Effects of antioxidant consumption on physical rehabilitation variables and quality of life in people with osteoarthritis: Protocol for a systematic review with meta-analysis

Introduction

Osteoarthritis (OA) is characterized by clinical symptoms and radiological indicators. While cartilage plays a pivotal role in its development, OA is a multifactorial disorder that affects the joint tissue components and its periphery.¹ This condition is often accompanied by bone neoformation and synovial proliferation, which can result in pain, loss of joint function, and disability.^2,3 Globally, the prevalence of osteoarthritis is 22.9% among individuals aged > 40 years.⁴ It is one of the most common and disabling forms of the disease, followed by hip osteoarthritis.⁵ This condition involves systemic factors such as increased body mass, chronic low-grade inflammation, progressive functional disability, and oxidative stress.^6–8 The primary risk factors include age, obesity, history of injuries, and abnormal load, with these factors interacting concurrently.⁹ Collectively, osteoarthritis is a prevalent cause of pain, functional impairment, and diminished quality of life in adults.^10,11

In accordance with the guidelines set forth by the National Institute for Health and Care Excellence (NICE), the therapeutic management of osteoarthritis primarily emphasizes symptom control. In terms of non-pharmacological strategies, the guidelines advocate for therapeutic exercise, patient education, and weight reduction.¹² Regarding pharmacological interventions, analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are the principal pharmacological strategies.¹³ Nevertheless, the extended or unsupervised use of these medications poses considerable risks, including adverse gastrointestinal, cardiovascular, and renal effects.^14–16 This scenario has led to the pursuit of safer, more sustainable, and long-term therapeutic alternatives.

Excessive production of reactive oxygen species (ROS) and ROS-induced lipid peroxidation are implicated in the pathogenesis of osteoarthritis.² As oxidative stress intensifies, there is a concomitant increase in collagen degradation, indicating that ROS play a crucial role in the catabolism of the collagen matrix.¹⁷ Antioxidants have emerged as a potentially advantageous intervention.^18,19 Antioxidants, which are naturally found in foods and supplements,²⁰ can neutralize free radicals and modulate inflammatory processes, both of which are integral to the pathophysiology of osteoarthritis.²¹ Compounds such as curcumin, vitamin D, resveratrol, and other antioxidants have been investigated for their potential beneficial effects on chronic diseases, including osteoarthritis.^22–24 Specifically, turmeric, owing to its anti-inflammatory and antioxidant properties, has demonstrated positive effects in alleviating pain associated with osteoarthritis²⁵ by suppressing the expression of various pro-inflammatory cytokines, thereby mitigating pain and cartilage degeneration.¹⁷ Similarly, the consumption of flavonoids has been shown to reduce TNF-α expression, as evidenced by existing research.²⁶

A recent systematic review indicated promising outcomes concerning the use of oral antioxidants for the prevention and alleviation of symptoms in individuals with osteoarthritis. Nevertheless, the existing evidence is characterized by heterogeneity and inconsistency, which complicates the generalization of these findings.²⁷ Consequently, a systematic review with meta-analysis, as derived from this protocol, is intended to evaluate the effects of antioxidant-based interventions compared to standard medical care on pain, physical function, and quality of life in individuals with hip and knee osteoarthritis.

Methods

Eligibility criteria

Sources of information

A comprehensive and sensitive systematic search will be performed using the following databases: Medline via PubMed, Scopus, Web of Science, ScienceDirect, and EBSCO. Furthermore, a manual search will be conducted within the reference lists of the included studies, as well as systematic and narrative reviews and clinical practice guidelines pertinent to the subject matter. If additional data are necessary, the authors of the included studies will be contacted via email.

Search strategy

The search strategy implemented in the MEDLINE database employed both controlled vocabulary (Medical Subject Headings [MeSH]) and free-text terms. The search terms were systematically combined using the Boolean operators “OR” and “AND.” This search string will be tailored to each respective database. Table 1 delineates the search strategy used in the MEDLINE database via the PubMed search engine. Furthermore, the table has been disseminated on the figshare (figshare.com) information platform to enhance the transparency and reproducibility of the search process.

Study registration

Outcome measures

Summary of results

A quantitative synthesis will be conducted utilizing Jamovi 2.2 software. The Revman calculator will be employed to ascertain the mean and standard deviation when studies report results using alternative measures of central tendency and data dispersion.

