Introduction
In patients with knee osteoarthritis (OA), lower muscle strength is associated with disease progression and activity limitations [
1‐
3]. Lower muscle strength in this group of patients is determined by several factors, including pain, avoidance of activities, and aging [
4,
5]. More recently, evidence from cross-sectional studies has suggested that inflammation is an additional factor influencing muscle strength in patients with knee OA [
6,
7].
A low grade of inflammation has been reported [
8‐
10] in patients with OA, and slight or moderate elevations of inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been described [
8,
11‐
15]. Recently, two cross-sectional studies have found an association between elevated inflammatory markers and lower muscle strength in patients with knee OA [
6,
7]. Although the mechanism has not been fully clarified, the association between elevated levels of inflammatory markers and muscle strength might be explained by the catabolic effect of inflammatory markers on muscle tissue [
16]. Elevated levels of inflammatory markers might also contribute to reducing the muscle’s regenerative potential, probably through lowering protein synthesis rates [
17]. Longitudinal studies analyzing the association of long-term inflammation with changes in muscle strength in patients with OA are needed in order to better understand the influence of inflammation on muscle strength. We hypothesized that if in patients with knee OA inflammatory markers (i.e., CRP and ESR) are elevated at both baseline and 2-year follow-up, this will be associated with a lower gain or decrease in muscle strength compared with patients who do not have elevated levels at both assessments.
Discussion
This study investigated the association of elevated serum inflammatory markers (i.e., CRP and ESR) and changes in knee muscle strength in a group of patients with established knee OA, for a period of 2 years. We found that a persistently elevated level of serum CRP values was associated with lower gain in muscle strength compared with patients with not elevated levels at both times of assessment. Previous studies have documented the cross-sectional relationship between elevated inflammatory markers and lower muscle strength in patients with knee OA [
6,
7]. However, to the best of our knowledge, this is the first study on the longitudinal association between levels of serum inflammatory and knee muscle strength in patients with knee OA.
There was an overall increase in knee muscle strength after 2 years in the study population. The improvement of muscle strength could be explained by the fact that the patients in this study were initially referred to our outpatient rehabilitation center to receive medical attention, and 80% of the study population reported that they had received some type of physical therapy intervention during the follow-up period. This may have resulted in increased muscle strength.
The relationship between elevated inflammatory markers and lower knee muscle strength is consistent with findings from previous cross-sectional studies carried out in patients with OA [
6,
7,
33], in patients with RA [
34], and in the general older population. Schaap and colleagues [
35] described an association between baseline elevated serum inflammatory markers and a decline in knee and hand strength after 5 years in a group of older adults [
36].
In the present study, when change in BMI [
29] at 2 years was incorporated in the fully adjusted model, elevated levels of serum CRP at both baseline and 2-year follow-up were still significantly associated with lower gain in muscle strength compared with patients with not elevated levels at both times of assessment. Nevertheless, in our previous cross-sectional study, the association between inflammatory markers and muscle strength was not independent of BMI [
6]. A possible production and secretion of several pro-inflammatory cytokines by the adipose tissue or a non-hepatic production of CRP through the stimulation of adiposities or both might help to explain the strong association, previously reported, between systemic inflammatory markers and BMI [
32,
37,
38]. BMI is a relevant confounder in the association between inflammatory markers and muscle strength. However, small changes in BMI over time do not influence the association between elevated inflammatory markers and change in muscle strength.
In older adults, elevated levels of inflammatory markers have been associated not only with lower muscle strength but also with loss of muscle mass and sarcopenia [
29,
35,
39]. These associations might be explained by the catabolic effect of inflammatory markers on muscle tissue [
16,
40]. Higher levels of inflammatory factors might contribute to reducing the muscle’s regenerative potential, probably through lowering protein synthesis rates in the skeletal muscle [
17]. Additionally, results from studies carried out in rats suggested that inflammatory factors might cause muscle breakdown [
41,
42]. Bodell and colleagues [
43] indicated that long exposure of skeletal muscle to interleukin-6 (IL-6) can retard muscle growth in rats, possibly due to the interaction with key growth factors. Although these mechanisms have not been intensively studied in humans, the same mechanism found in rat models might be involved in the development of muscle weakness in patients with knee OA.
