 |
|
Effect of Calcium Supplementation on Serum Cholesterol and Blood Pressure
A Randomized, Double-blind, Placebo-Controlled, Clinical Trial
Roberd M. Bostick, MD, MPH;
Lisa Fosdick, MS;
Greg A. Grandits, MS;
Patricia Grambsch, PhD;
Myron Gross, PhD;
Thomas A. Louis, PhD
Arch Fam Med. 2000;9:31-38.
ABSTRACT
| |
Objective To test the effect of daily supplemental calcium on serum total and high-density lipoprotein cholesterol (HDL-C) levels and blood pressure in adults.
Design Randomized, double-blind, placebo-controlled clinical trial; adjunct study to a trial of calcium and colon cell proliferation in patients with sporadic adenoma.
Setting Outpatient clinic.
Patients A total of 193 men and women, aged 30 to 74 years.
Intervention Treatment with 1.0 and 2.0 g/d of elemental calcium vs placebo over a 4-month period for cholesterol determinations and 6 months for blood pressure.
Main Outcome Measures Serum total cholesterol and HDL-C levels, systolic and diastolic blood pressure.
Results Because there were no apparent differences in responses between the 1.0-g and 2.0-g calcium groups, their data were combined and compared with those of the placebo group. Among all participants, the mean total cholesterol level dropped 0.07 mmol/L (2.9 mg/dL) (1.3%) (P = .43) more, and the mean HDL-C level dropped 0.01 mmol/L (0.4 mg/dL) (1.1%) (P = .71) less in the calcium group than in the placebo group. Among participants without a history of hypercholesterolemia, the mean total cholesterol level dropped 0.18 mmol/L (6.8 mg/dL) (3.3%) (P = .10), and the HDL-C level dropped 0.02 mmol/L (0.6 mg/dL) (1.5%) (P = .61) more in the calcium group than in the placebo group. Among all participants, there was no apparent change in blood pressure until 6 months, when the mean systolic blood pressure dropped 0.8 mm Hg (0.6%) (P = .85) and the mean diastolic blood pressure dropped 0.4 mm Hg (0.5%) (P = .80) more in the calcium group than in the placebo group.
Conclusions There were no substantial or statistically significant effects of calcium supplementation on total cholesterol or HDL-C levels or on blood pressure. There was a suggestion (not statistically significant) of a 0.07 to 0.18 mmol/L (3-7 mg/dL) or 2% to 4% drop in the total cholesterol level, a finding similar to that reported in other studies, which indicates the need for further study.
INTRODUCTION
ISCHEMIC HEART disease is the leading cause of death in the United States; however, much of the variability as to what causes it and how it could be prevented remain unexplained.1 It has long been known that calcium, if consumed in amounts greater than that required for absorption from the gut to maintain body calcium levels, binds bile acids in the gut and increases their excretion.2-7 Bile acid–binding resins, such as cholestyramine and colestipol, lower blood levels of cholesterol by just such a mechanism,8 and their use has been found to reduce the risk of ischemic heart disease.9 Animal experiments found that a higher consumption of calcium lowers blood cholesterol levels3-6,10-12 and that a higher consumption of calcium reduces aortic and cardiac cholesterol levels as well as aortic atherosclerosis.5, 10, 12 Also in animals, calcium was found to reduce blood pressure.13 From observational studies in humans, there are few data on the association of calcium with ischemic heart disease, most,14-17 but not all18-19 of which are from ecologic (or correlational) studies. These limited data, however, were largely consistent with the hypothesis that higher intakes of calcium may reduce the risk of ischemic heart disease. There have been numerous trials20-23 in humans to test the effect of calcium supplementation on blood pressure (primarily in hypertensive patients), which, in aggregate, suggest minimal efficacy; however, all but one of these trials had sample sizes of 90 or less.20-23 There have been 3 rigorously designed randomized placebo-controlled clinical trials of calcium supplementation on blood cholesterol in humans,24-26 and all found statistically significant reductions in blood cholesterol. However, all of the trials were small (sample sizes ranged from 13 to 56), one was limited to children with hypercholesterolemia,24 the others were limited to adults with hypercholesterolemia, and none examined the effects of different doses of calcium. We conducted a randomized clinical trial testing 2 doses of calcium supplements on colorectal epithelial cell proliferation in 193 men and women with sporadic adenoma in which we found a statistically significant favorable effect on the colon crypt proliferative zone.27 Herein, we present the results of an adjunct study to this trial in which we tested the 2 doses of calcium supplements on serum cholesterol levels and blood pressure in the 193 participating men and women who were with and without hypercholesterolemia or hypertension.
PATIENTS AND METHODS
This study was approved by the Committee on Use of Human Subjects in Research of the University of Minnesota, Minneapolis. Written informed consent was obtained from each study participant.
