attenuate both mechanically induced apoptosis and the expression of ECM degrading enzymes [ 16 , 37 ]. Caspase inhibitors prevented chondrocyte apoptosis in preclinical studies [ 17 ]; however, their clinical efficacy in humans is not proven. The mitoprotective peptide, SS-31, protects an important phospholipid constituent of the mitochondrial inner cell membrane, cardiolipin [ 36 ], thereby maintaining the integrity of the electron transport chain and ensuring proper ATP production, reduced ROS production, and reduced mitochondrial-induced cell death. The therapeutic efficacy of SS-31 was established in an ex vivo model of PTOA [ 36 ]. SS-31 prevents trauma-induced chondrocyte apoptosis, cell membrane damage, cartilage GAG loss, and matrix degeneration. Although inherent challenges with targeting mitochondrial-associated pathways exist as effects are not tissue-specific, the safety of SS-31 in humans has been reported [ 38 ], enhancing its potential as a candidate for OA therapy.

Effect of mechanical injury on mitochondria-associated pathways. Effects on MT dysfunction, oxidative response, and caspase activation leading to cell death, ECM degradation, and apoptosis and subsequently PTOA. Potential inhibitory roles of certain pharmacological interventions are depicted. Adapted from Delco et al. [ 15 ]. MT, mitochondria; ROS, reactive oxygen species; ECM, extracellular matrix

Inhibitors of the action of matrix degrading enzymes

Doxycycline.

Doxycycline is a broad-spectrum tetracycline antibiotic and inhibited the progression of joint OA in a murine ACLr model [ 38 ]. There is a positive correlation between doxycycline concentrations and the degree of MMP-13 inhibition, as observed by immunohistochemistry. There is a marked reduction in MMP-13 levels and significantly less cartilage damage and synovial inflammation. A systematic review of seven animal studies indicated mixed results, with some positive effects of doxycycline in PTOA treatment [ 39 ], making it a promising therapeutic candidate for OA.

Injection of ECM blood composites

Collagen type I is one of the main components of extracellular matrix-blood composite (EMBC). It is a competitive inhibitor of MMPs, preserving the cartilage matrix. Intra-articular injection of EMBC yielded chondroprotective effects in PTOA rat models, resulting in reduced cartilage degeneration and osteophyte formation [ 40 ].

Ipriflavone

Ipriflavone is a dietary supplement with anabolic effects on the bone and an inhibitor of the Indian hedgehog (IHH) pathway. Stimulation of the IHH pathway is crucial in the progression of OA, resulting in degenerative changes through the upregulation of MMP-13 [ 41 , 42 ]. Ipriflavone mitigates cartilage degeneration in vivo (rats) and in vitro (human cartilage explants), by reducing the levels of MMP-13 and collagen type X.

Sclerostin (SOST) is a Wnt antagonist that inhibits bone osteoblastic activity. The protective role of sclerostin was studied in a tibial compression overload model in SOST transgenic and knockout mice [ 43 ]. Prolonged sclerostin exposure resulted in the activation of the NF-kB pathway and downregulation of cartilage matrix degradation enzymes (MMP-2 and MMP-3). Sclerostin-treated mice exhibited milder OA articular changes and reduced development of osteophytes. Similar effects were observed with the intraarticular administration of recombinant sclerostin protein.

Anabolic mediators

Bisphosphonates.

The use of bisphosphonates is promising for OA, because of their significant bone remodeling potential and anti-osteoclastic activity. The chondroprotective effects of alendronate and its ability to preserve subchondral bone in PTOA models have been established in preclinical studies [ 44 , 45 , 46 , 47 ]. In a rat model of PTOA, alendronate significantly inhibited osteophyte formation by up to 51% at 8 weeks post-surgery [ 46 ] and reduced cartilage degeneration. The effects of alendronate were dose-dependent but not long-lasting in a mouse ACLr model [ 47 ]. One RCT showed that bisphosphonate zoledronic acid [ 48 ] provided better symptomatic pain relief and reduced primary knee OA structural changes when compared to placebo. A statistically and clinically significant reduction (39% vs 18%, p  = 0.044) in knee bone marrow lesion size and numbers at 6 and 12 months was seen. Further clinical studies, on the dose, time of administration, and safety in patients with OA, are required.

Growth factors

Bone morphogenetic protein 7 (bmp-7).

BMP-7, also known as osteogenic protein-1 (OP-1), is a potent member of the TGF-b family and promoter of osteoblast differentiation. It modulates chondrocyte metabolism and protein synthesis [ 16 ]. The cartilage regenerative capacity of BMP-7 has been demonstrated in preclinical studies, making it a robust anabolic candidate for treating both OA and PTOA [ 16 , 49 , 50 ]. Several clinical trials of BMP-7 have been conducted in patients with knee OA [ 51 ]. Intraarticular knee administration of BMP-7 results in a toxicology profile comparable to that of the placebo group, establishing its safety; however, it could not significantly alleviate the pain [ 52 ].

Sprifermin (FGF18)

Sprifermin is a synthetic recombinant human FGF18 with promising anabolic implications in OA. A 5-year, multicenter RCT studied the effect of sprifermin on femorotibial joint cartilage thickness in 549 patients with symptomatic knee OA [ 53 ]. Intraarticular injections of 100 μg of sprifermin every 6 or 12 months resulted in a statistically significant improvement in total femorotibial joint cartilage thickness after 2 years. The functional outcome scores, however, were not different between the treatment and placebo groups, suggesting clinical irrelevance. Evaluation of its application in OA and further investigations on the clinical outcomes and their duration is therefore necessary.

Mesenchymal stromal cells (MSCs)

MSCs are multipotent heterogenous cells that differentiate into chondrocytes and, therefore, play a critical role in cartilage repair [ 54 ]. They also exhibit anti-inflammatory and immunomodulatory effects [ 55 ]. They regulate the levels of IL-1β, TNF-α, and IFN-γ, and their immunosuppressive and anti-inflammatory effects are promising for clinical applications. The exact relationship is not fully understood; however, the stimulation of anti-inflammatory cytokines, phagocytic cells, and regulatory M2 macrophages have been proposed. Intraarticular administration of MSCs effectively prevents the development of OA and preserves bone thickness, in various strains of mice [ 24 ]. Intraarticular administration of MSCs exhibits positive clinical and radiological outcomes in cartilage quality, when compared to the hyaluronan control group, in an RCT [ 56 ]. Further understanding of the specific mechanisms, tissue source, immunogenicity (allogeneic vs autogenic), storage techniques, and the doses and safety of MSC treatments in OA is required.

Unconventional targets

Glutamate and GluR are upregulated following joint injury, facilitating the onset of OA. Intraarticular administration of NBQX, a glutamate receptor inhibitor, in an ACLr mouse model at the time of injury, suppressed inflammation, pain, and joint degeneration [ 57 ]. NBQX functions through the AMPA/kainate glutamate receptor and is more efficient than the conventional treatment using hyaluronic acid and steroids. GluR antagonists are used for treating numerous CNS conditions, establishing their safety profile in humans [ 57 ]. This makes it feasible to advance them into human trials for treating OA.

Intraarticular adenosine

Intraarticular adenosine is another unconventional agent for treating OA. It is an agonist of the A2A receptor and exhibits apparent chondroprotective effects. Extracellular adenosine is critical for articular cartilage homeostasis [ 58 , 59 ]. Stimulation of the A2A receptor has protective effects on cartilage, and it downregulates the catabolic matrix-degrading enzymes. In addition, it increases the nuclear P-SMAD2/3/P-SMAD1/5/8 ratio, thereby shifting the chondrocyte balance to a healthier quiescent state [ 60 ].

Bortezomib is a proteasome inhibitor that suppresses TGF-induced collagen II degradation and MMP-13 expression, in human chondrocytes [ 61 ]. The relationship between the synovial lymphatic system and the development of OA remains unclear [ 62 ]; however, it is believed that the obstruction of the joint lymphatic system exacerbates the inflammatory phase and the progression of OA. Intraarticular administration of bortezomib ameliorates synovial lymphatic drainage, cartilage loss, reduces the number of M1-macrophages, and inhibits the expression of proinflammatory genes [ 63 ].

Erlotinib, an inhibitor of epidermal growth factor receptor (EGFR), which reduces OA-induced cartilage loss, improved subchondral bone thickness and volume owing to the protective role of integrin α1β1 and the reduction in EGFR signaling in various strains of model mice [ 64 ]. Interestingly, these effects were gender specific and observed only in female mice.

KUS121, a valosin-containing protein (VCP) modulator, was effective in vitro and in a rat model of PTOA [ 65 ]. KUS121 significantly reduced the levels of the pro-inflammatory cytokines, TNF-α and IL-6, as well as the ECM catabolic enzymes, MMP-1, MMP-13, and ADAMTS5, in human articular chondrocytes. In addition, it alleviated cartilage damage and chondrocyte apoptosis in a rat model of PTOA induced by cyclic compressive load and, therefore, is a promising therapeutic option for OA.

Rebamipide has protective effects on articular cartilage degeneration, both in vivo and in vitro [ 66 ]. A once-weekly injection of rebamipide into the knee joints of mice and the treatment of human chondrocyte explants with rebamipide increased the expression of cellular protective factors, such as COL2A, TIMP3, TGFβ, and FGF2, in chondrocytes and suppressed the expression of pro-inflammatory and catabolic factors, such as IL-1β, TNF-α, NF-κB, MMP-3, MMP-13, and ADAMTS5.

Future directions

PTOA is one of the most debilitating subtypes of OA, because it affects the younger active population, resulting in a considerable impact on the healthcare system. However, it offers a massive opportunity for advancing our knowledge on osteoarthritis, understanding the underlying pathogenic mechanisms, and exploring therapeutic options. This opportunity arises from the fact that PTOA, unlike other OA phenotypes, is associated clearly with an onset event, the joint injury. Most of the studies described in this review are preclinical, conducted on animal and in vitro human chondrocytes models; however, therapeutic agents, such as IL-1Ra, dexamethasone, bisphosphonates, and MSCs are under clinical trials, with promising findings. The translation of these findings to clinical practice is challenging, because of the vast differences between lab models and humans, with respect to biomechanics, genetics, and systemic body response. Identification and validation of more sensitive biomarkers and radiographic signs with high OA predictive value will improve the practical application of the results from future clinical trials and circumvent the long-term follow-up periods. Finally, with osteoarthritis stratification gaining much recognition, precision-medicine can play key diagnostic and therapeutic roles in the field of OA, with opportunities for further exploration.

The burden of OA and the lack of consensus in early treatment options was the motivation for this review. A successful pharmacological treatment, along with conservative measures, could alleviate the need for surgical interventions in managing OA. Therapeutic agents, such as IL-1Ra, dexamethasone, bisphosphonates, and MSCs are in clinical trials, with promising findings. The future direction of OA treatment includes translating experimental findings to clinical practice by designing feasible clinical trials with short-term, objective outcomes, in addition to exploring other therapeutic options, such as genetics and nanotherapy-based interventions.

Abbreviations

• Osteoarthritis

Post-traumatic osteoarthritis

Anterior cruciate ligament

Anterior cruciate ligament rupture

Destabilization of the medial meniscus

Scale for the Assessment of Narrative Review Articles quality assessment tool

Extracellular matrix

Glycosaminoglycans

Interleukin

Matrix metalloproteinase

Tumor necrosis factor

Transforming growth factor

Nuclear factor kappa B

Cyclooxygenase-2

Inducible nitric oxide synthase

Indian hedgehog

Bone morphogenetic protein 7

Mesenchymal stem cells

Primary response genes

Bromodomain-containing-protein-4

Cyclin-dependent-kinase-9

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Salman, L.A., Ahmed, G., Dakin, S.G. et al. Osteoarthritis: a narrative review of molecular approaches to disease management. Arthritis Res Ther 25 , 27 (2023). https://doi.org/10.1186/s13075-023-03006-w

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Review article, exercise for osteoarthritis: a literature review of pathology and mechanism.

• 1 College of Kinesiology, Shenyang Sport University, Shenyang, China
• 2 Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
• 3 Department of Rehabilitation Medicine, Shanghai Shangti Orthopedic Hospital, Shanghai, China

Osteoarthritis (OA) has a very high incidence worldwide and has become a very common joint disease in the elderly. Currently, the treatment methods for OA include surgery, drug therapy, and exercise therapy. In recent years, the treatment of certain diseases by exercise has received increasing research and attention. Proper exercise can improve the physiological function of various organs of the body. At present, the treatment of OA is usually symptomatic. Limited methods are available for the treatment of OA according to its pathogenesis, and effective intervention has not been developed to slow down the progress of OA from the molecular level. Only by clarifying the mechanism of exercise treatment of OA and the influence of different exercise intensities on OA patients can we choose the appropriate exercise prescription to prevent and treat OA. This review mainly expounds the mechanism that exercise alleviates the pathological changes of OA by affecting the degradation of the ECM, apoptosis, inflammatory response, autophagy, and changes of ncRNA, and summarizes the effects of different exercise types on OA patients. Finally, it is found that different exercise types, exercise intensity, exercise time and exercise frequency have different effects on OA patients. At the same time, suitable exercise prescriptions are recommended for OA patients.

Introduction

Osteoarthritis (OA) has a very high incidence worldwide, and it is strongly associated with age ( van Saase et al., 1989 ). Most of the patients with OA are aged over 60. With the aging of the population, the disease has become a common joint disease today. Heredity, hormones, diet, obesity, smoking, and drinking can lead to OA ( Felson et al., 1997 ). Its early symptoms mainly include pain and joint stiffness, and later secondary changes such as muscle atrophy and joint contracture occur ( Bennell et al., 2012 ). Therefore, we advocate early intervention for patients with OA to prevent further deterioration of the disease. However, the disease treatment still encounters many shortcomings, and further research and exploration are needed. Currently, the treatment methods for OA include surgery, drug therapy, and exercise therapy ( Spahn et al., 2013 ). In recent years, the treatment of certain diseases by exercise has received increasing research and attention. Exercise is an economical and effective treatment ( Ettinger et al., 1997 ). Proper exercise can improve the physiological function of various organs of the body and improve the overall morphology of the body ( Benedetti et al., 2018 ). In addition, exercise can also relieve pain ( Belavy et al., 2021 ; Zheng et al., 2021 ; Peng et al., 2022 ; Wu et al., 2022 ). For OA patients, ladder treatment is generally adopted, starting with basic treatment. If it is ineffective, drug therapy or surgery can be used, and exercise therapy is one of the basic treatment methods. The effects of different exercise types on OA have been widely studied.

At present, the treatment of OA is usually symptomatic. Limited methods are available for the treatment of OA according to its pathogenesis. Exercise can alleviate OA at a molecular level. Only by clarifying the mechanism of exercise treatment of OA and the influence of different exercise intensities on normal joints and OA patients can we choose the appropriate exercise prescription to prevent and treat OA. This review mainly expounds the mechanism that exercise alleviates the pathological changes of OA by affecting the degradation of the ECM, apoptosis, inflammatory response, autophagy, and changes of ncRNA, and summarizes the effects of different exercise types on OA patients. Finally, it is found that different exercise types, exercise intensity, exercise time and exercise frequency have different effects on OA patients. At the same time, suitable exercise prescriptions are recommended for OA patients.

Pathological Change Mechanism of Osteoarthritis

For OA patients, the integrity of the entire joint tissue is damaged, including articular cartilage, subchondral bone, and synovial membrane ( Loeser et al., 2012 ). Articular cartilage is mainly composed of the extracellular matrix (ECM), consisting of water, collagen, proteoglycans, mucopolysaccharides, type II collagen, and chondrocytes ( Luo et al., 2017 ). With the presence of prolonged, excessive mechanical stimulation of the body, articular cartilage will suffer. In the early stage of articular cartilage injury, the concentration of growth factors in the ECM increases as chondrocytes gather in the damaged area, resulting in transient cell proliferation and ECM synthesis ( Suri and Walsh, 2012 ). As the damage worsens, the blood supply to the articular cartilage worsens to the point that the cartilage does not have adequate access to nutrients. This condition results in cartilage cell apoptosis, ECM synthesis, and the disappearance of the articular cartilage degeneration ( Eyre, 2004 ). The two bones constantly rub, resulting in joint pain, swelling, and function limitation. Its continuous development causes OA ( Rim et al., 2020 ). Subchondral bone includes subchondral cancellous bone and cortical plates. X-ray and Magnetic Resonance Imaging (MRI) diagnosis can reveal the abnormal remodeling of subchondral bone and a series of changes in bonemorphology, such as bone spurs, osteophytes, and wear in OA patients ( Braun and Gold, 2012 ). This sequence of changes may be caused by an imbalance in the production and destruction of osteoblasts and osteoclasts ( Burr and Gallant, 2012 ). This morphological change of subchondral bone may also cause damage to the articular cartilage overlying it. Patients with OA have an exceptionally high probability of suffering from synovitis, and this condition is related to the pain and function of the knee joint during OA development ( Sowers et al., 2011 ). The synovial membrane is the connective tissue membrane covered on the inner surface of the joint capsule, which can produce synovial fluid to reduce joint friction and the loss of cartilage and ensure the metabolism and nutrition supply of joint cartilage ( Pap et al., 2020 ). Synovial cells mainly include synovial macrophages, fibroblast-like synovial cells, and mesenchymal stem cells. The macrophages can engulf the damaged tissue. When synovitis occurs in the body, the macrophages decompose to produce inflammatory factors, and the generation and degradation of cartilage matrix are in dynamic balance under normal conditions. Inflammatory mediators can destroy this balance, decompose chondrocytes, and aggravate synovitis ( Da et al., 2007 ). Fibroblast-like synovial cells can produce hyaluronic acid, which is an essential component of joint synovial fluid. During OA progression, the content of hyaluronic acid is remarkably reduced, resulting in the reduction of joint function and damage to the integrity of the joint surface ( Scanzello and Goldring, 2012 ).

Above all, articular cartilage, synovium, and subchondral bone abnormalities are the main pathological changes of OA ( Valdes and Spector, 2010 ). Considering that articular cartilage receives nutrients through synovial fluid, articular cartilage in patients with synovitis may undergo pathological changes. Moreover, the increase of macrophages in patients with synovitis may cause subchondral bones in OA to form osteophytes. Ayral et al. (2005) evaluated the correlation between synovitis and the severity of cartilage structure damage in OA patients through a one-year multicenter longitudinal study involving 422 patients. After arthroscopic and pain scoring, they found that compared with patients with normal synovial membrane, patients with synovitis had more severe articular cartilage lesions. The degree of deterioration after 1 year was statistically different. Yusup et al. (2015) studied 40 patients with knee OA and scored the structures such as joint cartilage, subchondral bone, and synovial membrane by using 3.0-T MRI and found that synovitis mainly occurred in the early and late stage of OA patients. The destruction of joint cartilage and a series of changes in subchondral bone could induce synovitis, and a strong correlation was observed among the three parameters. Some studies ( Norrdin et al., 1998 ) use horse as a model to study the pathological changes of OA, in which the morphological changes of subchondral bone occur before articular cartilage injury. In other studies ( Brandt et al., 1991 ), dog is used as the model to investigate the pathological changes of OA, in which the morphological changes of early subchondral bone coincided with an articular cartilage injury. Generally, the pathological mechanisms of articular cartilage, synovium, and subchondral bone in OA mainly include the degradation of ECM, cell proliferation, cell apoptosis, inflammatory reaction, changes of non-coding RNA, and methylation ( Mobasheri et al., 2017 ) ( Figure 1 ).

Figure 1. Pathogenesis of Osteoarthritis (OA). (A) The degradation of ECM, apoptosis, inflammatory response, and autophagy mechanisms in OA. (B) Methylation in OA.

Degradation of Extracellular Matrix

The ECM is a complex network of large molecules such as polysaccharides and proteins around cells. This structure and special cells make up the cartilage ( Theocharis et al., 2019 ). Many diseases are associated with changes in the composition and properties of ECM, such as OA. In healthy articular cartilage, the synthesis and metabolism of ECM should always maintain a dynamic balance to maintain homeostasis. The secretion and operation of some components of ECM are completed by articular cartilage ( Rahmati et al., 2017 ). When the activities of synthesis and catabolism of articular cartilage are imbalanced, the details and homeostasis of ECM are also affected ( Guo et al., 2002 ). Considering that the degradation of ECM leads to the loss of cartilage tissue, ECM also plays a role in maintaining the function of chondrocytes. The continuous degradation of ECM will induce OA.

Based on the summarizing of articles related to the pathogenesis of OA and the function of chondrocytes, Goldring and Goldring (2007) found that the degradation of ECM and decomposition of collagen could lead to the gradual loss of the shape and position of articular cartilage to induce OA. Setayeshmehr et al. (2019) summarized the functions and effects of various ECM scaffolds through summarizing and analyzing the related articles on hybrid and composite scaffolds derived from chondrocyte ECM. They concluded that the degradation of chondrocyte ECM could lead to cartilage degeneration. Malemud (2017) analyzed the role of matrix metalloproteinases in OA. They found that in the ECM of the cartilage, some essential proteins would degrade. Matrix metalloproteinases can promote or inhibit the degradation of these proteins, change the biomechanical properties of tissues, and destroy articular cartilage. In addition, based on the analysis of the action mechanism of ECM and its degrading enzymes in OA, the ECM of cartilage in OA patients can release certain fibronectin, thereby inducing the expression of related proteases and degrading the components of the ECM ( Pérez-García et al., 2019 ).

Kapoor et al. (2011) and Theocharis et al. (2019) also found that the tissue protein would be hydrolyzed gradually during the development of OA. Then, some catabolic mediators will be produced, which will induce the expression of some related cytokines and proteases, and finally lead to ECM degradation. This situation will lead to prolonged OA. Based on the analysis of the changes of some macromolecules in the ECM of early OA patients, the content of proteins related to ECM was changed, such as collagen and cartilage protein. Hence, the degradation of ECM and even the deterioration of OA disease occurred ( Lorenzo et al., 2004 ).

Apoptosis is an active gene-determined process that automatically ends life, and it is often called programmed cell death, a basic biological phenomenon of cells ( Musumeci et al., 2011 ). Apoptosis involves endogenous and exogenous pathways, which play an essential role in maintaining the function of various tissues in the body ( Elmore, 2007 ). A correlation has been observed between the degree of cartilage injury and apoptosis, which is a vital mechanism of cartilage injury ( Hwang and Kim, 2015 ). Moreover, the apoptosis of OA chondrocytes is related to cartilage degradation ( Kim et al., 2003 ). When OA occurs, it will produce matrix-degrading enzymes, leading to the degradation of the ECM and the destruction of cell homeostasis. Cell stress induces an oxidation reaction, leading to the apoptosis of chondrocytes and regulating the pathological changes of cartilage tissues ( Bauer et al., 2006 ).

