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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To examine the cross-sectional association between dietary magnesium intake and radiographic knee osteoarthritis (OA) among African American and white men and women.

Methods

The presence of radiographic knee OA was examined among participants from the Johnston County Osteoarthritis Project and was defined as a Kellgren/Lawrence grade of at least 2 in at least 1 knee. The Block Food Frequency Questionnaire was used to assess magnesium intake. Effect modifiers were explored by testing interactions of magnesium intake and selected factors based on previous studies. The multivariable logistic regression model with standard energy adjustment method was used to estimate the relationship between magnesium intake and radiographic knee OA.

Results

The prevalence of knee OA was 36.27% among the 2,112 participants. The relationship between magnesium intake and radiographic knee OA was found to be modified by race (P for interaction = 0.03). An inverse threshold association was observed among whites. Compared to participants in the lowest quintile, the relative odds of radiographic knee OA were cut by one-half for participants in the second quintile of magnesium intake (odds ratio 0.52, 95% confidence interval 0.34–0.79); further magnesium intake did not provide further benefits (P for trend = 0.51). A statistically significant association was not observed among African Americans.

Conclusion

A modest inverse threshold association was found between dietary magnesium intake and knee OA in whites, but not in African Americans. Further studies are needed to confirm these results and to elucidate the possible mechanisms of action for the racial modification.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Osteoarthritis (OA) is the most common type of joint disorder in the US (1). OA can lead to difficulties in locomotor activities, and it is the principle reason for total knee replacement (2). Although the etiology of OA is not completely clear yet, several lines of evidence support the role of inflammation in OA pathogenesis (3–5). Previous studies have found higher levels of C-reactive protein (CRP) and other inflammatory markers in people with OA compared to those without OA (3). Elevated levels of CRP were associated with early knee OA risk and an increased progression of OA (4). Also, a body of evidence suggests the key roles of proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) in the pathogenesis of human OA (5).

Magnesium is one of the most important micronutrients for human health and is strongly associated with immune responses (6). In animals that were fed a magnesium-depleted diet, inflammatory cytokine production was stimulated and an elevated level of proinflammatory cytokines was observed (7–9). In human studies, individuals with a low intake of magnesium were more likely to have elevated CRP levels (10, 11).

Data directly relating magnesium to OA are limited. One study examining female twins showed that there was a significant reduction in serum magnesium levels among cotwins with OA (12). Also, low serum magnesium was observed in women living in OA-endemic areas (13). In addition, studies have been published on magnesium and some chronic diseases linked to inflammation. For example, patients with rheumatoid arthritis have been found to have inadequate magnesium intake (14–16). Dietary magnesium deficiency was associated with atherosclerosis, hypertension, osteoporosis, diabetes mellitus, and colon and breast cancer, which was suggested by several epidemiologic studies (17). The mechanism of low magnesium in relation to these health conditions was believed to be through promotion of inflammatory responses. Since low magnesium might incite inflammatory responses that may play a central role in OA, it was hypothesized that magnesium intake would be inversely associated with knee OA. In addition, previous findings on the presence of racial differences in the population distribution of inflammatory levels suggest that there might be a racial difference in the relationship between magnesium intake and knee OA (18). Therefore, a cross-sectional analysis was conducted to test these hypotheses using available data from African American and white men and women enrolled in the Johnston County Osteoarthritis Project.

Significance & Innovations

  • Osteoarthritis (OA) may have an inflammatory pathogenesis and magnesium may have an antiinflammatory property, but data directly relating magnesium intake to OA are lacking.

  • This study provides the first epidemiologic evidence of a relationship between magnesium intake and radiographic knee OA.

  • Magnesium intake has a modest inverse threshold association with knee OA among whites, but not in African Americans.

  • This study offers great value for hypothesis generation in studying the relationship between dietary factors and OA.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Study population.

