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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Loay A. Salman, Stephanie G. Dakin, Benjamin Kendrick & Andrew Price

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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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Knee Osteoarthritis: A Review of Literature

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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] .

Data Sources: This article was based on literature cited in Essential Evidence Plus, the Cochrane database, recently published InfoPOEMs, and a PubMed search using the Clinical Queries database for the term osteoarthritis. Search date: July 2017.

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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

• DOI: 10.1016/j.joca.2024.05.015
• Corpus ID: 270319219

Psychosocial Factors in Knee Osteoarthritis: Scoping Review of Evidence and Future Opportunities.

• Bryan Tan Yijia , Anthony Goff , +8 authors David J. Hunter
• Published in Osteoarthritis and Cartilage 1 June 2024
• Psychology, Medicine

43 References

Effects of psychological interventions for patients with osteoarthritis: a systematic review and meta-analysis, what interventions can improve quality of life or psychosocial factors of individuals with knee osteoarthritis a systematic review with meta-analysis of primary outcomes from randomised controlled trials, low back pain and the social determinants of health: a systematic review and narrative synthesis., are depression, anxiety and poor mental health risk factors for knee pain a systematic review, a qualitative study of psychosocial factors in patients with knee osteoarthritis: insights learned from an asian population, singapore knee osteoarthritis cohort (sketch): protocol for a multi-centre prospective cohort study, the multicenter osteoarthritis study: opportunities for rehabilitation research, effectiveness of pain coping skills training on pain, physical function, and psychological outcomes in patients with osteoarthritis: a systemic review and meta-analysis, social determinants and osteoarthritis outcomes., oarsi clinical trials recommendations: design, conduct, and reporting of clinical trials for knee osteoarthritis., related papers.

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Short-term clinical results of single-injection autologous bone marrow aspirate concentrate (bmac) as a therapeutic option/tool in knee osteoarthritis.

Graphical Abstract

1. Introduction

2. materials and methods, 2.1. patient recruitment, 2.1.1. inclusion criteria.

• Patients of KOA with radiological grading of KL grade II and III.
• Age group of the patients between 25 and 60 years of either gender.
• Only patients with primary KOA were included in the study.

2.1.2. Exclusion Criteria

• KOA patients with KL grade IV were excluded, as it has global cartilage loss with subchondral erosions and deformities.
• KOA patients with deformities like varus/valgus/genu recurvatum ligament imbalance and any gross anatomical malalignment of the joints were also excluded.
• Patients with secondary KOA and rheumatoid arthritis were also excluded.
• Patients with metabolic disorders like hyperuricemia were excluded.

2.2. Procedure for Bone Marrow Aspiration

Density gradient centrifugation method for the separation of mononuclear cells enriched with stem cells, 2.3. characterization of mscs, 2.4. primary clinical outcome measurements, 2.4.1. subjective assessment: it is assessed by vas and womac index score, 2.4.2. objective assessment, 2.5. statistical analysis, 3.1. baseline characteristics of the patients, 3.2. primary clinical outcome, 3.2.1. subjective assessment: clinical outcomes based on vas, 3.2.2. evaluation of statistical significance using the vas score, 3.3. subjective assessment: clinical outcomes with womac, 3.3.1. evaluation of statistical significance using womac, kl grade ii koa patients, kl grade iii koa patients, 3.4. objective assessment, 4. discussion.

• The unique features/highlights of the current study
• Limitations

5. Conclusions

Author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Subramanyam, K.; Poornima, S.; Kumar, S.; Hasan, Q. Short-Term Clinical Results of Single-Injection Autologous Bone Marrow Aspirate Concentrate (BMAC) as a Therapeutic Option/Tool in Knee Osteoarthritis. Biologics 2024 , 4 , 218-231. https://doi.org/10.3390/biologics4020015

Subramanyam K, Poornima S, Kumar S, Hasan Q. Short-Term Clinical Results of Single-Injection Autologous Bone Marrow Aspirate Concentrate (BMAC) as a Therapeutic Option/Tool in Knee Osteoarthritis. Biologics . 2024; 4(2):218-231. https://doi.org/10.3390/biologics4020015

Subramanyam, Krishna, Subhadra Poornima, Satish Kumar, and Qurratulain Hasan. 2024. "Short-Term Clinical Results of Single-Injection Autologous Bone Marrow Aspirate Concentrate (BMAC) as a Therapeutic Option/Tool in Knee Osteoarthritis" Biologics 4, no. 2: 218-231. https://doi.org/10.3390/biologics4020015

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• Risk Factors
• Physical Activity and Arthritis
• Caring for Yourself
• Osteoarthritis
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• Childhood Arthritis
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• Show All Home
• Osteoarthritis (OA) is the most common type of arthritis.
• It causes joint pain, stiffness, and swelling—usually in the hands, hips, back, or knees.
• There is no cure for OA, but you can effectively manage it.

Osteoarthritis is a disease that breaks down one or more joints in the body.

• It most commonly affects the hands, hips, back, and knees.
• It can cause pain, stiffness, and swelling in affected joint(s).
• Over time, it can lead to changes in bone, cartilage, and other joint tissues—resulting in disability or making it hard for someone to do work or daily tasks.

OA is common among adults 45 and older. But it is not a regular part of aging.

• There are things you can do to prevent or delay it.
• There are also things you can do to manage it, if you develop it.

U.S. adults with osteoarthritis‎

Signs and symptoms.

People with OA may experience a wide range of symptoms. These can include:

• Joint pain, especially when moving the joint.
• Stiffness after resting a joint.
• Swelling in and around the joint, especially after using it a lot.
• Feeling like the joint is loose or unstable.
• Less ability to move the joint.

Things that increase the risk for OA

Certain things can increase your chances of developing OA. These include:

• Repetitive joint stress or injury—Injuring or over-using a joint can damage it and increase your risk of OA.
• Obesity—Extra weight can affect a person's metabolism and increase the risk of OA, especially in weight-bearing joints like the hips or knees.
• Family history—People who have a family member with OA may be at higher risk of developing it.
• Older age—The chance of developing OA increases as people get older.
• Sex—Women are more likely to develop OA than men, especially after age 50.

Also, people who already have OA in one body part are more likely to develop it in other joints.

Finding out if you have OA

You should see a health care provider who specializes in arthritis, called a rheumatologist, to find out if you have OA.

A rheumatologist will diagnose OA by doing:

• A physical exam.
• A review of your health history.

Find a rheumatologist near you‎‎

What you can do.

While there is no cure, there are proven ways to manage OA symptoms and reduce pain. For example, ways you can manage your arthritis include:

• Being physically active .
• Keeping a healthy weight .
• Protecting your joints.
• Talking to a health care provider about symptoms and care plans.
• Learning skills to self-manage OA and improve quality of life.

CDC recognizes over 20 physical activity and self-management education programs that can help reduce OA symptoms like pain and disability.

Medical Options for OA

Some adults with OA may need extra assistance from providers to help manage their symptoms. These may include:

• Physical therapy to strengthen muscles around the affected joints.
• Over-the-counter pain relievers or prescription drugs.
• Supportive devices such as crutches or canes.
• Joint replacement surgery if other treatments haven't worked.
• National Institute of Arthritis and Musculoskeletal and Skin Diseases
• MedlinePlus, National Library of Medicine
• American College of Rheumatology
• Data from National Health and Nutrition Examination Survey 2017–March 2020.