PARTICIPANT POPULATION
This study was a pilot adjunct trial to a trial of calcium supplementation and colorectal epithelial cell proliferation in persons with a history of sporadic adenoma.27 Participants were recruited from the patient population attending a private practice gastroenterology group that performs approximately 60% of all colonoscopies in the Minneapolis–St Paul area. To be eligible for the study, subjects must have been 30 to 74 years of age, in general good health, and capable of providing informed consent. They must have had a history of pathologically confirmed adenomatous polyps within the previous 5 years; consumed a Western-style diet (ie, nonvegetarian; of relevance to the cell proliferation hypothesis); had no contraindications to calcium supplementation or rectal biopsy procedures; and had no medical conditions, habits, or medication usage that would otherwise interfere with the study as described below. Persons with or without hypertension or hypercholesterolemia, or taking or not taking antihypertensive or cholesterol-lowering medications were eligible to participate except as specified below.
Specific exclusions were calcium supplement use, vegetarian diet, major diet change within the previous 6 months, supplemental daily intake of cholecalciferol (vitamin D) greater than 400 IU or vitamin A greater than 10,000 IU, regular antacid use, bile acid–binding resin use, long-term tetracycline or indomethacin use, inability to refrain from aspirin use for 10 days, history of bleeding disorder or current use of anticoagulant medication, lithium therapy, current use of thiazide diuretics in amounts greater than the equivalent of 50 mg of hydrochlorothiazide daily, immunosuppression, childbearing potential, renal insufficiency, kidney stones within the previous 20 years, hyperparathyroidism or hypoparathyroidism, uncontrolled hypothyroidism or hyperthyroidism, abnormal serum calcium or creatinine levels at eligibility visit, familial polyposis or Gardner syndrome, inflammatory bowel disease, intestinal malabsorption syndromes, active liver or pancreatic disease, gastrectomy, bowel resection, enema or laxative dependence, active peptic ulcer disease, active malignancy other than nonmelanoma skin cancer, cardiovascular disease that moderately or severely limited activity, narcotic or alcohol dependence, nondeliberate weight loss of 10% or more in previous 3 months, and less than 80% compliance to a medication regimen in a 4-week placebo run-in trial.
CLINICAL TRIAL PROTOCOL
All age-eligible practice patients who had been diagnosed as having adenomatous polyps within the previous 5 years were identified as potential study participants. All patients passing initial chart screening for eligibility were sent an introductory letter, followed by a brief telephone interview. Potential participants were then scheduled for an eligibility visit at which time they were interviewed, completed questionnaires, and provided a blood sample. Their diet was assessed with a semiquantitative food frequency questionnaire.28 Medical records were reviewed. Those eligible entered a 4-week placebo run-in trial. Only participants without significant perceived side effects and who had taken at least 80% of their tablets were eligible for randomization. Compliance for the run-in was assessed by questionnaire, interview, and pill count. Eligible participants, if still willing to continue, were randomized (stratified by sex) to 1 of 3 groups. All who were involved in the trial, including study personnel, study participants, and laboratory personnel were blinded to treatment category. Of patients who passed initial chart eligibility, 42% were ultimately eligible and consented to participate.
Participants (N = 193) were randomly assigned to the 3 treatment groups: a placebo control group (n = 66), and 1.0 g (n = 64) and 2.0 g (n = 63) elemental calcium supplementation groups. The placebo was free of calcium, magnesium, cholecalciferol, or chelating agents. The calcium tablets were calcium carbonate tablets (OsCal; at time of study by Marion Merrill Dow, Inc, Kansas City, Mo, now by SmithKline Beecham, Pittsburgh, Pa) taken twice daily with meals (ie, 2.5 g and 5.0 g of calcium carbonate daily). Calcium carbonate was chosen because the calcium is relatively highly bioavailable, compliance is enhanced because it is the preparation that can deliver the required dose with the smallest number of pills, and it was the least expensive and most widely available calcium supplement form available. Placebo and calcium tablets were identical in size, appearance, and taste.
The treatment period was 6 months, and participants attended follow-up visits at 1, 2, 4, and 6 months after randomization (baseline). At follow-up visits, pill-taking adherence was assessed by questionnaire, interview, and pill count. Participants were instructed to maintain their usual diet during the study, and the food frequency questionnaire was readministered at the final follow-up visit. Factors hypothesized to be related to serum cholesterol levels or blood pressure (eg, diet, exercise, alcohol intake, smoking, hormone replacement therapy, medications, etc) were assessed at baseline, several were reassessed at each follow-up visit, and all were reassessed at the final follow-up visit. Participants did not have to be fasting for their visits. Visits for different participants could be at any time of day; however, the time of day was recorded and, when possible, all visits on a given patient were at the same time of day. The temperature of the room in which the visit took place was maintained at approximately 22°C to 23°C.
