Abstract
Association between calcium intake and premature mortality in the general population has been well studied, but little is known about the association among specific populations. The authors aim to evaluate the association among people with hypertension and to provide a proper reference range of dietary calcium intake. This prospective cohort study included 8534 US adults with hypertension from National Health and Nutrition Examination Survey cycles 2003–2014. Dietary calcium intakes were self‐reported and mortality status was ascertained by National Death Index records. During a median follow‐up of 5.9 years, 1357 death occurred. Compared with participants of dietary calcium intake in quintile 1, participants in quintiles 2 and 4 had a 27% (HR: 0.73, 95% CI: 0.60–0.89) and a 29% lower risk (HR: 0.71, 95% CI: 0.57–0.88) of all‐cause mortality respectively. The authors also observed a 34% lower risk (HR: 0.66, 95% CI: 0.45–0.97) of CVD death among participants in quintile 3 and a 37% lower risk (HR: 0.63, 95% CI: 0.40–0.99) of cancer‐related death in participants in quintile 4 respectively. Restricted cubic spline (RCS) regression revealed a consistent protective effect of dietary calcium in participants with a daily intake of over 1000 mg, but a daily intake over 1200 mg fails to show further protective effect. Our findings suggest that elevated dietary calcium was associated with lower mortality risk from all‐causes, cardiovascular disease (CVD) and cancer, and supplying sufficient dietary calcium intake, between 1000 and 1200 mg per day, in people with hypertension may be considered cost‐effective to decrease risk of premature death.
Keywords: cohort study, dietary calcium, hypertension, mortality, NHANES
1. INTRODUCTION
Calcium is essential for many physiological processes, especially in maintaining bone health. 1 , 2 While previous human studies have confirmed its aforementioned health benefits, recent research has shifted the focus on the association of calcium intake with non‐skeletal endpoints like cardiovascular disease (CVD) 3 , 4 , 5 , 6 and premature death. 6 , 7 , 8 , 9 , 10 , 11 , 12 Several cohort studies reported that high calcium intake was associated with reduced all‐cause mortality or CVD mortality, 6 , 7 , 9 , 10 while others reported excess mortality risk in people with high calcium intake. 8 , 12 These controversial findings may in part due to different forms of calcium intake (dietary calcium or calcium supplements) 8 , 12 and different populations the researchers based on. 6 , 7 , 8 , 9
The role of calcium in the development of hypertension and CVD like arteriosclerosis has been recognized 13 , 14 , 15 , 16 , 17 ; meanwhile, individuals with hypertension have lower calcium intake than the general population. 18 We therefore assume that calcium in the hypertensive population may have a unique effect on health compared with those without hypertension, and heterogeneity of previous studies on the association between calcium intake and mortality may be attributed to hypertension morbidity. However, to our knowledge, most studies investigated the association between calcium and mortality in the general population 6 , 8 , 9 , 12 ; for those studies which investigate the association among specific populations, sex is the most considered factor, 10 whereas evidence on the effect of calcium intake among people with hypertension is scarce. Moreover, the current diet guide for people with hypertension 19 neglects the benefits of calcium intake on non‐skeletal outcomes, thus if our study can validate the above‐mentioned assumption, the diet guide can be improved accordingly.
The National Health and Nutrition Examination Survey (NHANES), a long‐term epidemiologic survey in the United States, has collected high‐quality dietary nutrient intake data, together with demographic characteristics, comorbidity status and other personal information of each participant. 20 Based on its high‐quality survey data and available mortality data, we carried out a population‐based prospective cohort study to (1) evaluate the association between dietary calcium intake and all‐cause, cardiovascular disease and cancer‐related mortalities in people with hypertension; and (2) to provide evidence for a potential reference range of dietary calcium intake for this population.
2. MATERIALS AND METHODS
2.1. Study population
NHANES is a cross‐sectional survey in the USA that uses a complex, stratified, multistage probability sampling design carried out by the National Center for Health Statistics (NCHS) of the CDC. 20 Briefly, NHANES uses a multistage probability sampling design to collect information on health and nutritional status in the United States. Detailed sample design and analysis procedures needed for NHANES are included in the guidelines published by NCHS. 21 , 22 We included all adults aged 20 years or older who participated in the continuous NHANES survey cycles of 2003−2004 through 2013−2014, in whom dietary calcium intakes were assessed. A total of 61 087 people participated in the 2003−2004 through 2013−2014 NHANES surveys. Of them, the information on mortality and dietary nutrient intake was available for 35 848 participants. After excluding participants under 20 years and those without hypertension, our final cohort included 8534 participants. The detailed selection procedure of the participants is shown in the Figure S1.