Arthritis is a condition often characterized by inflammation or swelling of one or more joints. It includes more than 100 conditions that affect the joints, tissues around the joint, and other connective tissues.

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Osteoarthritis year in review 2017: clinical

Amanda e. nelson.

Thurston Arthritis Research Center and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7280, USA

This review is based on a systematic review of the literature relevant to clinical topics in osteoarthritis (OA) performed for the time period February 22, 2016 to April 1, 2017. A PubMed search using the terms “osteoarthritis” and “treatment or epidemiology” returned over 800 papers, of which 57 are reviewed here, with inclusion primarily based on relevance to clinical OA. Epidemiologic studies in this time frame focused on the incidence and prevalence of OA, comorbidities and mortality in relation to OA (particularly obesity and cardiovascular disease), and multiple joint involvement. Papers on therapeutic approaches to OA considered: non-pharmacologic options, a number of topical, oral, and intra-articular therapies, as well as the cost-effectiveness of some OA treatments. There an enormous need to identify novel strategies to reduce the impact of this highly prevalent and debilitating condition.

Introduction

Osteoarthritis (OA) remains a public health problem of global import, as outlined in the recent OARSI white paper, Osteoarthritis: A Serious Disease . 1 As noted in that paper, OA affects 240 million people globally, about 10% of men and 18% of women over 60 years of age, carrying with it substantial morbidity, including disability and reduced quality of life, and contributing to mortality. The lack of effective treatment strategies in this common chronic condition is also highlighted. 1 . This review summarizes the past year of OA research in the areas of epidemiology, including the frequency of OA involvement, associated comorbid conditions, mortality, and multiple joint involvement; and treatment approaches, including non-pharmacologic options such as weight loss and exercise, and pharmacologic therapies delivered topically, orally, and intra-articularly, and their cost-effectiveness.

A systematic literature search was conducted with PubMed ( http://www.ncbi.nlm.gov/pubmed ), using the terms “osteoarthritis” and “treatment or epidemiology” in all fields. The search was limited by date (February 22, 2016 to April 1, 2017), language (English), age (19+ years) and to human studies. The final search was performed on April 18, 2017 and resulted in 808 citations. After initial title review, 738 of these were excluded due to having a primary focus on one of the other areas covered in this issue (e.g. rehabilitation, mechanics, biomarkers, imaging, genetics, basic science, or a combination), lack of an OA or clinical focus, or discussion only of surgical techniques. Following full-text review, another 21 were excluded for the reasons noted above, leaving 53 articles. A hand search of relevant journals during this time frame was also conducted and provided another 12 papers. Eight studies were excluded in the final review due to study design issues, lack of full text availability, and/or overlap with included papers, resulting in discussion of a total of 57 papers ( Figure ).

Flowchart of search strategy and manuscript inclusion

Results: Epidemiology

Incidence and prevalence studies.

A current understanding of the global burden of OA is essential to inform and support ongoing research, and to understand general and population-specific risk factors. Three studies explored the prevalence of OA in Asia. Tang, et al., using data from the China Health and Retirement Longitudinal Study (CHARLS, a national random sample from 2011, mean age 60 years), reported an 8% prevalence of symptomatic knee OA (defined as knee pain with a self-reported physician diagnosis of arthritis). Knee OA by this definition was more common in women than men, increased with age until a plateau around age 70, and was inversely associated with education level and other markers of socioeconomic status (SES) including regional differences. 2 In Japan, data from the 3 rd follow up of the ROAD (Research on OA/Osteoporosis Against Disability) study revealed a very high prevalence (over 90%) of radiographic hand OA (defined as any hand joint with Kellgren-Lawrence Grade [KLG] of 2 or more), with less than a 5% prevalence of erosive hand OA. Higher prevalence was seen with older age (the mean age of the cohort was 66 years) and to some extent with BMI; hand pain was more frequent with more severe radiographic grades and particularly with erosive OA. 3 The 5 th Korean National Health and Nutrition Examination Survey (KNHANES, 2010–12) found marked differences in symptomatic OA frequency at the hip, knee, and spine by sex: 0.1%, 4.5%, and 5.6% in men and 0.2%, 19%, and 16% in women, respectively. Nine percent of men but nearly 30% of women had at least one joint involved; 11% of men and 23% of women had at least 2 painful OA joints. Again in this cohort, age, low SES, and rural location were associated with more frequent OA. 4

In the United States, a study using the National Health Interview Survey data from 2007–8, and incorporating information from the OAPol model, 5 estimated that around 7% of adults over age 25 (14 million people) had symptomatic knee OA (both pain/aching/stiffness and self-reported arthritis diagnosis), with about half of these having advanced disease; the greatest burden was noted in non-Hispanic white women, and OA was not infrequent in the younger age groups. 6

Another study, using data from the Johnston County OA Project, reported age- and sex-standardized incidence rates for hip symptoms, radiographic OA (rOA), symptomatic OA (rOA with symptoms), and severe rOA of the hip as 38, 24, 17, and 3.2 per 1000 person-years, respectively. Incidence rates were lower for African Americans that whites and higher for women and with increasing age; hip injury conferred the highest incidence rates but was infrequent in the cohort. The incidence of symptoms was higher with increasing BMI, but no clear trends were seen for rOA or symptomatic OA. 7 Given the available evidence about prevalence, incidence, and risk factors for OA, Michl et al., performed a study assessing perception of individual risk of knee OA using Amazon Mechanical Turk among adults aged 25–44 without knee OA. They found that the study participants, who did have a high burden of risk factors, substantially overestimated their risk, by about double for lifetime risk and by 6–7 times for 10-year risk. The authors stated that the “results suggest that people in this age group may perceive knee OA as an inevitable part of life” which may undermine prevention efforts. 8

Comorbidity and mortality

Two studies utilized data from a large Catalonian registry to explore associations with OA and obesity. In nearly 2 million individuals followed over 4 years, the incidence of symptomatic OA increased with weight, particularly at the knee, such that the incidence of knee, hip, and hand OA for normal weight individuals was 3.7, 1.7, and 2.6 per 1000 person-years, but for obese class II individuals was 19.5, 3.8, and 4.0 per 1000 person-years, respectively. 9 In the other study, among 5 million people, 100,000 cases of incident knee OA were identified from 2006–11, of whom 7% underwent TKA. The risk of TKA was proportional to obesity category such that, compared to normal weight individuals, those who were classified as overweight, obese class I, class II, or class III had 41%, 97%, 139%, and 167% higher odds of TKA, respectively. The authors note that the need for TKA would be reduced by 31% if patients moved from the obese category to normal or overweight, 10 demonstrating the power of a large registry to estimate public health impact and inform policy regarding interventions.