Histologically, Musumeci et al. (2011) studied the articular cartilage of normal individuals and OA patients by staining apoptotic cells. They found that the articular cartilage of OA patients changed in structure. The pro-apoptotic receptor on the cell surface could induce apoptosis through an exogenous pathway in the damaged articular cartilage. Aigner et al. (2004) summarized the incidence, induction mechanism, and morphology of apoptosis in OA patients and found that apoptosis occurred in patients with OA, but the incidence was not high. The body induced apoptosis through specific proteoglycans, signaling molecules, and other pathways to regulate the pathological changes of articular cartilage and accelerate or delay the progression of OA. Based on the synthesis of related articles on OA and apoptosis, some articles indicate that apoptosis induces OA, while other articles indicate that OA induces apoptosis. These two views are disputed, and more reports believe that these conditions affect and promote each other and have a correlation ( Zamli and Sharif, 2011 ). Chondrocytes in the knee joints of patients with OA and the apoptosis of chondrocytes and its relationship with cartilage degradation have been studied. Notably, the findings indicate that first, in some populations, the morphology and function of cartilage are normal ( Hashimoto et al., 1998 ). Still, many apoptotic cells appear, indicating that apoptosis may lead to degenerative changes in articular cartilage, thus inducing OA. Furthermore, the number of apoptotic articular cartilage cells in the OA population increased, and the number of apoptotic cells was related to cartilage degradation. Finally, when all subjects, including the average population and OA patients, were analyzed, a correlation was found between age and apoptosis of chondrocytes. Similarly, rabbit chondrocytes have been studied and compared with mature rabbits. Results show that the cell density of each layer of articular cartilage in rabbits decreased, and the expression level of pro-apoptotic genes increased. These studies further proved the correlation between age and chondrocyte apoptosis at the animal level and the phenomenon of apoptosis that existed in the early stage of OA ( Todd Allen et al., 2004 ). In another study involving horses, a positive correlation was found between the severity of chondrocyte injury and apoptosis. The expression level of pro-apoptotic factors is higher in horses that often suffer from OA. Apoptosis participates in the pathogenesis of OA. Apoptosis has been observed on human femoral head cartilage ( Thomas et al., 2011 ). In comparison with the average population, the expression of receptors and the degree of apoptosis in OA patients’ articular cartilage was much higher. In the late stages of OA, the degree of apoptosis become even worse ( Héraud et al., 2000 ).

Inflammatory Reaction

The inflammatory reaction is a basic pathological process mainly involving a defensive response when the body is stimulated. Inflammation is involved in the pathological process of many diseases, such as cancer ( Gianni et al., 2016 ), tendon or ligament injury ( Gracey et al., 2020 ). As early as the middle of the 19th century, studies pointed out that inflammation was closely related to OA. Articular chondrocytes and synovial cells all expressed inflammatory mediators ( Liu-Bryan, 2013 ). Inflammatory factors such as IL-1β and TNFα participate in the inflammatory response in articular chondrocytes and synovial cells ( Malfait, 2016 ). The cells mainly involved in the inflammatory response are macrophages and monocytes. The degree of inflammation is related to the degree of joint dysfunction and inflammatory factors ( Scanzello et al., 2011 ). In the early stage of OA, the expression of monocytes and inflammatory mediators increased, whereas with the continuous development of OA, the expression of monocytes and inflammatory mediators was gradually decreased ( Benito et al., 2005 ).

Rosshirt et al. (2019) used the knee joints of 55 OA patients as the research object, described the activation state of T cells, and found that a large proportion of T cells were activated to participate in OA inflammation, which mainly affected the joint itself the most. Inflammation can promote catabolism and participate in the pathogenesis of the disease. van den Bosch (2019) found a large number of inflammatory mediators in the tissues of patients with OA. These inflammatory mediators can induce the generation of degrading enzymes in articular cartilage, leading to the degradation of the ECM and the destruction of cartilage tissue. Lieberthal et al. (2015) established a post-traumatic OA model and observed the relationship between inflammation and OA progression. They found that an inflammatory reaction occurred in the early stage of OA. In patients with, multiple inflammatory pathways were activated and produced multiple inflammatory mediators such as cytokines and chemokines, which played an essential role in the pathogenesis of OA ( Scanzello, 2017a ). The genomic expression profiles of OA patients have been collected and subjected to meta-analysis, and the results show that MAP kinase, NF-κB activation, and oxidative phosphorylation can induce inflammatory signals and participate in the pathological change mechanism of OA ( Li et al., 2014 ). Macrophages are immune cells that play an essential role in the inflammatory response ( Bondeson et al., 2010 ). Woodell-May and Sommerfeld (2020) explored the role of immune cells such as macrophages in the synovial membrane of patients with OA. They found that in OA, macrophages could release oxygen free radicals, proteases, and inflammatory factors, thus affecting the microenvironment of inflammation. In the wound healing stage, macrophages also release IL-1, IL-6, and other inflammatory factors to regulate the inflammatory response. By stimulating protease, inflammation can cause cartilage degeneration and eventually induce OA. Based on the relationship between mechanical injury and OA, mechanical damage can lead to mechanical inflammation, which activates NF-kB and inflammatory mitogen-activated protein kinase, thereby causing a series of functional problems of the join ( Vincent, 2019 ). If the rash persists for a long time, it will affect the repair of cartilage tissue. Based on the summary of articles related to inflammation in OA ( Goldring and Otero, 2011 ), when some risk factors inducing OA appear, the expression of pro-inflammatory factors and various related enzymes are upregulated in articular cartilage and synovial tissue through specific signaling pathways. Inflammatory elements, which are essential for cartilage damage and repair, can change adjacent joint tissues and form a vicious circle ( Houard et al., 2013 ). The knee joint is damaged under severe mechanical stimulation, causing catabolism and stress response of chondrocytes, and finally inducing inflammation, leading to joint pain. Inflammation is one of the important mechanisms that lead to the pathological changes of joint cartilage and synovial membrane ( Scanzello, 2017b ).

During autophagy, cells degrade their damaged organelles and macromolecular substances by using lysosomes to regulate autophagy-related genes, which can achieve the renewal of organelles and is essential for cell metabolism ( Guo et al., 2021 ). Autophagy is involved in the occurrence of OA. Through cellular autophagy, the function of damaged articular cartilage can be restored, thereby alleviating the pathological process of OA. Excess ROS will lead to cartilage degradation and inhibit the synthesis of ECM. Kongara and Karantza (2012) showed that autophagy could maintain the typical morphology of cartilage and the dynamic balance of ECM synthesis and metabolism by regulating the body’s ROS.

Barranco (2015) found that the inhibition of the Akt-mTOR signaling pathway in chondrocytes can promote the autophagy of articular chondrocytes and regulate oxidative stress ( Xue et al., 2017 ), thus participating in the development process of OA. If autophagy is activated, the damaged mitochondria and peroxidase bodies are removed, thus inhibiting the production of reactive oxygen species in the body and protecting the articular cartilage from pathological changes. Based on the summary of the roles of autophagy in OA, in the early stage of OA, moderate autophagy contributes to the survival of chondrocytes and is essential for preventing and delaying OA ( Duan et al., 2020 ). Li et al. (2016) found that autophagy was mainly committed in the chondrocytes of patients with OA. By regulating oxidative stress response and apoptosis, the pathological changes of the knee joint can be alleviated, and chondrocytes can be protected from various stimulations. With the growth of age, the incidence of OA increases gradually, and this phenomenon is related to autophagy. Autophagy gradually weakens with age. Therefore, the structure and function of articular cartilage decreases with age, leading to pathological changes in the knee joint ( Mathew et al., 2009 ). Caramés et al. (2010) that in OA animal models, the expression of autophagy regulatory factors is downregulated, and the steady-state of cartilage is damaged, indicating that autophagy can protect articular cartilage and play an essential role in maintaining cartilage steady state. The decrease of autophagy will induce OA. Taking articular cartilage of OA and non-OA patients as the research object, we can find that autophagy regulates the expression of OA-related genes. In comparison with patients without OA, autophagy is expressed in the chondrocytes of OA patients at a higher level, and the manifestation of autophagy markers is also upregulated ( Sasaki et al., 2012 ). Similarly, Chang et al. (2013) took human chondrocytes as the research object and found that many autophagy-related proteins are expressed in the articular cartilage of patients with OA. In the pathogenesis of OA, autophagy plays a role in protecting chondrocytes and promoting metabolism. However, excessive autophagy causes a large number of chondrocyte deaths.

Changes in Non-coding RNA

Non-coding RNA (ncRNA) is an RNA that does not code for protein, mainly including miRNA, lncRNA, and circRNA. These RNAs can exert biological functions at the RNA level without being translated into proteins. ncRNA plays an essential role in the pathological process of many diseases, such as cardiovascular disease ( Jusic and Devaux, 2020 ), cancer ( Karreth and Pandolfi, 2013 ), diabetes ( Beltrami et al., 2015 ). ncRNA also plays a vital role in the process of OA. It can promote or inhibit cartilage formation by regulating the degradation of cell-matrix, cell proliferation, apoptosis, and inflammatory response, thereby inducing or treating OA ( Hong and Reddi, 2012 ).

Changes in the expression levels of many miRNAs can induce pathological changes in OA. MiR-204/-211 and miR-29b-3p are common miRNAs, which are differentially expressed in patients with OA. Huang et al. (2019) established an OA mouse model and found that miR-204/-211 was missing, and Runx2 was increased. Mesenchymal progenitor cells proliferated abnormally at the same time by Micro-CT and histological determination. Akt signal North is activated, thus inducing the dysfunction of various components in the joint and finally leading to OA. Therefore, miR-204/-211 can maintain intra-articular homeostasis and ensure that articular chondrocytes and synovial cells function usually. Chen et al. (2017) used rat chondrocytes as the research object. Through luciferase reporter gene detection, they found that miR-29b-3p in patients with OA was upregulated, and miR-29b-3p ultimately led to the degeneration of articular cartilage tissue by targeting and inhibiting the expression of rat GRN mRNA. In addition, microarray technology was used to detect the expression of miRNA in chondrocytes. They found that miRNA-140, miRNA-455, miR-146a, miR-155, and miR125b differed in OA patients and the average population, thus inducing pathological changes of articular cartilage, synovial membrane, and subchondral bone ( Swingler et al., 2012 ). lncRNA also plays a vital role in OA. Throughout the cartilage development, different lncRNA is regulated, and the regular expression of lncRNA can prevent cartilage differentiation disorders. During cartilage degeneration, other lncRNA plays various roles ( Zhu et al., 2019 ). Ye et al. (2018) studied the articular cartilage of patients with OA. They found that the expression of ZFAS1 in OA chondrocytes was downregulated, and ZFAS1 might reduce the activity of chondrocytes and induce pathological changes of articular cartilage tissues by targeting the Wnt3a signaling pathway. Similarly, the role of circa in OA has been widely studied. Cyclic RNA plays a multi-faceted regulatory role in the progression of OA ( Zhang W. et al., 2021 ). Chen et al. (2020) found that in OA tissues, the expression levels of circRNA-UBE2G1 and HIF-1a were significantly increased, while the expression of miR-373 was downregulated. Functional testing showed that circRNA-UBE2G1 could bind to miR-373, thereby inhibiting the interaction of miR-373 and HIF-1a, damaging the chondrocytes, and leading to a series of pathological changes. In conclusion, ncRNA is closely related to OA. The differential expression of miRNA, lncRNA and circRNA in healthy people and OA patients can lead to pathological changes in articular cartilage, synovial membrane, and subchondral bone and affect the pathological process of OA.

Methylation

Methylation is the catalyzed transfer of methyl groups from an active compound to another compound. This process can form various methyl compounds or result in chemical modification of particular proteins or nucleic acids to start methylation products ( Urnov, 2002 ). Methylation mainly includes DNA methylation and m6a methylation ( Dai et al., 2021 ).

DNA methylation is a chemical modification of DNA that alters genetic behavior without altering the DNA sequence. Its primary process is under the action of DNA methyltransferase. DNA methylation can cause changes in chromatin structure, DNA conformation, DNA stability, and the way DNA interacts with the protein, thereby controlling gene expression ( Reynard, 2017 ). When CtBP1 and CtBP2 are overexpressed, the pro-inflammatory factors are increased, while the NLRP3 signaling pathway is activated to induce OA. DNA methylation in the CtBPs promoter reduces the expression level of CtBPs in OA tissues and regulate CtBP-mediated signal transduction, finally participating in the pathogenesis of OA ( Sun et al., 2020 ). In addition, DNA methylation can participate in the pathogenesis of OA by affecting the expression of genes such as matrix metalloproteinase-3, matrix metalloproteinase-9, and type II collagen ( Cui and Xu, 2018 ).

N6- methyladenine (m6a) is one of the most abundant chemical modifications of eukaryotic messenger RNA. m6a modifications mainly include m6a methyltransferase catalysis, m6a demethylase removal, and m6a binding protein recognition ( Ma and Ji, 2020 ). This process is widely involved in regulating various life cycle stages such as mRNA splicing, processing, translation, and degradation. It is related to osteosarcoma, rheumatoid arthritis, osteoporosis, OA, and abnormal physiological functions ( Zhang W. et al., 2020 ). The strange expression of m6a-related gene and protein in OA can trigger the imbalance of m6a methylation, regulate the expression of OA-related genes to participate in the occurrence and development of OA, and is closely related to the poor prognosis of patients ( Yang et al., 2021 ). METTL3 is a methylated gene of m6a. He et al. (2021) studied mice in vivo and in vitro and induced the OA model with inflammatory stimuli such as TNF-α. The results showed that the expression of METTL3 was decreased in the OA model. Bcl2 is a downstream target gene of METTL3, and the presentation of METTL3 can promote m6A methylation of Bcl2 mRNA, thereby inhibiting chondrocyte apoptosis and autophagy. The detection of synovial tissue in patients with OA revealed that METTL3 could also induce autophagy by inhibiting ATG7 ( Chen X. et al., 2021 ). In addition, METTL3 may participate in OA by regulating the inflammatory response ( Sang et al., 2021 ). In summary, methylation is also an essential mechanism for pathological changes in OA. Furthermore, the epigenetic mechanism plays an essential role in the pathogenesis of OA.

Mechanism of Exercise Improving Osteoarthritis

Exercise is good medicine. An increasing number of studies supports that exercise can enhance physical fitness, build up the body, and prevent and treat certain diseases, playing an increasingly important role in people’s lives ( Ruegsegger and Booth, 2018 ). Studies ( Pedersen and Saltin, 2015 ) have summarized the mechanism of exercise in treating 26 different conditions, providing a theoretical basis for treating diseases by exercise. The treatment of OA by exercise has attracted increasing attention and has gradually become an OA research hotspot. In the present paper, the pathological mechanism of exercise in OA treatment was summarized through the induction of relevant literature, as shown in Table 1 . Exercise relieves the pathological changes of OA by affecting the degradation of the ECM, apoptosis, inflammatory response, autophagy, and changes of ncRNA. And training is used to treat OA ( Figure 2 ).

Table 1. Mechanism of exercise in the treatment of Osteoarthritis (OA).

Figure 2. Pathological change mechanism of Osteoarthritis (OA). Exercise relieves the pathological changes of OA by affecting the degradation of the ECM, apoptosis, inflammatory response, autophagy and changes of ncRNA. (A) Mechanism of pathological changes of OA through degradation of ECM, apoptosis, inflammatory response, and autophagy. (B) Mechanism of pathological changes of OA through ncRNA.

The Role of Exercise in the Degradation of Extracellular Matrix

Exercise can delay the pathological process of OA by inhibiting the degradation of the ECM. Articular cartilage degradation is an essential pathological change of OA. Blazek et al. (2016) used OA rats as the research object. Exercise and non-exercise were used as intervention means to compare the whole gene expression of the transcriptome of articular cartilage in rats. Microarray analysis showed 644 differentially expressed genes in the articular cartilage of exercise rats. Therefore, exercise can prevent OA by changing genes related to OA’s pathogenesis and regulating the degradation and synthesis of ECM by changing metabolic pathways to alleviate the pathological changes of articular cartilage with sound prevention effects on OA. An OA rat model has been established to evaluate the expression of IL-10, TGF-β, and collagen type I and II in articular cartilage. The presentation of the above biochemical indicators increased in the articular cartilage of mice after exercise, indicating that exercise is very beneficial to articular cartilage. Moreover, considering that collagen type II is an essential component of ECM, exercise may delay the progression of OA by inhibiting the degradation of ECM and promoting cartilage synthesis ( Assis et al., 2018 ). Vasilceac et al. (2021) conducted resistance training for eight weeks for OA rats. They analyzed whether ELISA changed the activity of MMP-2 in the tendons around the knee joint and finally found that exercise could reduce the activity of MMP-2 in the quadriceps tendon of OA rats and greatly relieve the adverse effects of OA on the knee joint. Results show that exercise may reduce the degradation of the ECM by inhibiting the activity of MMP-2 from achieving the purpose of treating OA. Exercise in different stages of the course of OA produces other effects. Type II collagen (CoII) and matrix metalloproteinase-13 (MMP-13) are essential components related to the degradation of the ECM. Hsieh and Yang (2018) established an OA rat model, in which the samples were allowed to swim in different stages of the course of OA. They found that swimming training in the early stage of OA could increase CoII. The level of MMP-13 can be reduced to maintain a balance between the degradation and anabolism of ECM and prevent cartilage damage through exercise training in the early stage of OA rather than that in the late stage.

Overall, the degradation of the ECM is the pathological change mechanism of OA. Exercise can protect articular cartilage and delay the progression of OA by inhibiting this mechanism, and it is a crucial intervention to prevent and treat OA.

The Role of Exercise in Apoptosis

Apoptosis is one of the mechanisms for the pathological changes of OA. Exercise delays the pathological process of OA by inhibiting apoptosis. Taking articular cartilage of OA rats as a research sample, Yang et al. (2020) detected the expression of relevant genes in articular cartilage after exercise through bioinformatics analysis. Results show that the levels of TRAIL, NF-κB p65, and NLRP3 in cartilage after activity were decreased. Exercise could inhibit apoptosis and prevent OA by regulating the TRAIL/NF-κB/NLRP3 signaling pathway of OA. By comparing OA rats with mild, moderate, and high-intensity training and comparing the expression of caspase three and Hsp70, we found that mild and moderate exercise could inhibit apoptosis and protect the articular cartilage ( Galois et al., 2004 ). Qian et al. (2014) established an OA rat model, and the experimental group was subjected to passive motion. Based on the measurements of the proteoglycan content of the cartilage matrix, the number of type II collagen fibers, and apoptotic chondrocytes in the experimental and control group, the changes in biochemical signals caused by passive exercise in the early and middle stages of OA differed. In comparison with the control group, the cartilage matrix proteoglycan content and type II collagen fiber level remarkably increased three weeks after passive motion in the early stage of OA. The number of apoptotic cells was significantly reduced. However, three weeks after passive exercise in the middle stage of OA, the number of apoptotic cells was not significantly changed. Therefore, passive exercise at the early stage of OA may delay articular cartilage degeneration by inhibiting apoptosis, preventing, and treating OA. After intermittent training for OA rats, the pathological changes of their subchondral bones were assessed by immunolabeling with cleaved caspase-3 in the cortical subchondral bone. Intermittent aerobic training may prevent the OA-induced reduction in bone mineral density by reducing apoptosis ( Boudenot et al., 2014 ). Studies ( Iijima et al., 2015 ) have established the OA rat model and analyzed the pathological conditions of rat articular cartilage and subchondral bone before and after four weeks of exercise. They found that exercise might inhibit apoptosis and protect cartilage tissue, thus delaying OA progression. Musumeci et al. (2013) established the OA rat model to study the effect of exercise on articular cartilage. First, drugs were used to induce pathological changes in the articular cartilage. Then, exercise intervention was performed on rats to observe the morphological changes of articular cartilage. The results show that exercise might induce the expression of lubricating oil and inhibit the activity of caspase-3, thereby reducing apoptosis and delaying or even reversing pathological changes of articular cartilage. In some studies ( Zhang J. et al., 2021 ) concerning establishing the OA rat model, the experimental group was intervened by swimming for four weeks. The morphological changes of cartilage were analyzed by hematoxylin-eosin (H&E) staining. The expression of caspase-3 was analyzed by Western blot and qPCR. The results showed that after four weeks of swimming, the abnormal morphology of articular cartilage was improved, and the level of caspase-3 protein decreased, indicating that exercise might reduce apoptosis by inhibiting the level of caspase-3 protein, thereby protecting articular cartilage and preventing and treating OA.

The Role of Exercise in Inflammatory Response

Exercise can inhibit the inflammatory response by reducing pro-inflammatory factors, thereby delaying the pathological changes of OA, which is the most common mechanism of activity in OA treatment. The inflammatory response mechanism of exercise therapy for OA has been widely studied, and many related pathways regulate the inflammatory response of OA, such as PI3k/Akt, NF-κB p65, JNK/NF-kB, HDAC3/NF-kappaB, and AMPK/NF-κB signaling pathways. Lu et al. (2021) established the OA rat model and allowed them to exercise on the treadmill. They found that after running exercise, the mice produced maresin-1, and the increased level of maresin-1 activated the PI3k/Akt pathway and inhibited the NF-κB p65 pathway, thus playing an anti-inflammatory role and delaying the pathological changes of OA. Griffin et al. (2012) established the OA mouse model by inducing a high-fat diet and then letting the mice run to observe the expression of inflammation-related factors. Finally, they found that exercise could regulate the expression of pro-inflammatory factors, promote joint health, and reduce the severity of pathological changes in joints of OA mice. To study the signal transduction of JNK/NF-kB in KOA patients, we established the 0A rat model and conducted a controlled intervention experiment. Finally, the knee joint diameter in the exercise group is lower than that in the OA group, indicating that exercise is conducive to KOA recovery. The IL-1b, IL-6, and TNF-a levels decreased, indicating that exercise can reduce the inflammatory response by regulating the JNK/NF-kB signaling pathway, which ultimately can delay the pathological changes of OA ( Chen et al., 2020 ). Osteoarthritis rats were subjected to moderate-intensity exercise on the treadmill. The H&E staining and toluidine blue O staining were used to detect cartilage injury. The expression levels of some biochemical signals in the articular cartilage were examined via immunohistochemistry and other methods. The results showed that moderate-intensity treadmill exercise could reduce the inflammatory response and protect the articular cartilage by inhibiting the HDAC3/NF-kappaB pathway ( Zhang H. et al., 2019 ). Similarly, Yang et al. (2019) intervened OA rats with treadmill exercise and used the articular cartilage as the research object. Observation and analysis results show that moderate-intensity exercise can reduce the sensitivity of articular cartilage and chondrocytes to inflammatory response through the AMPK/NF-κB signaling pathway, and it is an essential mechanism for reversing the pathological changes of articular cartilage. The analysis of biochemical indicators of OA rats after aerobic exercise show that the expression levels of IL-1β, caspase-3, and MMP-13 in OA rats decreased after exercise, and aerobic exercise could inhibit the inflammatory response of OA and prevent and treat the pathological changes of cartilage ( Assis et al., 2016 ). After water sports, OA rats’ articular cartilage and inflammatory mediators were changed. After eight weeks of the experiment, the cell damage degree of the rat was relieved, and the expression levels of IL-1β and caspase-3 were reduced. Therefore, sports can regulate OA inflammatory factors and inhibit inflammatory reactions to treat OA ( Milares et al., 2016 ).