2.2. Assessment of calcium intake
Daily nutrient intake data from 2003 to 2014 derived from in‐person or telephone questionnaires. Dietary calcium intake was estimated using the USDA's Food and Nutrient Database for Dietary Studies. The averaging nutrient intakes of the first 2 days from the 24 h dietary recall were used in analyses. Dietary calcium intake data were divided into five subgroups based on quintiles as we aimed to derive more information about specific calcium intakes without lowering statistical power significantly. The specific subgroups are as follows: the first quintile, <424 mg per day; the second quintile, 424–627 mg per day; the third quintile, 627–851 mg per day; the fourth quintile, 851–1189 mg per day; the fifth quintile, >1189 mg per day.
2.3. Assessment of outcomes
The outcomes of interest were all‐cause mortality, cardiovascular disease mortality, and cancer‐related mortality. Mortality status and cause of death were linked to and ascertained by National Death Index (NDI) records until December 31, 2015. CVD mortality was defined as codes I00‐I09, I11, I13, I20‐I51 in the 10th revision of the International Classification of Disease (ICD‐10) and cancer‐related mortality was defined as ICD‐10 codes C00‐C97. These codes are listed and specified as death causes in the data available from NDI records. Follow‐up time was defined as the interval from NHANES interview date to the date of death or December 31, 2015.
2.4. Covariates
Sociodemographic, physiological, and lifestyle factors at baseline were used in our analyses. Sociodemographic factors included age, sex, ethnicity (Hispanic, non‐Hispanic white, non‐Hispanic black, other non‐Hispanic, or others), education level (less than 9th grade, 9–11th grade, High school graduate/GED or equivalent, College graduate or above), and family poverty‐income ratio (0–1.0 and >1). Physiological factors included systolic blood pressure, diastolic blood pressure, serum calcium level (obtained by serum calcium ions), serum vitamin D level (as 25‐hydroxyvitamin D2 and 25‐hydroxyvitamin D3), and comorbidities conditions (diabetes, CVD, cancer, and lung diseases). Lifestyle factors included body mass index (BMI), consumption of cigarettes (never smoker, former smoker, or current smoker) and past‐year alcohol consumption (yes or no). Information on age, sex, ethnicity, family income, smoking and comorbidity status was obtained via household interview questionnaires. Systolic blood pressure, diastolic blood pressure, serum vitamin D level, height and weight of each participant were obtained from physical examinations at Mobile Examination Center. Drinking status was determined by a questionnaire at Mobile Examination Center and a past‐year drinker was defined as having at least 12 alcoholic drinks in the past year.
2.5. Statistical analyses
Continuous variables were described as mean value ± standard deviation or median (quartile range) while categorized variables were shown as frequency with percentage. One‐way analysis of variance (ANOVA) was used to examine differences of continuous variables among five groups, while the Rao‐Scott chi‐squared test was implemented to test the differences of categorized variables among these groups. We plotted cumulative incidence rate curves for all‐cause mortality during follow‐up according to the predefined groups of dietary calcium intake. For CVD mortality and cancer‐related mortality, we used sub‐distribution hazard model to plot cumulative incidence rates of CVD mortality, non‐CVD mortality, cancer‐related mortality and non‐cancer‐related mortality of each subgroup in consideration of competing events. 23 The mortality rate was defined as the ratio of mortality event numbers to follow‐up person‐years in each subgroup. While participants with a calcium intake in the first quintile group were set as the reference group, we used two Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association of dietary calcium intake with all‐cause mortality, cardiovascular mortality, and cancer‐related mortality. Model 1 included covariates of age, sex, and ethnicity. Model 2 additionally adjusted for other sociodemographic factors, physiological factors, and lifestyle factors. Restricted cubic spline (RCS) regressions were performed to investigate the nonlinear relationship between calcium intake and mortality and only HRs for calcium intake below 1500 mg per day were calculated in consideration of practical meanings. Stratified analysis and multiplicative interaction effect of sex and age (<65 or ≥65 years old) were also examined. Sensitivity analysis was performed with participants restricted to those with more than 2 follow‐up years to ensure that there is enough period of time to observe the outcome of death. Models with and without covariates of serum vitamin D and serum calcium level were also recalculated.