Modifiable risk factors, including BMI, smoking, and uric acid, remained a focus of OA research. Suh, et al., used data from the 5 th KNHANES (2010–11) to determine associations between measures of body composition and knee OA. Their cohort had a 41% prevalence of knee OA; those with OA had higher fat mass and lower muscle mass, and there was a linear increase in BMI by KLG. Among women only, there was an association between knee OA and low muscle mass, regardless of body weight. 11 Another study considered associations between smoking and OA using data from over 2000 OAI participants, revealing no association in carefully controlled longitudinal analyses between pack-years of smoking and OA assessed by WOMAC or radiographic joint space width. 12 Two cross-sectional studies considered the association between OA and hyperuricemia and gout. Bevis, et al., found no statistically significant associations between gout and rOA of the hand, knee, or foot from 3 observational cohorts (53 participants with gout and 211 matched non-gout subjects). 13 A Chinese study of nearly 5000 participants found a positive association between OARSI osteophyte scores and hyperuricemia in women only. 14

Three studies considered the relationship between OA and cardiovascular disease (CVD). First, Veronese, et al., used data from the Progetto Veneta Anziano (Pro. V.A.) study of Italians over 65 without CVD at baseline (n~2000). For these analyses, CVD included coronary artery disease, stroke, transient ischemic attacks, congestive heart failure, peripheral arterial disease, cardiac procedures, or CVD related death. Two-thirds of the cohort were women and 2/3 had OA at baseline (hand 37%; hip 28%; knee 44%; 34% had 2 or more joints involved). The frequency of incident CVD events was higher among individuals with OA versus those without (48% vs. 41%), with an adjusted hazard ratio (aHR) of 1.22 (95% CI 1.02–1.49); the association was present for hip or knee OA but not for hand OA, and was greater with polyarticular OA and in women. 15 Second, a large study of adults in Taiwan included individuals with OA and frequency matched (age, sex, entry year) non-OA controls (46,000 per group) and found that over 8 years, there were 5.4 incident acute coronary events per 1000 person-years in the OA group compared with 4.3 in the non OA group, aHR=1.15 (95% CI 1.08–1.23) after adjustment for covariates including sex, age, and comorbidities. 16 Finally, investigators using data from the Chingford cohort categorized participants (all women) into 4 groups: 1) no rOA and no pain, 2) pain only, 3) rOA only, 4) pain and rOA, separately for both the hand (n=808) and the knee (n=821). Compared to those without rOA or pain at the knee, those with both pain and rOA had twice the hazard for all-cause mortality and 4 times the hazard for CVD-related mortality. Knee pain alone also conferred higher aHRs for mortality (aHR=1.5 for all cause and aHR=3 for CVD-related), but rOA alone did not, and there were no associations with hand pain or rOA. 17 These studies confirm a higher risk of CVD among OA patients, and support the role of detailed phenotyping to identify the highest risk groups.

Consideration of multiple joint sites

Four studies specifically considered the high frequency of multiple joint OA and multiple joint symptoms, a key but often overlooked component of the burden of OA. First, in a Japanese study of 143 patients over 50 with medial tibiofemoral OA, 69% had concomitant patellofemoral (PFJ) OA. These individuals were heavier, had more varus knees, and more severe tibiofemoral OA, than those without PFJ disease; they also had more pain, particularly with stairs, greater disability and reduced quality of life. 18 Next, a study from Spain considered the effect of symptomatic low back pain (LBP) on recovery from TKA, and included 48 patients with low back pain and 96 matched (for gender, age, BMI, and Knee Society Score) patients without, undergoing TKA by a similar protocol with 3 year follow up and blinded assessors. All assessments (SF12, WOMAC, patient satisfaction, Knee Society Score) improved after TKA, but improvement was significantly greater among patients without LBP; greater LBP severity was correlated with worse post-operative outcomes. 19 Third, Raja, et al., identified a cohort of 201 individuals over age 50 with pain in one large and one other joint site for at least 6 weeks (excluding rheumatoid arthritis, gout, polymyalgia rheumatica, connective tissue disease, or fibromyalgia syndrome). The predominantly female participants (82%) had a mean age of 63 years, BMI of 31 kg/m 2 , and reported a mean of 14 years of pain, with a median of 6 painful joints per person; 96% had at least one joint with an OA diagnosis. Health care utilization was noted to be high in this group, although participants reported using medication for their most painful joint, rather than for their multi-site joint pain. 20 Finally, investigators using data from OAI and the Multicenter OA Study (MOST) explored the frequency of multiple pain sites in people who developed knee pain over 5–7 year follow up. They found that ½ of individuals without baseline knee pain also had pain elsewhere, while 80% of those with bilateral knee pain had remote site pain. Those who developed knee pain were more likely to develop pain in previously pain-free sites, but in no discernable pattern. 21

Results: Treatment

Non-pharmacologic.

Work over the past year has reinforced the role of weight loss and physical activity in improving symptoms and functional status in OA patients. An 18-week program out of Australia, OA Healthy Weight for Life, enrolled 1383 individuals with a mean age of 64 years and baseline BMI of 34 kg/m 2 (82% were obese). Almost all (94%) of those enrolled lost at least 2.5% of their baseline weight, and 1/3 lost more than 10%. The researchers noted a dose-response relationship between change in KOOS (Knee Injury and Osteoarthritis Outcome Score) and percentage weight change, concluding that loss of at least 7.7% of baseline weight was needed to achieve a minimal clinically important difference in WOMAC function (derived from the KOOS). 22 A study published in the Journal of the American Medical Association reported improvements in several OA-relevant measures in a cohort of 2200 people following bariatric surgery. The median pre-surgery BMI in this group was 46 kg/m 2 ; 70% had 3-year follow up where the median weight loss was 30% of baseline, accompanied by significant improvements in knee and hip pain and function by WOMAC. The majority of these patients had clinically significant improvements in body pain, physical function, and walking capacity, although the percent of patients with improvement in pain decreased between one and three years postoperatively. 23 An update to the Cochrane Review on aquatic exercise for knee and hip OA added 9 new trials and included over 1000 individuals, finding modest improvements in pain, disability, and quality of life immediately after completing this very safe treatment for a mean of 12 weeks (standardized mean difference around −0.3 for all outcomes). 24

Building upon results from the FIDELITY study (a double-blind sham surgery controlled trial of arthroscopic partial meniscectomy for degenerative medial meniscal tears), which found no benefit for surgery over conservative treatment, investigators assessed benefit specifically for mechanical symptoms. In this post-hoc analysis, they found that there was no difference in mechanical symptoms by treatment group, indicating that the presence of such symptoms is not an indication for surgical repair, and supporting their position that “degenerative meniscal tears represent an early sign of knee osteoarthritis, rather than a clinically important entity in their own right.” 25

Pharmacologic: Oral NSAIDs

Several studies over the past year considered the efficacy and safety of NSAID treatment in OA. The very large, multicenter PRECISION trial was published in the New England Journal of Medicine in December 2016. This study included about 24,000 patients with either OA or RA who were taking celecoxib, naproxen, or ibuprofen (~8000 per group) for about 2 years; all participants were also on a proton pump inhibitor. There was no significant difference between the three medications for the primary (first occurrence of myocardial infarction, stroke, or cardiovascular death) or secondary (coronary revascularization, hospitalization for unstable angina, or transient ischemic attack) outcomes, or for efficacy. Fewer GI events were seen in the celecoxib group compared with ibuprofen or naproxen, and fewer renal events and admissions for hypertension were seen in the celecoxib group compared to ibuprofen. 26 A study published in the Lancet focused on effectiveness of different NSAIDs through a network meta-analysis of randomized controlled trials of any NSAID (1980–2015, including coxibs), paracetamol, and placebo with over 100 participants per group. They identified 74 trials with over 58,000 participants, and found: 1) that all NSAID preparations regardless of dose improved pain vs. placebo; 2) no support for the effectiveness of paracetamol; 3) the greatest effect size for diclofenac and etoricoxib (~0.6), concluding that diclofenac 150 mg per day is the most effective currently available NSAID for pain and function in OA. 27 (Of note, although this paper was later republished in edited form, 28 , 29 the conclusions did not change substantially.) An accompanying editorial notes that one limitation of this work is that the medications were used daily at a fixed dose rather than as needed, which would be more representative of general use. 30 Additionally, this meta-analysis did not consider safety outcomes, particularly cardiovascular risk, which has been noted to be similar between coxibs and diclofenac 31 leading to reduced utilization of diclofenac in recent years. A six-week randomized trial at 31 U.S. centers compared celecoxib, naproxen, and placebo among Asian patients with knee OA (n=367) and found no difference in VAS pain among the groups, slight improvement in global assessments for active treatment vs. placebo, and slightly more GI adverse events in the naproxen group. 32 Finally, a group from Belgium and Luxembourg performed a cross-sectional study collecting data from nearly 200 providers on over 800 patients, and found that while over ¾ of the patients were classified as being at high GI risk according to known risk factors, only 37% of these were on a GI protective agent. 33 As always, providers should consider the risk-benefit ratio of these therapies, and oral NSAIDs should be used at the lowest effective dose and for the shortest possible time.