PROTOCOL FOR MEASURING SERUM CHOLESTEROL
Serum samples for total cholesterol and high-density lipoprotein cholesterol (HDL-C) were taken from study participants at their randomization visit (baseline) and again 4 months after onset of treatment. Blood was drawn before participants underwent rectal biopsies for determining colorectal epithelial cell proliferation and after the participant had been sitting quietly, legs uncrossed, for 5 minutes. Using a standard protocol, blood was drawn into specimen tubes (Vacutainer) containing EDTA, allowed to clot at room temperature, and centrifuged within 60 to 90 minutes at 4°C. The serum was immediately poured off and refrigerated at 4°C for transport, and then aliquoted and frozen at -70°C within 15 hours of the blood draw. Blinded duplicate samples for quality control were obtained on approximately 10% of blood draw visits.
Serum cholesterol was measured with the use of an enzymatic, timed end point method on a SYNCHRON CX5 system (Beckman Instruments, Inc, Brea, Calif).29-31 Cholesterol tests on SYNCHRON CX5 systems have been certified by the National Cholesterol Education Program.
PROTOCOL FOR MEASURING BLOOD PRESSURE
Blood pressure measurements were obtained on study participants at an initial eligibility visit and at random assignment to their treatment groups 1 month later and averaged to represent baseline measurements. Follow-up measurements were obtained 1, 2, 4, and 6 months after onset of treatment. Blood pressures were taken by 2 nurses trained, standardized, and certified in the blood pressure procedures. The nurses were tested and recertified every 6 months during the study. Blood pressure measurements were taken before blood draws or any other procedures. A standard protocol was followed. Briefly, arm circumference was measured, the appropriate size cuff was applied, then the participant remained quietly seated with both feet on the floor for 5 minutes. Using a standard manometer, the cuff was then inflated to determine the pressure at which the radial pulse was obliterated, then deflated. The standard manometer was replaced by a random zero manometer (RZ) (Hawksley Gammon, London, England). The RZ peak inflation level was determined as the pulse obliteration pressure plus 30 mm Hg plus the RZ maximum zero number found next to the mercury column on the RZ. After the participant raised his or her arm for 5 seconds followed by a 30-second rest, the cuff was rapidly inflated to the RZ peak inflation level, held constant for 5 seconds, then, with the bell of the stethoscope held over the brachial artery, the cuff was deflated at 2 mm Hg/s and the first and fifth blood pressure phases were recorded. The cuff was disconnected from the manometer, then, after the participant raised his or her arm for 5 seconds, was reconnected. After another 30 seconds at rest, the RZ blood pressure measurement was repeated. The average of the 2 recordings was taken as the blood pressure of the person on that visit.
STATISTICAL ANALYSIS
Treatment groups were assessed for comparability of characteristics at baseline and at final follow-up by  2 tests for categorical variables and by analysis of covariance for continuous variables; sex was included as a covariate.
For evaluating cholesterol, mean total cholesterol and HDL-C and total cholesterol/HDL-C ratios were calculated for each treatment group at baseline and at 4-month follow-up. Changes in cholesterol levels over time were computed within each treatment group as person-specific follow-up minus baseline differences, and then mean changes were calculated and compared using analysis of covariance (with sex, baseline value of the relevant cholesterol variable, and daily total fat intake as a percentage of total energy intake as covariates).
For evaluating blood pressure, mean systolic and diastolic blood pressure was calculated for each treatment group at baseline and at 1-, 2-, 4-, and 6-month follow-ups; the average across the 4 follow-up visits was also calculated. For descriptive summaries, changes in blood pressure over time were computed within each treatment group as person-specific follow-up minus baseline differences, and then mean changes were calculated. Treatment effects were assessed with a repeated-measures mixed model using PROC MIXED.32 The model included the intercept, follow-up visit effects (1, 2, 4, and 6 months or the average of the 4 visits), sex, interaction between sex and follow-up visit effects, and interaction between treatment group and the follow-up visit effects (ie, the treatment effects). The covariance matrix for the repeated measures included a random intercept.
Because there were no apparent differences between the 2 calcium groups in the results for any of the end points, the data for the 2 calcium groups were combined and compared with those of the placebo group as above. The results from only the latter analyses are presented herein. In addition, all analyses were performed in the raw and the natural logarithm transformed scales (to improve normality); since transformation did not materially affect the results, for simplicity, only the analyses on the raw scale data are presented. All statistical tests were 2-sided. A cutoff level of P .05 was used for assessing statistical significance.
RESULTS
Treatment groups did not differ significantly on characteristics measured at baseline (Table 1) or at the end of the study (data not shown) except for total daily fat intake as a percentage of total daily energy intake where the intake in the 2-g calcium group was slightly higher (3%) than in the 1-g calcium or placebo groups (P = .01) (thus why this variable was adjusted for in the subsequent cholesterol analyses). The mean age of the participants was 59 years, 63% were men, and 99% were white. Thirty-six percent of participants had a history of hypercholesterolemia, 9% were taking cholesterol-lowering medications, 32% had a history of hypertension, and 25% were taking antihypertensive medications.
|
|
|
|
Table 1. Selected Baseline Characteristics of 193 Participants*
|
|
|
Adherence to visit attendance did not differ among the 3 treatment groups and averaged 95%. The mean percentage of pills taken in each group was 97%, and more than 98% of all participants in each group took at least 80% of their pills. There were no treatment complications. From the 40 pairs of cholesterol quality-control samples, the coefficients of variation for the total cholesterol and HDL-C measurements were, respectively, 6% and 8%. There was no evidence for laboratory drift in cholesterol measurements over the course of the study. Mean blood pressure recordings by the 2 nurses were virtually identical. There was no evidence for drift in mean blood pressure recordings over the course of the study.