Sample weights, clustering, and stratification were incorporated in all analyses to ensure the nationally representative point and interval estimate due to complex sample design and oversampling of certain subgroups of the cohort population. All analyses were conducted using SAS 9.4 software and R software (version 3.6.1). A two‐sided p‐value of below .05 was considered to be statistically significant.
3. RESULTS
3.1. Baseline characteristics of participants
During a median follow‐up of 5.9 (interquartile range: 3.3–8.7) years, we observed 1357 deaths (25.6 per 1000 person‐years), including 267 CVD deaths and 291 cancer deaths. The characteristics of study participants at baseline are summarized in Table 1. Participants with higher dietary calcium intake were likely to be younger, to be males, to have higher education levels, to have higher family income, to have lower systolic blood pressure but to have higher diastolic blood pressure, to have a lower prevalence of diabetes and CVD, have higher serum vitamin D level, and to be non‐smokers and past‐year alcohol drinkers. There was no significant difference in serum calcium level and prevalence of lung diseases between the five quintile groups.
TABLE 1.
Characteristics of participants with hypertension in NHANES from 2003 to 2014
| <424 (N = 1655) | 424–627 (N = 1701) | 627–851 (N = 1715) | 851–1 189 (N = 1724) | ≥1189 (N = 1739) | p‐value | |
|---|---|---|---|---|---|---|
| Age, years | 61.64 ± 14.56 | 61.07 ± 14.73 | 61.50 ± 14.64 | 59.67 ± 15.38 | 56.21 ± 15.90 | <.001 |
| Sex (%) | <.001 | |||||
| Male | 707 (42.72) | 731 (42.97) | 814 (47.46) | 876 (50.81) | 1058 (60.84) | |
| Ethnicity (%) | <.001 | |||||
| Mexican American | 193 (11.66) | 177 (10.41) | 199 (11.60) | 227 (13.17) | 220 (12.65) | |
| Other Hispanic | 96 (5.80) | 91 (5.35) | 111 (6.47) | 126 (7.31) | 115 (6.61) | |
| Non‐Hispanic White | 700 (42.30) | 825 (48.50) | 909 (53.00) | 919 (53.31) | 1025 (58.94) | |
| Non‐Hispanic Black | 565 (34.14) | 513 (30.16) | 404 (23.56) | 362 (21.00) | 304 (17.48) | |
| Others | 101 (6.10) | 95 (5.58) | 92 (5.36) | 90 (5.22) | 75 (4.31) | |
| Education (%) | <.001 | |||||
| Less than 9th grade | 288 (17.40) | 206 (12.11) | 192 (11.20) | 178 (10.32) | 153 (8.80) | |
| 9‐11th grade | 322 (19.46) | 265 (15.58) | 262 (15.28) | 264 (15.31) | 244 (14.03) | |
| High school graduate/ GED or equivalent | 421 (25.44) | 445 (26.16) | 430 (25.07) | 421 (24.42) | 432 (24.84) | |
| Some college or AA degree | 411 (24.83) | 487 (28.63) | 504 (29.39) | 509 (29.52) | 533 (30.65) | |
| College graduate or above | 210 (12.69) | 297 (17.46) | 324 (18.89) | 351 (20.36) | 377 (21.68) | |
| Family PIR (%) | <.001 | |||||
| ≤1 | 404 (24.41) | 330 (19.40) | 308 (17.96) | 288 (16.71) | 321 (18.46) | |
| >1 | 1251 (75.59) | 1371 (80.60) | 1407 (82.04) | 1436 (83.29) | 1418 (81.54) | |
| BMI, kg/m2 | 29.55 ± 6.37 | 30.14 ± 6.47 | 30.09 ± 6.76 | 30.14 ± 6.63 | 30.54 ± 6.68 | <.001 |
| Systolic blood pressure, mmHg | 135.09 ± 22.04 | 134.19 ± 21.49 | 133.32 ± 20.45 | 132.69 ± 19.04 | 131.08 ± 19.30 | <.001 |
| Diastolic blood pressure, mmHg | 70.42 ± 15.75 | 70.14 ± 15.11 | 70.22 ± 15.20 | 71.03 ± 15.46 | 72.17 ± 14.96 | <.001 |
| Serum calcium, mmol/L | 2.36 ± 0.10 | 2.37 ± 0.10 | 2.37 ± 0.10 | 2.37 ± 0.10 | 2.37 ± 0.10 | 0.256 |
| Serum vitamin D, nmol/L | 57.25 ± 28.09 | 61.96 ± 27.34 | 65.30 ± 27.32 | 65.19 ± 25.99 | 66.80 ± 25.61 | <.001 |
| Smoking status | .004 | |||||
| Never smoking | 768 (46.40) | 829 (48.74) | 847 (49.39) | 827 (47.97) | 860 (49.45) | |
| Ever smoking | 353 (21.33) | 297 (17.46) | 264 (15.39) | 314 (18.21) | 323 (18.57) | |
| Current smoking | 534 (32.27) | 575 (33.80) | 604 (35.22) | 583 (33.82) | 556 (31.97) | |