The changes in muscle strength after 2 years were not associated with persistently elevated levels of serum ESR. A possible explanation is that ESR can be affected by multiple factors such as gender, age, temperature, smoking, levels of plasma proteins, and red blood cell factors [
44]. Additionally, ESR is less sensitive than CRP to changes in the onset of acute inflammation and has shown low/moderate reproducibility with a wide range of normal results compared with the high reproducibility of CRP with a narrow range of normal results. Looking at different inflammatory markers—i.e., IL-6 and tumor necrosis factor (TNF)—in future studies might provide further support for the long-term association between inflammation and muscle strength.
There were no statistically significant differences in muscle strength changes in the groups with elevated inflammatory markers at only one point of assessment (baseline or follow-up) compared with the reference group (not elevated levels at both baseline and follow-up), before or after adjusting for relevant confounders. We suggest that longer exposure of skeletal muscle tissue to elevated levels of inflammatory markers might be required to induce changes in muscle strength, especially when using systemic inflammatory markers such as CRP, which is highly sensitive to changes in the onset of acute-phase response. On the other hand, it is important to consider that the small number of subjects in the groups with elevated inflammatory markers at only one time of assessment might have affected these results.
Some limitations of this study have to be considered. First, 25% of patients dropped out of the study at follow-up. However, the relevant baseline characteristics were not statistically different between patients who completed and those who did not complete the follow-up assessment, and this makes us believe that this loss of patients at follow-up did not impact the results of our study. Second, although this is a longitudinal study, we can prove only that associations exist, but it is not possible to establish the causality underlying them. Therefore, further experimental studies should be undertaken to clarify the causality. Third, the absence of standard conditions at the time of the blood collection (i.e., fasting conditions, preceding physical activity, time of sample collection, and so on) might have caused random variations in the levels of inflammatory markers. However, in the present study, blood samples were collected as part of the medical care, and additional parameters could not be controlled. Fourth, we gathered information on inflammatory markers and muscle strength at baseline and at 2-year follow-up, but we have no information about those variables in between these measurement points. Studies that include more than two time measurements might be necessary to further understand the longitudinal association between inflammation and muscle strength. Fifth, information about the percentage of body fat of the patients was not available. Therefore, we cannot conclude whether changes in fat mass during the follow-up period were or were not associated with changes in CRP and ESR levels. However, BMI, a proxy measure of body composition, was used as a potential cofounder in the present study. Sixth, in the present study, only knee muscle strength was assessed. However, other skeletal muscles might be affected by persistently elevated levels of inflammatory markers. A key strength of our study is the large number of patients with knee OA (n = 186) studied and the longitudinal design, compared with the smaller sample populations included in previous cross-sectional studies [
7,
45].
From a clinical perspective, the results of this study may contribute to more targeted treatment. Although further evidence is needed, targeting low-grade inflammation by pharmacological, nutritional, or lifestyle factors [
46] or a combination of these might contribute to limiting sarcopenia and decreased muscle strength in patients with knee OA. On the other hand, it is possible that an increase in muscle strength (through muscle training) contributes to a decrease in circulating inflammatory markers in patients with OA. In this respect, previous literature has suggested that physical activity might contribute to mitigating inflammation [
47]. Furthermore, decreases in circulating levels of inflammatory markers (i.e., CRP and TNF) were associated with an increase in muscle strength in a group of post-menopausal women receiving resistance training [
48] as well as in older individuals with knee OA receiving a whole-body vibration program [
49]. It is also feasible that both mechanisms are involved. Indeed, further longitudinal studies involving controlled and tailored interventions are needed to elucidate the clinical relevance of the association between inflammation and lower muscle strength in patients with knee OA.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
DCS-R, MvdL, and JD participated in the conception and design of the study, contributed to the statistical analysis of data and to the interpretation and preparation of results, and helped to draft the manuscript. MvdE and WFL participated in the conception and design of the study. SV participated in the conception and design of the study and contributed to the statistical analysis of data and to the interpretation and preparation of results. LDR participated in the conception and design of the study and contributed to the acquisition of data, to the statistical analysis of data, and to the interpretation and preparation of results. JHvD contributed to the statistical analysis of data and to the interpretation and preparation of results. All authors read and approved the final manuscript.