CHOLESTEROL
The cholesterol results are summarized in Table 2. The total cholesterol and HDL-C levels were comparable between the placebo and calcium groups. In the intention-to-treat analysis, the total cholesterol dropped 0.07 mmol/L (2.9 mg/dL) (proportionately, 1.3%) more in the calcium group than in the placebo group. The HDL-C dropped 0.01 mmol/L (0.4 mg/dL) (proportionately, 1.1%) less in the calcium group than in the placebo group. The total cholesterol/HDL-C ratio was virtually unchanged in the calcium group but increased by 3% in the placebo group. When the analyses were restricted to participants without a history of hypercholesterolemia, the total cholesterol level dropped 0.18 mmol/L (6.8 mg/dL) (proportionately, 3.3%) more in the calcium group than in the placebo group. The HDL-C level dropped 0.02 mmol/L (0.6 mg/dL) (proportionately, 1.5%) more in the calcium group than in the placebo group. The total cholesterol/HDL-C ratio increased 0.14 (proportionately, 2.8%) more in the placebo group than in the calcium group.
|
|
|
|
Table 2. Summary of Clinical Trial Serum Cholesterol Results in Placebo and Calcium Groups
|
|
|
BLOOD PRESSURE
The blood pressure results are summarized in Figure 1 and Table 3. The systolic and diastolic blood pressures were comparable between the placebo and calcium groups (Table 3). As seen in Figure 1, in the calcium group, there was a pattern of declining blood pressure over the 6-month treatment period; whereas, in the placebo group, there was an initial decline followed by a leveling off or slow rise back to baseline levels. However, at no point did there appear to be a large difference between the treatment and control groups except for the suggestion of one for the systolic blood pressure at the 6-month follow-up. These latter points are emphasized in Table 3: in the intention-to-treat analysis, there were no substantial or statistically significant changes in blood pressure in the calcium group relative to the placebo group. For example, the only time point at which there was a qualitative reduction in blood pressure in the calcium group relative to the placebo group was at the 6-month follow-up where the systolic blood pressure dropped 0.8 mm Hg (proportionately, 0.6%) more in the calcium group than in the placebo group. The diastolic blood pressure dropped 0.4 mm Hg (proportionately, 0.5%) more in the calcium group than in the placebo group. Findings were not different when analyses were restricted to those with or without a history of hypertension or who did or did not take antihypertensive medication (data not shown). In addition, there were no substantial or statistically significant changes in pulse or weight among groups during the trial (data not shown).
|
|
|
|
Summary of clinical trial blood pressure results: placebo group vs calcium group (combined 1.0- and 2.0-g/d calcium groups) (see Table 3 for exact blood pressure values, SEs, and P values).
|
|
|
|
|
|
|
Table 3. Summary of Clinical Trial Blood Pressure (BP) Results in the Placebo and Calcium Groups
|
|
|
COMMENT
None of the findings from this study were statistically significant; however, the sample size was small and thus the statistical power was low (for example, the power to detect a difference in the cholesterol level of 0.26 mmol/L [10 mg/dL] or of diastolic blood pressure of 3 mm Hg, was estimated as approximately 0.4). The data suggest that 1.0 to 2.0 g/d of supplemental calcium may reduce total cholesterol levels by about 2% to 4% (with negligible impact on HDL-C) and the total cholesterol/HDL-C ratio (perhaps the best single indicator of coronary heart disease risk related to blood cholesterol levels33-34) by about 2% to 3%, and may be more efficacious in persons who have not already developed hypercholesterolemia. That there were no differences in results between the 1.0-g and 2.0-g calcium groups is consistent with the calculations of Newmark et al,2 that there is probably little extra to be gained by increasing the total daily intake (average dietary intake of approximately 740 mg plus supplemental intake) above 2.0 g. If it is true that a total daily intake of 1.5 g to 2.0 g can lower total cholesterol levels 2% to 4% with negligible impact on HDL-C, then ensuring a total daily calcium consumption of close to 2.0 g/d may lower the risk of cardiovascular disease by 4% to 8%,9 and thus may play a useful role in a total program to reduce the risk of cardiovascular disease. This study provides no evidence for an effect of calcium on blood pressure in adults consuming a Western-style diet. However, the pattern of results suggests that an intervention of longer than 6 months may be required to see an effect if there is one. A study conducted in a general population sample with a larger sample size, a duration of longer than 6 months, and with more than 1 cholesterol follow-up visit would be required to definitively address the question of whether calcium supplementation can reduce total cholesterol levels (without adversely impacting the HDL-C level or the total cholesterol/HDL-C ratio) or blood pressure.