| Past‐year alcohol drinking | <.001 | |||||
| No | 664 (40.12) | 615 (36.16) | 623 (36.33) | 528 (30.63) | 453 (26.05) | |
| Yes | 991 (59.88) | 1086 (63.84) | 1092 (63.67) | 1196 (69.37) | 1286 (73.95) | |
| Diabetes (%) | 395 (23.87) | 398 (23.40) | 400 (23.32) | 399 (23.14) | 350 (20.13) | .065 |
| CVD comorbidities (%) | 437 (26.40) | 418 (24.57) | 415 (24.20) | 369 (21.40) | 331 (19.03) | <.001 |
| Cancer comorbidities (%) | 212 (12.81) | 283 (16.64) | 263 (15.34) | 258 (14.97) | 264 (15.18) | .040 |
| Lung comorbidities (%) | 183 (11.06) | 210 (12.35) | 188 (10.96) | 183 (10.61) | 195 (11.21) | .566 |
3.2. Dietary calcium intake and all‐cause, cause‐specific mortality
The unadjusted cumulative incidence rate analysis revealed similar statistically significant differences within five dietary calcium intake groups for all‐cause mortality, CVD mortality and cancer‐related mortality (p < .001). The cumulative incidence rate plots (Figure 1) indicated that participants in the first calcium intake quintile (<424 mg per day) had the lowest survival rate for all three outcomes, while participants in the fifth quintile (≥1189 mg per day) had the highest survival across five groups. Analyses adjusting for sociodemographic factors, lifestyle factors and comorbidity status found that participants in the second (424–627 mg per day) and the fourth quintile (851–1189 mg per day) had 27% lower (HR: 0.73, 95% CI: 0.60–0.89) and 29% lower (HR: 0.71, 95% CI: 0.57–0.88) risk of all‐cause mortality compared with those in the first quintile, respectively (Table 2). Though dietary calcium intake showed a protective effect in participants of other quintiles, the association was not statistically significant. A 34% lower risk (HR: 0.66, 95% CI: 0.45–0.97) of CVD death was also observed among participants in the third quintile (627–851 mg per day). HR of cancer‐related mortality was 0.63 (95% CI: 0.40–0.99) for participants in the fourth quintile. In general, there exists a lower risk of mortality in participants with higher calcium intake, while some of the groups have no statistical significance (Table 2).
FIGURE 1.
Cumulative incidence rate of (A) all‐cause mortality, (B) CVD mortality, and (C) cancer mortality according to quintiles of dietary calcium intake.
TABLE 2.
Hazard ratios (95% CIs) of all‐cause and specific‐cause mortality according to dietary calcium intake
| Mortality type and dietary calcium intake per day (mg) | No. of death | Rate (per 100 person‐years) | Hazard ratio (95% CI) | |
|---|---|---|---|---|
| Model 1 | Model 2 | |||
| All‐cause mortality | ||||
| <424 | 435 | 3.43 | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 340 | 2.65 | 0.75 (0.61–0.92) | 0.73 (0.60–0.89) |
| 627–851 | 348 | 2.84 | 0.82 (0.67–1.01) | 0.85 (0.70–1.03) |
| 851–1189 | 295 | 2.39 | 0.68 (0.55–0.84) | 0.71 (0.57–0.88) |
| ≥1189 | 270 | 2.22 | 0.82 (0.66–1.02) | 0.88 (0.72–1.01) |
| CVD mortality | ||||
| <424 | 84 | 0.66 | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 76 | 0.59 | 0.78 (0.53–1.14) | 0.93 (0.67–1.28) |
| 627–851 | 62 | 0.51 | 0.63 (0.43–0.92) | 0.66 (0.45–0.97) |
| 851–1189 | 59 | 0.48 | 0.70 (0.47–1.04) | 0.68 (0.45–1.03) |
| ≥1189 | 44 | 0.36 | 0.63 (0.38–1.02) | 0.66 (0.41–1.07) |
| Cancer‐related mortality | ||||
| <424 | 104 | 0.82 | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 75 | 0.59 | 0.90 (0.60–1.36) | 0.80 (0.51–1.23) |
| 627–851 | 71 | 0.58 | 0.89 (0.62–1.29) | 0.91 (0.61–1.35) |
| 851–1189 | 62 | 0.50 | 0.65 (0.43–0.98) | 0.63 (0.40–0.99) |
| ≥1189 | 47 | 0.39 | 0.67 (0.42–1.05) | 0.75 (0.48–1.18) |
Abbreviations: CI, confidence interval; CVD, cardiovascular disease; No., number; Ref, reference.