The Role of Exercise in Autophagy

In OA, autophagy is a cellular protective response. Exercise can protect the knee joints of KOA patients by inducing autophagy, which is mainly regulated by oxidative stress. Relatively few studies have demonstrated the specific mechanism pathways through which exercise protects the knee joint through autophagy. Zhang X. et al. (2019) used sodium iodoacetate to induce OA rat model, and the experimental group was subjected to treadmill exercise for four weeks. The study found that serum IL-1β was decreased, IL-4 was increased, and the expression of type II collagen in articular cartilage was increased in rats undergoing treadmill exercise compared with those in OA rats that did not experience any activity. Therefore, treadmill exercise may protect the knee joints of OA patients by promoting the autophagy of articular cartilage. Baur et al. (2011) established an OA mouse model to study the effect of running on articular cartilage and bone of OA patients and observed the changes of biochemical signals and articular cartilage of running mice after eight weeks. They found that the content of reactive oxygen species in mice increased after exercise. Exercise can promote autophagy and protect the articular cartilage and bone of OA patients by regulating oxidative stress. Another study ( Cifuentes et al., 2010 ) has established an OA rat model. The experimental group was exposed to treadmill exercise for 8 weeks to observe the pathological changes of articular cartilage. In comparison with OA rats that did not undergo exercise, the protein and polysaccharide contents on the surface of the articular cartilage of rats after eight weeks of the exercise was relatively high. This experiment confirmed that training can enhance the oxidative stress mechanism and protect articular cartilage. Moderate-intensity exercise plays different roles in different stages of OA progression. In the early stage of OA, the average power of movement can delay the progression of OA by promoting autophagy. In the late stage of OA, moderate-intensity exercise can over-activate purinergic receptor P2X ligand-gated ion channel 7 and increase the number of apoptotic cells, thus aggravating the progression of OA. Throughout the OA progression, the body may promote autophagy or apoptosis through the IRE1-mTOR-PERK signal axis to delay or accelerate the pathological process of OA ( Li Z. et al., 2021 ).

The Role of Exercise in Non-coding RNA

Exercise can alleviate the pathological changes of OA by regulating the expression of ncRNA. The practice affect the face of miRNA, lncRNA, and circRNA in articular cartilage, synovial membrane, and subchondral bone of OA patients.

miRNA is related to maintaining the typical morphology of articular cartilage. The detection of miRNA expression in OA rats revealed that compared with the non-exercise rats, 394 differentially expressed miRNAs were detected in the exercise rats ( Yang et al., 2020 ). The analysis of articular cartilage from different animals revealed that exercise could change the miRNA expression and improve the pathological changes of articular cartilage through a series of mechanisms. Dunn et al. (2009) analyzed the expression of miRNA in bovine articular cartilage. They found that the expression patterns of miR-221 and miR-222 in weight-bearing medial anterior condylar articular cartilage was higher than those in non-weight-bearing medial posterior condylar articular cartilage. When the articular cartilage was loaded with weight, miR-221 downregulated type II collagen and Sox9, and miR-222 downregulated HDAC4 and MMP-13, maintaining the typical morphology of articular cartilage. Guan et al. (2011) subjected chicken chondrocyte samples to mechanical stimulation to analyze the roles of relevant miRNA in the mechanical stimulation using microarray technology. Results show that mechanical stimulation could upregulate the miR-365 expression in chondrocytes. miR-365 stimulated the differentiation of chondrocytes by targeting histone deacetylase 4 (HDAC4) and finally alleviated the pathological process of cartilage tissue. In addition, the expression levels of many lncRNA changed during exercise. Zhou et al. (2021) established an OA mouse model. Mice with moderate-intensity exercise intervention had an upregulated lncRNA H19 expression, thickened articular cartilage, and resolved OA compared with mice without exercise intervention. Under the stimulation of mechanical stress, lncRNA-MSR was activated and then competitively bound to miR-152, thereby promoting the expression of TMSB4 and leading to the degradation of the ECM ( Liu Q. et al., 2016 ). The regulatory role of circRNA during exercise is also crucial. A total of 104 circRNA were differentially expressed (44 upregulated and 60 downregulated), with increased circRNA-MSR expression, in damaged articular cartilage compared with intact articular cartilage. circRNA-MSR expression was downregulated after mechanical stress was applied to the cartilage. The downregulation of circRNA-MSR can inhibit the expression of TNF-α and promote the degradation of the extracellular chondrocyte matrix, thus enhancing the structure and function of cartilage ( Liu et al., 2017 ). In addition, circRNA-MSR can directly target miR-643 to u-regulate MAP2K6. The downregulation of circRNA-MSR expression can promote cell proliferation and reduce cartilage damage ( Jia and Wei, 2021 ). qRT-PCR and Western blot have been used to analyze the genes related to cartilage differentiation in cartilage tissues. The results show that the expression of circUNK was upregulated, which improved the cartilage injury in OA rabbit and promoted the expression of molecules related to cartilage differentiation, such as PCNA, SOX9, Col II, Aggrecan, and protein-polysaccharide. These molecules had sound effects on the proliferation and differentiation of articular cartilage. In conclusion, exercise or mechanical stimulation can lead to changes in the expression of ncRNA, which prevents and improves the pathological changes of articular cartilage, synovial membrane, and subchondral bone through a series of mechanisms, thereby delaying the progression of OA ( Fang et al., 2021 ).

Effects of Different Exercise Types on Human Osteoarthritis

Many types of training can relieve pain, enhance muscle strength and improve joint stiffness ( Daenen et al., 2015 ). For healthy people, exercise can promote good health, while for OA patients, dysfunction can be improved and diseases can be treated ( Skou et al., 2018 ). At present, there are many types of sports for the treatment of OA, such as aerobic exercise, anti-resistance exercise, neuromuscular training, etc ( Jansen et al., 2011 ). In addition, Chinese traditional sports such as Baduanjin, Wuqinxi, and yoga are also applied to the prevention and treatment of OA ( Li et al., 2020 ). This paper summarizes the research on training types of OA patients by summarizing related literature, as shown in Table 2 .

Table 2. Different exercise types on human Osteoarthritis (OA).

Conclusion and Outlook

At present, the incidence of OA is very high, and its pathogenesis remains unclear. The treatment of OA by exercise has received increasing research attention. Not all types of sports used can alleviate OA. The result of different types, intensity, and time of sports on OA differs.

Some studies believe that exercise does not affect OA. For example, Rios et al. (2020) intervened in KOA rats with aerobic exercise for 12 weeks and measured bone mineral density and knee joint injury. The results showed that training did not affect the common knee injury, accelerate the progression of OA, and alleviate the pathological changes of OA. Other studies believe that exercise accelerates the progression of OA. For example, Liu S.-S. et al. (2016) established a rat model of exercise-induced OA. They analyzed and compared the expression levels of various related mRNA, protein, and pathways in the standard and injury group of exercise-induced OA by using RT-qPCR, Western blot analysis, and immunohistochemical staining. The results showed that excessive pressure would lead to abnormal expression of many biochemical signals and abnormal activation of the Wnt/β-catenin pathway, leading to induced OA. Exercise has different effects on healthy and damaged articular cartilage ( Rojas-Ortega et al., 2015 ). Notably, for articular cartilage injury, if high-intensity practice is continued, the activity of catabolic proteins is more vital than that of anabolic proteins. The body’s metabolism is imbalanced, thus efficiently inducing OA. Twelve weeks of high-intensity treadmill training in rats will increase the levels of some apoptosis-related proteins and inflammation-related factors, such as caspase-3, IL-1α, and TNF-α, which is the precursor of OA ( Franciozi et al., 2013 ). The results indicate that high-intensity exercise may lead to the occurrence and development of OA. In addition, moderate exercise can delay the pathological process of OA. For example, a daily external force has been used to compress OA mice under low or medium intensity, and the pathological changes of articular cartilage were observed in the second and sixth weeks. Moreover, low- and medium-intensity compression can reduce the degeneration of articular cartilage and osteophytes of subchondral bone in mice and is very beneficial to the damaged joints, making it an effective method for the treatment of OA ( Holyoak et al., 2019 ).

At present, many exercises have therapeutic effects on OA, such as aerobic exercise, strength training, swimming, neuromuscular exercise, proprioceptive training, and balance training. Different types of motion produce other effects. Aerobic exercise is the most widely used in OA patients, and it can reduce the expression of IL-1β, caspase-3 and MMP-13 and prevent cartilage degradation in KOA rats ( Assis et al., 2016 ). Aerobic exercise may be the best training method to reduce pain and improve body function ( Goh et al., 2019 ). However, aerobic exercise with different intensities has different effects on OA patients with varying degrees of injury. Low-intensity aerobic exercise had a better therapeutic effect in patients with severe OA ( Messier et al., 2021 ), while high-intensity aerobic exercise had a better therapeutic effect in patients with mild OA ( Multanen et al., 2017 ). In addition, strength training could reduce the activity of MMP-2 in the quadriceps tendon of the OA rat model ( Vasilceac et al., 2021 ), which was the most effective in improving muscle strength, and neuromuscular training was the best training method to relieve OA pain ( Ageberg and Roos, 2015 ). Swimming intervention in the early stage of OA can alleviate the stiffness of the knee joint and is better than land exercise ( Lund et al., 2008 ; Hsieh and Yang, 2018 ; Munukka et al., 2020 ). Land exercise can be performed after the patients’ joints have a certain degree of flexibility. Land exercise is better than water exercise in improving pain and enhancing function ( Escalante et al., 2011 ). Many traditional techniques are being applied more and more in OA, such as Baduanjin ( An et al., 2008 ), tai chi chuan ( Zhang Z. et al., 2020 ), Wuqinxi ( Xiao and Li, 2021 ), and yoga ( Kuntz et al., 2018 ). They can improve the physical function of OA patients and have a significant impact on the psychological status of OA patients. In addition, new intervention methods such as virtual reality and sports games have been gradually used to improve people’s physical and psychological conditions ( Sadeghi and Jehu, 2022 ). These sports have excellent development prospects in the treatment of OA.

Although many types of exercise can be used to prevent or treat OA, our most recommended method is to formulate a unique exercise prescription for each patient with OA based on the FITT (Frequency, Intensity, Time, and Type) principle. According to the exercise prescription, a study ( de Rooij et al., 2017 ) formulated a personalized rehabilitation program for 126 OA patients for 20 weeks. It was finally found that personalized exercise therapy could effectively improve the OA of the knee joint and the body function of the patients. Exercise prescription recommendations for patients with OA are as follows ( Bennell et al., 2014a ): (1) Exercise frequency: It is recommended that in the initial stage, the patient had better exercise at least 12 times within three months to master the skills and ensure compliance, and then the frequency was gradually increased and maintained to two to three times a week, and a week of moderate-intensity exercise lasting 150 to 300 min was accumulated; (2) Exercise intensity: Moderate intensity exercise is recommended. Namely, the heart rate is 120–150 beats/min, and the oxygen consumption during exercise is 50–70% of the maximum oxygen consumption; (3) Exercise time: The recommended exercise time is 30–60 min per day. The exercise time was gradually increased from a short time to 30–60 min/d; (4) Exercise type: generally, aerobic exercise and strength training are recommended. Aerobic exercise such as swimming, Tai Ji Chuan, unfavorable for mountaineering, climbing stairs and other excessive weight-bearing movements, strength training have equal length, such as Zhang or isokinetic resistance movement, etc., recommend the weight-bearing exercise is given priority to; (5) Precautions: Pain relief can be obtained only after 8–11 weeks of exercise therapy. Continuous exercise for more than 12 weeks is generally recommended to relieve decreased muscle strength and muscle atrophy associated with OA. Patients should also receive regular education during training to improve their self-management awareness, compliance and exercise efficacy. It is normal to feel some discomfort or pain during exercise. Ice application is required at the joints for 15–20 min after training. If severe pain occurs during exercise or swelling aggravates the next day, you should timely adjust the amount of activity. Different types of patients may have other exercise prescriptions. Patients with higher obesity are more suitable for aquatic exercise. For patients with upper limb OA, emphasis should be placed on improving the affected joints’ range of motion and flexibility. For patients with lower limb OA, emphasis should be placed on improving patients’ muscle strength and body stability. Therefore, we should formulate individualized exercise prescriptions according to the degree of lesion and needs of OA patients.

This review describes the pathological change mechanism of OA and the molecular mechanism of exercise in the treatment of OA. By using RT-qPCR, Western blot analysis, and immunohistochemical staining, we have found that the expression levels of related mRNA, protein, and pathways were changed in OA patients after exercise. This review also summarized animal experiments related to exercise and OA and the role of different exercise types in human OA, described the research progress of exercise in the prevention and treatment of OA, and provided a basis for exercise intervention to treat OA in the future. Exercise, as an intervention means, has a great development prospect in the treatment of OA.

Author Contributions

X-AZ and X-QW: conceptualization, project administration, and funding acquisition. HK, X-AZ, and X-QW: writing – review and editing. All authors contributed to the article and approved the submitted version.

This study was supported by the Innovative Talents Support Program for Universities of Liaoning Province, No. WR2019024 and Shanghai Frontiers Science Research Base of Exercise and Metabolic Health.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords : osteoarthritis, exercise, pathology, mechanism, therapy

Citation: Kong H, Wang X-Q and Zhang X-A (2022) Exercise for Osteoarthritis: A Literature Review of Pathology and Mechanism. Front. Aging Neurosci. 14:854026. doi: 10.3389/fnagi.2022.854026

Received: 13 January 2022; Accepted: 11 March 2022; Published: 03 May 2022.

Reviewed by:

Copyright © 2022 Kong, Wang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Xin-An Zhang, [email protected] ; Xue-Qiang Wang, [email protected]

This article is part of the Research Topic

Physical Exercise for Age-Related Neuromusculoskeletal Disorders

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• Volume 9, Issue 9
• Experience of living with knee osteoarthritis: a systematic review of qualitative studies
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• Jason A Wallis 1 , 2 ,
• Nicholas F Taylor 1 , 2 ,
• http://orcid.org/0000-0002-5747-9361 Samantha Bunzli 3 ,
• Nora Shields 1
• 1 School of Allied Health, Human Services and Sport , La Trobe University , Melbourne , Victoria , Australia
• 2 Allied Health Clinical Research Office , Eastern Health , Melbourne , Victoria , Australia
• 3 Department of Surgery , The University of Melbourne, St Vincent's Hospital , Melbourne , Victoria , Australia
• Correspondence to Dr Jason A Wallis; Jwallis{at}cabrini.com.au

Objectives Systematically review the qualitative literature on living with knee osteoarthritis from patient and carer perspectives.

Design Systematic review of qualitative studies. Five electronic databases (CINAHL, Embase, MEDLINE, PsycINFO, SPORTDiscus) were searched from inception until October 2018. Data were synthesised using thematic and content analysis.

Participants Studies exploring the experiences of people living with knee osteoarthritis, and their carers were included. Studies exploring experiences of patients having participated in specific interventions, including surgery, or their attitudes about the decision to proceed to knee replacement were excluded.

Results Twenty-six articles reporting data from 21 studies about the patient (n=665) and carer (n=28) experience of living with knee osteoarthritis were included. Seven themes emerged: (i) Perceived causes of knee osteoarthritis are multifactorial and lead to structural damage to the knee and deterioration over time (n=13 studies), (ii) Pain and how to manage it predominates the lived experience (n=19 studies), (iii) Knee osteoarthritis impacts activity and participation (n=16 studies), (iv) Knee osteoarthritis has a social impact (n=10 studies), (v) Knee osteoarthritis has an emotional impact (n=13 studies), (vi) Interactions with health professionals can be positive or negative (n=11 studies), (vii) Knee osteoarthritis leads to life adjustments (n=14 studies). A single study reporting the perspectives of carers reported similar themes. Psychosocial impact of knee osteoarthritis emerged as a key factor in the lived experience of people with knee osteoarthritis.

Conclusions This review highlights the value of considering patient attitudes and experiences including psychosocial factors when planning and implementing management options for people with knee osteoarthritis.

Trial registration number

CRD42018108962

• lived experience
• qualitative
• systematic review
• osteoarthritis

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https://doi.org/10.1136/bmjopen-2019-030060

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Strengths and limitations of this study

The systematic review was reported consistent with the Enhancing Transparency in Reporting the Synthesis of Qualitative Research and registered prospectively with PROSPERO.

A comprehensive search strategy of qualitative studies about patient and carer perceptions about their lived experience with knee osteoarthritis was conducted.

Comprehensive data synthesis was applied using thematic and content analysis leading to results that went beyond the summary of the selected studies.

The findings of this review are limited to the experience of living with knee osteoarthritis, and not the experience of receiving specific interventions, including surgery.

Exclusion of non-English language articles limits the generalisability as other cultures with other languages might have different perceptions of knee osteoarthritis.

Introduction

The experience of living with chronic pain associated with knee osteoarthritis is multidimensional comprising biological dimensions such as subchondral bone pathology and inflammation, 1 and psychological and social dimensions such as pain catastrophising, depression, avoidance of activities and social support. 2–4 The current management of knee osteoarthritis is focussed on pain management to address biological dimensions (joint pathology), through joint-specific exercises, pharmacology and in advanced stages, joint replacement surgery. 5 6 However, levels of pain and disability reported by people with osteoarthritis are poorly correlated with radiographic severity of joint pathology, suggesting other factors apart from biological dimensions can affect the experience of living with knee osteoarthritis. 7 Further, knee replacement surgery to address joint pathology, does not always have a successful outcome. Only about 40% of patients report being pain-free 2 years after surgery, 8 and about 20% were not satisfied with surgical outcome 1 year after surgery. 9

The role of psychological and social dimensions in the management of knee osteoarthritis has received relatively little attention in comparison with management of joint pathology. 2 In other chronic musculoskeletal conditions, the role of psychological and social dimensions has been studied extensively. 10 For example, in chronic low back pain, psychological and social factors have been shown to play a role in the persistence of pain, and interventions designed to target these factors can improve pain, disability and quality of life in this population. 11 12 Targeting the psychological and social dimensions of knee osteoarthritis in addition to the biological dimensions, consistent with a biopsychosocial approach, may optimise outcomes. There is preliminary evidence from a systematic review and meta-analysis of 12 randomised controlled trials showing psychological interventions, such as cognitive behavioural therapy, are associated with short-term reductions in pain for people with knee osteoarthritis. 13 Further, there is preliminary evidence from a randomised controlled trial that combining physiotherapist-delivered pain coping skills training with exercise therapy, can lead to greater improvements in function compared with either treatment alone. 14 In order to design targeted interventions consistent with a biopsychosocial approach, we must first understand the psychological and social dimensions of knee osteoarthritis from the perspectives of people living with the condition.

Qualitative research provides insight into the lived experience of health and how individuals’ make sense of their health symptoms. Rather than relying on the a priori assumptions of researchers or clinicians, qualitative research prioritises the voice of the ‘expert’ participant, thus shedding light on aspects of the lived experience that cannot be reached by quantitative approaches. 15 Two recent systematic reviews have synthesised qualitative research related to knee pain, including people living with osteoarthritis. 16 17 Wride 17 explored the feelings and experiences of people living with knee pain from nine studies, three of which included people with non-osteoarthritic related knee pain. This review found many people with knee pain struggle to adapt to normal living, and that their negative experiences were exacerbated by a lack of knowledge and available information to help them plan for the future. In another review, Smith et al 16 explored the perceptions of people diagnosed with hip and/or knee osteoarthritis from 32 studies (18 of which sampled people with knee osteoarthritis only) to determine their attitudes and perceptions towards living with their musculoskeletal condition. Participants in these studies reported a number of factors that contributed to their negative attitude and perception about their hip and/or knee osteoarthritis, such as their understanding of the pathology of osteoarthritis, the activity limitations they experienced and their perceptions of other people’s beliefs towards their condition.

The two previous systematic reviews synthesising qualitative data have limitations as they did not consider the experience of knee osteoarthritis separately to the experience of non-osteoarthritic related conditions (eg, Wride 17 ), and to the experience of hip osteoarthritis (eg, Smith et al 16 ). Empirical evidence suggests hip and knee osteoarthritis are distinct conditions that impact people in different ways. 18 In addition, neither review 16 17 looked at the perspectives of carers. Those in the immediate social environment may exert an influence on how an individual copes with their condition. In the case of knee osteoarthritis, family members and significant others often adopt the role of carer. By investigating the perceptions and experiences of both patients and carers, health professionals can gain a greater understanding of how living with knee osteoarthritis effects their lives, which may lead to improved management of people with knee osteoarthritis.

Therefore, the aim of this study was to systematically review the qualitative literature on the experience of living with knee osteoarthritis from the perspectives of patients and carers.

Methods and analysis

A systematic review of qualitative studies was conducted. The review was reported consistent with the Enhancing Transparency in Reporting the Synthesis of Qualitative Research. 19

Patient and public involvement

Patients and public were not involved in the development of the research question, outcome measures or research design.

Search strategy

Five electronic databases (CINAHL, Embase, MEDLINE, PsycINFO, SPORTDiscus) were searched from inception until October 2018. The search strategy comprised two key concepts: knee osteoarthritis and qualitative research. For each concept, key words and Medical Subject Headings terms were combined using the ‘OR’ operator and the results were combined using the ‘AND’ operator (Appendix). The search results were downloaded into bibliographic software (Endnote V.18). Two reviewers independently reviewed the titles and abstracts according to the selection criteria ( table 1 ). If eligibility was uncertain based on title and abstract, the full-text of the study was obtained. Reference lists of included articles were manually searched for additional relevant articles, and citation tracking of included articles was completed using Google Scholar.