STRENGTHS AND LIMITATIONS
This study has several strengths and limitations. Other than the small sample size, the most obvious limitation is the restriction of the patient population to persons with a history of sporadic adenoma. Although we do not know of a reason why persons with sporadic adenoma would respond differently from others, the possibility exists. Also, since 99% of participants were white, the findings may not be applicable to other racial groups. Other limitations include not obtaining triglyceride or low-density lipoprotein cholesterol (LDL-C) levels (only total and HDL-C levels were obtained because of budget constraints and to avoid the need for fasting). Not obtaining fasting samples or standardizing the time of day for patient visits may have contributed variability that obscured treatment effects to a small, but not likely important, extent. On balance, however, the study has several strengths. These include the randomized, double-blinded, placebo-controlled design; the dose-response design; the largest sample size of any trial yet of calcium and cholesterol; the investigation of both cholesterol and blood pressure in the same trial; the investigation of persons with or without a history of hypercholesterolemia or with or without a history of hypertension; the high protocol adherence by the participants; and the rigorous quality-control activities.
CALCIUM AND CHOLESTEROL
The biological plausibility for a cholesterol-lowering effect of calcium is that calcium is known to bind with bile acids to form insoluble soaps and thus presumably can remove cholesterol entering the gut via the enterohepatic circulation.2-7 Experimental animal evidence strongly supports calcium in amounts equivalent to 1.5 to 2.0 g/d in humans as having a cholesterol-lowering effect. Supplemental calcium was found to lower cholesterol levels in rats, rabbits, and goats,3, 12, 35-38 but not in young pigs39; was associated with an increased excretion of fecal bile acids in most,3-7 but not all studies37; and was most pronounced when the diet contained higher proportions of saturated fats.4, 7
A few small clinical trials have been reported on the relationship between calcium and serum lipids in humans. Four early, small, clinical trials7, 40-42 using calcium supplements demonstrated positive findings for a hypocholesterolemic effect for calcium but generally had important design limitations and were subject to significant criticism. A 12-subject, 2-week, metabolic study7 produced a 0.21-mmol/L (8-mg/dL) mean drop in total cholesterol level in subjects in whom the dietary fat was primarily saturated. Cholesterol levels in subjects were around 4.14 mmol/L (160 mg/dL), a range not only lower than that of the average American, but at which cholesterol reductions can be more difficult to achieve. That study also documented increased fecal excretion of neutral sterols. An uncontrolled 8-week study of 16 hyperlipidemic patients40 produced a drop in total cholesterol level from 8.30 to 7.84 mmol/L (321-303 mg/dL) but that may well represent a classic example of regression to the mean. In an uncontrolled study in 13 volunteers,41 total cholesterol level dropped 0.06 mmol/L (2.2 mg/dL) during a run-in period, but with calcium supplementation dropped 0.61 mmol/L (23.6 mg/dL) in healthy subjects and 34.5% in hypercholesterolemic subjects. A placebo-controlled trial (use of blinding not specified) of 20 hyperlipidemic subjects42 produced a drop in mean cholesterol level from 9.03 to 7.19 mmol/L (349-278 mg/dL) in 6 months and to 6.78 mmol/L (262 mg/dL) in 12 months in the 2.0-g calcium carbonate group compared with only a 0.10-mmol/L (4-mg/dL) drop in the control group.
Results of 3 more recent trials with more rigorous designs found statistically significant reductions in LDL-C levels with calcium treatment vs placebo.24-26 In a placebo-controlled crossover study in 50 children with type II-A familial hypercholesterolemia, there was a 4.4% reduction in LDL-C level (P = .05).24 In a placebo-controlled crossover study in 13 men with moderate hypercholesterolemia, there was an 11% reduction in LDL-C (P < .05) without an effect on the HDL-C level.25 Finally, in a randomized, double-blind, placebo-controlled crossover study in 56 adults with mild to moderate hypercholesterolemia, there was a 4.4% reduction in LDL-C level (P = .001) and a 4.1% increase in HDL-C level (P = .031).26
CALCIUM AND BLOOD PRESSURE
The potential for a role for calcium in lowering blood pressure and/or preventing hypertension has received considerable attention and is reviewed more extensively elsewhere.20-22 Briefly, first, there are several proposed plausible mechanisms of action for an effect of calcium on blood pressure in persons in general, and for persons genetically or otherwise at higher risk of developing essential hypertension in particular. None of the proposed mechanisms, however, can be considered clearly established. Second, blood pressure was lowered in animal experiments using calcium. Third, of more than 25 observational studies relating intake of calcium or calcium-rich foods to blood pressure, most, but not all, found some evidence of an inverse association. Notably, of the 2 prospective studies, the Nurses' Health Study43 and the Health Professionals' Follow-up Study,44 risks for developing hypertension were reduced approximately 20% to 25%. Fourth, of approximately 30 trials of calcium supplementation and blood pressure levels, only about two thirds indicated a reduction in blood pressure, with average blood pressure decreases over the studies estimated by different reviewers as 1.8 to 4 to 7 mm Hg systolic and 0 to 2 to 4 mm Hg diastolic. However, these estimates differ from those of a recent meta-analysis23 in which data from 28 active treatment arms or strata from 22 randomized clinical trials were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. The total sample was composed of 1231 persons. Pooled estimates of the effect of calcium supplementation on blood pressure were almost identical to those in the present study: a 0.18–mm Hg reduction in diastolic blood pressure (not statistically significant), and a statistically significant 0.89–mm Hg reduction in systolic blood pressure. When the analyses were stratified by hypertension status, the pooled estimates for an effect of calcium on systolic blood pressure was a reduction of 0.53 mm Hg in normotensive persons (not statistically significant), and a statistically significant 1.68–mm Hg reduction in hypertensive persons. Diastolic blood pressure was not significantly affected in either the normotensive or the hypertensive subgroups. Results of some trials and the meta-analysis suggest that calcium may be more effective in subsets of individuals. Thus, (1) there is animal and human intervention support for the hypothesis that calcium supplementation can lower blood pressure, but this support is weak and at best indicates a modest reduction (1 mm Hg) in systolic blood pressure that may be limited to certain not yet clearly defined subsets of individuals; and (2) there is some support for the hypothesis that long-term consumption of higher calcium intakes, aside from its ability to act pharmacologically to directly lower blood pressure, may prevent the development of hypertension.