Model 1 adjusted for age, sex, and ethnicity. Model 2 adjusted for covariates in model 1 and further adjusted for education level, family poverty‐income ratio, systolic blood pressure, diastolic blood pressure, serum vitamin D level, comorbidities conditions (diabetes, CVD, cancer, and lung diseases), body mass index, consumption of cigarettes, and consumption of alcohol in the past year.
We further investigated the association between dietary calcium intake mortality in RCS regression (Figure 2). A non‐linear relationship between dietary calcium intake and mortality was revealed, as risk for all three types of mortality in the participants decreased rapidly when dietary calcium intake increased. We found that participants with dietary calcium intake below 500 mg per day were at higher risk of all‐cause and cancer‐related mortality. However, the association between low calcium intake and CVD mortality remained insignificant. For participants with calcium intake beyond 1000 mg per day, the HR kept consistent below 1, while the confidence interval had no statistical significance (Figure 2B).
FIGURE 2.
Restricted cubic spline plot for daily dietary calcium intake and (A) all‐cause mortality, (B) CVD mortality, and (C) cancer mortality.
3.3. Subgroup analysis and sensitivity analysis
For all‐cause mortality, analyses stratified by gender suggested stronger protective effect of calcium in females than in males but some of the quintiles had no statistical significance as the whole population (see Table S1). Although female participants showed a lower HR estimate, the interaction effect between dietary calcium intake and gender was statistically insignificant (p = .708). Subgroup analysis by age also showed similar trends as the main results. However, in the elderly population (age ≥65 years old), we observed that compared with younger people, the elderly participants needed to obtain higher dietary calcium intake for a lower mortality risk (see Table S2). Interaction effect between dietary calcium intake and age was also statistically insignificant (p = .615). For cause‐specific mortalities, the associations were statistically insignificant among all five quintiles with few observed events.
Sensitivity analyses excluding deaths within 2 years of follow‐up yielded similar point estimates as those from the primary analyses, however, the upper limits of the confidence interval exceeded 1, which suggested no statistical significance. The Cox model without adjusting for serum vitamin D or serum calcium also showed consistent point estimate, however, the association had no statistical significance or at borderline statistical significance (Table 3).
TABLE 3.
Sensitivity analysis of the association of dietary calcium intake and all‐cause and cause‐specific mortality.