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Selection criteria

Eligibility criteria

Studies reporting the experiences of people living with knee osteoarthritis, and their carers were included. Studies that explored experiences of participation in specific interventions for knee osteoarthritis, including perioperative management and attitudes about the decision to proceed to total knee replacement were excluded as the focus of the review was on the lived experience of knee osteoarthritis, and not about the response to treatment from receiving a specific intervention ( table 1 ). Since the aim of our review was to explore the experience of living with knee osteoarthritis, with a focus on the psychological and social dimensions, it was decided not to include studies that explored perceptions about biological interventions including surgery.

Methodological quality of the included studies

The Critical Appraisal Skills Programme (CASP) checklist was used to assess methodological quality of the included studies. 20 The CASP checklist includes 10 questions in three sections about the validity of the results (questions 1 to 6), ethical considerations, trustworthiness and clarity of results (questions 7 to 9) and the value of the results (question 10). Two reviewers (JW, SB) independently answered each question as ‘yes’, ‘no’ or ‘can’t tell’, by reading the decision rules and instructions on how to interpret checklist criteria. Discrepancies between reviewers were discussed with a third reviewer (NT) until consensus was reached with the overall judgement scored as yes or no. The CASP checklist has been used in other qualitative systematic reviews in musculoskeletal research. 21 22

Data collection process

Data were extracted from each study on participant age, sex, disease severity and body mass index, where available. Data were also extracted on the study design including sample size, data collection method (eg, interview or focus group) and qualitative framework informing the analysis. From the results section of each included paper, we extracted the main themes and subthemes as outlined below.

Data analysis

Data were analysed using a three-stage approach adapted from Sandelowski and Barroso. 23 In stage one, the results sections of each paper including direct quotations were read and re-read so the authors familiarised themselves with the content, prior to extracting main themes and subthemes. Themes and subthemes were then extracted and assigned descriptive codes using an inductive process. In stage two, the identified codes were then reviewed and codes were grouped together according to their topical similarity. In stage three, these groupings of codes were subsequently organised into themes and subthemes in a process of thematic analysis. To help understand the relative importance of the emergent themes and subthemes relative to each other, and consistent with content analysis methods, the number of studies that identified each theme was counted. The process of data extraction, initial coding, grouping of codes and identification of emergent themes and subthemes was completed by one researcher (NS). The data analysis process was subsequently checked independently by two other researchers (JW, NT) before the final themes and subthemes were confirmed by the research team.

Study selection

The search strategy yielded 720 articles. After screening the titles and abstracts of these articles, 42 underwent full text review. Sixteen articles were excluded after full text review resulting in a final library of 26 articles ( figure 1 ). The most common reasons for exclusion were that articles were abstracts, and the results of knee osteoarthritis were not reported separately from osteoarthritis at other joints. The 26 included articles reported data from 21 studies ( table 2 ) on the experience of living with knee osteoarthritis from the perspectives of people themselves (n=20) or their carers (n=1).

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Yield of studies.

Characteristics of included studies of experiences of living with knee osteoarthritis

Methodological quality of included studies

All studies had a clear rationale for using qualitative methods, used appropriate qualitative designs and included explicit statements of findings that were considered high value. Two studies did not report approval from an ethics committee 24 25 and four studies reported insufficient details about data analysis reducing the trustworthiness of the results. 24–27 Only 2 of the 21 studies adequately reported the relationship between the researcher and the participant. 28 29 A pre-existing relationship between the participant and researcher increases the risk of social desirability, 30 whereby there is the tendency of the participants to answer questions in a manner that will be viewed favourably by the researchers ( table 3 ).

Critical Appraisal Skills Programme assessment

Study participant characteristics

The 21 studies included 665 people with knee osteoarthritis (71% women; mean age 65 years, age range 25 to 87) and 28 carers of people with knee osteoarthritis (46% women; mean age 48 years) ( table 2 ). The studies were conducted in Asia (n=6), North America (n=6), Europe (n=8) and New Zealand (n=1) and 15 of the 21 studies were published since 2011. Participants’ comorbidities as described in six studies included diabetes, depression/anxiety, polyarthritis, hypertension, heart disease, haemophilia, silicosis, vascular problems, cancer, gout, osteoarthritis in other joints and multiple knee surgeries. Participants in nine studies self-assessed their pain severity at the time of their participation as mild-to-severe, 25 27 31–37 and participants in four studies had severe osteoarthritis and were awaiting total knee replacement. 29 38–40 Thirteen studies provided details on participant employment status; the majority of participants were retired or not working, except for three studies 28 35 41 in which the majority of participants were employed at the time of the study.

Major themes reported by included studies

Seven major themes emerged from the data: (i) The perceived causes of knee osteoarthritis are multifactorial and lead to structural damage to the knee and deterioration over time, (ii) Pain and how to manage it predominates the lived experience, (iii) Knee osteoarthritis impacts activity and participation, (iv) Knee osteoarthritis has a social impact 5 , (v) Knee osteoarthritis has an emotional impact, (vi) Interactions with health professionals can be positive or negative and (vii) Knee osteoarthritis leads to life adjustments. Themes were consistent between studies that included people with severe osteoarthritis and mild-to-moderate osteoarthritis. The study including cares (family members of the participants from one trial), captured six of the seven major themes, with no new themes identified by cares.

The perceived causes of knee osteoarthritis are multifactorial and lead to structural damage to the knee and deterioration over time

Thirteen studies reported what participants perceived the causes of knee osteoarthritis were. 24–28 32–35 37 38 42 43 Perceived cause of knee osteoarthritis included internal factors (eg, being overweight, family history of osteoarthritis, ageing, working in occupations requiring heavy manual work such as extensive kneeling or lifting, past sporting activities and menopause) and external factors (eg, trauma and the weather). Participants perceived knee osteoarthritis as preventable or partially attributable to actions or incidents that were modifiable (eg, pushing too far or knee injury) had they changed their behaviour earlier in life. Participants in four studies expressed strong beliefs and concerns about their knee osteoarthritis being caused by structural deterioration 25 28 33 34 using language such as ‘bone on bone’ with the joint worn away by movement. Carers of people with knee osteoarthritis attributed the cause of their relative’s knee osteoarthritis to ageing, working too hard or to unknown causes. 42

The prognosis of knee osteoarthritis was discussed by participants in six studies. 26 28 32–35 Participants believed their symptoms would get worse over time as knee osteoarthritis was ‘a progressive degenerative disease’ and could not be ‘cured’. However, participants in one study 35 also felt they could halt or slow the progression of their symptoms through diet and exercise.

Pain and how to manage it predominates the lived experience

The participants’ experience of pain and its management emerged as a theme in 19 studies. 25–29 31–33 35–45 Pain was described by participants as the predominant ‘omnipresent’ feature of knee osteoarthritis. Pain was perceived to interrupt and deter daily activities such as walking, to make people less confident in their bodies and to slow people down. Participants in one study described two distinct patterns of pain: ‘mechanical’ pain described as ‘sharp’ pain related to discrete movements or activities, and ‘inflammatory’ pain described as a ‘burning’ pain which was more unpredictable and associated with the weather or prolonged activity. 27 Pain was perceived as insurmountable when there was no foreseeable end to it and made some participants feel ‘old’. Carers reported their relatives with knee osteoarthritis rarely mentioned pain until they needed help. 42 Participants reported managing their pain with medication but that this was not always a satisfactory strategy due to feelings of dependence, undesirable side-effects and only partial relief from symptoms. Other pain management strategies described were activity-related (including exercise, avoidance of certain activities, brief rest, pacing and physiotherapy), psychological-related (having a positive life philosophy, humour, continuing to engage in pleasurable activities), passive treatment modalities (including ice, heat, massage, Chinese traditional medicine) and weight loss. Some believed joint replacement was inevitable and the only real solution for their pain. 25 28 Similarly, carers of relatives with knee osteoarthritis believed the most promising method to reduce pain was a knee replacement, and often persuaded their relatives to see a doctor about having surgery. 42 In contrast, participants from one study preferred a natural solution only as they had a negative perception of surgery and saw it as a last resort. 43

Knee osteoarthritis impacts activity and participation

Participants in 16 studies reported functional limitations due to their knee osteoarthritis particularly mobility restrictions. 25–29 31 32 35–42 45 Participants predominantly reported limitations in movements involving weight-bearing such as standing, stair climbing, squatting, carrying, lifting, kneeling, bending; limitations in self-care activities such as dressing, toileting, sleeping, cooking; limitations in leisure pursuits such as walking, gardening, sport and other forms of exercise, and a fear of falling. Living with knee osteoarthritis was reported by participants to reduce their physical activity and exercise, and to become sedentary. Participants described the impact on physical activities and associated this with the severity of their knee osteoarthritis. The combined consequences of pain and functional limitations was an inability for some participants to participate in paid employment, or a reduction in work hours affecting household income, or other impacts on work such as requiring modifications, tiring easily or being less efficient. For others, living with knee osteoarthritis meant a loss of independence, and a loss of sleep. 28

Knee osteoarthritis has a social impact

Participants in 10 studies felt their knee osteoarthritis had a substantial social impact. 27 29 34–36 38–41 45 It limited their ability to stay socially connected because of reduced participation in leisure activities and because of difficulties with taking public transport. For some participants, the inability to take part in socially-based physical activity, such as walking with friends or playing sport was the most difficult aspect of this condition. Participants described social isolation marked by doing fewer activities outside of home. Participants felt mobility limitations made it conspicuous to others that they had poor health. Living with knee osteoarthritis reduced their enjoyment of activities, particularly when travelling. Others described a change in their social relationships conveying that they related more to older individuals with health problems. Participants also described the repercussions of knee osteoarthritis on family life, reporting difficulties taking care of the family including looking after grandchildren and playing with their children.

Knee osteoarthritis has an emotional impact

Thirteen studies reported data on the emotional impact participants said they experienced as a result of having knee osteoarthritis. 25–29 31 32 35 36 40–42 45 Living with knee osteoarthritis was described as being ‘difficult’ and often described as having a negative impact on the participant’s mood, resulting in feelings of loss, anxiety, inadequacy, frustration, irritability, emotional distress, depression, embarrassment, fear for the future and uncertainty of the outcomes of knee pain. Carers reported their relatives with knee osteoarthritis could lose their temper easily when experiencing severe pain. 42 Some participants reported their mobility limitations in particular devalued their sense of self-worth because mobility was integral to their identity. Living with knee osteoarthritis made them feel like ‘a partial person’, ‘less valuable’ and losing their identity, since they had to give up something that was part of their normal life. Other participants talked of a reduced sense of control or of being ‘lost’ after being ‘told’ to eliminate athletic activities and change their lifestyles. Other participants reported grieving for activities they could no longer take part in, or their vision of ageing. Participants in one study 27 felt the unpredictability and uncertainty of living with knee osteoarthritis caused the most stress. While participants in another study 40 said they dreamed of regaining their previous level of physical activity, their knee was a major barrier to achieving their dreams.

Interactions with health professionals can be positive or negative

Eleven studies explored the interactions people with knee osteoarthritis described having with health professionals. 24 25 31–33 35 41 43–46 Participants said the impact of their diagnosis was a positive step towards successful management; although for people with low expectations of treatment, the impact of their diagnosis resulted in limited contact with health professionals. Participants who had positive interactions with health professionals described being listened to, being offered hope for the future and being provided with recommendations for managing knee osteoarthritis including weight loss and exercise. Participants who had negative experiences interacting with health professionals described their dissatisfaction with receiving limited information about their condition and the management options available including ways to avoid aggravating their condition, a sense of not being listened to, not being given sufficient attention or not understanding the information provided to them. For example, in one study 35 participants recounted how their symptoms were viewed by health professionals as something that could not be changed, which they ‘just had to live with’ or were dismissed as an inevitable part of ageing.

Knee osteoarthritis leads to life adjustments

Fourteen studies 25 27–29 31 32 34 35 37 39–42 45 reported participants’ descriptions of adjusting to having knee osteoarthritis in terms of role changes or modifications, ownership of their health management, awareness of their condition and developing coping strategies. Participants described taking measures to alleviate their symptoms and protect their knee joint including lifestyle adjustments by keeping active and controlling their weight, adapting their work, modifying activities or postures to manage everyday routines (eg, climbing stair less frequently and looking for escalators, not carrying heavy things, planning ahead, looking for places to sit, avoiding situations whereby pain would be intolerable and avoiding public transport) and seeking out health-related information. In one study, 28 participants described living with knee osteoarthritis as a balancing act recognising the health benefits from being physically active as well as beliefs about further joint deterioration and pain. Two studies 29 39 described a ‘tipping point’ whereby participants arrived at the point where they were giving up all their enjoyable activities with an extensive feeling of loss, and felt their best option was a knee replacement.

This systematic review provides insights into the experience of living with knee osteoarthritis as described by the seven emergent themes. While the experience of persistent pain and disability were the main features of everyday living with knee osteoarthritis, psychological and social factors such as emotional distress, loss of social contact and fear for the future were commonly expressed concerns of the participants. Other common views were the perceptions of knee osteoarthritis as an inevitable part of ageing, attributing their osteoarthritic knee to ‘wear and tear’ and finding ways to adjust their lives until they reach the ‘tipping point’ characterised by a perceived need for a knee replacement. A theme highlighted was unsatisfying relationships between people with knee osteoarthritis and healthcare professionals if there was limited information about the knee osteoarthritis and effective management options. Importantly, patient and health professional interactions were also perceived to provide a positive step towards effective management, particularly when health professionals listened to their patients, conveyed hope for the future and provided recommendations for managing knee osteoarthritis.

This review, comprising data from 21 studies involving 665 people with knee osteoarthritis and 28 carers, adds to the literature by highlighting the magnitude of the psychosocial impact of living with knee osteoarthritis that permeates all aspects of life. A previous systematic review of the experience of hip and knee osteoarthritis focussed on the functional impacts of osteoarthritis, as well as people’s lack of understanding and the stigma of their disease. 16 One small previous review of nine studies focussed on the lived experience of knee pain, but did not limit this to osteoarthritis. 17 While the assessment of the lived experience of a health condition should be disease-specific, 47 the finding by Wride that ‘knee pain affects every aspect of life, redefining what people are able to do, who they do it with and how they do it’ complements our findings among people with knee osteoarthritis.

The anxiety, depression and feeling of hopelessness that we identified in our review only recently received attention in published clinical practice guidelines. For example, clinical practice guidelines for management of knee and hip osteoarthritis 48 49 emphasise the importance of a holistic assessment to ascertain the impact of osteoarthritis on the whole person. This includes specific recommendations for a psychosocial evaluation to identify unique factors that may affect a person’s quality of life and participation in usual activities, and to embed patient-centred care principles in the management of patients with knee osteoarthritis. Patient-centred care encourages patient participation in decision-making and communication with patients about their management options. Hence, offering a psychological intervention such as cognitive behavioural therapy 13 may be important to improve the lived experience and self-management of osteoarthritis. Recent Australian clinical practice guidelines conditionally recommend offering cognitive behavioural interventions (eg, pain coping skills training) delivered by trained health professionals to people with knee osteoarthritis presenting with psychological impairments. 48 Combined with exercise, the guidelines suggest these interventions may improve pain, self-efficacy, pain coping, depression and anxiety. 48

Psychological and social factors such as emotional distress, concerns about disability and learning to live with pain have been identified among people living with other chronic musculoskeletal pain conditions. 50 51 Some of the experiences of living with knee osteoarthritis we identified, such as the perception among the participants in the included studies that their condition was an inevitable part of ageing, the perceived poor prognosis due to the ‘progressive degenerative disease’ and the pre-occupation with the existing damage to their joint and their perceived need for surgery have also been recognised in people with low back pain. 52 53 An explanation for the perception of ‘damage’ for people with knee osteoarthritis is likely to have been influenced by the results of imaging as well as the messages people receive from their health professionals. 54 This highlights the importance that health professionals not only focus on reducing joint-related pain and improving function, but to also include strategies to dispel patient misconceptions about knee osteoarthritis. 55 Strategies may include providing education that osteoarthritis is not a ‘wear and tear’ disease, that it does not necessarily worsen with ageing and that people can remain healthy and active with osteoarthritis. 33 56 One strategy could be to apply audit and feedback which has been used to change clinician behaviour in the management of other clinical groups. 57 Audit and feedback to health professionals could be applied to improve the education and language used to describe osteoarthritis, to overcome and dispel patient misconceptions as well as help patients participate in decisions about their management. 58 It may also be important that carers are invited to be involved in conversations and education sessions with health professionals. This approach could potentially dispel carer misconceptions about the causes of osteoarthritis and its management, may be empowering for family members 59 and may lead to improved patient adherence to treatment and better outcomes.

The overall findings highlight the importance of equipping patients and carers with information and self-management strategies to reduce the impact of knee osteoarthritis on their lives, beyond simply providing information about osteoarthritis. In particular to improve their psychosocial well-being, by reducing pain, maintaining function, increasing social and physical activity participation, helping patients to remain in employment and achieve optimal mental health. For example, one option to address patients’ harmful beliefs and attitudes towards pain and damage is to address the negative or mistaken language and beliefs about their knee through education. Emphasising facts such as ‘hurt does not equal harm’ and ‘exercise is safe’ 60 and dismissing myths such as ‘exercise is damaging’ 55 may be fundamental to alter people’s negative attitudes and may be best combined with interventions such as exercise programmes to potentially improve patients’ overall perception of their knee. Beliefs about a health condition are formed not only from personal experiences, but also from observing others and external sources of information such as the media. Thus, negative beliefs about knee osteoarthritis can predate the onset of the condition. 61 Therefore, there may be a role for public health campaigns to dispel myths about knee osteoarthritis across society more broadly.

The main limitation of this systematic review was the exclusion of studies exploring patients’ perceptions of interventions they received such as exercise or perioperative management for knee osteoarthritis. These were excluded because experiences in response to biological interventions would be expected to be different from the daily experience of living with knee osteoarthritis (the focus of this review), and should be the subject of further study. Only one study reported carer perceptions about living with knee osteoarthritis. Although the themes identified in this single study converged with six of the seven themes, further enquiry may be required to confirm their perceptions. Further, given the pattern of recurring themes we identified, it is unlikely that the inclusion of subsequent studies would have substantially added to the themes we described in this review. Finally, exclusion of non-English language articles limits the generalisability as other cultures with other languages might have different perceptions of knee osteoarthritis.

This review highlighted the value of taking patient attitudes and experiences into account, consistent with patient-centred care, when planning and implementing management options for people with knee osteoarthritis. These findings could inform clinical practice guidelines, to help clinicians better understand the lived experience of knee osteoarthritis, optimise the patient-clinician interaction and provide insights into how patient education may be conducted. These findings could also lead to new research questions to address patients lived experience with knee osteoarthritis and interventions to target modifiable psychological and social factors.

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Contributors JAW, NFT, SB, NS: contributed to the conception and design of the review, acquisition of data, analysis and interpretation of data, contributed to the writing of the paper by revising it critically for important intellectual content and read and approved the manuscript. Patients and public were not involved in this review.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

Read the full text or download the PDF:

The Role of Nutrition in Osteoarthritis: A Literature Review

Affiliations.

• 1 Department of Rheumatology, Dongfang Hospital, Beijing University of Chinese Medicine, No. 6 Fangxingyuan 1st Block, Fengtai District, Beijing 100078, China. Electronic address: [email protected].
• 2 Sydney Pharmacy School and the Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Centre for Health Systems and Safety Research, Australian Institute of Health Innovation, Macquarie University, Level 6 |75 Talavera Road, Sydney, NSW 2109, Australia.
• PMID: 35410682
• DOI: 10.1016/j.cger.2021.11.006

A literature review to identify nutritional factors and the prevention and management of knee or hip osteoarthritis (OA) suggests that nutritional interventions offer some health benefits in OA through mechanisms such as weight loss, reduced inflammation, and antioxidant capacity. However, because data are limited with mixed results, high-quality evidence, including longitudinal studies and clinical trials, are needed to understand whether nutritional supplementation effectively prevents or manages OA. Therefore, healthcare professionals should consider promoting diets rich in fiber, including whole grains, fruit, vegetables, nuts, seeds, and legumes or dietary patterns such as the Mediterranean diet, to their patients to manage OA.

Keywords: Antioxidant; Fatty acids; Fiber; Nutrition; Obesity; Osteoarthritis; Supplements; Vitamin D; Vitamin K.

Copyright © 2021 Elsevier Inc. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Diet, Mediterranean*
• Dietary Fiber
• Nutritional Status
• Osteoarthritis* / therapy

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• Published: 18 March 2024
• Osteoarthritis

Limitations of the updated EULAR recommendations for osteoarthritis

• Marius Henriksen   ORCID: orcid.org/0000-0003-1091-2962 1 , 2  

Nature Reviews Rheumatology ( 2024 ) Cite this article

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EULAR’s 2023 updated recommendations for the non-pharmacological treatment of hip and knee osteoarthritis reiterates and confirms, in an abbreviated form, what we have known for more than a decade. Unfortunately, the abbreviated format of the updated recommendations lacks specificity and clinical usefulness. More detailed guidance could have facilitated wider uptake and improved care.

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Acknowledgements

M.H. would like to thank A.S. Grønbech from The Parker Institute, Bispebjerg Frederiksberg Hospital, Copenhagen, Denmark, for valuable contributions to the creation of Fig.  1 . The work of M.H. is supported by a core grant from The Oak Foundation given to The Parker Institute (OCAY-18-774-OFIL), which had no role in the preparation, review or approval of the manuscript.

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• Systematic review update
• Open access
• Published: 19 March 2024

The effects of manual therapy in pain and safety of patients with knee osteoarthritis: a systematic review and meta-analysis

• Bowen Zhu 1   na1 ,
• He Ba 2   na1 ,
• Lingjun Kong 1 ,
• Yangyang Fu 3 ,
• Jun Ren 1 ,
• Qingguang Zhu 3 , 4 &
• Min Fang 1 , 4  

Systematic Reviews volume  13 , Article number:  91 ( 2024 ) Cite this article

Metrics details

Manual therapy (MT) is frequently used in combination with management of osteoarthritis of the knee, but there is no consensus on the exact efficacy of this treatment strategy. The purpose of this systematic review and meta-analysis was to evaluate the pain relief and safety of MT for treatment of knee osteoarthritis (KOA).