CALCIUM AND ISCHEMIC HEART DISEASE
That a higher calcium consumption may plausibly reduce the risk of ischemic heart disease by cholesterol-lowering and/or other mechanisms is supported by animal experimental and human observational studies. In animals, increased dietary calcium levels were shown to reduce both aortic and cardiac cholesterol levels as well as aortic atherosclerosis in rabbits,6, 10, 35 (26, 10 of 3 studies) and in goats,12 but not in rats36 fed hypercholesterolemic rations.
There are very few epidemiological data on the potential relationship between calcium and the risk of ischemic heart disease. Given the substantial interest in the relation of calcium to blood pressure, and to a lesser extent to cholesterol, the reasons for this lack of data are unclear, but are perhaps related to the inconsistency in the few available ecologic data,14-17 which pertain primarily to milk product intake. Based on the results of some ecologic studies that populations living in hard water areas (high calcium content) have lower cardiovascular disease mortality than people living in soft water areas, the association of calcium intake and cardiovascular and coronary heart disease mortality was investigated in a 28-year follow-up in a prospective cohort study of 2605 Dutch civil servants who completed a limited 1-week food frequency recall in 1953 to 1954.19 The findings in that study were not statistically significant, were qualitatively close to null (relative risks for cardiovascular disease mortality for those in the highest vs the lowest quintile of calcium intake were 0.77 for men and 0.91 for women), but were in an inverse direction. The Iowa Womens' Health Study,18 a prospective cohort study, using a Willett semiquantitative food frequency questionnaire, investigated calcium intake and risk of ischemic heart disease mortality in 34,486 Iowa women, aged 55 to 69 years, from 1986 to 1994. After multivariate adjustment for total energy intake and multiple risk factors for ischemic heart disease, the relative risks for the highest vs lowest quartiles of total calcium was 0.67 (95% confidence interval, 0.47-0.94; P for trend = .09). The relative risks were 0.63 (95% confidence interval, 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% confidence interval, 0.36-1.23) for high supplemental calcium but low dietary calcium intake.
CONCLUSIONS
In summary, this pilot study demonstrated no statistically significant effects of supplemental calcium intake on total cholesterol or HDL-C levels , or on blood pressure. However, the sample size was small and the estimate of a 2% to 4% drop in the total cholesterol level is similar to that in other studies (which were all smaller than the present study). A larger, more definitive study may be indicated, since, if these estimates are true, ensuring a total daily calcium consumption of close to 2.0 g/d may lower the risk of cardiovascular disease by 4% to 8%, and thus may play a useful role in a total program to reduce the risk of cardiovascular disease. Our findings provide little or no support for the hypothesis that supplemental calcium can lower blood pressure in either normotensive or hypertensive persons. At best, they provide weak support for previous findings of approximately a 1–mm Hg drop in systolic blood pressure. If calcium plays a role in reducing the risk of ischemic heart disease, it would appear that it may do so by modestly reducing cholesterol, perhaps by reducing the risk of developing hypertension, and/or by other as yet unidentified potential mechanisms.
AUTHOR INFORMATION
Accepted for publication April 5, 1999.
This study was supported in part by Biomedical Research Support grant S07 RR 055448 (Division of Research Resources) and by grant R01CA-51932 (National Cancer Institute), from the Public Health Service, Department of Health and Human Services, National Institutes of Health, Bethesda, Md.
The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Cancer Institute.
Corresponding author: Roberd M. Bostick, MD, MPH, Division of Population Studies, 15 Richland Medical Park, Suite 301, Columbia, SC 29203 (e-mail: roberd.bostick{at}rmh.edu).