| Hazard ratio (95% CI) | |||||
|---|---|---|---|---|---|
| Mortality type and dietary calcium intake per day (mg) | Original fully adjusted model | Excluding participants with follow‐up <2 yrs | Excluding serum vitamin D level in fully adjusted model | Including serum calcium level in fully adjusted model | Including total water drinking in fully adjusted model |
| All‐cause mortality | |||||
| <424 | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 0.73 (0.60–0.89) | 0.81 (0.63–1.05) | 0.74 (0.59–0.92) | 0.74 (0.60–0.92) | 0.76 (0.62–0.95) |
| 627–851 | 0.85 (0.70–1.03) | 0.95 (0.77–1.18) | 0.85 (0.69–1.05) | 0.86 (0.70–1.07) | 0.89 (0.73–1.09) |
| 851–1189 | 0.71 (0.57–0.88) | 0.78 (0.61–0.99) | 0.72 (0.58–0.90) | 0.72 (0.58–0.91) | 0.75 (0.61–0.93) |
| ≥1189 | 0.88 (0.72–1.01) | 0.96 (0.77–1.20) | 0.88 (0.71–1.10) | 0.91 (0.73–1.13) | 0.95 (0.76–1.18) |
| CVD mortality | |||||
| <424 | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 0.93 (0.67–1.28) | 0.99 (0.63–1.57) | 0.83 (0.56–1.22) | 0.85 (0.58–1.24) | 0.83 (0.58–1.19) |
| 627–851 | 0.66 (0.45–0.97) | 0.71 (0.46–1.10) | 0.67 (0.44–1.00) | 0.70 (0.46–1.05) | 0.68 (0.46–1.01) |
| 851–1189 | 0.68 (0.45–1.03) | 0.88 (0.53–1.45) | 0.72 (0.47–1.10) | 0.71 (0.45–1.10) | 0.72 (0.47–1.11) |
| ≥1189 | 0.66 (0.41–1.07) | 0.75 (0.42–1.31) | 0.71 (0.43–1.17) | 0.71 (0.42–1.18) | 0.68 (0.42–1.12) |
| Cancer‐related mortality | |||||
| <424 | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) | 1.00 (Ref) |
| 424–627 | 0.80 (0.51–1.23) | 0.91 (0.54–1.53) | 0.81 (0.52–1.27) | 0.82 (0.52–1.29) | 0.88 (0.57–1.38) |
| 627–851 | 0.91 (0.61–1.35) | 1.20 (0.74–1.94) | 0.95 (0.62–1.45) | 0.97 (0.64–1.47) | 1.01 (0.67–1.51) |
| 851–1189 | 0.63 (0.40–0.99) | 0.68 (0.39–1.19) | 0.64 (0.41–1.00) | 0.64 (0.41–1.02) | 0.69 (0.44–1.08) |
| ≥1189 | 0.75 (0.48–1.18) | 0.75 (0.41–1.35) | 0.69 (0.42–1.12) | 0.73 (0.45–1.18) | 0.78 (0.49–1.25) |
Abbreviations: CI, confidence interval; CVD, cardiovascular disease; Ref, reference; yrs, years.
Covariates of age, sex, ethnicity, education level, family poverty‐income ratio, systolic blood pressure, diastolic blood pressure, serum vitamin D level, comorbidities conditions (diabetes, CVD, cancer, and lung diseases), body mass index, consumption of cigarettes, and consumption of alcohol in the past year were adjusted.
4. DISCUSSION
In our study involving 8534 participants with hypertension from a nationally representative cohort from NHANES 20 with a median follow‐up of 5.9 years, we found that higher dietary calcium intake was significantly associated with lower all‐cause, cardiovascular and cancer‐related mortality. RCS regression showed a consistent protective effect in participants with a dietary calcium intake of over 1000 mg per day, suggesting an optimum reference range of calcium intake for people with hypertension of ≥1000 mg per day. After exceeding a threshold of about 1200 mg dietary calcium intake per day, hazard ratios of dietary intake remained a relatively consistent lower risk of mortality in women was also observed compared with men with similar calcium intake.
Previous population‐based studies on the association between calcium intake and mortality have yielded heterogeneous results. 6 , 7 , 8 , 9 , 10 , 11 , 12 One study of 388 229 participants aged over 50 years from the NIH‐AARP Diet and Health Study found ta hat high intake of calcium was associated with excess risk of CVD mortality only in men but not women. 8 Another prospective cohort study, which was also based on NHANES, found that calcium intake that exceeded tolerable upper intake level could increase cancer‐related mortality risk, but further associations of calcium with other outcomes were statistically insignificant. 12 In contrast, the findings from the British population, 6 the older Chinese community‐dwelling population 7 or the US population, 9 discovered that higher calcium intake was associated with decreased mortality rate. We at first attributed the contradictory results to different forms of calcium intake, but in studies taken forms of calcium intake into consideration, some found higher dietary calcium intake was not associated with premature death, 8 , 9 , 12 while others found a statistically significant relationship with lower mortality risk. 6 , 7 , 10 , 11 Thus we assumed that certain characteristics of the different populations may confound the association, so herein we carried out analyses in people with hypertension from NHANES based on previous physiological evidence. 13 , 14 , 15 , 16 , 17 Although several studies have discovered the effect calcium on mortality in the general population, between association of dietary calcium intake and mortality in people with hypertension has not yet been discussed. This is the first study to investigate the effect of calcium in one specific population. Calcium may play a role in hypertension development, but the protective effect of high dietary calcium intake is similar to that in the general population. We found that higher dietary calcium intake was associated with lower all‐cause, cardiovascular and cancer‐related mortality, which was in accordance with four studies mentioned above. 6 , 7 , 10 , 11 The results were further supported by RCS curves, which reflected the non‐linear relationship between calcium intake and mortality risk. The curves displayed a consistent L‐shaped pattern between dietary calcium intake and mortality risk from all causes, CVD and cancer, as participants with low dietary calcium intake had significantly higher mortality risk, and when dietary calcium intake increased, the HR estimates gradually decreased and remained relatively constant below one, which also suggested that blindly increasing the amount of calcium intake is inadvisable. The results from RCS curves also corresponded to the latest dietary guidelines for Americans, 24 as an adult's dietary nutrition goal for calcium is around 1000 mg per day. While this nutrition goal is established mainly in the prevention of bone diseases, our result provides new insights into the relationship between dietary calcium level and non‐skeletal endpoints, and further research are needed in a larger, more diversified cohort to confirm the effect of calcium.