The Johnston County Osteoarthritis Project is a population-based study of OA in African American and white people ≥45 years of age residing in one of the 6 townships of Johnston County for at least 1 year at the time of recruitment from 1990–1998 and who were capable of completing the study protocol. The participants were recruited without regard to their arthritis symptoms. The details of this study cohort and design have been described elsewhere (19). In brief, this project sampled potential participants from 6 townships in Johnston County and did not find a significant difference between respondents and nonrespondents in age, sex, ethnic group, education level, or presence of knee pain. From 1999–2003, a total of 1,934 participants completed a survey that included dietary intake measurement and radiographic knee OA assessment. A second recruitment was conducted from 2003–2004 to deliberately enrich the sample with African Americans and younger individuals using a similar protocol as before; 1,146 individuals were enrolled and assessed. As described elsewhere (20), the newly recruited participants were younger (mean age 59.3 years for the newly enrolled participants versus 65.8 years for the first recruitment) and more likely to be African American (40% versus 28%). The 2 recruitments established the study cohort that comprised 3,080 participants. The present analysis excluded participants with radiographic evidence of an inflammatory arthropathy of the knee (n = 6) due to its distinct cytokine patterns from OA (21) and participants who had missing data on diet (n = 921) or OA (n = 59, not mutually exclusive). A total of 2,112 participants remained in the analyses. This study was approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill and the Centers for Disease Control and Prevention. All participants gave written informed consent at the time of recruitment.

Dietary assessment.

Dietary information was collected by a computer-based 68-item modified version of the National Cancer Institute (NCI) Block Food Frequency Questionnaire (FFQ) inquiring about the average consumption of foods and drinks over the past 10 years. The participants were asked how often they consumed each food in the past 10 years and the portion size of the food. The questions included up to 9 possible responses from never to ≥2 per day for food and from never to ≥6 per day for drinks. The respondents were asked to indicate if their usual serving size was a medium portion size as specified by the questionnaire for each food item, or one-half of the medium size, or 1.5 times of that size. The NCI Block FFQ has been well validated and adopted by previous epidemiologic studies of dietary magnesium (22, 23). Information on multivitamin or magnesium supplement use was also collected through the NCI Block FFQ. Nutrient intakes, including magnesium intake, were calculated using the NCI DietSys software (24).

Radiographic knee OA.

All participants underwent bilateral anteroposterior radiography of the knee with weight bearing. A single radiologist (JBR), without knowledge of the participants' clinical status, read all radiographs by using the Kellgren/Lawrence (K/L) radiographic atlas. OA was divided into 5 categories according to K/L grades: 0 = absence of OA, 1 = doubtful OA, 2 = minimal OA, 3 = moderate OA, and 4 = severe joint OA (25). Radiographic knee OA was defined as a K/L grade of at least 2 in at least 1 knee. As previously described (19), interrater reliability assessed with another trained radiologist and intrarater reliability between radiographic readings from 2 separate times were high (κ = 0.86 and κ = 0.89, respectively).

Statistical analysis.

In this cross-sectional analysis, the means and SDs were calculated for the continuous variables (age, body mass index [BMI], years of education, and total energy intake) and the percentages for the categorical variables (sex, smoking status, and alcohol consumption) across quintiles of magnesium intake for both African Americans and whites. Effect modifiers were explored by testing interactions of magnesium intake and selected factors based on previous studies and statistical significance inferred by P values less than 0.10. Multivariable logistic regression with a standard energy adjustment method was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for knee OA according to the quintiles of magnesium intake, with the lowest quintile as the reference group. The median magnesium intake value of each quintile was used for creating a continuous variable to test for trend. The analyses were conducted separately for whites and African Americans. The model simultaneously adjusted for age, sex, BMI, smoking status, alcohol consumption, education, and total energy intake. Second- to fourth-order polynomial terms for continuous magnesium variables were tested to assess potential nonlinear associations.