From the Department of Family and Preventive Medicine, School of Medicine, University of South Carolina, Columbia (Dr Bostick); and the Divisions of Biostatistics (Ms Fosdick, Mr Grandits, and Drs Grambsch and Louis) and Epidemiology (Dr Gross), School of Public Health, University of Minnesota, Minneapolis.
REFERENCES
| |
1. Fraser GE. Preventive Cardiology. New York, NY: Oxford University Press; 1986.
2. Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate and calcium: a hypothesis. J Natl Cancer Inst. 1984;72:1323-1325.
3. Fleischman AI, Yacowitz H, Hayton T, Bierenbaum ML. Effects of dietary calcium upon lipid metabolism in mature male rats fed beef tallow. J Nutr. 1966;88:255-260.
4. Yacowitz H, Fleischman AI, Amsden RT, Bierenbaum ML. Effects of dietary calcium upon lipid metabolism in rats fed saturated or unsaturated fat. J Nutr. 1967;92:389-392.
5. Fleischman AI, Bierenbaum ML, Lenz PH. The hypolipidemic effect of calcium containing compounds and vitamin D2 in the rat. Lipids. 1972;7:263-266.
FULL TEXT
|
ISI
| PUBMED
6. Renaud S, Ciavatti M, Thevenon C, Ripoll JP. Protective effect of dietary calcium and magnesium on platelet function and atherosclerosis in rabbits fed saturated fat. Atherosclerosis. 1983;47:187-198.
FULL TEXT
|
ISI
| PUBMED
7. Bhattacharyya AK, Thera C, Anderson JT, Grande F, Keys A. Dietary calcium and fat: effect on serum lipids and fecal excretion of cholesterol and its degradation products in man. Am J Clin Nutr. 1969;22:1161-1174.
PUBMED
8. Brown MS, Goldstein JL. Drugs used in the treatment of hyperlipoproteinemias. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The Pharmacologic Basis of Therapeutics. 8th ed. New York, NY: Pergamon Press; 1990: 874-896.
9. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.
FREE FULL TEXT
10. Yacowitz H, Fleischman AI, Bierenbaum ML, Kritchevsky D. Calcium and lipid metabolism: effects of increased dietary calcium on atherosclerosis in rabbits. Trans N Y Acad Sci. 1971;33:344-350.
ISI
| PUBMED
11. Iacono JM. Effect of varying the dietary level of calcium on plasma and tissue lipids of rabbits. J Nutr. 1974;104:1165-1171.
12. Hines TG, Jacobson NL, Beitz DC, Littledike ET. Dietary calcium and vitamin D: risk factors in the development of atherosclerosis in young goats. J Nutr. 1985;115:167-178.
13. Sallinen K, Arvola P, Wuorela H, Ruskoaho H, Vapaatalo H, Pörsti I. High calcium diet reduces blood pressure in exercised and nonexercised hypertensive rats. Am J Hypertens. 1996;9:144-156.
FULL TEXT
|
ISI
| PUBMED
14. Comstock GW. Water hardness and cardiovascular diseases. Am J Epidemiol. 1979;110:375-400.
FREE FULL TEXT
15. Knox EG. Ischaemic heart disease mortality and dietary intake of calcium. Lancet. 1973;1:1465-1467.
FULL TEXT
|
ISI
| PUBMED
16. Dawson EB, Frey MJ, Moore TD, McGanity WJ. Relationship of metal metabolism to vascular disease mortality rates in Texas. Am J Clin Nutr. 1978;31:1188-1197.
FREE FULL TEXT
17. Hopkins PN, Williams RR. A survey of 246 suggested coronary risk factors. Atherosclerosis. 1981;40:1-52.
FULL TEXT
|
ISI
| PUBMED
18. Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999;149:151-161.
FREE FULL TEXT
19. van der Vijver LPL, van der Waal MAE, Weterings KGC, Dekker JM, Schouten EG, Kok FJ. Calcium intake and 28-year cardiovascular and coronary heart disease mortality in Dutch civil servants. Int J Epidemiol. 1992;21:36-39.
FREE FULL TEXT
20. Smith HT. Electrolytes in the epidemiology, pathophysiology, and treatment of hypertension. Primary Care. 1991;18:545-557.
ISI
| PUBMED
21. Stein PP, Black HR. The role of diet in the genesis and treatment of hypertension. Med Clin North Am. 1993;77:831-847.
ISI
| PUBMED
22. Reusser ME, McCarron DA. Micronutrient effects on blood pressure regulation. Nutr Rev. 1994;52:367-375.
ISI
| PUBMED
23. Allender PS, Cutler JA, Follman D, Cappuccio FP, Pryer J, Elliott P. Dietary calcium and blood pressure: meta-analysis of randomized clinical trials. Ann Intern Med. 1996;124:825-831.
FREE FULL TEXT
24. Groot PHE, Grose WFA, Dijkhuis-Stoffelsma R, Fernandes J, Ambagsheer JJ. The effect of oral calcium carbonate administration on serum lipoproteins of children with familial hypercholesterolaemia (type II-A). Eur J Pediatr. 1980;135:81-84.