Many previous studies considered gender as an important confounder and thus performed stratified analysis on gender, 6 , 9 or even only included male participants from the beginning. 10 We observed that females generally had lower all‐cause or cause‐specific mortality risk than males, though multiplicative interaction between dietary calcium intake and gender is not statistically significant. Some researchers hypothesized that abrupt change in serum calcium may result in adverse effects, 8 as females were more likely to achieve calcium balance and stable calcium level, 8 , 25 high calcium intake in females led to less abrupt changes in serum calcium than males, which eventually resulted in less adverse effects. Therefore, females with high calcium intake may generally have a lower mortality risk, which is also consistent with the results in the general population. In the elderly population, the calcium metabolism may be different from that of young or middle‐aged people, so we observed a higher dietary calcium intake for a similar lower mortality risk. However, high calcium intake may be detrimental for the heart and peripheral vascular system of the elderly people, thus interpretation of the results requires special caution and further clinical evidence.
Several mechanisms could explain this association between dietary calcium intake and mortality. 13 , 18 , 26 , 27 , 28 , 29 , 30 , 31 Calcium metabolism in healthy individuals keeps body calcium level in homeostasis and thus calcium can serve its physiological function appropriately; however, in people with hypertension, calcium deficiency is essentially prevalent and their calcium metabolism is abnormal, 13 , 14 , 26 so physiological functions related to calcium, like blood pressure regulation, also fail to work as normal. 13 , 14 , 26 But by supplementing calcium through dietary approaches, calcium deficiency and abnormalities in calcium metabolism can be alleviated, thus hypertensive patients may attain optimal blood pressure control and further decrease subsequent CVD risks or mortality risks related to blood pressure. 13 , 14 , 26 Some researchers have offered other explanations for the association, for example, the effect of low calcium intake on all‐cause or CVD mortality may be mediated through dyslipidemia, insulin resistance or inflammatory stress. 27 , 28 In terms of cancer mortality, calcium may play a role in the cancer‐suppressive autophagy process through multiple calcium ion signaling pathways, 30 , 31 including transient receptor potential channels (TRPCs), 30 voltage‐gated Ca2+ channel (VGCC) and purinergic P2 Receptors, 30 IP3 receptors, 31 or Ca2+ release‐activated Ca2+ (CRAC) channels. 31 Therefore, disruption of calcium homeostasis may induce both CVD death or cancer related death, but through different physiological pathways. Such cell mechanism may help explain the phenomenon of people in different quintiles having lowest mortality risk with regard to different types of mortality.
However, the fact that health benefits of high calcium intake on mortality ceased to take effect further in individuals with calcium intake above 1200 mg per day may be explained by the strong association between extremely high serum calcium levels and carotid artery plaque thickness, which is also a risk factor for coronary and cerebrovascular events or mortality. 29 Therefore, the excessive portion of calcium intake may attenuate the protective effect of moderate intake and become potentially harmful by inducing vascular diseases. Accumulating evidence also revealed a strong association between hypercalcemia and CVDs, 32 and a serum calcium level of over 2.30 mmol/L is reported to be in high relevance to hypertension, 33 thus we need to be cautious with the interpretation of high calcium intake.