In the current study, we conducted sensitivity analyses to test the robustness of the results by including additional dietary variables (i.e., dietary fiber, calcium, and potassium) in the models. In addition, to explore the effects of supplementation, we analyzed the data with adjustment for supplement use and by excluding supplement users separately. The effects of nonsteroidal antiinflammatory drug (NSAID) use and aspirin use in particular were also evaluated by additionally adjusting for the use of NSAIDs or aspirin, and by conducting a sensitivity analysis on non-NSAID users or non-aspirin users. A 2-sided P value less than 0.05 was considered significant, except for the interaction P value where the cutoff was set at 0.10.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The baseline characteristics of the study population according to quintiles of total magnesium intake stratified by race are shown in Table 1. For both African Americans and whites, when compared to the individuals in the lowest quintile of magnesium intake, those in the highest quintile were more likely to be men and to be a smoker, and to have higher education levels, higher alcohol consumption, and higher total energy intake. For African Americans, those in the highest quintile of magnesium intake tended to be younger, while whites tended to be older, compared with the lowest quintile of magnesium intake.

Table 1. Baseline characteristics by quintiles of dietary magnesium by race*
CharacteristicsQuintile 1Quintile 2Quintile 3Quintile 4Quintile 5P
  • *

    Values are the mean ± SD unless otherwise indicated. BMI = body mass index.

  • P values are for test of difference across all quintiles of magnesium intake.

African Americans (n = 665)      
 Magnesium intake, median mg/day129.8182.7234.8304.7469.7
 Age, years64.4 ± 11.161.7 ± 10.660.5 ± 10.661.2 ± 10.761.3 ± 11.20.01
 BMI, kg/m230.9 ± 6.631.2 ± 7.631.3 ± 8.030.8 ± 8.131.1 ± 5.60.96
 Women, %83.576.467.259.762.0< 0.001
 Smoking status, %      
  Never66.766.553.743.755.70.006
  Former17.218.726.830.225.3
  Current16.114.819.526.219.0
 Alcohol consumption, %12.07.818.921.114.70.03
 Education, years11.0 ± 4.111.8 ± 3.712.4 ± 3.711.8 ± 3.812.5 ± 3.50.008
 Total energy intake, kcal/day1,141 ± 3411,573 ± 3781,973 ± 4692,442 ± 6312,750 ± 1,284< 0.001
Whites (n = 1,447)      
 Magnesium intake, median mg/day135.8185.3234.4307.2523.9
 Age, years64.2 ± 10.465.4 ± 10.465.3 ± 10.562.9 ± 10.064.8 ± 10.00.02
 BMI, kg/m228.4 ± 5.228.7 ± 5.628.3 ± 5.528.7 ± 6.028.3 ± 5.90.74
 Women, %73.870.267.755.959.8< 0.001
 Smoking status, %      
  Never68.150.462.752.053.4< 0.001
  Former18.930.727.129.735.2
  Current13.018.910.218.211.4
Alcohol consumption, %6.915.114.624.923.1< 0.001
Education, years12.0 ± 4.313.2 ± 3.713.7 ± 6.514.1 ± 4.414.4 ± 4.3< 0.001
Total energy intake, kcal/day1,099 ± 2841,481 ± 3601,812 ± 4292,119 ± 6262,046 ± 945< 0.001

The overall prevalence of knee OA in the current study was 36.27%. The associations between magnesium intake and knee OA were significantly modified by race (P for interaction = 0.03). After stratifying the data, a modest inverse threshold association between magnesium intake and knee OA was observed in whites when adjusted for sex, BMI, smoking status, alcohol consumption, education, and total energy intake (Table 2). The multivariable-adjusted ORs of radiographic knee OA across quintiles of magnesium intake were 1, 0.52 (95% CI 0.34–0.79), 0.75 (95% CI 0.49–1.15), 0.60 (95% CI 0.38–0.95), and 0.65 (95% CI 0.42–1.02; P for trend = 0.51). This observed threshold association was confirmed by fitting a fourth-order model (P = 0.03). No significant association was found among African Americans.