Pharmacologic: Topical NSAIDs

Topical NSAIDs are an attractive option for OA management given their safety profile. The Cochrane Review of topical NSAIDs for musculoskeletal pain was updated to include more than 10,000 participants in 39 studies (all randomized, double-blind, placebo-controlled trials in adults with moderate to severe musculoskeletal pain and at least 10 subjects per arm). All included studies were of OA and were moderate to high quality. In studies lasting 6–12 weeks, topical diclofenac and ketoprofen were more effective than carrier alone, with number needed to treat of 7 for ketoprofen and 10 for diclofenac. 34 Another study compared a novel topical NSAID, s-flurbiprofen plaster, to standard flurbiprofen commercially available in Japan in 633 individuals with knee OA and suggested a modest but significant benefit to the investigational drug; both were shown to be safe. 35

Pharmacologic: other

No or minimal benefit was found for other pharmacologic agents and combinations in several papers. A randomized controlled trial of vitamin D for symptomatic knee OA (n=474) with 3-year follow up found no difference in radiographic medial joint space width between vitamin D and placebo, despite appropriate increases in serum vitamin D in the treatment group. The authors concluded that “vitamin D supplementation has no role in the management of knee OA”. 36 Glucosamine either in novel combination (with mud bath therapy) 37 or formulation (N-acetyl glucosamine and chondroitin sulfate) 38 had minimal benefit in 2 studies. Three other small studies considered novel herbal and plant extracts including Artemisia annua (ginghao) 39 , 40 and bromelain (pineapple extract). 41

Intra-articular corticosteroid

Two groups performed reviews of the literature on intra-articular corticosteroids (IASI), finding significant although short-lived benefits. First, McCabe, et al., reviewed all randomized controlled trials of any IA steroid preparation for painful hip OA, identifying 5 studies with 346 participants, of whom 134 received hip IASI. All injections were image-guided (ultrasound or fluoroscopy), most patients had severe disease and were eligible for THA, and all patients reported reduction in pain at 3–4 weeks post IASI. Two studies reported clinically significant reduction in pain at 8 week follow up, yielding a number needed to treat of 2.4 to achieve one OMERACT-OARSI response at 8 weeks (based on 50 IASI and 40 controls). 42 Investigators from the OA Trial Bank performed an individual patient data meta-analysis of published randomized controlled trials of IASI in hip or knee OA by requesting data from corresponding authors of all eligible trials (n=30). Only 7 corresponding authors provided data, from 620 patients. Of these, 4 studies compared IASI to placebo, 2 to IAHA, 2 with tidal irrigation, and one with botulinum toxin; two were of hip OA and 5 were of knee OA. The authors found that IASI had significant short- (<4 weeks) and mid- (1–3 months) term benefits, but no effect on long-term (up to 12 month) outcomes, with no difference in signs of inflammation. 43

Intra-articular hyaluronic acid

Many studies of intra-articular hyaluronic acid (IAHA) preparations were published in the year of this review. Zhang, et al., considered the importance of aspiration of a joint prior to IAHA administration, randomizing 92 symptomatic knee OA patients to maximal aspiration and 88 to no aspiration prior to weekly IAHA for 5 weeks, with 25-week follow-up. The authors noted that visual analog scale (VAS) pain with walking and WOMAC function improved more in the aspiration group, but there was no difference in global “overall effectiveness” as rated by the patient or the investigator. 44 Two studies used claims databases to study IAHA in large populations. Altman, et al. considered the impact of IAHA on the time to TKA in individuals who did (n~8000) or did not (n~14,000) receive IAHA prior to TKA. They found that the median time to TKA for those who did not receive IAHA was 326 days, versus 908 days for those who did; the time to TKA increased with additional courses of IAHA. 45 Another group focused on payment information in the 12 months prior to TKA among 250,000 patients undergoing TKA from 2005–12. They found that 15% of these patients received at least one IAHA treatment, and that such treatments were responsible for 16% of all knee OA related payments, second only to MRI at 18%, and higher than any other treatment category. 46

Two articles compared IAHA to IASI for symptomatic knee OA. A randomized double blind controlled trial in 99 individuals compared a single dose of IAHA to a single dose of 40mg triamcinolone with 1% lidocaine (total injected was 6 mL for both groups); similar improvements in pain, function, and range of motion were observed in both groups at 6 months, but the IASI group reported better outcomes for short-term (1–2 weeks) VAS pain and WOMAC function. 47 Another group compared 2 injections one week apart of either IAHA (n=75) or IASI (n=75) for symptomatic knee OA in a single-center single-blind randomized trial. Both groups improved by WOMAC total score, with a peak therapeutic effect at 6 weeks, although improvements were greater in the IAHA group through 26 weeks (no difference at 52 weeks). For VAS pain, both groups had similar improvements through 6 weeks; improvement was greater for IAHA at weeks 12 and 26, and again no difference by 52 weeks. 48 Other studies not discussed further here were either unblinded 49 , 50 or compared one type of IAHA to another. 51 – 53

Other intra-articular treatments

Two preliminary studies identified no specific safety concerns for novel IA therapies, namely rhFGF-18 54 and mesenchymal stem cells. 55 There were several studies of various regimens and preparations of IA platelet rich plasma (PRP) for OA. Three small studies of leukocyte-poor PRP (vs. oral acetaminophen, saline, or IASI) for symptomatic knee OA suggested modest improvements in pain and function from PRP injection at week 12. 56 – 58 An Italian group randomized 111 patients with symptomatic hip OA to one of 3 groups: PRP alone, HA alone, or a combination of PRP and HA. All patients received 3 ultrasound-guided IA injections one week apart (PRP: 5mL; HA: 2mL; PRP+HA: 7mL) with evaluations at 2, 6, and 12 months post-injection. In this study, the group receiving PRP alone had greater efficacy than the HA or combined group, particularly at 2 and 6 months, with more adverse events (“transient pain reaction”) in the combination group. 59 One small pilot study of 10 patients considered PRP injections for basal thumb OA, although the follow up was short and there was no control group. 60 Consistent results from large well-designed trials using standard protocols are lacking, however, and PRP is not currently recommended in any OA management guideline.