4.1. Strengths and limitations
The advantages of our study are as follows. First, our study was carried out based on NHANES, a large, population‐based, nationally representative sample of US adults, which has high data quality. Second, we adjusted for a wide range of confounders, such as socioeconomic factors and other factors associated with calcium metabolism. Third, we used both quintiles and RCS curves in our analyses, thus a whole picture of the effect of dietary calcium intake on mortality was depicted, as RCS curves allow us to assess exposure in a continuous way and it has great performance in assessing non‐linear relationship between exposures and outcomes.
Our study has important limitations. First, human blood pressure may be affected various factors, such as PTH, vitamin D or thyroid function, and so on. However, data about these information are not available in NHANES or are very hard to obtain. Moreover, our dietary calcium intake measurement was based on only one or two 24‐h dietary recalls which are essentially fallible, thus our results may not correspond with usual intake and may be subject to recall bias, measurement bias and residual confounding. We included each participant's serum calcium and vitamin D level from laboratory data as one covariate in our sensitivity analyses and the results showed similar trends with our primary results. Since laboratory data are more precise than questionnaire data and serum calcium levels are relatively stable to day‐to‐day calcium intake variations, actual dietary calcium intake and long‐term body calcium level can be represented in this way. Second, there still exist some factors like meal time, hormone levels, renal functions or genetic factors that are unable to be identified or adjusted. Therefore, our results may be subject to residual confounding. But we tried to control confounding to the greatest extent by adjusting for serum vitamin D levels and serum calcium levels, which may be important confounders in the association between calcium and mortality 34 , 35 and solve this problem to some extent. The sensitivity analyses revealed similar point estimates, which minimized the possibility of potential reverse causation. However, wider interval estimates and statistical insignificant results may subject to limited statistical power in the sensitivity analyses. Well‐designed randomized controlled trials may help address these limitations above in future studies.
5. CONCLUSIONS
Findings of our study in the US cohort suggest that elevated dietary calcium was associated with a lower all‐cause and cause‐specific mortality among the population with hypertension, which is consistent with results in the general population. A daily dietary calcium intake of above 1000 mg but below 1200 mg might be considered optimum. Interpretation of the results should be cautious.
AUTHOR CONTRIBUTIONS
Yongfu Yu, Guoyou Qin, and Jiaohua Chen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the study design and data analysis. Conceptualization: Yongfu Yu, Guoyou Qin, Jiaohua Chen and Ruilang Lin. Data curation; Formal analysis; Writing—review & editing: All authors. Funding acquisition; Project administration; Resources; Validation: Yongfu Yu, Guoyou Qin, and Jiaohua Chen. Methodology; Software; Visualization: Yongfu Yu, Guoyou Qin, Jiaohua Chen, Wen Feng, and Ruilang Lin. Supervision: Yongfu Yu, Guoyou Qin, Jiaohua Chen, Jiong Li. Writing—original draft: Ruilang Lin, Wen Feng.
CONFLICT OF INTEREST STATEMENT
The authors declare that there is no conflict of interest regarding the publication of this article.
Supporting information
Supporting Information
ACKNOWLEDGMENTS
This research was supported by the National Natural Science Foundation of China (Grant number 82173612 and 82273730), Shanghai Rising‐Star Program (Grant number 21QA1401300), Shanghai Municipal Natural Science Foundation (22ZR1414900), Shanghai Municipal Science and Technology Major Project (Grant number ZD2021CY001). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Lin R, Feng W, Yang Y, et al. Association of dietary calcium with mortality from all causes, cardiovascular disease and cancer in people with hypertension. J Clin Hypertens. 2023;25:480–488. 10.1111/jch.14657
Ruilang Lin and Wen Feng equally contributed as co‐first authors.
Guoyou Qin, Yongfu Yu, and Jiaohua Chen are joint corresponding authors and senior authors who contributed equally to this study.
Contributor Information
Guoyou Qin, Email: gyqin@fudan.edu.cn.
Yongfu Yu, Email: yu@fudan.edu.cn.
Jiaohua Chen, Email: jiairchen@126.com.
DATA AVAILABILITY STATEMENT
Publicly available and de‐identified datasets were analyzed in this study. Datasets and further information about the datasets can be accessed on: https://www.cdc.gov/nchs/nhanes/index.htm.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information
Data Availability Statement
Publicly available and de‐identified datasets were analyzed in this study. Datasets and further information about the datasets can be accessed on: https://www.cdc.gov/nchs/nhanes/index.htm.