Table 2. Multivariable-adjusted relationship between magnesium intake and knee OA by quintiles of magnesium intake*
 Quintile 1Quintile 2Quintile 3Quintile 4Quintile 5P for trend
  • *

    OA = osteoarthritis; OR = odds ratio; 95% CI = 95% confidence interval.

  • OR adjusted for age (years), sex, body mass index (kg/m2), smoking status (never smoker, former smoker, or current smoker), alcohol consumption (yes/no), education (school years), and total energy intake (kcal/day).

African Americans (n = 665)      
 Median magnesium intake, mg/day129.80182.44234.77303.98469.74
 Total no. of participants18215112512879
 No. of participants with knee OA7164505733
 Adjusted OR (95% CI)1.00 (ref.)1.57 (0.92–2.68)1.40 (0.76–2.58)1.76 (0.89–3.47)1.34 (0.60–2.98)0.73
Whites (n = 1,447)      
 Median magnesium intake, mg/day135.77186.35234.36306.62523.87
 Total no. of participants240272297295343
 No. of participants with knee OA937911090119
 Adjusted OR (95% CI)1.00 (ref.)0.52 (0.34–0.79)0.75 (0.49–1.15)0.60 (0.38–0.95)0.65 (0.42–1.02)0.51

Because dietary fiber, calcium, and potassium are likely to be correlated with dietary magnesium intake, a sensitivity analysis was performed by testing each based on the multivariable-adjusted model. None of these nutrients appreciably altered the result with or without adjusting for them or modified the observed association.

Approximately 35% of the participants in this cohort used supplements. To eliminate the possible confounding by supplement use, we further adjusted supplement use in the multivariable-adjusted model and analyzed the data for supplement nonusers only. The relationship between magnesium intake and radiographic knee OA remained unchanged. We additionally adjusted NSAID use and aspirin use in the model and conducted a sensitivity analysis on NSAID nonusers or aspirin nonusers, and the results remained unchanged (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

In a population-based cohort, a modest inverse threshold association between magnesium intake and knee OA was found among white participants independent of major lifestyle variables. This relationship was not observed in African American participants.

The results of the present study in whites are in accordance with previous findings in serum magnesium levels and OA. One previous study examining twins reported that there was a significant reduction in serum magnesium levels among twins with OA by discordant twin pair analysis of 66 monozygotic and 163 dizygotic twins (12). Another study found a low serum magnesium concentration in women living in an OA-endemic area (13), which indicates a possible inverse association between magnesium intake and OA. To the best of our knowledge, no studies directly relating magnesium intake and OA have been reported.

Although the magnitude is relatively small, the observed inverse association of magnesium intake and knee OA in whites is biologically plausible. Magnesium deficiency has long been considered to result in an inflammatory response (26), which is currently recognized as etiologic to OA formation and progression. Several studies, such as the Women's Health Study and the Nurses' Health Study, where the majority of the study participants were white, have suggested that magnesium intake or its serum level was inversely associated with human plasma CRP levels (10, 11, 27–29). Also, an elevated CRP level was found in early OA patients compared to healthy individuals and was associated with greater OA progression (4). In addition, proinflammatory cytokines, especially IL-1 and TNFα, were found to mediate OA pathogenesis. One animal study suggested that magnesium deficiency was related to an up-regulated gene expression of IL-1 receptor and TNF receptor in rat thymocytes (30). Moreover, magnesium has been recognized to initiate innate immune response by stimulating macrophages and promote a proangiogenesis environment, which is believed to be intimately integrated in the progression of OA (3, 31, 32). The deficiency of this divalent cation may also impair the chondrocyte-matrix interactions in the pathogenesis of OA through inhibition of the expression and activity of integrins (33).

