Connections between atherosclerosis and osteoarthritis – a literature review

Introduction

Osteoarthritis (OA) is the most common joint disease, primarily affecting older individuals. According to projections by the United Nations, by 2010, OA was expected to affect 25% of the population in the Western world aged over 65 years [1]. It is the leading cause of disability in this age group. The etiology of OA remains largely unknown and is considered multifactorial, involving factors such as mechanical overload, obesity, trauma, joint inflammation, repetitive movements, and genetic predispositions [2].
Although OA has traditionally been associated with obesity, primarily due to mechanical overload of the joints, newer research suggests that it is also a metabolic disease. This is supported by observations that it often affects joints that do not bear body weight. Changes in lipid metabolism may be a key factor in the pathogenesis of OA [3]. Adipokines, such as leptin and adiponectin, play a significant role in regulating inflammatory processes in the joints. Additionally, epidemiological studies have shown a link between high blood cholesterol levels and the development of OA [4].
An intriguing observation is the early deposition of lipids in the joints, even before the appearance of histological changes. Proteomic analyses demonstrate significant correlations between OA and lipid metabolism, while studies on gene expression suggest dysregulation of processes related to cholesterol influx and efflux, as well as the expression of genes associated with lipid metabolism [5–7].
Atherosclerosis, on the other hand, is a degenerative disease in which lipids and their metabolism play a key role. Given the similarities in the pathogenic mechanisms of OA and atherosclerosis, there is speculation that chondrocytes in OA may transform into foam cells, potentially opening new therapeutic avenues based on knowledge gained from atherosclerosis research [8]. Clinical manifestations of atherosclerosis, such as coronary artery disease, heart attack, and stroke – which are the leading causes of morbidity and mortality in developed countries – primarily occur in middle-aged and elderly individuals [9, 10].

The aim of the study

The aim of this study is to analyze the impact of atherosclerosis on the development and progression of OA. The study seeks to enhance understanding of the pathophysiological mechanisms that may link these two degenerative diseases, with a particular focus on the role of lipid metabolism. The intended outcome is to identify new therapeutic targets derived from atherosclerosis research that could be applied to the treatment of OA.

Methodology

This study was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure a transparent approach to literature selection and analysis. A comprehensive literature search was performed in the PubMed, Elsevier, NCBI, and Google Scholar databases, including publications available in both Polish and English, covering the years 2005–2025. The search used the following key words and their combinations: “atherosclerosis” and “osteoarthritis,” “lipid metabolism” and “osteoarthritis,” and “adipokines” and “osteoarthritis”.
The inclusion criteria encompassed studies and review articles analyzing the relationship between atherosclerosis and OA, publications discussing the role of lipid metabolism and adipokines in both conditions, and articles published in peer-reviewed journals. Exclusion criteria involved studies with low methodological quality or lacking relevant data, publications that were not directly related to the topic, and duplicated studies or those without new scientific contributions.
The initial search identified 103 studies. After removing 15 duplicates, 88 publications remained for further analysis. Following title and abstract screening, 21 additional articles were excluded due to irrelevance. The full texts of 67 publications were assessed, out of which 10 studies were excluded as they were used only for theoretical background and did not contribute to the review. Ultimately, 57 publications were included in the final review (Fig. 1).