Cost-effectiveness

Three studies by the same investigators utilized the OAPol model 5 to explore the cost-effectiveness of various pharmacologic treatments for OA. The first of these found that naproxen- and ibuprofen-containing regimens were both more effective and more cost-effective than were opioids, celecoxib, or standard of care (i.e. acetaminophen, physiotherapy, and/or IASI). 61 Next, they considered 3 strategies leading up to TKA: 1) opioid-sparing, 2) tramadol, and 3) tramadol with addition of oxycodone if tramadol was not effective, and found that while both tramadol alone and tramadol with oxycodone delayed TKA (by 7 and 9 years, respectively), these regimens reduced quality-adjusted life expectancy and increased costs (although tramadol alone was potentially cost-effective in patients who were unwilling or unable to undergo TKA). 62 Finally, they considered hypothetical scenarios for the cost-effectiveness of anti-nerve growth factor (NGF) treatments currently under study using data from clinical trials. All subjects were presumed to have failed usual measures for pain. They concluded that the addition of anti-NGF therapy could increase quality-adjusted life expectancy and reduce primary TKA, and could be cost-effective depending on drug price and delivery setting, particularly among those with severe pain. However, this therapy would be unlikely to be cost-effective in any setting if priced over $1000 per dose. 63

Conclusions

In summary, there have been many clinical studies exploring both epidemiologic factors and treatment options in OA over the past year. These studies continue to highlight the high prevalence of OA around the globe, the importance of the obesity epidemic in this disease, and the associations between OA and other chronic conditions. Several studies provided further data regarding the importance of considering multiple joint OA and symptoms, although this area remains under-explored. Treatment options, including weight loss, exercise, oral and topical NSAIDs, and intra-articular therapies received further study as did the cost-effectiveness of some of these therapies. There remains, however, an enormous need to identify novel strategies to reduce the incidence and progression of this highly prevalent and debilitating condition which continues to increase in frequency in the worldwide population.

Acknowledgments

Role of funding source

This work was supported in part by NIH/NIAMS P60AR064166. The funding body had no role in the performance of this review or writing the manuscript.

Author contributions

Competing interest statement

The author is a consultant to GSK, has received honoraria for online presentations on MedScape and QuantiaMD, book royalties from Health Press, Ltd., and has received grant funding from NIH/NIAMS, CDC, and the Rheumatology Research Foundation. This review represents the opinion of the author and does not reflect the official view of these or any other agencies.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Intrinsic Capacity and Its Biological Basis: A Scoping Review

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• Published: 10 April 2024

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• Melkamu Bedimo Beyene   ORCID: orcid.org/0000-0003-4349-9887 1 , 2 ,
• Renuka Visvanathan   ORCID: orcid.org/0000-0002-1303-9479 2 , 3 &
• Azmeraw T. Amare   ORCID: orcid.org/0000-0002-7940-0335 1 , 2 , 4  

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In 2015, the World Health Organization (WHO) introduced the concept of intrinsic capacity (IC) to define healthy aging based on functional capacity. In this scoping review, we summarized available evidence on the development and validation of IC index scores, the association of IC with health-related factors, and its biological basis. The review specifically focused on identifying current research gaps, proposed strategies to leverage biobank datasets, and opportunities to study the genetic mechanisms and gene-environment interactions underlying IC.

The literature search was conducted across six databases, including PubMed, CINAHL, Web of Science, Scopus, AgeLine, and PsycINFO, using keywords related to IC.

This review included 84 articles, and most of them (n=38) adopted the 5-domains approach to operationalize IC, utilizing correlated five factors or bifactor structures. Intrinsic capacity has consistently shown significant associations with socio-demographic and health-related outcomes, including age, sex, wealth index, nutrition, exercise, smoking, alcohol use, ADL, IADL, frailty, multimorbidity, and mortality. While studies on the biological basis of the composite IC are limited, with only one study finding a significant association with the ApoE gene variants, studies on specific IC domains — locomotor, vitality, cognitive, psychological, and sensory suggest a heritability of 20–85% of IC and several genetic variants associated with these subdomains have been identified. However, evidence on how genetic and environmental factors influence IC is still lacking, with no available study to date.

Our review found that there was inconsistency in the use of standardized IC measurement tools and indicators, but the IC indices had shown good construct and predictive validity. Research into the genetic and gene-to-environment interactions underlying IC is still lacking, which calls for the use of resources from large biobank datasets in the future.

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I n 2020, one billion of the world’s population was 60 years or older, with an increase of 400 million expected between 2021 and 2030 ( 1 – 3 ). As this demographic shift continues, exploring innovative mechanisms to promote healthy aging is an important global health and economic policy agenda. Advocacy for improved health across the lifespan to increase the likelihood of older people being functionally able and capable of doing what they value in older age is increasing.

The World Health Organisation (WHO) redefined Healthy Aging in 2015, taking a life-course approach in preparation for the predicted demographic shift globally. It was redefined as the life-long process of developing and maintaining functional ability ( 1 ), determined by intrinsic capacity (IC), the environment, and the interaction between these two factors ( 1 ). Intrinsic capacity refers to the composite of an individual’s physical and mental capacities across the five domains: locomotor, vitality, cognitive, psychological, and sensory ( 4 ). Higher IC levels are associated with decreased disability risk and better overall quality of life ( 5 – 7 ).

In the last two years, four scoping reviews relating to IC have been published ( 8 – 11 ). These reviews have focused on the sensitivity and specificity of WHO’s Integrated Care for Older People (ICOPE) step 1 tool in detecting loss of IC ( 11 ), demonstrated that IC predicts physical function, frailty, falls and quality of life over time ( 10 ), highlighted that there was a lack of consistency in terms of the domains and metrics used across studies ( 9 ), and queried if IC was as an underlying latent trait of all capacities rather than an aggregate summary measure of the sub-domain capacities ( 8 ). The scoping reviews thus far are yet to address IC’s biological (genetic) underpinnings. Intrinsic capacity is influenced by the person’s underlying genetic as well as the interaction between the person’s genetic make-up and their environment (including lifestyle). Also, research on IC is rapidly increasing, providing a basis for more recent reviews.

Our research group is researching to understand IC genetics better, leveraging existing cohorts where genetic data were collected. Within that context, the primary aim of this scoping review was to explore the existing literature to identify factors (especially genetics) relating to IC and to provide a current overview of knowledge regarding the measurement of IC, along with its predictive and construct validities.

Scoping Review Framework

We used the Joanna Brigs Institute’s (JBI’s) Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) and Arksey and O’Malley methodological framework ( 12 – 14 ). The process involved five stages, including defining the purpose, the research question, and the search terms (Stage 1); identifying relevant studies (stage 2); selecting studies that met the predetermined inclusion criteria (stage 3); mapping and charting the data obtained from the selected studies (stage 4); and collating, summarizing, and reporting of the review findings (stage 5).

Stage 1: Defining the research questions and search terms

This initial phase involved refining the scope and direction of the review based on a preliminary search conducted on Google Scholar. Through this step, we had background information on studies and search terms related to IC measurement, IC measures’ validity, health and health-related functional outcomes associated with IC, and its underlying biologic(genetic) basis.

“Generally, the research questions for this review were:

What are the IC measurement tools in literature? What are the approaches to computing composite IC scores and assessing the validity of the scores? This question aims to summarize research findings on IC domains used/found, their indicators, approach to developing composite scores, and the validation of indexes.