A number of chronic diseases are involved in conditions associated with low-grade inflammation, such as obesity (34), insulin resistance and type 2 diabetes mellitus (35–37), hypertension (38), and coronary heart disease (39). Various studies have suggested that these health conditions were associated with low magnesium intake or low serum magnesium level. For instance, one study found that serum magnesium levels were lower in obese subjects than in lean individuals and were correlated with elevated concentrations of inflammatory indicators (40). In addition, other studies reported that magnesium intake or serum magnesium levels were inversely related to the risk of type 2 diabetes mellitus (41, 42), hypertension (41, 43), cardiovascular disease (41, 44, 45), and metabolic syndrome (10). These findings on magnesium and the risks of low-grade inflammation-related diseases are consistent with the results in whites showing an inverse threshold association between magnesium intake and knee OA, which is considered an inflammation-related disease.

A similar inverse relationship was not observed among African Americans as in whites. Although the mechanism for the racial modification found in this study was not clear, there are several possible explanations. First, ∼30% of participants in this cohort were African American. Consequently, the number of prevalent cases of OA in African American participants was relatively small enough that the results among African Americans might be explained by chance. Second, studies have suggested that African Americans tend to have higher background levels of inflammation and oxidative stress than whites. Therefore, African Americans may be more prone to inflammatory diseases, which is consistent with the result of the current study that the prevalence of OA in African Americans was 41%, while in whites the prevalence of OA was 34% (18). Studies have also indicated that serum concentrations of antioxidants, such as vitamin E and α-carotene, were lower in African Americans than in whites (46, 47). Given the increased inflammation and lower levels of antioxidants in African Americans, it may be that the potential antiinflammatory effects of magnesium intake are not sufficient to substantially reduce the odds of OA among African Americans. Third, since the median level of the first quintile of magnesium intake (130 mg/day) was nearly 50% of the estimated average requirement (265 mg/day for women and 350 mg/day for men) (48), a possible threshold association existing in African Americans might be masked because of the relatively high reference level. In addition, African Americans may have a poorer quality of diet as compared to whites (49–51). Possible racial differences in the quality of diet may partially account for the observed racial modification in the relationship between magnesium and knee OA. Finally, the possibility cannot be completely ruled out that the observed racial difference is, at least in part, due to unknown or unmeasured confounders such as socioeconomic status, although the multivariable model in this study accounted for different education levels, a reasonable proxy for socioeconomic status.

Some limitations need to be highlighted. The nature of the cross-sectional analysis did not allow us to establish the temporal association and causal inference between magnesium intake and radiographic knee OA. It is therefore premature to discuss using magnesium as a therapeutic tool in OA; however, since this study may be the first to investigate the relationship between magnesium intake and knee OA, the cross-sectional nature does not compromise the value of the study. The findings from this analysis can help generate hypotheses for future research. In addition, since magnesium intake was assessed by the NCI Block FFQ, some degree of measurement error was inevitable; however, the NCI Block FFQ has been well validated and widely used in previous epidemiologic studies of magnesium intake (22, 23). Nevertheless, any measurement error in the current study was likely to be nondifferential, and the information collected should enable ranking participants and calculating the relative risks.

A strength of this study is that all of the radiographs were assessed by a single experienced bone and joint radiologist, which generated accurate and consistent measurement of knee OA. Also, the consistent results in several sensitivity analyses suggest that the findings from the current study are robust. In addition, the findings of the current study were less likely to be confounded by supplement use since the results were found to be similar among supplement nonusers.

The increasing recognition that nutrition is involved in joint health and the potential benefits of dietary manipulation in patients with joint disorders highlight the need for more research on nutritional factors that either prevent or benefit the treatment of joint disease (33). This study provides the first epidemiologic evidence of a relationship between magnesium intake and knee OA. A modest inverse threshold association between magnesium intake and knee OA risk was observed among whites. Further studies are certainly needed to confirm the findings of the present study and to elucidate the potential mechanisms of action, particularly for the racial difference we observed.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. He had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Qin, Renner, Jordan, He.

Acquisition of data. Renner, Jordan.

Analysis and interpretation of data. Qin, Shi, Samai.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We thank Dr. Pengcheng Xun for his helpful comments. We also thank all of the study participants for their support and contributions.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
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