Common features of the etiopathogenesis of atherosclerosis and osteoarthritis

Osteoarthritis and atherosclerosis are chronic diseases that develop subclinically over a long period and, at first glance, seem unrelated. The generally accepted definition of OA states that it is the progressive degradation of articular cartilage along with associated changes in the subchondral bone layer, synovial fluid, synovial membrane, and other structures supporting the proper functioning of the joint [10]. Atherosclerosis, on the other hand, is the most common form of cardiovascular disease, rooted in the accumulation of lipids and inflammation of arterial vessels, which can ultimately lead to clinical complications [11].
Both disease entities, despite appearing unrelated, share several common pathomechanisms. The current hypothesis even suggests that atherosclerosis is a key factor leading to the progression of OA and the occurrence of its troublesome symptoms [12]. Among the common factors confirming the connection between the two entities is the transmembrane protein Z39Ig. Its presence is detected both in foam cells located in atherosclerotic carotid arteries and in the synovial membrane of joints where degenerative changes have been observed [13]. Another confirmation of the interaction between these diseases is a study on an animal model. It was shown that chronic inflammatory states occurring in the course of OA led to increased synthesis of factors responsible for inflammation, which translated into plaque instability and increased vascular changes [14].
A common confirmed risk factor for both OA and atherosclerosis is obesity. It is believed that metabolic syndrome, which includes obesity among other factors, predisposes to the development of atherosclerosis and OA – especially of the hand – through a constant low-grade systemic inflammatory state. The direct impact of weight gain translates primarily into an increased risk of changes in the knee joint [15, 16]. A number of studies have shown a correlation between increased body weight and the development of OA in weight-bearing joints [17, 18]. However, this did not explain the increased frequency of changes in small joints of the hand, such as proximal interphalangeal and distal interphalangeal joints (i.e., proximal and distal interphalangeal joints), in individuals who simultaneously had conditions like obesity or atherosclerosis, which suggests a metabolic character [19–21].
Current studies highlight the influence of adipokines such as adiponectin, resistin, and leptin in the development of OA. Their levels correlate with the amount of adipose tissue, which explains the metabolic nature of changes resulting from obesity [22, 23]. Adiponectin plays a protective role in joints by inhibiting cartilage destruction. It increases the amount of tissue inhibitor of metalloproteinases-2 and decreases MMP-13. Obesity leads to a decrease in adiponectin levels [24]. It is noteworthy that in patients with advanced OA, an increase in adiponectin concentration is observed [25]. All these data suggest a very important role of adiponectin in the pathomechanism of OA [26].
Leptin is a peptide hormone that primarily influences the regulation of food intake and body weight. It acts pro-inflammatory and affects angiogenesis and lipolysis [27, 28]. In obese individuals, its level is elevated [29]. The main mechanism predisposing to the development of OA associated with increased leptin levels appears to be its pro-inflammatory nature [30].
An increase in leptin concentration correlates positively with an increase in IL-6, which can lead to decreased synthesis of proteoglycans necessary for the construction of articular cartilage. Additionally, it inhibits the NOTCH pathway and stimulates MMP-13, which further intensifies cartilage degeneration [31, 32]. Studies on obese mice in which the action of leptin was nullified showed that they did not have an increased incidence of OA, indicating a crucial but indirect influence of leptin on the development of this disease entity [33].
Resistin is a protein hormone secreted by macrophages [34]. It plays a major role in obesity, insulin resistance, diabetes, as well as in rheumatoid arthritis and OA [35, 36]. It influences the development of OA by stimulating increased production of pro-inflammatory cytokines, increasing the synthesis of enzymes causing cartilage degradation, and decreasing the synthesis of structural proteins of hyaline cartilage [37, 38]. Moreover, some studies confirm that point mutations in the resistin gene (–420 C > G and +299 G > A) are associated with a higher frequency of degenerative changes in the knee joint. This emphasizes the very important influence of this adipokine on the pathomechanism of this disease [39].
One of the main and most important causes of the development of atherosclerosis is hypercholesterolemia [40]. A number of studies also suggest that it may have an impact on the development of OA [41, 42]. This is indirectly confirmed by studies in which it was observed that the introduction of supplementation with polyunsaturated omega-3 fatty acids had a beneficial effect on cartilage composition and reduced pain sensations in patients [43, 44].
The occurrence of cardiovascular diseases, including atherosclerosis, in the presence of osteoarthritic changes in specific joints
As society ages, the prevalence of cardiovascular diseases, including atherosclerosis, is becoming increasingly common. This disease is one of the factors promoting the development of OA [45], making it crucial to understand the correlation between the severity of the atherosclerotic process and OA for proper treatment. Osteoarthritic changes most commonly affect the knee, hip, spine, and hand joints, but the disease can affect any joint [46]. Obesity plays a significant role in the pathogenesis of this disorder as excessive load on specific joints leads to fibrosis and degradation of cartilage tissue [47]. This disease also affects joints that are not subjected to excessive body weight, such as hand joints, which are more frequently affected in overweight individuals than in those with a normal weight [48]. This suggests that OA is a condition in which pathogenesis is influenced not only by chronic excessive joint loading but also by a broad range of metabolic disorders associated with lipid dysregulation and, consequently, atherosclerosis. Therefore, analyzing the impact of dyslipidemia on OA development is essential to planning appropriate treatment, which should not only focus on non-pharmacological interventions such as physical exercise, diet, and proper management of mechanical joint load but also include pharmacological therapy aimed at reducing lipid levels. During the study, a review of publications was conducted to observe the relationship between the occurrence of atherosclerosis and OA diagnosed in the knee joint, spinal joints, and hand joints.
All studies included in Table 1 demonstrated a significant association between atherosclerosis and OA, with odds ratios (OR) ranging from 1.39 [49] to 3.33 [50].
The strongest correlation was observed in hand joints, suggesting that atherosclerotic changes may influence degenerative processes even in joints that are not subjected to constant mechanical loading [50].
The results of Koutroump et al. [51] and Wang et al. [50] indicate a clear link between the presence of atherosclerosis and hand OA, supporting the hypothesis that OA is not only a mechanical disorder but also a metabolic disease. This suggests that dyslipidemia and chronic inflammatory processes play a key role in the pathogenesis of OA, regardless of the patient’s body weight.
Belen et al. [53] found a correlation between atherosclerosis and OA in the knee joint (OR = 1.43), while Estublier et al. [54] confirmed a similar association in the spine (OR = 1.44). These findings suggest that atherosclerosis may affect both weight-bearing joints (knee, spine) and non-weight-bearing joints (hands), implying common pathophysiological mechanisms such as microcirculatory disturbances and chronic inflammation.
Different diagnostic techniques were used across studies: ultrasonography of the carotid arteries, X-ray imaging of the spine, Kellgren-Lawrence scale. Variations in methodology may affect the comparability of results and highlight the need for standardization in future research. The findings suggest that OA treatment should not only focus on pain management and rehabilitation but also include the control of cardiovascular risk factors, such as hypercholesterolemia and hypertension. Lipid-lowering pharmacotherapy (e.g., statins) could potentially have a protective effect on cartilage, but further clinical studies are needed to confirm this hypothesis.
The results indicate a positive correlation between the presence of atherosclerotic changes in blood vessels and the frequency of OA development in the hand joints. This supports the involvement of metabolic factors in the pathogenesis of OA. Similarly, when the disease affects other joints, such as the spine, these factors play a significant role. However, in such cases, an additional component – obesity – substantially worsens the course of the disease through mechanical compression of the joints, demonstrating a correlation between disease prevalence and body weight [57]. It is worth noting that increased body weight does not always translate to abnormal fat tissue volume. The development of OA in specific joints is also influenced by the distribution of fat tissue (subcutaneous or visceral), its volume, and metabolic disorders [58]. This complexity in the pathogenesis of OA should encourage a detailed analysis of risk factors for disease development to tailor prevention strategies. These strategies should include weight reduction, dietary modification, adjustment of physical activity, and lipid-lowering treatment [59, 60].