FULL TEXT
|
ISI
| PUBMED
25. Denke MA, Fox MM, Schulte MC. Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men. J Nutr. 1993;123:1047-1053.
26. Bell L, Halstenson CE, Halstenson CJ, Macres M, Keane WF. Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia. Arch Intern Med. 1992;152:2441-2444.
FREE FULL TEXT
27. Bostick RM, Fosdick L, Wood JR, et al. Calcium and colorectal epithelial cell proliferation in sporadic adenoma patients: a randomized, double-blinded, placebo-controlled clinical trial. J Natl Cancer Inst. 1995;87:1307-1315.
FREE FULL TEXT
28. Willett WC, Sampson L, Browne ML, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol. 1988;127:188-199.
FREE FULL TEXT
29. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475.
ABSTRACT
30. Roeschlau P, Bernt E, Gruber W. Enzymatic determination of total cholesterol in serum. Z Klin Chem Klin Biochem. 1974;12:165-166.
31. Trinder P. Simple turbidometric method for the determination of serum cholesterol. Ann Clin Biochem. 1969;6:165-166.
32. SAS Institute Inc. The mixed procedure. In: SAS Technical Report P-229: SAS/STAT Software Changes and Enhancements. Cary, NC: SAS Institute Inc; 1992:287-366.
33. Castelli WP, Abbott RD, McNamara PM. Summary estimates of cholesterol used to predict coronary heart disease. Circulation. 1983;67:730-734.
FREE FULL TEXT
34. Castelli WP. The role of plasma lipids as predictors of risk for coronary heart disease. Drugs. 1990;40(suppl 1):1-6.
35. Dougherty RM, Iacono JM. Effects of dietary calcium on blood and tissue lipids, tissue phospholipids, calcium and magnesium levels in rabbits fed diets containing beef tallow. J Nutr. 1979;109:1934-1945.
36. Fleischman AI, Yacowitz H, Hayton T, Bierenbaum ML. Long-term studies on the hypolipemic effect of dietary calcium in mature male rats fed cocoa butter. J Nutr. 1967;91:151-158.
37. Diersen-Schade DA, Richard MJ, Jacobson NL. Effects of dietary calcium and fat on cholesterol in tissues and feces of young goats. J Nutr. 1984;114:2292-2300.
38. Fleischman AI, Yacowitz H, Hayton T, Bierenbaum ML. Effect of calcium and vitamin D3 upon the fecal excretion of some metals in the mature male rat fed a high fat, cholesterol diet. J Nutr. 1968;95:19-22.
39. Foley MK, Galloway ST, Luhman CM, Faidley TD, Beitz DC. Influence of dietary calcium and cholecalciferol on composition of plasma lipids in young pigs. J Nutr. 1990;120:45-51.
40. Carlson LA, Olsson AG, Orö L, Rössner S. Effects of oral calcium upon serum cholesterol and triglycerides in patients with hyperlipidemia. Atherosclerosis. 1971;14:391-400.
FULL TEXT
|
ISI
| PUBMED
41. Yacowitz H, Fleischman AI, Bierenbaum ML. Effects of oral calcium upon serum lipids in man. BMJ. 1965;1:1352-1354.
42. Bierenbaum ML, Fleischman AI, Raichelson RI. Long term human studies on the lipid effects of oral calcium. Lipids. 1972;7:202-206.
FULL TEXT
|
ISI
| PUBMED
43. Witteman JCM, Willett WC, Stampfer MJ, et al. A prospective study of nutritional factors and hypertension among US women. Circulation. 1989;80:1320-1327.
FREE FULL TEXT
44. Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study of nutritional factors and hypertension among US men. Circulation. 1992;86:1475-1484.
FREE FULL TEXT
RELATED ARTICLE
Begin at the Beginning
Roberd M. Bostick
Arch Fam Med. 2000;9(1):39.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Supplementation with calcium + vitamin D enhances the beneficial effect of weight loss on plasma lipid and lipoprotein concentrations
Major et al.
Am. J. Clin. Nutr. 2007;85:54-59.
ABSTRACT
| FULL TEXT
Influence of Saturated Fat and Linolenic Acid on the Association Between Intake of Dairy Products and Blood Pressure
Djousse et al.
Hypertension 2006;48:335-341.
ABSTRACT
| FULL TEXT
Cholesterol Metabolism Is Affected by Calcium Phosphate Supplementation in Humans
Ditscheid et al.
J. Nutr. 2005;135:1678-1682.
ABSTRACT
| FULL TEXT
Does Fat in Milk, Butter and Cheese Affect Blood Lipids and Cholesterol Differently?
Tholstrup et al.
J. Am. Coll. Nutr. 2004;23:169-176.
ABSTRACT
| FULL TEXT
Begin at the Beginning
Bostick
Arch Fam Med 2000;9:39-39.
FULL TEXT
|