What are the different sociodemographic, health, and health-related factors associated with intrinsic capacity?

Does IC have a biological/genetic basis? What are the biomarkers associated with IC?

Inclusion and exclusion criteria

The Participant, Concept, Context (PCC) approach was employed to develop the eligibility criteria for study inclusion. The inclusion criteria were; studies conducted on human subjects of all ages (populations), focusing on the measurement of IC, its validation, association with socio-economic and health outcomes (concept), and in any setting – whether the studies were conducted in the community or institutional setting (context), published in the English language and published between 01/01/2015 – 20/10/2023. However, abstracts, conference proceedings, commentary, editorials, reviews, and personal opinions were excluded. No research records were available until WHO experts released the initial article operationalizing IC measurement ( 15 ).

Stage 2: Identifying relevant studies (Search strategy)

The literature search was conducted across Six Databases: PubMed, CINAHL, Web of Science, Scopus, AgeLine, and PsycINFO using the mesh terms and keywords “intrinsic capacity”, “intrinsic capacity decline”, “intrinsic capacity domains”, “intrinsic capacity impairment”, “intrinsic capacity index”, “intrinsic capacity model”, and “intrinsic capacity score” in the context of Aging. Each database’s detailed search string is presented in Supplementary Table 1 (Supplementary Table- 1).

Stage 3: Selection of relevant articles

Identified articles were imported into Clarivate Analytics EndNote 20 after the completion of the search, and duplicates were removed. Following this, two researchers (MB and AT) independently evaluated the titles and abstracts of the articles against the inclusion criteria. The two assessors thoroughly reviewed the full text of the selected articles. Articles that did not meet the inclusion criteria were excluded, and the reasons for their exclusion were documented and reported. Disagreements that arose during the selection process were resolved through discussion. The search outcomes and procedure for selecting or excluding studies can be observed in the PRISMA-ScR flowchart (Figure 1 ).

PRISMA flow chart showing the steps of the literature search

Stage 4: Data extraction and synthesis

Using a data extraction tool, MB and AT collected various information from selected articles, including name of authors, publication year, characteristics of study participants, design and setting of the study, domains of IC measured, method used to calculate composite IC scores, validation approaches, and other relevant information. Supplementary Table 2 provides the data extraction form and the summary of information collected from the articles (Supplementary Table 2). The results collected from these selected articles were presented primarily using narrative descriptions and tables.

Descriptive Summary

Our search strategy yielded 1498 articles, of which 398 were identified as duplicates and, thus, removed. After screening titles and abstracts (Figure 1 ), 986 publications were excluded, and full-text screening of 114 articles was conducted, resulting in 72 publications for full-text review. With a targeted citation search strategy, we found 12 additional articles relevant to our topic, and the final list for this scoping review was 84 articles.

Of the total 84 articles reviewed, the majority, 77 articles (92%), were published in the last two years, between 2021 and 2023.

The majority (51 articles, 61%) of the publications were carried out using samples sourced from Asia, of which 33 were from China. The remaining studies utilized study participants distributed across other geographical regions, including 20 (24%) studies in Europe (France (n=9), UK (n=4), Belgium (n=3), Spain (n=2), and Netherlands (n=1), and Norway (n=1)), North America (n=3), South America (n=5), New Zealand (n=1) (Supplementary Table-2). Four articles involving study samples from multiple continents. Out of the 84 reviewed articles, 33 were cross-sectional studies, 43 had a longitudinal approach (involving cohort, case-control, or longitudinal designs), and 8 were randomized control trials (Supplementary Table- 2).

Most (64 studies) have explored the validity of IC measurement in different ways. Some studies assessed the predictive validity ( 16 – 20 ) by assessing if IC predicts future health outcomes, whereas others assessed construct validity through the cross-sectional association of IC with socio-demographic variables ( 21 – 23 ), health and health-related functional outcomes ( 7 , 20 , 24 , 25 ), mortality ( 26 – 29 ), and quality of life ( 7 ).

Some of the studies have inquired into the structural validity of IC ( 30 , 31 ), sensitivity and specificity analyses ( 23 , 32 – 34 ), tested internal consistency using Cronbach alpha ( 20 , 35 ), performed ROC curve analysis ( 19 ), assessed criterion validity through logistic regression analysis ( 28 ), and conducted validation analysis by dividing the population into two as 70% for training and 30% validation cohort ( 26 ). The WHO has also published an expert consensus article on the measurement and validation of IC, providing a comprehensive working definition of vitality capacity ( 36 ).

The association of biological and environmental factors with IC

Biological markers with ic.

Eight studies explored the association of IC with aging-related biomarkers. While specific studies estimating the heritability of IC are currently lacking, evidence based on the five IC domains suggests a heritability estimate of 20–85% ( 37 – 54 ). Thus far, only one candidate gene study has been conducted, and this study showed a significant association of IC with ApoE carriage ( 26 ).

Research conducted by Lu WH, et al. (2023) showed an increased level of inflammatory markers such as Plasma C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNFR-1), monocyte chemoattractant protein-1 (MCP-1) and growth differentiation factor-15 (GDF-15) in individuals with lower IC ( 55 ). Another study by Lee WJ, et al. (2023) found that high serum levels of IL-6, CRP, hyperglycemia, and low dehydroepiandrosterone sulfate (DHEA-S) were associated with low IC ( 26 , 56 ). Lower levels of serum albumin and folate ( 26 ), high homocysteine ( 55 ), Tumor Necrosis Factor Receptor 1 level (TNFR1) ( 57 ), Plasma N-Terminal Pro-B-Type Natriuretic Peptide level ( 58 ), or E-selectin ( 26 ) and increased allostatic load ( 26 ) were significantly associated with low IC. Recent studies have also reported associations between IC and plasma biomarkers reflecting inflammation (such as CRP, IL-6, TNFR-1, and MCP-1) and mitochondrial impairment (such as GDF-15, IF1) such that elevated levels of plasma interleukin-6 (IL-6), tumor necrosis factor receptor-1 (TNFR-1), CRP, growth differentiation factor-15 (GDF-15) and IF1 were associated with lower IC or faster decline in IC ( 59 – 61 ). Details of all factors associated with intrinsic capacity are presented in Table 1 (Table 1 ).

Lifestyle and socio-economic factors with IC

Exercise and lifestyle choices play a crucial role in IC, with studies revealing significant associations. Smoking is linked to lower IC ( 23 , 64 , 68 , 70 – 73 ), as is alcohol consumption ( 23 , 71 ), and reduced meat intake ( 64 ). Interventional and cohort studies, respectively, underscore the positive impact of healthy eating ( 77 ) and fruits and vegetables and protein-rich diets on IC ( 96 ). A multidomain intervention has also been shown to enhance IC ( 102 ).

The exploration of socio-economic factors demonstrates noteworthy associations with IC. Age is inversely correlated, with lower IC found in older age ( 7 , 20 – 23 , 32 , 57 , 62 – 69 ), and women tend to exhibit lower IC (7, 20–23, 62, 63, 66, 67). Lower educational status ( 7 , 20 , 21 , 23 , 32 , 64 , 66 – 68 ), low economic status ( 20 – 22 , 62 , 64 , 65 , 67 , 91 ), unmarried status ( 21 , 23 , 32 , 64 , 68 ), and urban residence are associated with lower IC.; however, being white race was associated with a higher IC ( 23 , 64 ), and higher IC was observed in Chinese individuals compared to non- Chinese in Singapore ( 23 , 97 ).