Randomized controlled trials evaluating MT in patients with KOA in major English and Chinese journals were searched in the following databases: Wanfang, China Science and Technology Journal Database (VIP database), China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and the Cochrane Library databases through June 2023. The methodological quality and quality of evidence of the included studies were assessed using Cochrane’s risk-of-bias 2 (ROB 2) tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Data analysis was performed using Stata version 15.0 software. After use of Galbraith plots to exclude studies that could lead to heterogeneity, random effects models were used to analyze the remaining data and test the consistency of the findings. We used meta-regression to assess the effect of treatment period, patient age, and sex ratio on outcomes. Funnel plots and Egger’s test were used to evaluate publication bias. Sensitivity analyses were used to determine the reliability of the results.

A total of 25 studies, with 2376 participants, were included in this review. The overall methodological quality of the included studies was limited. Our findings suggest that MT has a positive impact on pain relief outcomes in KOA patients. The meta-analysis showed that MT was superior to usual care ( SMD  = 2.04, 95% CI 0.94, 3.14, I 2  = 96.3%; low evidence quality) and exercise ( SMD  = 1.56, 95% CI 0.41, 2.71, I 2  = 96.3%; low evidence quality) for reducing pain. In terms of improvement in visual analogue scale (VAS) scores, MT treatment beyond 4 weeks ( SMD  = 1.56, 95% CI 0.41, 2.71, I 2  = 96.3%) may be superior to treatments less than or equal to 4 weeks ( SMD  = 1.24, 95% CI 0.56, 1.95, I 2  = 94.7%). No serious adverse events associated with MT were reported.

Conclusions

MT may be effective at reducing pain in patients with KOA and may be more effective after a 4-week treatment period. Compared with usual care and exercise therapy, MT may be superior at reducing KOA pain in the short term (9 weeks), but its long-term efficacy requires careful consideration of evidence-based outcomes. MT appears to be safe for KOA patients, though clinicians should inform patients of the potential risk of MT-related adverse events.

Peer Review reports

Knee osteoarthritis (KOA) is a chronic degenerative disease of the knee joint, and knee joint pain is the most common clinical manifestation [ 1 ]. The worldwide prevalence of radiographically confirmed symptomatic KOA is estimated to be 3.8%, and the prevalence of this disease has increased to more than 10% in people older than 60 years [ 2 ]. In China, the prevalence of KOA among older people is approximately 8.5% [ 3 ], and the incidence of KOA has increased significantly among younger people [ 4 ]. KOA has a serious impact on the health status of patients and overall quality of life and can even cause a serious economic burden on society [ 5 ]. Clinical guidelines recommend that relieving pain in the knee is a primary target of KOA treatment [ 6 , 7 ].

Manual therapy (MT), including massage therapy and manipulative therapy, is a widely used conservative treatment strategy [ 8 ]. MT may have a positive effect on reducing pain [ 9 , 10 ] and is reportedly used by approximately 15.4 million people in the USA for treatment of KOA, for example [ 11 ]. In some countries, MT is considered a first-line treatment option [ 12 ], whereas in others, it is recommended to be used as part of a broader treatment program that includes exercise; alternatively, MT is not recommended because of a lack of evidence [ 13 ]. Despite widespread use of MT, few studies have reported the efficacy of MT alone for treatment of KOA, with poor methodological quality [ 14 ]. Due to the lack of evidence, there is no consensus about recommending MT for KOA patients.

In recent years, several randomized controlled clinical trials (RCTs) have been conducted to assess the efficacy of manipulation in management of KOA, particularly in China. Indeed, Chinese massage therapy, including soft tissue manipulation and joint manipulation, has been used by practitioners for management of KOA, and trials have shown good results in terms of reducing pain [ 15 , 16 ]. Therefore, additional evidence-based evidence is needed to explore the analgesic efficacy of MT.

This study was conducted by performing a systematic review and meta-analysis to assess the benefits of MT alone in management of KOA, mainly in terms of improving pain and updating the effects of MT on patients with KOA, to provide empirical evidence and reference for clinical application of MT in treatment of KOA.

The protocol was registered after all phases of the review process were completed, and the manuscript was finished. This study was performed strictly by following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines [ 17 ]. The INPLASY registration number was INPLASY 202360030.

Literature search

We conducted a literature search of the following databases for articles published from inception to December 2021 with the language restricted to English or Chinese, with an updated search conducted in July 2023: Wanfang Database, China Science and Technology Journal Database (VIP database), China National Knowledge Infrastructure (CNKI), PubMed, Embase, Web of Science, and the Cochrane Library databases. All keywords were mapped to “indexed items” (e.g., MeSH) using a combination of the following in Embase.

#1'knee'/exp.

#2knee*:ti,ab,kw.

#3[< 1966–2023]/py.

#4 (#1 OR #2) AND #3

#5'arthritis'/exp OR 'osteoarthritis'/exp.

#6arthrit*:ti,ab,kw OR osteoarthr*:ti,ab,kw.

#7[< 1966–2023]/py.

#8 (#5 OR #6) AND #7

#9'massage'/exp OR 'musculoskeletal manipulation'/exp.

#10massage*:ti,ab,kw OR 'zone therap*':ti,ab,kw OR manipul*:ti,ab,kw.

#11[< 1966–2023]/py.

#12 (#9 OR #10) AND #11

#13'western ontario and mcmaster universities osteoarthritis index'/exp OR 'visual analog scale'/exp.

#14'western ontario and mcmaster universities osteoarthritis index*' OR womac.

#15'visual analog scale' OR vas.

#16 #13 OR #14 OR #15

#17'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 'controlled clinical trial'/exp OR 'randomization'/exp OR 'double blind procedure'/exp OR 'single blind procedure'/exp.

#18 (clinic* NEAR/2 trial*):ti,ab,kw.

#19random*:ti,ab,kw OR placebo*:ti,ab,kw OR blind*:ti,ab,kw OR mask*:ti,ab,kw.

#20 #17 OR (#18 AND #19)

#4 AND #8 AND #12 AND #16 AND #20

The detailed search strategy is shown as an example in Appendix 1 .

Study selection

Only RCTs that reported the method of randomization to MT alone for KOA were included. In the case of a three-arm or multiarm RCT, articles were included if two of the groups met the inclusion criteria [ 18 ]. All patients with KOA were included, regardless of age, race, sex, age limit, or severity. If a study did not report information on the randomization method, ethics approval, or clinical study registration, it was excluded. Case reports, empirical reports, and laboratory studies were not included.

Eligibility criteria

Patients included in the study had a clear diagnosis of KOA and met other diagnostic criteria, such as the American College of Rheumatology criteria or the Chinese Medical Association Orthopaedic Branch Guidelines for the Treatment of Osteoarthritis (2018), with no restrictions on the severity of the disease. Interventions in the experimental group involved only MT, and those in the control group involved any therapy other than MT (such as acupuncture treatment, medication, exercise, and usual care). In addition, if the observed differences were thought to be due to the unique contribution of MT, we included studies that may encompass research in which MT was provided as part of a package of care, that is, if the effects of MT could be isolated. For example, studies comparing MT plus usual care with usual care alone were included, whereas investigations comparing MT plus usual care with MT alone were not. We also excluded studies in which MT was combined with other therapies because it was difficult to distinguish the effect of MT.

Outcome analyses

The effect of MT in combination with any other therapeutic adjuncts (including usual care, herbal application, oral analgesics, exercise, acupuncture) was examined. The primary outcome was the VAS pain assessment scale [ 19 ]. Secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale [ 20 ], follow-up data, and adverse events.

Data extraction

Two authors (B. Z. and H. B.) independently collected the data, including the following: number of subjects, sex, age, body mass index (BMI), duration of disease, country, MT intervention period, diagnostic criteria for KOA, Kellgren–Lawrence grade, VAS score, WOMAC pain score, follow-up duration, and incidence of adverse events. In the meta-analysis, VAS and/or WOMAC pain scores were extracted. In the absence of sufficient data, the corresponding authors were contacted for additional data.

Risk-of-bias assessment

Risk of bias in RCTs was assessed according to the revised Cochrane risk of bias in randomized trials tool (RoB2) [ 21 ]. All risk-of-bias assessments were conducted in duplicate by 2 reviewers (L. K. and R. J.). Disagreements were resolved by recruiting a third author (Y. F.) to reach a consensus.

Quality of the evidence: Cochrane GRADE assessment

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology [ 22 ] is a system for grading the quality of evidence for health recommendations and assessing the quality of evidence [ 23 ]. The quality of the evidence is rated from “very low” to “high”: (a) high (the true effect is considered close to the estimated effect), (b) moderate (confidence in the estimated effect is moderate), (c) low (confidence in the effect is limited), and (d) very low (confidence in the effect is very limited, and there is a high degree of uncertainty about the outcome) [ 24 ]. Scores were reviewed by the senior author (L. K.).

Data synthesis and analysis

All the search results were imported into NoteExpress v3.5.0.9054 for management. Two reviewers independently screened all potentially eligible studies. Titles and abstracts were screened first to exclude irrelevant citations. The full texts of all articles with potentially relevant abstracts were retrieved and screened according to the study eligibility criteria. Disagreements were resolved by consensus or discussion with a third reviewer.

The primary endpoint of this meta-analysis was the difference in VAS score between patients receiving MT and those receiving other therapies. Adverse events are summarized narratively. All pain scales were converted to a 10-point scale. The secondary endpoint was the difference in WOMAC pain scores (0–20) between these two groups of patients. The negative effect size of the VAS score or WOMAC score indicates that MT was more beneficial than other therapies, indicating that the participants had less pain. Primary and secondary outcomes were collected, and the data were analyzed after randomization and at the end of treatment. Minimum clinically important difference (MCID) thresholds for the VAS and WOMAC scores were defined as a 20% fluctuation from the baseline of the included studies based on previous studies and were calculated as follows: 1.18/10 for the VAS for pain and 2.12/20 for the WOMAC pain score [ 25 ].

We extracted final value scores (means and standard deviations) for the meta-analysis and converted change scores into mean values [ 26 , 27 ]. Heterogeneity among the included studies was assessed using the Q -test and is presented as I 2 and P -values. An I 2  > 50% and/or a P -value < 0.1 indicated significant heterogeneity among the studies. If the heterogeneity test showed significant heterogeneity, a random effects model was used; otherwise, a fixed effects model was applied [ 28 ]. To explore the source of heterogeneity, we conducted subgroup analysis of VAS scores based on differences in treatment methods. The subgroup analysis of VAS scores was based on the course of treatment (set cut-off value of 4 weeks); although we considered the effect of the course of MT because it was not included in our previously designed protocol, we included this comparison because it represents a point for continuing discussion. We also used the Galbraith plot to explore studies that may have contributed to the heterogeneity and excluded them.

Then, we used a random effects model to analyze the remaining data, and we observed that the results were consistent with those obtained previously [ 29 ]. Meta-regression was used to evaluate the effect of the treatment period and sex ratio on the results, and the threshold for statistical significance was set at P  < 0.05. We used a funnel plot and Egger’s test to evaluate publication bias ( P  < 0.1 was considered to indicate significant publication bias among the enrolled studies). To assess the reliability of the findings in this study, sensitivity analyses were also conducted. All analyses were carried out with Stata version 15.0 (Stata Corporation, College Station, TX, USA).

There were no public or patient representatives directly involved in the drafting or process of this review.

Search and selection

The literature search identified 6990 records, and a total of 3184 potential studies were identified after removing duplicates. After screening the titles and abstracts, 3072 studies were excluded, and the remaining 119 full texts were screened for inclusion. After the detailed full-text screening, 39 studies were included in the qualitative synthesis. Finally, 25 RCTs were included in the current review [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. The detailed process of the search and selection is shown in Fig.  1 .

Selection of studies through review

Risk-of-bias assessment of pain outcomes

Three of the 25 included studies were considered to have a moderate risk of bias [ 22 , 30 , 44 ]; the remaining 22 studies all showed a high risk of bias. The randomization process revealed some concern, with a high risk of bias. The common areas of bias were selection bias (allocation concealment) and performance bias (blinding of participants and/or healthcare providers). All the included studies failed to meet at least one of the two criteria. The detailed risk-of-bias assessment of pain outcomes is shown in Fig.  2 and Appendix 2 .

Results of the risk-of-bias assessment using RoB2

Effects of interventions

The treatment effects, quality of the evidence, and GRADE summary of VAS scores for all comparisons among the included trials are summarized in Table  1 . The GRADE approach to evidence synthesis and operationalization of criteria items are shown in Appendix 3 .

MT compared with other therapies in VAS score of KOA patients

The included studies and population.

Twenty trials (25 cohorts) published between 2013 and 2023 included 2376 patients (mean age was 61.38 years) and reported changes in the VAS scores of KOA patients who received MT or other therapies. Eleven trials [ 31 , 32 , 36 , 38 , 44 , 45 , 49 , 50 , 51 , 52 , 53 ] reported the severity of the disease in patients using the Kellgren-Lawrence criteria, and the remaining studies included patients with severity levels of III or less, except for two trials [ 31 , 38 ] that were graded IV. Five trials were published in English and 15 in Chinese. A detailed description of the characteristics of the studies is available upon request from the primary author. The sample sizes of the studies ranged from 40 to 448. The detailed characteristics of each included study are listed in Table  2 .

Patients treated with MT had a significantly greater VAS score than did those who received other therapies (standardized mean difference (SMD) 0.68, 95% CI : 0.31 to 1.06), with a significantly greater effect size ( Z  = 3.56, P  < 0.01); however, the effect was considered small. Significant heterogeneity was found among the enrolled studies ( I 2  = 94.4%, P  = 0.000) (Fig.  3 ).

Forest plot comparing the VAS score reductions of KOA patients who received MT and other treatments

Compared with other therapies

The results of subgroup analysis based on the type of intervention showed that compared with those in the usual care group, improvements in the VAS score were more significant in the MT group ( P  = 0.000). Moreover, improvements in the VAS score in the MT group were significant ( P  = 0.008). However, compared with that in the herbal application, oral analgesic, acupuncture, and intra-articular injection groups, the VAS score in the MT group showed no significant improvement ( P  > 0.05) at the end of intervention (Fig.  4 ).

Subgroup analysis of VAS score outcomes based on the type of intervention in the control group

Compared with other interventions, MT treatments of more than 4 weeks ( P  = 0.000) may be superior to treatments of less than or equal to 4 weeks ( P  = 0.136) in terms of improvement in VAS score (Fig.  5 ).

Subgroup analysis of VAS score outcomes based on course of treatment

Secondary outcome

The effect of mt compared with other therapies on the womac pain score in koa patients.

Eight trials (9 cohorts) that included 877 patients reported changes in the WOMAC pain scores of KOA patients who received MT or other therapies. As shown in Fig.  6 , compared with patients who received other therapies, patients treated with MT did not show significant changes in WOMAC pain scores (standardized mean difference (SMD) 0.27, 95% CI : − 0.07 to 0.61), with a small effect size ( Z  = 1.561, P  = 0.119). Significant heterogeneity was found among the studies ( I 2  = 83.5%, P  = 0.000). MT failed to improve the WOMAC pain score of KOA patients compared with that of patients receiving other therapies.

Forest plot comparing the WOMAC pain score reductions of KOA patients who received MT and other treatments

Follow-up and treatment cycle

The included studies ranged from 1.5 to 9 weeks of treatment for MT. Eight studies [ 30 , 32 , 34 , 37 , 39 , 40 , 41 , 54 ] reported follow-up results, with a minimum follow-up of 1 month and a maximum follow-up of 1 year, as shown in Table  3 . In terms of pain relief, 6 [ 30 , 32 , 37 , 39 , 40 , 41 ] of these follow-ups found moderate to satisfactory long-term effects of MT in the treatment of KOA, 1 [ 34 ] study showed only short-term benefits for MT, and 1 [ 54 ] study did not report follow-up statistics.

Adverse reactions

Fourteen studies reported adverse events [ 30 , 31 , 32 , 34 , 37 , 38 , 40 , 41 , 44 , 49 , 50 , 51 , 52 , 53 ]. Muscle soreness was the most common side effect of MT after treatment. Mild aggravation of pain occurred in one patient [ 44 ]. In most studies, adverse events were not reported.

Galbraith plot for analysis of heterogeneity across studies

Galbraith plots are an alternative to the forest plots proposed by Galbraith for visualizing the results of studies and meta-analyses, and Galbraith plots also aid in detecting sources of heterogeneity [ 55 , 56 ]. Two lines are drawn at a vertical distance of ± 2 above and below the regression line, and these two lines together with the regression line constitute an interval. According to the relevant literature, studies that were published completely outside this interval may be responsible for the observed heterogeneity [ 33 ]. Therefore, we excluded all 15 studies outside the interval and performed a secondary analysis on the remaining 10 studies (Fig.  7 ). As shown in Fig.  8 , the secondary analysis reached the same conclusion as before: compared with other treatments, MT was more effective at improving the VAS score of KOA patients (standardized mean difference (SMD) = 0.23, 95% CI  = 0.009 to 0.36, Z  = 3.233, P  = 0.001). Moreover, the heterogeneity between studies was reduced ( I 2  = 44.7%, P  = 0.061).

Using Galbraith plot to infer studies that might be the source of heterogeneity

Comparing the VAS score reductions of KOA patients who received MT and other treatments with the remaining studies

Publication bias and sensitivity analysis

In this meta-analysis, we assessed publication bias using funnel plots and Egger’s test [ 57 ], and our results indicated no significant publication bias ( P egger  = 0.442) in the included studies (Appendix 4 ). We examined the effect of classifying MT with other therapies in sensitivity analysis, which did not affect our results. Sensitivity analysis indicated that the results were stable (Appendix 5 ).

Meta-regression

As differences in the treatment period, patient age, and sex ratio may have affected the analysis results, we performed meta-regression to evaluate whether the above factors had a significant impact on the results. Overall, the treatment duration, mean age of patients, and sex ratio did not significantly affect the results (Appendix 6 ).

This study constitutes an update of a comprehensive systematic review to assess the efficacy of MT in conservative management of patients with KOA for pain relief, with more stringent inclusion criteria to ensure the quality of the source RCTs. Considerable effort was made to conduct an extensive literature search. Twenty of the 25 studies were conducted in China, 3 in the USA, and 1 each in New Zealand and Thailand. Most of the included studies used MT.

This study integrated evidence from existing clinical RCTs of MT for KOA pain and identified proposed research targets that remain to be addressed. Our findings on VAS score improvement in patients with KOA were statistically significant but may not be clinically meaningful when compared to those for patients receiving other therapies in addition to usual care and exercise. Although no significant differences in WOMAC pain scores were found for the secondary outcomes, MT appears to have the potential and is undeniably effective at reducing pain in KOA patients. In this meta-analysis, we used the MCID as a threshold to assess the clinical significance of the difference between the MT group and the control group rather than relying solely on statistical significance. There are anchor-based and distribution-based methods for calculating the MCID, and based on previous studies, we set the threshold at 20% using the anchor-based method [ 58 , 59 , 60 ]. According to our subgroup analyses, the effect of MT on the VAS score at the end of the intervention exceeded the effect of the MCID in both the usual care and exercise groups but not in other control groups. These findings suggest that MT may have better clinical applicability in the short term than usual care and exercise. The findings, including the Chinese database search, support previous meta-analyses in the literature [ 61 ]. Although guidelines [ 62 ] report that exercise treatment might be more effective than MT at reducing pain intensity at short-term follow-up, our meta-analysis showed that MT was no less effective than exercise interventions for pain relief in patients with KOA and was superior to usual care. Nevertheless, because most of the studies included in this systematic review were carried out in China, the results may be influenced to some extent by the limitations of factors such as geographic location and cultural group, and additional dimensions of data should be added in the future to assess the stability of the findings.

In terms of outcome indicators, MT did not significantly differ with regard to WOMAC pain score, indicating that MT has limitations in relieving pain and does not cover the full range of patients’ daily lives, especially for those in pain situations such as walking, moving up and downstairs, sleeping, standing, sitting, and lying down. However, the VAS for global pain had a slightly greater assay sensitivity at the trial and meta-analysis levels than the WOMAC pain subscale [ 63 ]. In contrast to comprehensive assessment of the efficacy of the VAS, the WOMAC pain score consists of five questions, and the results are inherently multidimensional; e.g., the pain relief effect of MT might be limited in some specific activities, resulting in biased scores, but this needs to be validated by additional studies [ 64 ]. Furthermore, RCTs of MT for KOA treatment are still rare because of the lack of research on long-term treatment in particular, and additional RCTs on the effects of MT for KOA treatment are needed, as are studies integrating MT with biomechanics.

MT appears to be safe for individuals with KOA. In our review, 56% of the included studies reported safety information, with few adverse events described and no serious adverse events shown. A meta-analysis of adverse events of MT in RCTs found that most of the observed adverse events were musculoskeletal related, transient in nature, or mild to moderate in severity [ 65 ]. Our review also supports this conclusion by revealing that muscle discomfort and pain caused by MT were the most common adverse events. However, most existing meta-analyses on MT in KOA patients do not include safety/adverse effects because poor reporting of safety information in MT clinical trials is common in other populations. We strongly suggest that future investigators monitor and report safety/adverse events of MT in clinical trials for KOA, as recommended by CONSORT.

We could better explain the effects if more attention was given to the qualitative components of the intervention, such as the context of the visit, patient beliefs, and preferences. Although we focused on the impact of MT on the level of pain in KOA patients in this review, the economic costs associated with care and psychophysiological mechanisms should also be considered. In particular, this approach has the following advantages: changes in parasympathetic activity (as measured by heart rate, blood pressure, and heart rate variability) and hormonal levels (as measured by cortisol levels) following MT result in a relaxation response (physiological mechanisms); a reduction in anxiety and an improvement in mood state after MT cause relaxation (psychological mechanisms) [ 66 ]. The treatment cycle of MT is typically 1.5 to 9 weeks, and follow-up results show that MT is more effective for pain relief in the short term and appears to have improved efficacy in the long term, which may be maintained for up to 1 year; however, the outcome may not be completely stable or reliable. One study [ 34 ] indicated that MT results were unsatisfactory at follow-up to 1 year. This may also be limited by the short treatment period of MT, and the effectiveness and long-term efficacy of interventions with long MT sessions may be worth exploring. Furthermore, the most recent systematic review [ 67 ] on the cost-effectiveness of noninvasive and nonpharmacologic interventions for KOA concluded that studies of other economic assessments of MT for KOA are rare. For example, with other conservative treatment options, assessing whether a long course of MT treatment (> 4 weeks) provides the best economic benefit, and therefore, whether MT is a cost-effective option for treating KOA remains to be determined.