The impact of the pleiotropic effects of statin therapy on the development and progression of osteoarthritis

When the first statin – lovastatin – entered the pharmaceutical market in 1987, its primary purpose was to reduce blood cholesterol levels and address its related complications. Today, it has been revealed that the use of statins may be broader than previously assumed [61]. The mechanism underlying the action of these substances is the inhibition of HMG-CoA reductase, which plays a key role in the synthesis of many chemical compounds, including cholesterol [62]. Elevated cholesterol levels lead to health-threatening atherosclerosis, which is a dominant cause of OA progression [63]. Moreover, a correlation has been demonstrated between high cholesterol levels in OA patients and increasing joint pain [64].
Statins, characterized by their pleiotropic effects, inhibit the progression of OA not only by reducing cholesterol levels but also by mitigating inflammation. They inhibit, among other factors, interleukin IL-1, which plays a critical role in this process, modulating chronic inflammation, a factor that increases discomfort in patients [65]. Statins also possess chondroprotective properties, which more effectively protect the joint from degradation [66].
A Mendelian randomization study conducted in 2022 demonstrated that individual statins differ in their range of action and have varying protective effects on specific joints. This finding holds significant value for OA therapy using these substances [67]. The results of this study are presented in Table 2.
Appropriate and skillful use of statins in therapy can bring numerous benefits in the treatment of OA. However, further research is needed on this topic, particularly regarding the beneficial effects of specific statins on particular joints.

Conclusions

Osteoarthritis and atherosclerosis predominantly affect older individuals and lead to a reduced quality of life, often resulting in disability. Both can be classified as metabolic diseases. While this is widely acknowledged for atherosclerosis, it is less commonly recognized for OA. Osteoarthritis can affect any joint, and its metabolic nature is evident in its involvement of smaller, non-weight-bearing joints, such as those in the hand. The early pathomechanism of both diseases appears to be similar. It is also believed that atherosclerotic changes predispose individuals to joint degeneration.
Adipokines (adiponectin, resistin, leptin) and other factors such as the Z39Ig protein seem to play a crucial role in the pathogenesis of both diseases, suggesting shared degenerative and inflammatory pathways among these patients. Osteoarthritis is accompanied by inflammation and oxidative stress, which contribute to metabolic changes and, consequently, an increased risk of atherosclerosis. For example, leptin indirectly influences cartilage degeneration through IL-6 synthesis, leading to chronic inflammation – a factor in the development of both atherosclerosis and OA. It is also hypothesized that atherosclerosis impairs the blood supply to the synovial membrane, predisposing it to degenerative changes.
Obesity, a component of metabolic syndrome, plays a role in the development of both OA and atherosclerosis. It also exacerbates disease progression, highlighting the importance of patient education, encouraging physical activity, and adopting an appropriate diet. Statins, commonly used to treat atherosclerosis, exhibit pleiotropic effects, suggesting they might modulate the progression of degenerative changes in OA. They reduce inflammation and have chondroprotective properties. Although statin therapy is not specifically used for OA, it should be noted that these patients often have comorbidities. Using statins in such cases, primarily for treating atherosclerosis, appears to have a protective effect on joints. Rosuvastatin seems to be the best option, but further research is essential in this area. A key strength of this study is its comprehensive analysis of research on pathophysiological mechanisms and potential therapeutic interventions. The interdisciplinary approach, combining knowledge from orthopedics, rheumatology, and cardiology, opens new therapeutic directions and may contribute to the development of innovative treatment strategies.
The main limitations of this review include the diverse diagnostic methods used in the analyzed studies, which may affect result comparability. Additionally, most of the included research is based on observational and experimental studies, while clinical evidence regarding the impact of metabolic therapies on OA remains limited. Another confounding factor is obesity and other metabolic disorders, which may independently influence OA development, making it difficult to assess the direct impact of atherosclerosis. In conclusion, both OA and atherosclerosis share a similar etiopathogenesis, which may help uncover new therapeutic methods for OA patients in the future, leveraging insights from atherosclerosis therapy.

Disclosures

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

References