Social factors also play a role in IC. Lower social engagement, lower subjective social status, fewer social activities, and lower housing index are linked to lower IC ( 7 , 32 , 66 ).

Mortality and morbidity with IC

IC is a significant predictor of various health outcomes. It predicts multimorbidity ( 20 , 65 ), mortality ( 10 , 27 , 28 , 35 , 56 , 65 , 74 , 81 , 93 – 95 ), quality of life ( 5 , 6 , 10 , 76 ), risk of dementia ( 87 ), cardiovascular diseases mortality ( 17 ), respiratory disease mortality ( 16 ), hospitalization ( 27 ), and complications related to hospitalization ( 95 ). Conversely, multimorbidity predicts declines in IC ( 68 ). In addition to predictive relationships, IC index has shown cross-sectional associations with quality of life ( 7 ), medication adherence ( 89 ), sleep health ( 21 ), nursing home-acquired pneumonia ( 90 ), polypharmacy ( 82 ), hypertension status ( 32 ), hospitalization ( 90 ), presence of chronic neurological illness ( 69 ), low self-rated health ( 82 ) and various health conditions, such as insomnia, memory loss, constipation, slowness, chronic obstructive pulmonary disease, and osteoarthritis ( 64 ).

Functional ability with IC

IC predicted functional difficulty parameters, including the future incidence of ADL ( 20 , 24 , 27 , 35 , 74 – 81 ), IADL (20, 24, 27, 31, 66, 74, 76, 78, 82, 83), Frailty ( 24 , 84 – 88 ), disability/functional decline/dependence ( 6 , 28 , 65 , 75 ), and have shown cross-sectional associations with ADL ( 7 , 23 , 25 , 69 ), frailty ( 7 , 25 , 63 ) and IADL ( 7 , 23 , 25 , 63 ). Moreover, IC was associated with fragility fracture ( 99 ), nursing home stay ( 35 ), life-space mobility ( 30 ), falls ( 24 ), incontinence ( 64 , 82 ), and sarcopenia ( 18 ).

Measurement and validation of IC and its domains

Various approaches have been utilized in the process of constructing IC, each involving a different number and type of domain. Although most studies (n=38; 45%) utilized the five domains methodology ( 6 , 7 , 24 , 26 – 28 , 30 , 31 , 55 – 57 , 62 , 64 , 71 , 74 , 79 , 81 , 84 , 85 , 94 , 96 , 98 , 103 – 107 ), seven studies utilized the bifactor structure (with one general domain (IC) and five sub-domains) ( 20 , 22 , 23 , 35 , 66 , 67 , 86 ). Five of these studies ( 20 , 23 , 35 , 66 , 67 ) comparing the goodness of fit when the bifactor approach was applied instead of the correlated factors and hierarchical model options found that the bifactor structure has better model fit statistics. Eight other studies adopted the six domains construct by dividing the sensory domain into two components, namely hearing and vision ( 21 , 33 , 75 , 83 , 87 , 89 , 91 , 108 ), whereas eleven studies considered only four domains by excluding the sensory domain ( 34 , 59 – 61 , 70 , 73 , 77 , 88 , 90 , 93 , 102 ) and another two studies used four domains excluding the cognition domain ( 16 , 17 ). Three studies utilized other methods, including seven domains ( 65 ), eight domains ( 78 ), and no domain but summing up indicators directly ( 5 ).

Studies comparing the traditional (correlated factors) method, the bifactor method, and the hierarchical method consistently demonstrate that the bifactor model provides a superior fit compared to both the hierarchical model and the correlated factors models ( 20 , 23 , 35 , 66 , 67 ). In measuring IC, various methods have been used, ranging from simple approaches involving a single variable to complex composite assessments. Details of all methods used to operationalize each domain under the reviewed articles are shown in Table 2 (Table 2 ).

Computation of IC scores

Sixty-seven articles have created IC composite scores. Standard methods for constructing IC composite scores involve using factor analysis or principal component analysis ( 7 , 25 , 73 ), in line with original research relating to IC ( 20 ). Out of the nine studies utilizing factor analysis methods, two employed the traditional correlated five-factors approach ( 30 , 98 ), while the remaining seven utilized the bifactor method, incorporating five specific factors and one general factor ( 20 , 22 , 23 , 35 , 66 , 67 , 86 ).

However, the majority 32 (47.8%) papers calculated the IC score by summing individual IC domains scores without weighting, using either a two-point scale (0-impaired/bad and 1-unimpaired/good) or a three-point scale (0-impaired, 1-slightly impaired, or 2-unimpaired) ( 18 , 19 , 21 , 24 , 32 , 33 , 55 – 58 , 61 – 64 , 68 , 69 , 71 , 74 , 75 , 80 , 82 – 85 , 94 , 95 , 97 , 100 , 106 , 109 , 113 , 114 ). Other ways employed to compute IC were averaging the z-scores of the domains ( 70 , 72 , 81 , 90 , 93 , 96 , 102 ), direct summation of the values of indicators ( 5 , 16 , 17 , 88 , 101 , 115 ), the latent growth modeling (LGM) method ( 31 ), weighted linear combination of indicators with loading greater than 0.3 ( 78 ), direct summation of indicators associated with domains in the regression model ( 26 , 65 , 79 ), averaging the domains’ average values ( 28 , 59 , 60 ), and a 2-parameter domains item response theory (IRT) which refers to direct categorization of IC as “0” for impairment in any domain and “1” for no impairment in any of the domains ( 6 , 27 ).

Some eight years since the WHO redefined Healthy Aging, there has been an exponential growth in research relating to IC, with almost all publications in the last 2 years and the majority (61%) leveraging data from Asia. Whilst studies have explored the association and predictive ability of IC with inflammatory, lifestyle, health, and socio-economic factors, research relating to genes and IC is rare. Many methods have been used to assess and score IC, making it vital that a consensus is reached globally.

While specific studies estimating the heritability of IC are currently lacking, evidence based on the five IC domains suggests a heritability range of 20–85%; specifically, genetic factors contribute to the variability in cognitive 50–70% ( 37 – 39 ), sensory 20–30% ( 40 – 43 ), locomotor 30–85% ( 44 – 47 ), vitality 25– 65% ( 48 – 50 ) and psychological 35–70% ( 51 – 54 ) domains. There has been one attempt, through a candidate gene study approach, to identify genes associated with the broader IC domain. This particular study showed a significant association of IC with ApoE carriage ( 26 ). Understanding the interaction between genes and environment (including lifestyle factors) and IC is important. Before this, it is essential to identify genetic markers associated with IC. Such research may confirm the benefits of lifestyle or behavioral changes in helping people age well, including allowing the personalization of this intervention to the individual.

As outlined in the results section, our scoping review introduces new elements beyond those explored in the initial review addressing adverse health outcomes associated with IC. In addition to investigating biological and inflammatory biomarkers which are new, this review also identifies additional factors previously unexplored, which are related to socioeconomic (such as educational status, economic standing, marital status, ethnicity, residence, housing index, and social engagement); functional ability (such as fragility fracture, life-space mobility, nursing home stay, incontinence, and sarcopenia are also assessed); morbidity and mortality (such as multimorbidity, medication adherence, polypharmacy, hospitalization and its associated complications, sleep health, cardiovascular diseases mortality, and respiratory diseases mortality which were not addressed in the previous review) and behavioral and lifestyle-related factors (such as exercise, alcohol consumption, smoking, eating habits, and dietary patterns).