Limitations

First, because of the different settings and populations (age, occupation, and socioeconomic status) in the studies and use of different recruitment methods and MT techniques, we could not perfectly address the issues related to statistical heterogeneity. Although we implemented subgroup analyses of different techniques (results not shown) and validated the results using Galbraith plots, such results will be difficult to address in future reviews. Second, some studies were excluded, even though WOMAC pain scores were collected. These studies did not report methods for evaluating WOMAC pain or matching our inclusion criteria, which made it difficult to integrate the WOMAC pain data. Finally, most studies ignore classifying the severity of KOA unreported in the Kellgren–Lawrence grading system. Hence, the inconsistency of the severity of the disease limits the number of studies, and we were unable to conduct subgroup analysis according to the severity of the disease to explore its effect in more depth.

Implications

The findings suggest that MT as a stand-alone treatment may not produce satisfactory meaningful pain relief, especially in some elderly KOA patients who present with pain only in certain circumstances. The method of adverse event assessment was unclear. In general, MT may result in a temporary mild increase in muscle soreness but is essentially safe. Therefore, if a patient chooses nonsurgical conservative treatment, clinicians treating KOA patients may safely prioritize MT in anticipation of a possible short-term improvement in pain.

MT is potentially effective at reducing pain in KOA patients, and long-term treatment periods may be more effective. While there may be limitations to the effectiveness of MT, it may be more advantageous than usual care and exercise therapy, but the results need to be referenced with caution. MT seems to be safe in patients with KOA, but better monitoring and reporting of security information are strongly recommended. Overall, there is a lack of large samples of randomized controlled trials and active research evaluating the economic benefits of MT. More high-quality studies are needed in the future to determine the beneficial effects of MT on pain in patients with KOA.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article.

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Acknowledgements

We would like to thank Guangxin Guo from the Shanghai University of Traditional Chinese Medicine for their contributions and constructive comments in developing the prephase literature search and study selection used in this review.

This study was supported by the National Natural Science Foundation of China (No. 81973973), the Clinical Research Plan of SHDC (SHDC2020CR4055), the Support Program for Chinese Medicine Innovation Teams and Talents of the State Administration of Traditional Chinese Medicine (ZYYCXTD-C-202008), the Construction of Research-oriented Wards of SHDC (SHDC2022CRW010), and the Three-Year Action Plan to Promote Clinical Skills and Innovation Capabilities of SHDC (SHDC2022CRT018).

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Bowen Zhu and He Ba contributed equally to this work.

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Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Bowen Zhu, Lingjun Kong, Jun Ren & Min Fang

Department of Integrative Oncology, Shanghai Cancer Center, Qingdao Institute, Fudan University, Qingdao, China

Department of Traditional Chinese Massage, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Yangyang Fu & Qingguang Zhu

Institute of Traditional Chinese Medicine and Massage, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China

Qingguang Zhu & Min Fang

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The conception and design of this study were performed by MF and BZ. HB and BZ collected the data. Risks-of-bias assessments were conducted by LK and RJ. QZ and LK screened all potentially eligible studies. Data acquisition, analysis, and interpretation were performed by HB and BZ. The manuscript was drafted by HB and BZ. MF supervised this study and critically revised the manuscript for intellectual content. QZ and YF were responsible for the integrity of the entire work.

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Correspondence to Qingguang Zhu or Min Fang .

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Additional file 1:.

  Appendix 1. Search terms and strategies.  Appendix 2. Detailed risk of bias judgment by domains for Stress (Rob2 Tool): at the end of the intervention.  Appendix 3. The GRADE approach to evidence synthesis and operationalization of criteria items.  Appendix 4. Funnel plot for VAS score.  Appendix 5. Sensitivity analysis for VAS score.  Appendix 6. Meta-regression (Table S1–5).

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Zhu, B., Ba, H., Kong, L. et al. The effects of manual therapy in pain and safety of patients with knee osteoarthritis: a systematic review and meta-analysis. Syst Rev 13 , 91 (2024). https://doi.org/10.1186/s13643-024-02467-7

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DOI : https://doi.org/10.1186/s13643-024-02467-7

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Systematic Reviews

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MARK H. EBELL, MD, MS

Am Fam Physician. 2018;97(8):523-526

Patient information: A handout on this topic is available at https://familydoctor.org/condition/osteoarthritis .

Osteoarthritis (OA) should be suspected in patients with pain in the fingers, shoulders, hips, knees, or ankles, especially if they are older than 40 years. Patients older than 50 years who have joint pain, minimal morning stiffness, and functional impairment likely have OA. Radiography can confirm the diagnosis and may be helpful before surgical referral, but findings generally do not correlate well with symptoms. Exercise, physical therapy, knee taping, and tai chi are beneficial for knee OA. Medical therapy provides modest benefits in pain reduction and functional improvement; however, nonsteroidal anti-inflammatory drugs, tramadol, and other opioids have significant potential harms. Joint replacement may be considered for patients with moderate to severe pain and radiographically confirmed OA. Corticosteroid injections may be helpful in the short term. Vitamin D supplements, shoes specifically designed for persons with OA, antioxidant supplements, physical therapy for hip OA, ionized wrist bracelets, lateral wedge insoles for medial knee OA, and hyaluronic acid injections are not effective.

Osteoarthritis (OA) is a condition commonly encountered in primary care. This article provides a brief summary and review of the best available patient-oriented evidence for OA.

Epidemiology

The prevalence of OA by age is shown in Table 1 . 1 Risk factors include:

Older age (especially older than 50 years)

Overweight or obesity

Previous joint injury

Job that requires bending or squatting

Family history

Participation in sports associated with repetitive impact (e.g., soccer, American football). 2

OA should be suspected in patients with pain in the fingers, shoulders, hips, knees, or ankles, especially if they are older than 40 years. 2 , 3

Alternative diagnoses should be considered in patients with inflammation, erythema, or pain that increases or changes significantly.

The differential diagnosis includes collagen vascular disease, gout and pseudogout, trauma, septic arthritis, ankylosing spondylitis, and psoriatic arthritis.

SIGNS AND SYMPTOMS

Signs and symptoms that are common in OA include:

Pain that is typically worse later in the day and relieved by rest.

Joint swelling and tenderness, with or without crepitus.

Bony enlargement in prolonged or severe OA.

Joint pain, minimal morning stiffness, and functional impairment in patients older than 50 years. 2 , 3 The presence of these findings is moderately helpful in ruling in OA, but their absence does not rule it out 3 ( Table 2 4 ) .

Older age, obesity, difficulty walking down stairs, and clinical findings of decreased range of motion, effusion, and crepitus in patients with knee pain. 5

DIAGNOSTIC TESTING

Radiography is not required to diagnose OA in patients with risk factors and typical symptoms. 3

Radiographic findings in patients with OA do not always correlate well with symptoms. Two studies found that only 16% of patients with frequent hip pain had radiographic evidence of OA; conversely, only 21% of patients who met the radiographic criteria for hip OA had frequent pain. 6

Typical radiographic findings in patients with OA include joint space narrowing, osteophytes, and subchondral sclerosis.

Radiography can be helpful before referral for joint replacement, as radiographic severity is an important factor in determining whether surgery is appropriate.

Magnetic resonance imaging detects joint abnormalities in about 90% of both obese and nonobese adults older than 50 years who do not have joint pain. 7

Figure 1 presents a suggested approach to the treatment of OA. Several therapies are supported by good-quality evidence. However, some widely used treatments (e.g., hyaluronic acid injections, arthroscopic surgery) are not effective and should be abandoned.

EXERCISE, DIET, AND PHYSICAL THERAPY

Aquatic exercise has small short-term benefits for OA. 8

Vitamin D supplements, antioxidant supplements, shoes specifically designed for persons with OA, and ionized wrist bracelets are ineffective for OA. 9 – 13

Exercise, tai chi, knee taping, and physical therapy are beneficial for knee OA and can be recommended based on patient preference and acceptability. 14 – 18

Lateral wedge insoles are ineffective for medial knee OA. 19

Knee bracing has insufficient evidence to draw conclusions about its effectiveness. 20

Physical therapy was not beneficial for hip OA in a well-designed trial. 21

Weight loss has been recommended for patients with knee and hip OA 22 ; however, a systematic review found only low-quality evidence that bariatric surgery reduces pain and improves function in morbidly obese persons with knee pain. 23

Ginger consumption significantly reduced pain and disability in five studies (N = 593) included in a systematic review. 24 However, patients were more likely to stop taking it, and the overall quality of studies was moderate. Similarly, avocado unsaponifiables may be effective at dosages of 300 to 600 mg per day. Both of these interventions, although likely safe, are limited by the small number and methodologic flaws of studies. 25

MEDICAL THERAPY

Acetaminophen is less effective than nonsteroidal anti-inflammatory drugs (NSAIDs) for OA, but given its safety, a trial at an adequate dosage is appropriate. 26 , 27

Of the NSAIDs currently available in the United States, diclofenac, 150 mg per day, is most likely to be effective for OA, followed by naproxen, according to a systematic review. 26 A Cochrane review concluded that topical diclofenac and ketoprofen are moderately effective. 28

Topical capsaicin appeared to be somewhat effective in several small trials, although it is associated with a transient burning sensation. 29 – 32

Tramadol is moderately effective for OA, according to a systematic review of 11 randomized trials (N = 1,019), and has a number needed to treat (NNT) of 6 for one person to report at least moderate improvement. 33 Conversely, the number needed to harm (NNH) for one person to stop taking tramadol because of adverse effects is 8.

Duloxetine (Cymbalta) is a serotonin–norepinephrine reuptake inhibitor approved for treatment of painful conditions. Its NNT is 7 for clinically significant pain reduction in OA. 34 , 35 The most common adverse effect is mild to moderate nausea (23% vs. 7% for placebo; NNH = 6). 36

Because tramadol and duloxetine have harms and adverse effects similar in magnitude to their potential benefits, they should be used only in select patients.

Propoxyphene (not available in the United States) plus acetaminophen is no better than acetaminophen alone, has more adverse effects, and should be avoided. 37

Oral and transdermal opioids (not including tramadol) have only modest benefits that are of questionable clinical significance, according to a Cochrane review. 38 These medications also have significant adverse effects, and long-term use is discouraged. Patients taking opioids should be closely monitored, and the dose should be kept as low as possible. Daily dosages of more than 50 mg of hydrocodone or 30 mg of oxycodone are discouraged. 39

In general, it is reasonable to begin treatment with full-dose acetaminophen and/or topical therapy and progress to an NSAID such as naproxen or diclofenac, then, if necessary, to tramadol or duloxetine.

SURGICAL THERAPY

Joint replacement is an option for patients with moderate to severe pain and radiographically confirmed OA. 40 A randomized trial found that patients with moderate radiographically confirmed knee OA had significantly improved pain and function after joint replacement compared with those receiving usual care, although serious adverse effects can occur, including deep venous thrombosis, infection, and the need for further surgery or mobilization under anesthesia. 41 Obese and nonobese patients have similar outcomes after knee replacement. 42 – 44

Arthroscopic meniscectomy with or without debridement is no more effective than sham procedures or exercise for knee OA, according to a systematic review of nine studies (N = 1,279). 45 It is also ineffective for patients with degenerative meniscal tears. 46

Corticosteroid injections improve function and provide short-term pain relief, but do not improve overall quality of life, according to systematic reviews. 47 , 48 A recent large randomized trial found no benefit and greater cartilage loss in patients receiving corticosteroid injections. 49

Hyaluronic acid injections are not effective for OA, according to a review of the highest-quality studies and unpublished research. 50 – 52

Dextrose prolotherapy injections showed a modest benefit for knee OA in two small randomized trials, but the evidence base is limited, and the technique may be operator-dependent and not easily reproduced. 53 , 54

Platelet-rich plasma or bone marrow aspirate concentrate injections are not effective for OA. 55 , 56

COMPLEMENTARY THERAPY

The following complementary therapies have been studied for the treatment of OA:

Acupuncture is at best minimally effective for OA of the knee or hip. 57 – 59

Oral glucosamine with or without chondroitin does not appear to be effective in well-designed trials. 60 – 62

S -adenylmethionine and methylsulfonylmethane have uncertain effectiveness based on systematic reviews. 63 , 64 Observed benefits were small in magnitude and probably not clinically significant.

Symptoms of OA tend to progress over time, although they may temporarily improve in the short term.

Editor's Note: Rapid Evidence Review is a new article format that was created with the goal of providing key clinical information that can be read quickly and that answers questions at the point of care. These articles are unique in that the references are only available online and the SORT table recommendations are linked to the corresponding areas of the text in the online version of the article. Please let us know what you think of the new format by commenting online or e-mailing us at [email protected] .

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• v.10(2); 2021 Dec

Management of Osteoarthritis: Expert Opinion on NSAIDs

Alberto magni.

1 Italian College of General Practitioners and Primary Care, Via Del Sansovino 179, Florence, Italy

Piergiuseppe Agostoni

2 Centro Cardiologico Monzino, IRCCS, Via Carlo Parea, 4, Milan, Italy

3 Dipartimento di scienze cliniche e di comunità, Università degli Studi di Milano, Via Carlo Parea 4, Milan, Italy

Cesare Bonezzi

4 Unità di Terapia del dolore, Istituti Clinici Scientifici Maugeri, Via Salvatore Maugeri 10, Pavia, Italy

Giuseppe Massazza

5 Division of Physical Medicine and Rehabilitation, Department of Surgical Sciences, University of Turin, Via Zuretti 29, Turin, Italy

6 “Città della Salute e della Scienza” University Hospital, Corso Bramante, 88, Turin, Italy

Paolo Menè

7 Division of Nephrology and Dialysis, Sant’Andrea University Hospital, “Sapienza” University of Rome, Via di Grottarossa, 1035/1039, Rome, Italy

Vincenzo Savarino

8 Department of Internal Medicine, University of Genoa, Viale Benedetto XV, 6, Genoa, Italy

Diego Fornasari

9 Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Vanvitelli, 32, 20133 Milan, Italy

Associated Data

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Osteoarthritis (OA) is a leading cause of disability among older adults worldwide. Treatment aims are to alleviate inflammatory pain and improve physical function through non-pharmacological and pharmacological interventions. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line therapy. However, selection is challenged by patient age, comorbidities and polypharmacy, and by the drug’s benefit/risk balance, all of which together influence the risk of cardiovascular (CV), gastrointestinal (GI) and renal adverse events (AEs). While the efficacy profile of the various NSAIDs is delineated, the differences in their safety profile are not straightforward. This narrative review provides practical indications by a multidisciplinary Italian expert panel for general practitioners and specialists managing OA patients with chronic inflammatory pain; the goal is to maximize therapy efficacy while reducing untoward effects caused by inappropriate NSAID use. The discussion on the best approach to NSAIDs spanned the following topics: (1) patient evaluation: investigate pain origin, duration and components together with possible risk factors for CV, GI and renal AEs; (2) non-pharmacological interventions: the physiatrist provides a person-centered, holistic approach accounting for all patient aspects; (3) pharmacological interventions: patient profile and drugs’ pharmacological properties affect NSAID selection, which drugs to be used in combination or to be avoided, formulation and therapy duration; (4) the pharmacologist’s, general practitioner’s and pain therapist’s points of view; (5) NSAID safety: the individual baseline risk and the drug’s safety profile are major determinants of CV, GI and renal risk; consider possible drug–drug interactions; (6) periodical re-evaluation of treatment response and adherence, using scales to assess pain and function.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40122-021-00260-1.

Key Summary Points

Digital features.

This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to 10.6084/m9.figshare.14308292.

Introduction

Osteoarthritis (OA) is the most frequent form of arthritis worldwide and a leading cause of disability among older adults [ 1 ]. In Italy, its prevalence is 24.9% in women and 16% in men and is highest in persons aged > 85 years (63.0% in women and 50.9% in men) [ 2 , 3 ]. After hypertension, it is the second most common chronic disease managed by general practitioners (GPs) [ 2 ].

The main risk factors for OA are age, gender, obesity and adverse mechanical factors [ 4 ]. Knees, hips and hands are the most commonly affected appendicular joints, and patients often suffer from pain, stiffness, swelling and loss of normal joint function, with a negative impact on their quality of life and a relevant socioeconomic burden.

The goal of treatment in OA is to reduce pain intensity and improve function and quality of life through a combination of non-pharmacological and pharmacological interventions [ 5 , 6 ]. As first-line therapy, guidelines [ 4 – 8 ] recommend the non-steroidal anti-inflammatory drugs (NSAIDs), a chemically heterogeneous group of agents that inhibit the production of prostaglandins (PG) and thromboxane A through the blockade of cyclooxygenase (COX). Traditional NSAIDs (tNSAIDs), which target the COX-1 and COX-2 isozymes to varying degrees, have a consolidated role in the symptomatic treatment of pain in musculoskeletal disorders [ 9 – 11 ], but their long-term use is limited by toxicity, mainly cardiovascular (CV), gastrointestinal (GI) and renal toxicities. Although COX-2-selective NSAIDs (coxibs) were initially introduced as a safer alternative to tNSAIDs, their use has been associated to a high risk of CV events [ 12 ].

The frequent, inappropriate use of over-the-counter NSAIDs is a matter of concern as it rises the risk of untoward events [ 13 – 15 ]. According to a recent Italian long-term active pharmacovigilance study, NSAIDs are responsible for 8.4% of the emergency department visits and 24.4% of emergency department visits resulting in hospitalizations [ 16 ].

In practice, both drugs’ and patients’ characteristics influence the choice of therapy. The efficacy profile of NSAIDs has been delineated by meta-analyses of randomized controlled trials (RCTs) [ 17 – 23 ]. Among these, the network meta-analysis by da Costa and colleagues, comparing the effectiveness of various NSAIDs, paracetamol and placebo on pain and physical function improvement, included the highest number of preparations and doses and provided also information on the dose–response relation [ 21 ]. It included 74 RCTs, for a total of 58,556 OA patients. Overall, there was not enough statistical evidence to support the superiority of diclofenac 70 mg/day, naproxen 750 mg/day and ibuprofen 1200 mg/day over placebo for pain and physical function improvement. In contrast, for pain reduction, diclofenac 150 mg/day and etoricoxib given at 30 mg/day, 60 mg/day and 90 mg/day had a probability of reaching the minimum clinically important difference compared to placebo of ≥ 95%, reaching 100% only in the case of diclofenac 150 mg/day and etoricoxib 60 mg/day. Notably, a significant linear dose–effect response was found only for celecoxib ( P  = 0.030), diclofenac ( P  = 0.031) and naproxen ( P  = 0.026). As for the physical function improvement, a minimum clinically important treatment effect was observed solely for diclofenac 150 mg/day. The authors concluded that diclofenac at 150 mg/day is the best NSAID in terms of both pain and function amelioration in OA, superior to the maximum doses of frequently used NSAIDs, including ibuprofen, naproxen and celecoxib. Albeit etoricoxib at the maximum dose of 60 mg/day was as effective as diclofenac 150 mg/day for the treatment of pain, its effect estimates on physical disability remain unclear. Finally, paracetamol had no clinical effect and should not be recommended for the symptomatic treatment of OA. This study demonstrates that the same NSAID at different doses has different effects and provides important information on the minimal effective dosages of a number of compounds [ 21 ].

While the efficacy profile of the various NSAIDs is clear, the differences in their safety profile are not straightforward and are affected by individual characteristics [ 20 , 24 ]. In the last 10 years, several meta-analyses of RCTs and observational studies have compared the safety profile of these drugs [ 20 , 25 – 33 ]. Yet, study design and endpoints are heterogeneous [ 24 ], and data are biased, for instance, by the fact that they often rely on prescriptions rather than on actual administrations (i.e. no consideration of the exposure duration and dose) without accounting for the reason for the prescription, nor for concomitant diseases and risk factors. For some compounds, the lack of robust data from large cohort studies may be mistakenly regarded as a guarantee of safety.

To support healthcare providers in the optimization of OA patient management, i.e. trying to maximize therapy efficacy while reducing untoward effects caused by inappropriate NSAID use [ 14 ], a multidisciplinary expert panel (i.e., 1 GP, 1 pharmacologist, 1 pain therapist, 1 cardiologist, 1 gastroenterologist, 1 nephrologist and 1 physiatrist) thoroughly discussed the best approach in this complex setting. To inform the group’s discussion, a literature search was performed via PubMed using the following items as the main keywords: “NSAID,” “osteoarthritis,” “chronic pain,” “effectiveness,” “efficacy,” “safety,” “cardiovascular,” “gastrointestinal” and “renal.” We limited the search to articles in English. Electronic Supplementary Material (ESM) Table 1 presents the systematic reviews and/or meta-analyses of RCTs and observational studies on NSAID efficacy and safety published in the past 10 years and included in the present work. This work is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

This narrative review summarizes the main messages and practical indications for GPs and specialists.

Chronic Pain

Definition of chronic pain.

The term “chronic” refers to a pain persisting over time (according to the International Association for the Study of Pain [IASP], chronic pain either persists or recurs for > 3 months [ 34 ]) but provides no details on whether the stimuli persist or if other pathogenetic mechanisms intervene. Certainly, pain persistence affects patients’ life and complicates their clinical status.

For some investigators, “chronic” implies the involvement of the central nervous system, where pathogenetic mechanisms able to maintain chronicity even in the absence of peripheral stimuli develop. Others believe that “chronic” relies on the occurrence of nervous mechanisms typical of neuropathic pain and refer to it as to a mixed or neuropathic-like pain.

There are degenerative and neurological disorders characterized by chronic injuries and in which pain is induced chronically (erythromelalgia, fibromyalgia, deafferentation pain, OA, rheumatoid arthritis [RA], etc.). Many conditions are accompanied by episodes of pain of variable persistence that affects distinct parts of the body over time.

Finally, pain could be defined as chronic if it is not effectively treated or if it is related to undiagnosed diseases.

Types of Chronic Pain

The IASP describes three types of pain: nociceptive, neuropathic and nociplastic [ 34 ]. Nociceptive pain is of inflammatory or degenerative origin depending on the presence or absence of a mechanism of nociceptor sensitization. Inflammatory pain starts in the tissue nociceptive nerve endings and represents the type of chronic pain experienced by patients with OA. The responsible mechanism, i.e. peripheral sensitization, consists in a threshold reduction at the peripheral ends of the sensory nerve fibers, which become responsive to low-intensity stimuli (i.e. allodynia) or may even become spontaneously active. Peripheral sensitization depends on biochemical modifications of nociceptive fibers triggered by mediators of inflammation, such as PGs and cytokines. If the sensitizing agents are removed, the biochemical processes revert, and the normal threshold is re-established.