A quantitative synthesis will be conducted using Jamovi 2.2 software. The Revman calculator will be used to ascertain the mean and standard deviation when studies report results using alternative measures of central tendency and data dispersion. A fixed-effects or random-effects model will be selected based on statistical heterogeneity, which will be assessed using the I² statistic. If the method for evaluating results is homogeneous, the mean difference (MD) with a 95% confidence interval will be utilized; otherwise, the standardized mean difference (SMD) will be employed to calculate the effect size (adjusted Hedges’ g). In cases of substantial (I2 = 50%–90%) or considerable (I2 = 75%–100%) heterogeneity, a DerSimonian and Laird random-effects model will be applied. Conversely, if heterogeneity is low (I2 = 0%–40%) or moderate (I2 = 30%–60%), a Mantel-Haenszel fixed-effects model will be applied.²⁹ A p-value < 0.05 will be considered statistically significant. Subgroup analyses will be conducted based on the type of antioxidant, osteoarthritis, and duration of the interventions. Moderator variable analysis will be performed on studies reporting data such as age, body mass index, pain duration, and others. If sufficient data are available, a dose-response analysis will be conducted based on the antioxidant dose for the variables, following the recommendations by Crippa and Orsini (2016).⁴³ Sensitivity analyses will also be conducted if clinical and methodological heterogeneity justifies it, such as restricting studies with a high risk of bias or imputing missing data for the main variables.

If the studies presented show clinical heterogeneity, are insufficient, or there are not enough studies to perform a meta-analysis, a narrative synthesis of the effects of the intervention for each variable will be performed.

Any deviations from the protocol will be documented and justified in the final report, in accordance with the PRISMA 2020 guidelines. Additionally, the corresponding information will be updated on the PROSPERO platform. Finally, synthesis and assessment of the certainty of evidence will be performed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method.

Discussion

Osteoarthritis is a significant source of pain, disability, and socioeconomic costs.^7,46 Previously, it was believed to be simply due to wear and tear; however, it is now understood to be a complex interaction of local and systemic factors.⁴⁷ The usual management of the disease involves traditional palliative measures, such as topical and systemic analgesics, including nonsteroidal anti-inflammatory drugs, therapeutic exercise, weight loss, education, and orthoses. However, researchers continue to discover new therapeutic targets that are effective in osteoarthritis.⁴⁸ In this context, the possible outcomes of this research indicate that antioxidants may be potentially beneficial owing to their effects on variables such as pain, inflammatory biomarkers, and overall assessment of disease activity, as well as their safety and low incidence of serious adverse effects in therapeutic applications.⁴⁹ Furthermore, this addresses a clinical and scientific need, as well as the possibility that antioxidants may represent a low-cost and relatively safe adjuvant therapeutic approach.⁵⁰ Their appeal lies in their ability to neutralize reactive oxygen species and modulate key inflammatory pathways,⁵¹ which can not only alleviate symptoms but also help slow the structural progression of the disease. Unlike conventional drugs, such as nonsteroidal anti-inflammatory drugs, the long-term use of which is associated with gastrointestinal, cardiovascular, and renal adverse effects,^52,53 antioxidants generally have a more favorable safety profile, positioning them as useful adjuncts to reduce medication dosages and improve treatment tolerability.²⁷

Likewise, the systematic review with meta-analysis developed from this protocol will help identify the effect sizes of antioxidant consumption on relevant clinical variables in the context of physical rehabilitation in adults with osteoarthritis. Similarly, it will allow for the identification of the most studied types of antioxidants and those that show the greatest effectiveness, as well as analyze whether their use provides additional benefits beyond standard medical care in this population group. The synthesis of the resulting evidence may guide clinicians and decision-makers in choosing therapeutic strategies aimed at improving the quality of life of people with osteoarthritis.

Nevertheless, despite the increase in studies on antioxidants in osteoarthritis, the evidence remains inconsistent and is characterized by marked heterogeneity in study design, populations, interventions, dosages, durations, and outcome measures.²¹ This variability makes it difficult to draw solid conclusions about their effectiveness, as the reported effects differ considerably between studies, limiting both the evaluation of their actual clinical impact and their general applicability. Along these lines, a foreseeable limitation is that methodological and clinical heterogeneity among the included studies may restrict the comparability of different antioxidant interventions. Finally, our results will open various lines of research for future projects, as this is a topic about which there is very little knowledge.