In the context of developing IC indices, no consistent method has been used thus far. New indicators for IC domains continue to be used, often without goodness of fit testing. Goodness of fit tests must be done while new indicators are used to determine whether those indicators are appropriate ( 118 ). Similarly, some studies used quick and direct tools, and others employed more complex and time-consuming composite measures. Balancing the precision of variable measurement with tool simplicity is crucial, and in the realm of measurement science, it is recommended to utilize straightforward yet robust instruments to assess variables like IC ( 119 , 120 ). Studies also reveal that the bifactor method correlates with the five factors method and performs better than the correlated factors and hierarchical methods ( 20 , 23 , 35 , 66 , 67 ). There is also evidence of better explanatory power of the bifactor model when compared to the other two methods ( 121 – 123 ). Whilst evidence supports that the bifactor method results have better conceptual clarity and fit than the other structures, the lack of standardization may introduce bias (128).

Furthermore, there needs to be an effort to reach a consensus in defining indicators for individual domains. Consensus about the indicators and methods is necessary to inform the planning of future cohort studies. Planned cohort studies, as opposed to leveraging already collected data, may have the advantage of enabling the collection of appropriate indicators to measure IC. Two primary approaches are being applied to compute the IC composite score: the CFA ( 20 , 22 , 23 , 30 , 66 , 67 , 86 , 96 ) and the arithmetic sum/average of the values of the domains ( 19 , 24 , 32 , 55 – 58 , 62 – 64 , 71 , 74 , 75 , 82 , 84 , 85 , 94 , 106 , 114 ). Both have demonstrated good construct and predictive validity. Concerning the approaches for measurement, the reflective versus formative nature of the IC measurement (i.e. whether IC should be considered as an underlying latent trait of all capacities or an aggregate summary measure of the subdomain capacities) shall also be considered in future studies ( 124 ).

Limitations and Strengths

The major strength of this review is that we followed a rigorous and stepwise screening process with the involvement of independent assessors. The findings were reported following the JBI’s PRISMA guideline extension for scoping review (PRISMA-ScR). The scope of the literature search was limited to peer-reviewed articles, and as a result, unpublished studies and organizational reports were not included. Due to logistic limitations, only articles published in the English language were reviewed, although studies published in other languages may have provided information on the external validity of IC tools in a multicultural setting.

Conclusion and recommendations

Since the introduction of IC for defining healthy aging and functional capacity, extensive research has been conducted to measure these indices and validate them, as well as to assess their relevance in medical, social, and behavioral sciences. This review identifies that there is a knowledge gap (no evidence) when it comes to our understanding of the genetics of IC. Such understanding can be improved by leveraging existing longitudinal studies but there is also a need for planned cohort studies where IC measurements are collected prospectively, and genetic data is also available. This review highlights the current difficulties in comparing existing studies given the lack of standardization in defining indicators that ought to be collected for each IC domain and how best to assess and score IC. Reaching such consensus is imperative because it will not only define the approach for the use of already collected data but will also support the planning and conduct of new longitudinal studies focused on IC and functional ability. The pooling of data globally to advance our understanding collectively would also be more likely through a standardized approach.

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Acknowledgments

MB Beyene is Ph.D. student with scholarship support from University of Adelaide (The University Adelaide Research Scholarship).

Funding: AT Amare is currently supported by the National Health and Medical Research Council (NHMRC) Emerging Leadership (EL1) Investigator Grant (APP2008000). Open Access funding enabled and organized by CAUL and The University of Adelaide.

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Beyene, M.B., Visvanathan, R. & Amare, A.T. Intrinsic Capacity and Its Biological Basis: A Scoping Review. J Frailty Aging (2024). https://doi.org/10.14283/jfa.2024.30

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Bicycling over a Lifetime Is Associated with Less Symptomatic Knee Osteoarthritis: Data from the Osteoarthritis Initiative

Affiliations.

• 1 Division of Rheumatology, Allergy, & Immunology, Tufts Medical Center, Boston, MA.
• 2 Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA.
• 3 Department of Kinesiology, Michigan State University, East Lansing, MI.
• 4 Department of Medicine and Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD.
• 5 University of Arizona Arthritis Center, University of Arizona College of Medicine, Tucson, AZ.
• 6 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
• 7 Department of Medicine, Baylor College of Medicine, Houston, TX.
• 8 Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, MA.
• PMID: 38600648
• DOI: 10.1249/MSS.0000000000003449

Introduction: To evaluate the relationship between a history of bicycling and symptomatic and structural outcomes of knee osteoarthritis (OA), the most common form of arthritis.

Methods: This was a retrospective, cross-sectional study within the Osteoarthritis Initiative (OAI), where we investigated OAI participants with complete data on bicycling, knee pain, and radiographic evidence of knee OA. We used a self-administered questionnaire at the 96-month OAI visit to identify participation in bicycling during four time periods throughout a participant's lifetime (ages 12-18, 19-34, 35-49, and > 50 years old). Using logistic regression, we evaluated the influence of prior bicycling status (any history, history for each time period, number of periods cycling) on three outcomes at the 48-month OAI visit: frequent knee pain, radiographic OA (ROA), and symptomatic radiographic OA (SOA), adjusting for age and gender.

Results: 2607 participants were included; 44.2% were male; mean age was 64.3 (SD 9.0) years; body mass index was 28.5 (SD 4.9) kg/m 2 . The adjusted risk ratio for the outcome of frequent knee pain, ROA, and SOA among those who reported any history of bicycling compared to non-bicyclers was 0.83 (0.73-0.92), 0.91 (0.85-0.98), and 0.79 (0.68-0.90), respectively. We observed a dose-response among those who participated in bicycling during more time periods.

Conclusions: People who participated in bicycling had a lower prevalence of frequent knee pain, ROA, and SOA. The benefit appeared cumulative. This study indicates that bicycling may be favorable to knee health and should be encouraged.

Copyright © 2024 by the American College of Sports Medicine.

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Conflict of interest statement

Conflict of Interest and Funding Source: This work was supported by K23 AR062127, a National Institutes of Health/ National Institute of Arthritis and Musculoskeletal and Skin Diseases funded mentored award, providing support for the design and conduct of the study, analysis, interpretation of the data, and preparation and review of this work to [GHL]. This work was supported in part with resources at the VA’s Health Services Research and Development Service Center for Innovations in Quality, Effectiveness, and Safety (#CIN 13-413), at the Michael E. DeBakey VA Medical Center, Houston, TX to [GHL]. This research was supported in part by generous donations to the Tupper Research Fund at Tufts Medical Center. The Osteoarthritis Initiative is a public-private partnership comprised of five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the Osteoarthritis Initiative Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation, GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the Osteoarthritis Initiative is managed by the Foundation for the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institutes of Health, or the Department of Veterans Affairs. We also confirm the independence of researchers from funders and that all authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis is also required. The sponsors had no role in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. JBD declares that he is a consultant for Pfizer Inc. and Eli Lilly and Company. TEM declares that he is a consultant for Remedium-Bio, Anika, Chemocentryx, Grunenthal, Kolon Tissue Gene, Novartis, BioSplice, MEDIPOST, Organogenesis, and Pfizer Inc. The other authors state they have no conflict of interest concerning this work.

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