Neuropathic pain is classified as peripheral or central, based on the site of injury and, thus, of the ectopic activity: the site of pain origin is along the somatosensory pathway affected by a disease or a lesion (from peripheral nociceptors to central neurons). Other definitions, such as neuropathic-like pain, neuropathic component and mixed pain, are frequently associated to nociceptive pain to underline a central component of pain (spinal cord sensitization) that becomes responsible for neuropathic symptoms. It cannot be considered a real neuropathic pain because of the lack of neurological deficit signs.

Patient Evaluation

The diagnostic work-up.

Osteoarthritis is a heterogeneous disease with distinct phenotypes [ 35 ]. Before commencing a therapy with NSAIDs, it is fundamental to

• Collect all relevant clinical information to define the disease characteristics, clinical status and possible risk factors for OA, with particular attention to pain description, psychosocial aspects, comorbidities and risk of CV, GI and renal complications.
• Perform the I- and II-level assessments as per current guidelines [ 4 ].

Pain Assessment

As a first step in pain assessment, the GP must define the pain type, as NSAIDs are effective against inflammatory nociceptive pain but not against non-inflammatory mechanical–structural pain (occurring in approximately 10–15% of OA patients). To infer the type of pain (i.e. somatovisceral or neurological condition), symptoms should be measured using the scales for neuropathic pain, keeping in mind that many symptoms are typical of both types of pain. The most used tools to discriminate neuropathic pain from non-neuropathic pain in clinical settings include painDETECT [ 36 ], the Leeds assessment of neuropathic symptoms and signs Pain Scale [ 37 ] and the Douleur Neuropathique 4 questions [ 38 ]; all of these tools rely on the description of pain and on the bedside examination of sensory dysfunction. Moreover, painDETECT has been recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials to screen for neuropathic pain phenotypes [ 39 ]. Although these scales are easy to use and allow a preliminary clinical assessment, they are considered to be useful screening tools and cannot replace a thorough clinical assessment and their accuracy varies across different populations [ 40 , 41 ].

When considering the pathogenetic mechanisms, it is appropriate to investigate whether the pain is localized, evoked, radiating or referred (by identifying the pain area and inspecting it, evoking pain with non-painful stimuli and testing skin sensitivities), as well as the negative symptoms, which predominate at the sites of neuropathic pain. The following tools should be employed: the generic and unidimensional pain assessment tools Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS), to rapidly and easily measure pain intensity [ 42 ]; the Western Ontario and McMaster Universities Arthritis Index (WOMAC), to measure arthritis symptoms, pain and physical functional disability specifically in patients with OA of the knee and the hip [ 43 ]. Both the VAS and NRS are self-administered and can detect changes over time [ 42 ]. The NRS may be preferred over the VAS because of its simpler score calculation and because it may be administered both verbally and in writing, while the VAS can be administered only in writing. However, due to their nature, they do not provide a comprehensive pain evaluation in patients with rheumatic disease [ 42 ]. As for the WOMAC, it is one of the most appropriate patient-reported outcome measures to be employed in trials of knee and hip OA; however, interpretation of the results and comparisons among studies are frequently challenged by the different versions available (Likert, VAS or NRS) and by the wide variation in its use and analysis [ 44 , 45 ].

A definitive diagnosis is made by combining the clinical and neurophysiological evaluations with the diagnostic nerve block test.

Often, in a context of degenerative pain, patients experience periods of inflammation. The test of the response to NSAIDs (acting on PGs) and cortisone (acting on cytokines) may be helpful, but it must follow—not replace—the clinical evaluation. PGs and cytokines act by sensitizing the peripheral nociceptive endings, i.e. increasing their responsiveness to stimuli below the normal threshold. PGs are the first mediators of inflammation released during the inflammatory process that follows the injury, while cytokines are released later on. When performing the test, it is important to keep in mind that the central analgesic activity of certain NSAIDs may interfere with the result.

Function and patient global assessment (PGA) of disease severity have to be assessed as well. The most frequently used tools are the WOMAC, VAS or Likert scales and global function score for function and the VAS or 5-point Likert scale for PGA of disease severity.

Atypical Presentation

In case of atypical presentation, imaging is recommended to confirm the diagnosis of OA and/or make alternative or additional diagnoses [ 4 ]. Radiological imaging allows potential changes in bone, cartilage and inflammation to be monitored [ 35 ] and includes cartilage evaluation to verify possible interjoint space reduction, increased density of subchondral bone and abnormal reactive growth of the bone at the edge of joint (osteophytes). Conventional radiography is the gold standard.

Differential Diagnosis

It is important to exclude RA and other types of chronic arthritis in OA patients. According to the updated recommendations of the Italian Society of Rheumatology, laboratory tests (blood count, inflammation, urinalysis or synovial fluid) should be performed for OA patients with marked inflammatory symptoms and/or signs, especially when atypical sites are involved, for differential diagnostic purposes, particularly to exclude chronic or crystal-induced arthropathies [ 4 ].

Comorbidities and Risk Assessment

During the visit and before starting the chosen therapy with NSAIDs, GPs should consider the conditions at the highest risk of potental complications upon NSAID treatment and verify the presence of a number of important factors that increase the risk of CV, GI, and renal adverse events (AEs) (Table  1 ):

• Prior CV events (major acute myocardial infarction [AMI], stroke, peripheral venous and arterial thrombosis). The CV risk should be calculated using the European Society of Cardiology score [ 46 ]; however, in outpatient practice, it is rarely calculated and is frequently overlooked, although it is a key determinant of the choice of the most appropriate treatment option. Patients are considered at high risk when the score of the 10-year fatal CV disease (CVD) risk is 5–10% or if they have familial dyslipidemia, severe hypertension, diabetes without CV risk factors and organ damage or moderate chronic renal failure [ 46 , 47 ].
• GI intolerance (abdominal pain, constipation, diarrhea, dyspepsia and nausea) and major GI events (e.g. perforation and bleeding, which depends on age and comorbidities [ 48 ]).
• Kidney function: diseases like acute kidney failure, interstitial nephritis and chronic kidney failure should be considered. A thorough screening and a complete laboratory work-up should be undertaken for each patient at risk of renal AEs based on age, comorbidities such as diabetes and chronic renal failure and concurrent antihypertensive therapies (anti-angiotensin [ANG] II, anti-aldosterone treatment).

Table 1

The main factors that increase the risk of cardiovascular, gastrointestinal and renal complications to be considered before starting a therapy with non-steroidal anti-inflammatory drugs in patients with osteoarthritis

ACE Angiotensin-converting-enzyme, AEs adverse events, ANG angiotensin, ASA acetylsalicylic acid, COPD chronic obstructive pulmonary disease, CV cardiovascular, CVD cardiovascular disease, GI gastrointestinal, NSAIDs non-steroidal anti-inflammatory drugs, OTC over-the-counter

The patient must be educated on lifestyle and prevention.

The panelists agreed that the ideal pathway for OA patients suffering from chronic inflammatory pain is the process illustrated in Fig.  1 .

The ideal pathway for osteoarthritis patients suffering from chronic inflammatory pain. GP General practitioner, NSAIDs non-steroidal anti-inflammatory drugs

When to Consult the Pain Therapist

It is necessary to refer a patient to a pain center if:

• The origin of pain was not identified (lack of pathogenetic diagnosis).
• The pharmacological treatment was not successful. The pain therapist should be consulted before referring the patient to specialists and before administering opioids.
• Treatment reduced pain but not disability.
• The patient presented intolerance or contraindications to NSAIDs.

Practical Indications

• pain origin and duration
• component (inflammatory or degenerative)
• NSAID activity (peripheral or central)
• Consider possible factors that increase the risk of CV, GI and renal AEs.
• Calculate the CV risk.
• Prescribe a complete laboratory work-up, including serum chloride measurement, to test the kidney function.

Non-pharmacological Therapy

Orthopedic treatment, supplements, and physiotherapy.

In the setting of OA, beyond pharmacological therapy, it is important to consider specific orthopedic treatments (surgical and non-surgical), use of dietary supplements and physiatrist assessment, especially for rehabilitative interventions and supplemental physical therapies.

The specialist in orthopedics and traumatology is a surgeon and, as such, should be consulted to determine whether a patient suffering from OA may benefit from a surgical approach. In all the other cases, the reference specialist is the physiatrist, who takes charge of OA patients and makes a prospective evaluation of their functional needs. Once the patient has been evaluated, the physiatrist makes an individual rehabilition plan to estimate the functional aspects as well as rehabilitative prognosis.

Role of the Physiatrist

In first place is the GP, who prescribes I-level instrumental/imaging examinations (i.e. radiography and musculoskeletal ultrasound) for OA patients before a surgical consultation with the orthopedic surgeon. The physiatrist will then take charge of the patient and design the individual rehabilitation project (i.e. “the set of propositions, elaborated by the rehabilitation team, coordinated by the medical doctor specialist”) [ 49 ]. This represents the basis of a person-centered, holistic approach that accounts for the individual conditions globally: indeed, it includes the main scales of motor, cognitive and social assessments characterizing the clinical history of the patient. The physiatrist is the leader of the rehabilitation team that takes charge of patients undergoing or not undergoing surgery.

Based on the individual rehabilitation project, the physiotherapist sets up the individual rehabilitation program aimed at achieving the therapeutic objectives established in the individual rehabilitation project.

Rehabilitation Therapies and Physical Exercises

The prerequisite to optimization of the process of care for OA patients is pain reduction/treatment. Physical antalgic therapies, similar to minimally invasive interventional treatments (i.e. intra- or extra-articular injections), represent an integral part of the rehabilitative approach, with its rationale built into the individual rehabilitation project.

OA causes a reduction in the mechanical functioning and overall clinical status. Most patients suffering from OA are frail with several comorbidities, and thus the physiatrist consults with other specialists, including neurologists, geriatrists, anesthesiologists, internists, among others. Sarcopenia and frailty increase the risk of falls, leading to the need for a broader range of therapeutic strategies, including adequate diet and exercise, to support OA patients.

• Use functional scales for the clinical assessment.
• Consider consulting a physiatrist during the post-operative rehabilitation.
• Account for all patient aspects.
• Pay close attention to prevent falls and the sequelae of reduced mobility caused by OA.

Pharmacological Therapy: NSAIDs

The pharmacology of nsaids, rationale for the use of nsaids in oa.

In case of inflammation, NSAIDs can switch off peripheral sensitization by inhibiting a relevant amount of PGs. Thus, their use as first-line therapy aimed at treating inflammatory nociceptive pain is virtually always appropriate; however, the feasibility of such strategy depends on the condition of the patient.

Conversely, the use of paracetamol (very common in OA although it is not an NSAID) is inappropriate in inflammatory pain, since it is a weak inhibitor of COX-1 and a very weak inhibitor of COX-2 and, as such, it does not interfere with peripheral sensitization. In addition, in tissues with inflammation, the free radicals inactivate paracetamol, abolishing any action on COX-2 [ 50 ]. In line with these observations, its analgesic effect cannot depend on COX inhibition. Paracetamol is actually a central analgesic with multiple effects, the main one being the stimulation of the endogenous cannabinoid system [ 51 ]. Hence, paracetamol has a lower efficacy than NSAIDs in reducing inflammatory pain [ 21 ] and its central analgesic efficacy is also lower than that of opioids.

Are All NSAIDs Equal?

All NSAIDs have an inhibitory activity on COX-1 and COX-2 but there are several differences among NSAIDs (for details on the mechanisms of action of the most common NSAIDs refer to [ 52 – 54 ]) that impact on their efficacy and safety [ 54 ]. These include:

• Chemical similarity

Importantly, the kinetics of COX-1 and COX-2 inhibition are different (non-linear and linear, respectively [ 56 ]).

In clinical practice, to achieve a significant anti-thrombotic effect through the blockade of thromboxane A synthesis, 95–97% of platelet COX-1 must be inhibited. If 90% of the enzyme is blocked, no anti-thrombotic effect occurs. The only NSAID able to inhibit 95% of COX-1 is acetylsalicylic acid (ASA), which irreversibly blocks the enzyme and, if administered at the dose of 100 mg per day every day, maintains this level of inhibition. No other NSAID is able to produce this effect, with the exception of naproxen but at non-conventional doses and regimens. Thus, it is not completely true that NSAIDs alone interfere with platelet function. Certainly, there are COX-1-independent antiplatelet effects that may play a role. NSAIDs induce mostly GI bleeding as they block COX-1 in surface epithelial cells. Given in concomitance with other drugs, such as the selective serotonin reuptake inhibitors, the antiplatelet effects of NSAIDs are enhanced.

• Plasma half - life . This feature impacts on the occurrence of AEs. Indeed, the NSAIDs inhibiting gastric COX-1 for a longer time are more harmful for the stomach. For example, piroxicam and diclofenac have a half-life of about 60 and 1 h, respectively, but the latter is a more potent inhibitor of COX-1 and is associated to a relative risk of gastric bleeding of 3.61 compared to 8.00 for piroxicam [ 57 ].

According to the pharmacologist, patients on ASA must not take any NSAID. In particular cases, such as of a gout flare or of a renal colic, they may take such therapy for 1–2 days.

• Penetration into the synovial liquid . Not all NSAIDs adequately penetrate into the synovial liquid (e.g. ibuprofen does not while diclofenac does), so even in the case of a short half-life, the higher the absorption at the synovial site, the longer the pharmacological effect [ 59 ].
• Passage through the blood – brain barrier . This aspect related to the central action of NSAIDs may be of interest when selecting the most appropriate drug. Some compounds, such as diclofenac, pass through the barrier and reach the spinal cord, where the PGs produced by neurons and astroglia play a role in central sensitization. Therefore, at this site, inhibition of COX-1 and COX-2 adds to the peripheral effect (possible synergism) so that the analgesic activity resulting from the anti-inflammatory action adds to a central analgesic effect occurring when high drug doses reach the central nervous system.

Factors Influencing the Individual Response to NSAIDs

Several players affect the inter-patient variability observed in the response to NSAID therapy:

• Genetic variations in the enzymes that metabolize NSAIDs (cytochrome P450 2C9 [CYP2C9] in many cases) and COXs.
• The microbiota, for its capability to inactivate drugs. However, data in this regard are scarce.
• The possibility of phenotyping OA (e.g. coxarthrosis vs. gonarthrosis), which is rather concrete [ 35 ] and may help to decide if and how to use an NSAID therapy—the choice should rely on the evidence from head-to-head comparisons or network meta-analyses [ 19 – 21 ].
• Gender, which is responsible for relevant differences in the incidence, prevalence and prognosis of several immunoinflammatory diseases. Pre-clinical studies have demonstrated that the molecular mechanisms of inflammation and pain may differ between men and women. All of these differences provide a plausible background to understand why women use more NSAIDs than men. However, the pharmacological mechanisms underlying the gender-driven NSAID responses remain elusive [ 60 ].

By When Should We Expect the Response to NSAID treatment?

Usually, the maximum peak plasma concentration is reached within 2–3 h of administration, but the efficacy also depends on other factors (e.g. plasma protein binding and tissue distribution with particular regard to the inflammatory osteoarticular tissue). The rapid effect is pain reduction, which is achieved also through the central activity of NSAIDs; the delayed effect is the reduction of inflammation and thus the rise of the threshold; the variable effect is the improvement in disability. The analgesic effect occurs within about 1 week and the full anti-inflammatory effect is often achieved in 3 weeks (which questions the 3-day test validity, as the specificity is very low) [ 61 ]. A recent study has shown that the NSAID-induced improvement in pain and function peaks at 2 weeks and starts to decline by 8 weeks, while minor CV and GI AEs occur as early as 4 weeks after the initiation of NSAID treatment [ 62 ].

What is the Adequate Duration of NSAID Therapy?

In general, NSAIDs should be used for the shortest duration possible and at the lowest dose that guarantees both inflammation reduction and physical function improvement, as established in efficacy studies [ 21 , 61 ]. Therapy duration must be tailored to the patient profile [ 61 ]. Usually, the treatment duration is at least 7–10 days, taking into account the time required to achieve both the analgesic and full anti-inflammatory effects [ 61 ]. If at the end of the 3-week period no result has occurred, a switch to another agent should be attempted [ 61 ].

Monotherapy or Combination Therapy?

It is possible to combine NSAIDs with central analgesics, such as paracetamol and opioids. By targeting different mechanisms, such combinations permit the dose to be limited, thus reducing the risk of AEs. In contrast, the combination of NSAIDs with steroids should be avoided: in fact, although they are very effective against inflammation and cause only marginal gastric erosion in subjects without risk factors, these drugs delay the healing of possible microulcers, highly enhancing the NSAID-induced gastric erosion. In this context, the number of administrations plays a central role.

General Considerations on the Different Formulations

Oral intake through the direct contact between drugs and the GI tract mucosa increases the likelihood of topical damage until absorption. Topical formulations are usually preferred over systemic treatments for safety reasons, such as in patients aged > 75 years [ 4 , 5 ]. In patients with comorbidities, to favor compliance, formulations relying on one or few administrations (e.g. modified release) should be considered.

• Avoid the use of paracetamol in case of inflammatory pain.
• NSAIDs should be used for the shortest duration and at the lowest dose that guarantees the effect on inflammation and improvement in physical function.
• Define therapy duration based on the patient profile and avoid the on-demand use of NSAIDs: in the case of inflammatory pain, therapy must be administered for at least 10 days to achieve analgesia and for 3 weeks to achieve the full anti-inflammatory effect.
• It is possible to combine NSAIDs with central analgesics such as paracetamol and opioids.
• Avoid the combination of NSAIDs with steroids.
• Consider formulations relying on one or few administrations to improve adherence.

Making Sense of NSAID Therapy: The Specialists’ Point of View

In clinical practice, in-depth knowledge of each NSAID’s efficacy and safety profile, together with the patient characteristics, is critical to define the benefit/risk balance of each compound for a specific individual and drive the therapeutic choice.

Table  2 summarizes the considerations made by the GP, the pharmacologist and the pain therapist of the multidisciplinary panel.

Table 2

Considerations driving the choice of therapy according to the general practitioner, the pharmacologist and the pain therapist

GP General practitioner, OA osteoarthritis

The Safety Profile of NSAIDs

The main AEs that may occur upon NSAID therapy are illustrated in Fig.  2 .

The main adverse events observed in osteoarthritis patients upon NSAID therapy (see text for discussion). AKI Acute kidney injury, AMI acute myocardial infarction, CKD chronic kidney disease, COX cyclooxygenase, coxibs COX-2 inhibitors, CV cardiovascular, GFR glomerular filtration rate, GI gastrointestinal, tNSAIDs traditional non-steroidal anti-inflammatory drugs, TXA2 thromboxane A2

NSAIDs and CV Risk

Nsaid-related cv aes.

The CV safety of NSAIDs is a very controversial matter. Following the observation that NSAIDs could increase the risk of CV events at therapeutic doses or higher, in 2005 the U.S. Food and Drug Administration added a black box warning to their use [ 63 ], while the European Medicines Agency decided to contraindicate coxibs (but not tNSAIDs [ 64 ]) in patients with coronary heart disease or stroke and to advise those at risk for coronary heart disease to use these agents with caution [ 65 ].

The possible mechanisms proposed to explain CV complications include (1) the unbalance between the vasodilator effect of PGI2 and PGE2 in favor of vasoconstriction by thromboxane A2 in the endothelium, which results in a prothrombotic effect; and (2) sodium and water retention promoted by COX inhibition, which worsens heart failure, hypertension and ventricular remodeling.

The Coxib and Traditional NSAID Trialists’ (CNT) Collaboration meta-analysis is the largest meta-analysis on NSAID safety, based on 639 RCTs in which tNSAIDs/coxibs were used for long periods [ 26 ]. It investigated the vascular effects of coxibs (celecoxib, etoricoxib and lumiracoxib) and high-dose tNSAIDs (diclofenac, ibuprofen and naproxen) in older patients with rheumatic diseases [ 26 ]. Coxibs, diclofenac and ibuprofen displayed a similar relative risk for CV events (range 1.37–2.49), whereas naproxen did not seem to increase it (range 0.39–1.87). Coxibs, diclofenac and ibuprofen also displayed a comparable annual absolute risk for major vascular events, which varied according to the baseline predicted risk: in low-risk subjects, the predicted absolute risk of major vascular events was low regardless of the NSAID administered (2 per 1000 in all cases for coxibs, diclofenac and ibuprofen; 0 per 1000 for naproxen); in high-risk patients, the risk increased and was similar for high-dose diclofenac and coxibs (8 per 1000 and 7 per 1000, respectively) and possibly ibuprofen (9 pe 1000), while it seemed to be lower for high-dose naproxen (− 1 per 1000). [ 26 ]. A subsequent network meta-analysis found no difference in the risk of major CV events with diclofenac, ibuprofen, naproxen, celecoxib and etoricoxib for the treatment of pain in patients with OA or RA [ 20 ].

The PRECISION trial, conducted in subjects with OA or RA at increased CV risk and treated with celecoxib, naproxen and ibuprofen, showed a similar number of CV-related deaths, nonfatal myocardial infarction (MI) or nonfatal stroke among the three groups of NSAIDs, but ibuprofen and naproxen had been used at doses and for periods not in line with guidelines [ 66 ].

The absolute risk for CV effects increases to a greater extent in patients with or at risk for active atherosclerotic processes (e.g. with recent bypass surgery, unstable angina or ischemic cerebrovascular events) receiving a COX inhibitor. The excess number of events depends on the underlying risk of the patient, the relative risk of the drug and the duration of the follow-up [ 58 ].

A recent meta-analysis of individual patient data in real-world settings [ 30 ] has shown that all traditional NSAIDs are associated with an increased risk of AMI, similar to that reported with celecoxib therapy. Using a high daily dose (celecoxib > 200 mg, diclofenac > 100 mg, ibuprofen > 1200 mg, naproxen > 750 mg) for 8–30 days was associated with the greatest risk, which did not increase further beyond the first 30 days. Based on these findings, prescribers should consider weighing the risks and benefits of NSAIDs before selecting the treatment, particularly for higher doses.

