DIETARY MAGNESIUM INTAKE AND FRACTURE RISK: DATA FROM A LARGE PROSPECTIVE STUDY

Data source and subjects

Data were obtained from subjects enrolled in the Osteoarthritis Initiative (OAI) database, which is available for public access at http://www.oai.ucsf.edu/. Specific datasets used are those recorded during baseline and screening evaluations (V00) and each database reporting data on fractures until 96 months from baseline (V10). All participants in this study were recruited as part of the ongoing, publicly and privately funded, multicenter, and longitudinal OAI study. Patients at high risk of knee OA were recruited from four clinical sites in the US (Baltimore, MD; Pittsburgh, PA; Pawtucket, RI; and Columbus, OH) between February 2004 and May 2006.

All of the participants provided written informed consent. The OAI study protocol was approved by the institutional review board of the OAI Coordinating Center, University of California at San Francisco.

Exposure

Dietary Mg intake was obtained through a food frequency questionnaire recorded during baseline visit of the OAI. Since this questionnaire included data on Mg supplementation, also this intake was calculated. Mg intakes were computed as residuals from the regression model, with total caloric intake as the independent variable (residual method).⁽¹⁴⁾ The entire cohort was divided in quintiles of Mg intake according to gender using 205, 269, 323 and 398 mg/daily for men and 190, 251, 306, and 373 for women.

Outcomes

The presence of fractures at baseline and during follow-up was obtained through self-reported history of fractures at the most common sites, i.e. hip, spine and forearm. Since hip, spine and forearm are the most common sites of osteoporotic fractures, these outcomes were initially evaluated separately although, for convergence problems, analyses for hip (n=44) and spine (n=77) were not reliable.

Covariates

A number of variables were identified from the OAI dataset to explore the relationship between dietary Mg intake and incident fractures. These included: (1) race was defined as “whites” vs. others; (2) smoking habits as “previous/current” vs. never; (3) educational level was categorized as “college” vs. others; (4) yearly income as < or > 50,000 $ and missing data; (5) body mass index (BMI), measured by a trained nurse; (6) co-morbidities assessed through the modified Charlson comorbidity score, with higher scores indicating an increased severity of conditions⁽¹⁵⁾; (7) daily intake of vitamin D, calcium, potassium (from food and from supplements) and total energy intake; and (8) physical activity, evaluated using the Physical Activity Scale for the Elderly (PASE), a validated scale for assessing physical activity level in the elderly. The scale covers 12 different activities including: walking, sports and housework, and is scored from 0 upwards, without a maximum score.⁽¹⁶⁾ Moreover, data regarding the use of drugs affecting positively bone (teriparatide, bisphosphonates, hormones) were also recorded.

Statistical analyses

Since Mg intake was significantly different between men and women, such as the incidence of fractures during follow-up (p-value<0.0001 for both comparisons), and the interaction between dietary Mg intake and gender in predicting fracture onset at follow-up was significant (p-value for interaction=0.04), all the findings are reported by gender.

For continuous variables, normal distributions were tested using the Kolmogorov-Smirnov test. The data are shown as means and standard deviations (SD) for quantitative measures, and frequency and percentages for all discrete variables by dietary Mg intake at baseline. For continuous variables, differences between the means of the covariates by quintiles of dietary Mg intake were analyzed using an analysis of covariance (ANOVA); chi-square test was applied for discrete variables. Bonferroni’s correction was used in all the analyses. Levene’s test was used to test the homoscedasticity of variances and, if its assumption was violated, Welch’s ANOVA was used.

Multivariate Cox’s regression models were conducted using as exposure total Mg intake (sum of the Mg from supplements and from foods) at baseline categorized as quintiles and as outcome incident fractures at follow-up. Factors which reached a statistical significance between participants with OA vs. those without or significantly associated with depressive symptomatology at follow-up (taking a p-value<0.05 as statistically significant) were included. Multi-collinearity among covariates was assessed through variance inflaction factor (VIF), taking a cut-off of 2 as reason of exclusion, but no variable was excluded for this reason. Data of Cox’s regression analysis were reported as hazard ratios (HRs) with their 95% confidence intervals (CIs). A similar analysis was run modelling total Mg intake as continuous variable.

All analyses were performed using the SPSS 21.0 for Windows (SPSS Inc., Chicago, Illinois). All statistical tests were two-tailed and statistical significance was assumed for a p-value <0.05.

Study participants

At baseline, among 4,796 potentially eligible individuals, 243 reported data not reliable regarding FFQ (i.e. less than 500 or more than 5,000 Kcal), 788 had a fracture at baseline, and 117 were lost at follow-up (i.e. did not have the first follow-up visit), leaving 3,765 participants eligible for this research.

Baseline analyses

Overall, 3,765 participants (1,577 men; 2,071 women) with a mean age of 60.6±9.1 (range: 45–79) years were eligible for inclusion in the current study. The mean intake of Mg was 295±116 daily, with 53±47 mg derived from oral supplementation. Only the 27.0% of the whole cohort reached correspondent RDA (i.e. 420 mg for men and 320 for women, respectively).⁽¹⁷⁾

The baseline characteristics by dietary Mg intake and by gender are summarized in the Tables 1 and 2. Independently from gender, those with higher Mg intake were more significantly old, white, consumed a significant higher calorie intake including a higher dietary intake of micronutrients (potassium, calcium, vitamin D), but they consumed a significant lower amount of alcohol than participants with lower Mg intake. Conversely, no significant differences emerged regarding physical activity level and presence of co-morbidities. Finally, men with higher Mg intake were significantly leaner than those consuming less Mg (Table 1). In women, individuals consuming more Mg were also more likely to be prescribed bisphosphonates than those consuming less Mg, although this different did not reach the significance (p=0.06). In the sample as whole, only four participants used teriparatide, which may be due to the fact that people who already had a diagnosis of fractures were excluded.

Follow-up analyses and incident fractures onset

After a mean period of 6.2 years, 560 individuals (198 men and 362 women) developed a new fracture. As shown in Table 3, men (Q5: 20; 95%CI: 13–27 vs. Q1: 27; 95%CI: 18–36; Figure 1a) and women (Q5: 27; 95%CI: 20–34 vs. Q1: 31; 95%CI: 23–39; Figure 1b) with higher Mg intake reported a significant lower incidence of fractures compared to those with lower Mg intake.

After adjusting for 14 potential confounders at baseline and taking those with lower Mg intake as reference (i.e. those in Q1), men (HR=0.47; 95%CI: 0.21–1.00, p=0.05) and women (HR=0.38; 95%CI: 0.17–0.82, p=0.01) in the fifth quintile reported a significant lower risk of fracture (Table 3). Since height is a better predictor than BMI in predicting fractures⁽¹⁸⁾, in a secondary analysis we introduced height in the fully-adjusted model. Compared to subjects with lower Mg intake, men in the fifth quintile reported a non-significant association with incident fractures (HR=0.75; 95%CI: 0.45–1.25, p=0.75), whilst women with the highest Mg intake reported a significant reduced risk of fractures (HR=0.47; 95%CI: 0.33–0.68, p<0.0001).

When divided by RDA, only women reaching the RDA for Mg had a significant reduction in fracture risk of 27% (95%CI: 0.51–0.98, p=0.04).

On the contrary, total Mg intake modelled as continuous variable, was not associated with any decreased risk of having fracture at follow-up (for 10 mg increase in Mg intake: HR=1.00; 95%CI: 0.97–1.03; p=0.99 in men and HR=0.99; 95%CI: 0.96–1.02; p=0.55 in women).