In patients with a prior MI, the excess risk of mortality has been estimated to be  approximately six deaths per 100 person-years of treatment with a COX-2 inhibitor compared with no NSAID treatment [ 67 ]. A Danish large-scale study based on national administrative registers and conducted in healthy individuals demonstrated an increased risk for death/MI in diclofenac and celecoxib users (hazard ratio [95% confidence interval] vs. non-users: 1.63 [1.52–1.76] and 2.01 [1.78–2.27], respectively), which increased in a dose-dependent fashion [ 68 ]. Moreover, in low-risk patients, an increased risk of pooled CV events was found with lower doses of diclofenac versus paracetamol, ibuprofen and naproxen (which, however, varied based on the event considered) over 1 month; surprisingly, the relative risk decreased in patients at high CV risk [ 69 ], but the explanation remains unclear [ 24 ]. Finally, the SOS project, which included millions of Europeans, showed a similar modest increase in CV risk with diclofenac and other NSAIDs, compared to non-use [ 70 ]. Nonetheless, bias linked to the design of the available studies do not allow definitive conclusions to be drawn.

A recent study showed that patients on anticoagulant therapy with both vitamin K antagonists and dabigatran should avoid NSAIDs due to a greater risk of hemorrhage, especially GI bleeding, and more frequent complications (such as strokes and embolisms) [ 71 ]. The use of NSAIDs has always been discouraged in patients receiving antivitamin K therapy, but this is valid advice also for those who receive dabigatran and likely all direct anticoagulants. No specific data are currently available for rivaroxaban, edoxaban and apixaban.

Finally, it must be pointed out that the concomitant administration of certain NSAIDs weakens the protective CV effects of ASA [ 72 – 74 ]. Co-administration of ibuprofen in patients with documented CVD on low-dose ASA therapy significantly increased the risk of all-cause and CV mortality (hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.30–2.87; HR 1.73, 95% CI 1.05–2.84, respectively) compared to ASA alone [ 72 ]. No difference was observed when diclofenac or other NSAIDs were used with ASA versus ASA alone [ 72 ].

In conclusion, the main determinant of the risk of AEs is the patient profile. A slight increase in CV risk occurs mainly in case of high doses and long-term use, which, however, are not recommended by current guidelines. The only indication to limit the CV risk is to adhere to the recommended dosages and duration and, possibly, undergo cycles of therapy with periodical interruptions.

• In patients with a prior MI, extra caution is needed in the use of NSAIDs/coxibs.
• Use only the recommended doses and for the shortest period necessary to control or relieve symptoms.
• Monitor renal function and blood pressure in NSAID/coxib users, especially if they present preexisting conditions such as hypertension, renal disease and heart failure [ 75 ].

NSAIDs and GI Risk

Nsaid-related gi aes.

Non-steroidal anti-inflammatory drugs-induced GI AEs are various and sometimes severe even though their prevalence is not high [ 16 ]. The most frequent GI AEs assocated with NSAID therapy are gastric injuries, which range from subjective manifestations, such as dyspepsia, to ulcers with complications. In elderly patients with arthritis, the incidence of GI intolerability AEs was reported to be significantly lower with celecoxib (16.7%) than with naproxen (29.4%; P  < 0.0001), ibuprofen (26.5%; P  = 0.0016) and diclofenac (21.0%; P  < 0.0001). The discontinuation rate due to these AEs was similar for celecoxib (4.0%) and diclofenac (4.2%; P  = 0.75) and significantly lower than for naproxen (8.1%; P  < 0.0001) and ibuprofen (7.3%; P  < 0.05) [ 76 ].

Up to 70% of NSAID users experience minimal mucosal lesions as early as within a few hours of intake [ 77 ]; these may indicate gastric mucosa frailty and the tendency to become real ulcers [ 78 ]. NSAID-induced ulcer, mainly gastric, is becoming more and more frequent due to the increased use of these drugs, especially in the elderly. As NSAID use and Helicobacter pylori are two independent determinants of ulcer development, they may have additive effects on the ulcer risk in the same subject. Thus, the most recent international guidelines recommend that patients be tested for the presence of the infection and, if present, to eradicate it in those who have to start a prolonged therapy with NSAIDs [ 79 ]. The most frequent ulcer complication is bleeding, with a rate ratio (RR) of 1–2% per year. The underlying disease seems to be important: for example, the rate of bleeding is 1.3–2% per year in RA patients and 0.7–10% per year in those with OA [ 80 ].

NSAID users may also experience intestinal disorders, including small bowel injuries [ 77 ], which may be caused by the mucosal inflammatory pathway triggered by microbiota changes [ 81 ].

Liver toxicity events are much less frequent than gastric injuries. Paracetamol used at high doses, at least 4 g per day, may damage the liver [ 82 ]. Other studies found that the RR of liver damage defined by hypertransaminasemia was higher for nimesulide (2.2) and sulindac (5) than for diclofenac (1.5) [ 82 ].

Most of the patients who develop a serious GI AE while on NSAID therapy are asymptomatic prior to the event [ 83 ], particularly the elderly. Among the risk factors for the onset of NSAID-associated ulcer complications (Table  1 ), advanced age is a primary risk factor for GI events [ 84 ]: indeed, NSAID users aged 75–89 years have a twofold higher risk of bleeding (RR 4.1) compared to users aged 60–74 years (RR  2.0) [ 85 ]. It is frequent to observe, in the emergency department, elderly patients who use NSAIDs chronically and present severe anemia with hemoglobin levels of 4–5 gr/dl without having ever experienced any dyspeptic symptom. Therefore, physicians must check their patients periodically for the presence of anemia (fecal occult blood test, hematocrit) and symptoms associated with this condition (headache, asthenia, dyspnea, etc.). Conversely, many patients with troublesome symptoms (e.g. epigastric pain and dyspepsia) may have a normal endoscopy at the upper GI tract [ 86 ]. As for steroids increasing the risk of complications, it must be pointed out that, when used alone, they do not represent an actual risk for ulcerogenesis [ 87 ].

The type of non-selective NSAID impacts on the frequency of GI damage. The results from two epidemiological studies have led to establish a scale of risk for different tNSAIDs (i.e. ibuprofen, diclofenac, naproxen, ketoprofen, indomethacin, piroxicam and azapropazone); azapropazone and piroxicam were associated to the highest risk of gastroduodenal bleeding (odds ratio [OR] 23.4–31.5 and 13.7–18, respectively) and diclofenac and ibuprofen with the lowest (OR 3.9–4.2 and 2.0–2.9, respectively) [ 88 , 89 ]. Table  3 presents the results from two recent meta-analyses of RCTs that report the rate of risk for bleeding associated with tNSAIDs and coxibs versus placebo [ 26 ] and for major GI events associated with tNSAIDs and coxibs versus diclofenac [ 20 ]. In particular, the CNT meta-analysis reported that the annual absolute risk of upper GI complications for coxibs, diclofenac, ibuprofen and naproxen depended on the baseline risk [ 26 ]. Both in patients at low and high risk, diclofenac and coxibs yielded a similar risk (in low-risk patients: 2 per 1000; in high-risk patients: 6 per 1000, respectively) that was lower than that of ibuprofen and naproxen (in low-risk patients: 4 per 1000; in high-risk patients: 15 and 16 per 1000, respectively), in line with the results from previous epidemiological studies [ 88 , 89 ].

Table 3

Risk of gastroduodenal bleeding or overall gastrointestinal complications according to the NSAID administered

coxibs Cyclooxygenase 2 (COX-2)-selective NSAIDs, CNT Coxib and Traditional NSAID Trialists

a Data are expressed as rate ratio (RR) with the 95% confidence interval (CI) in parentheses vs. placebo

b Data refers to major GI events, not only bleeding, which are expressed as the RR with the 95% CI in parentheses vs. diclofenac (i.e., a RR < 1 favors diclofenac and > 1 favors the comparator)

c Celecoxib, etoricoxib, rofecoxib, lumiracoxib

Among the NSAID features that may impact on gastrolesivity, plasma half-life plays a major role. A study conducted in elderly subjects [ 90 ] evaluated the presence of gastroduodenal bleeding through the measurement of fecal blood loss and found that it was higher with drugs with a longer plasma half-life, such as naproxen (2.76 ml fecal blood loss) and piroxicam (1.16 ml), compared to diclofenac (0.53 ml), a NSAID with a shorter half-life, and placebo (0.28 ml). Other factors responsible for a different gastrolesive effect among NSAIDs are the level of pK (higher levels increase the toxic effect) and the dosage.

When is it Adequate to Use Proton Pump Inhibitors with NSAIDs in the Prevention of NSAID-Induced Damage?

Non-steroidal anti-inflammatory drug-induced GI damage can be significantly reduced by increasing the gastric pH through the administration of proton pump inhibitors (PPIs), which are the most potent acid inhibitors available. Unlike H2-antagonists that prevent only the onset of duodenal ulcers, PPIs can protect both the stomach, the main site of NSAID-induced damage, and the duodenum [ 91 ]. The protective action of PPIs depends on the fact that the weakening of the mechanisms of mucosal defense induced by NSAIDs implies that even a reduced amount of acid, such as in the case of the chronic gastritis that is always associated to gastric ulcers, may be dangerous [ 92 ]. A number of important risk factors must be considered due to the need to administer an appropriate prophylactic therapy with PPIs [ 93 ] (Table  4 ).

Table 4

Risk factors in NSAID users requiring prophylaxis with proton pump inhibitors

PPIs proton pump inhibitors, NSAIDs non-steroidal anti-inflammatory drugs, coxibs COX-2-selective NSAIDs, Plus ASA acetylsalicylic acid, SSRIs selective serotonin reuptake inhibitors

PPIs have to be administered throughout the period of NSAID use; even half the standard dose seems to be sufficient to achieve the benefit [ 94 ].

• There are no dietary or behavioral suggestions to prevent or reduce NSAID-induced GI lesions.
• When selecting a NSAID, in high-risk patients or in case of prolonged therapy duration, compounds with the lowest risk of GI events should be preferred.
• The optimal treatment duration depends on the disease and corresponds to the period of acute symptoms or of functional joint impairment.
• Use PPIs in the presence of particular risk factors.

NSAIDs and Renal AEs

Nsaid-induced renal and reno-vascular events and risk factors.

At the center stage of the untoward effects of NSAIDs is the inhibition of endogenous or inflammatory renal PGs, a subfamily of eicosanoids. Endogenous eicosanoids fine-tune renal microcirculation and water and electrolyte transport across renal tubules. PGs, such as PGE1 and 2 or PGF2α, control sodium reabsorption and the concentration/dilution mechanism. Likewise, endothelial PGI2 and platelet thromboxane A2 balance each other to control vascular tone in glomeruli and renal arterioles, including the vasa recta. As this counterbalance mechanism is marginal in the normal kidney, NSAID inhibitors of eicosanoid biosynthesis have very modest effects in the healthy kidney and/or younger individuals and are usually well tolerated in persons with normal renal function.

Elderly individuals or patients with chronic kidney disease (CKD) are likely to experience at least some mild AEs, ranging from local edema (e.g. hands, lower limbs, water retention with rapid weight gain) to worsening of glomerular filtration rate (GFR) and/or hyperkalemia. This is usually more frequent in patients with certain comorbidities: in particular, in hypertensive subjects NSAID therapy may lead to intensification of anti-hypertensive regimen [ 95 ]. The effects are usually reversible but tend to synergize with other agents affecting renal function, such as anti-hypertensive drugs. In selected circumstances, acute kidney injury (AKI) may occur with severe oligoanuria. A meta-analysis of observational studies [ 28 ] found a statistically significant elevated AKI risk in patients treated with indomethacin, piroxicam, ibuprofen, naproxen and sulindac versus non-users, with pooled RRs ranging from 1.58 to 2.11. In all other cases (i.e. diclofenac, meloxicam, and celecoxib), the increase in AKI risk was not significant. Another meta-analysis of observational studies [ 29 ] reported that, in the general population, the pooled OR of AKI for ongoing NSAID exposure was 1.73 (95% CI 1.44–2.07) and was higher in older people (OR 2.51, 95% CI 1.52–2.68); in people with CKD, it was 1.63 (95% CI 1.22–2.19) and ranged from 1.12 to 5.25. Notably, the risk was higher for NSAIDs with no COX-2 selectivity (OR 1.84, 95% CI 1.54–2.19) and decreased with increasing COX-2 selectivity (≥ 5-fold, OR 1.41, 95% CI 1.07–1.87).

Various NSAIDs have been implicated in glomerular disorders leading to proteinuria and/or the nephrotic syndrome, possibly due to some podocyte-specific type of injury [ 96 ]. In other instances, interstitial nephritis can occur bacause of NSAID immuno-allergic effects that are most likely unrelated to COX inhibition [ 97 ]. Under most circumstances, proteinuria or non-oliguric AKI rapidly disappear upon therapy discontinuation.

Another issue that may impact on the renal adverse effects of NSAIDs is the lack of apparent recognition of renal dysfunction by prescribing physicians. Notably, sudden changes of GFR may go unnoticed if serum creatinine, blood urea nitrogen or serum K + are not measured during NSAIDs therapy. Thus, the real prevalence of renal untoward effects of NSAIDs may be largely underestimated. A recent systematic review [ 98 ] noted a cross-sectional point prevalence of NSAID use of between 8 and 21% in 49,209 patients with CKD, demonstrating that despite guidelines recommending against their use, a substantial proportion of CKD patients continue to receive NSAIDs.

NSAIDs and Arterial Pressure

The pro-hypertensive effects of NSAIDs are believed to stem from three major mechanisms [ 99 ]:

• Na + and Cl − retention and increased antidiuretic hormone-mediated water reabsorption at the distal collecting duct
• Blockade of the vasodilator effects of PGE2 and PGI2 on the kidney microcirculation
• Unbalanced activity of the renin/angiotensin/aldosterone axis, normally regulated by local vascular and tubular eicosanoid biosynthesis.

No effect on blood pressure (BP) has been observed in ASA [ 100 – 102 ] and coxib users [ 103 , 104 ]. Among non-selective NSAIDs, ibuprofen and indomethacin—but not diclofenac—were shown to increase the risk of hypertension in arthritis patients [ 103 ]. In a meta-analysis of 19 RCTs including 45,000 patients with arthritis treated for > 4 weeks with COX-2 inhibitors, non-selective NSAIDs or placebo, coxibs caused a weighted mean difference point estimate increase in systolic and diastolic BP compared with placebo and non-selective NSAIDs, and were associated with a non-significantly higher RR of causing hypertension compared with placebo and non-selective NSAIDs [ 105 ]. Another meta-analysis of 49 RCTs with 130,000 patients—mostly with arthritis—found that coxibs caused greater hypertension than either non-selective NSAIDs or placebo after at least 4 weeks of treatment. However, the effect was heterogeneous, with a marked BP increase in etoricoxib users and a slight effect in users of celecoxib, valdecoxib and lumiracoxib [ 106 ]. The review did not report absolute risk changes or provide numbers needed to treat or harm.

Monitoring the Renal and Nephrovascular Effects of NSAID Therapy

We suggest that patients with cardio-renal risk factors receive a complete nephrological assessment, including calculation of the estimated GFR, age-adjusted renal function, urinalysis, electrolyte and acid–base profiling (acidosis/hyperkalemia), microalbuminuria, proteinuria (if any), concurrent anti-hypertensive therapy (anti-ANG II, anti-aldosterone treatment). Measurement of serum chloride is particularly useful [ 107 ]: at < 100 mmol/l, Cl − predicts a setting of metabolic alkalosis (diuretics, hyperaldosteronism); at > 105 mmol/l, it suggests a hyperchloremic metabolic acidosis (renal failure with normal anion gap). Failure of Cl − to increase in the presence of metabolic acidosis with low HCO 3 − levels implicates an elevated anion gap acidosis, resulting from an unmeasured anion (ketones, lactate, alcohol metabolites, salicylate or other intoxications, sepsis). Both alkalosis and acidosis usually drive significant changes of serum K + , potentially relevant to treatment with NSAIDs, which tend to increase K + by interfering with prostacyclin-mediated K + secretion in the distal tubule. If used in conjunction with an angiotensin-converting enzyme inhibitor (ACEi) or ANG II receptor antagonist in a diabetic patient, the risk of hyperkalemia is greatly increased.

• NSAIDs have very modest effects in the healthy kidney and/or younger individuals and are usually well tolerated in subjects with normal renal function.
• Any patient with chronic renal disease should be warned against possible sideeffects of NSAIDs, both in terms of renal function and/or blood pressure control. Should a course of NSAIDs be deemed necessary, the following measures should be taken:
• i. Obtain a baseline measurement of renal function (i.e. estimated [e]GFR by Cockroft-Gault, CKD-EPI or MDRD equations) and serum K + .
• ii. Withdraw any concurrent anti-hypertensive therapy with ACEi or ANG II receptor blockers (known to decrease eGFR in elderly patients with widespread atherosclerotic vascular lesions).
• iii. Keep daily doses of the chosen NSAID to the lowest effective level, for no longer than 1 week to 10 days.
• iv. Avoid dehydration or concurrent diuretic therapy, unless mandatory.
• v. Monitor eGFR and serum K on weekly basis. Virtually all non-selective COX-1 and -2 inhibitors have the potential to induce or aggravate AKI; selective COX-2 inhibitors (rofecoxib, celecoxib) can also affect renal function, whereas NSAIDs with higher COX-2 selectivity (diclofenac, meloxicam) also have renal effects, however not statistically significant.
• vi. Closely monitor individuals with increased risk of AKI due to underlying comorbidities (arterial hypertension, diabetes, heart failure, stroke).
• vii. Withdrawal of NSAIDs is almost always followed by recovery of renal function, although not all cases of AKI are entirely reversible.

Tables  5 and ​ and6 6 summarize the indications on the selection of the most adequate NSAID according to the CV, GI and renal risk (low vs. high).

Table 5

Indications on the selection of the most adequate NSAID according to the cardiovascular and gastrointestinal risk, in patients with low renal risk

In italics, compounds indicated based on the available randomized controlled trials. Underlined, compounds contraindicated based on the available randomized controlled trials

GI gastrointestina, PPI proton-pump inhibitor, CV cardiovascular, NSAID non-steroidal anti-inflammatory drug, LDA low-dose aspirin

a Up to 1200 mg per day

b Use only if NSAID therapy is strictly necessary, and for a limited period of time

Table 6

Indications on the selection of the most adequate NSAID according to the cardiovascular and gastrointestinal risk, in patients with high renal risk

GI gastrointestinal, COX-2 cyclooxygenase, NSAID non-steroidal anti-inflammatory drug, CV cardiovascular, LDA low-dose aspirin

Patient Management During NSAID Therapy

The management of pain relies on a sequential pharmacologic approach. Following the core principles of patient-centered care [ 108 ], the treatment plan must be periodically revised based on the assessment of response (in terms of both efficacy and tolerability) and adherence, taking into consideration the possibility to switch to other options in case of inefficacy or intolerance.

When is it Appropriate to Re-evaluate the Patient Receiving NSAID Therapy and What Aspects Should Be Re-evaluated?

In OA, an effective treatment improves both pain and physical function: as already stated, the same NSAID at different dosages exerts different effects and the minimum effective dose is defined in efficacy studies [ 21 ]. Therapy duration must be tailored to the patient profile [ 61 ] and the revision of the treatment plan must be periodic.

When revising the treatment plan, efficacy, tolerability, and adherence must be assessed.

A complete assessment should include the following: evaluation of pain through any of the available scales (VAS, NRS and WOMAC), impact on the quality of life, pain tolerability, functional recovery and therapy duration. Factors that may help increasing compliance are dosage, regimens and formulations.

Treatment response and adherence should be periodically re-evaluated, using scales to assess pain and function.

Conclusions

This narrative review provides practical indications for GPs and specialists managing patients with OA who suffer from chronic inflammatory pain. Selection of the appropriate therapy is hampered by the patients often being elderly and burdened with comorbidities and polypharmacy. Thus, both patient and drug characteristics (i.e. pharmacology, interactions and benefit/risk balance) must be carefully evaluated, keeping in mind that the same NSAID at different doses has different effects on pain and physical function. To summarize:

• During the first visit , the GP must investigate the origin, duration and component of pain, and collect information on possible risk factors for CV, GI and renal AEs, including comorbidities and concomitant therapies.
• If a non - pharmacological intervention is planned , the physiatrist comes into play, providing a person-centered, holistic approach that accounts for the individual conditions globally.
• in OA patients with inflammatory pain, the use of paracetamol must be avoided as it is ineffective.
• the dose to be administered is the minimum effective dose as determined by available studies.
• in low-risk patients, therapy must be administered for at least 10 days to achieve analgesia and 3 weeks to achieve the full anti-inflammatory effect.
• to limit the CV risk, the only indication is to adhere to the recommended dosages and duration and, possibly, undergo cycles of therapy with periodical interruptions. The use of ASA limits the choice of NSAIDs.
• NSAID-induced GI damage can be significantly reduced through the administration of PPIs in the presence of particular risk factors.
• NSAIDs have very modest effects in the healthy kidney and/or younger individuals and are usually well tolerated in subjects with normal renal function. Adjust treatment to the individual needs, keeping it as short as possible, while monitoring key renal function parameters in elderly patients or subjects with known renal disease, reduced renal function, or high-risk conditions, including diabetic nephropathy or cardio-renal syndromes.
• Periodically re - evaluate treatment response and adherence , using scales to assess pain and function.

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Acknowledgements

This editorial project and sponsorship for the journal’s Rapid Service Fee were supported by Alfasigma SpA.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authors’ Contributions

AM: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. PA: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CB: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GM: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. PM: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. VS: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DF: substantial contribution to the conception of the work; drafting and revising the work critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Medical Writing and Editorial Assistance

Medical writing support and editorial assistance were provided by Clara Ricci, PhD (Edra SpA, Milan, Italy), and unconditionally funded by Alfasigma SpA.

Disclosures

Alberto Magni has been a consultant for Angelini, Pfizer, Ibsa Farmaceutici, Grunenthal, Alfasigma and Alfasigma. Piergiuseppe Agostoni, Cesare Bonezzi, Giuseppe Massazza, Paolo Menè and Vincenzo Savarino have nothing to declare; Diego Fornasari has received fees from Abiogen, Alfasigma, Astellas, Bayer, Daiichi Sankyo, Grunenthal, Kyova Kirin, Lundbeck, Molteni, Recordati, Scharper, SPA and Zambon.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability

Contributor information.

Alberto Magni, Email: [email protected] .

Piergiuseppe Agostoni, Email: [email protected] .

Cesare Bonezzi, Email: [email protected] .

Giuseppe Massazza, Email: [email protected] .

Paolo Menè, Email: [email protected] .

Vincenzo Savarino, Email: ti.eginu@niravasv .

Diego Fornasari, Email: [email protected] .