Published online before print September 29, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114991
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(Hypertension. 2008;52:847.)
© 2008 American Heart Association, Inc.
Original Articles |
Effect of Calcium and Vitamin D Supplementation on Blood Pressure
The Women’s Health Initiative Randomized Trial
From the Health Partners Research Foundation (K.L.M.), Minneapolis, Minn; Division of Public Health Sciences (R.M.R.), Fred Hutchinson Cancer Research Center, Seattle, Wash; Department of Preventative Medicine (L.V.H.), Feinberg School of Medicine, Northwestern University, Chicago, Ill; Division of Preventive Medicine (J.E.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Family and Preventive Medicine (M.A.A.), University of California San Diego; Department of Medicine (H.R.B.), Rush Medical College, Chicago, Ill; Department of Epidemiology (S.A.A.B.), University of Washington, Seattle; Department of Preventative Medicine (S.A.C.), University of Tennessee, Memphis; Department of Geriatric Medicine (J.D.C.), University of Hawaii, Honolulu; Berman Center for Outcomes of Clinical Research (R.H.G.), Minneapolis, Minn; Department of Medicine (T.A.K.), Medical College of Wisconsin, Milwaukee; Department of Epidemiology (L.H.K.), University of Pittsburgh, Pa; Department of Epidemiology and Population Health (S.W.-S.), Albert Einstein College of Medicine, New York, NY; Department of Nutritional Sciences (C.A.T.), University of Arizona, Tuscon; and the Department of Epidemiology (J.C.T.), University of Iowa, Iowa City.
Correspondence to Karen L. Margolis, HealthPartners Research Foundation, Box 1524, Mailstop 21111R, Minneapolis, MN 55440-1524. E-mail Karen.L.Margolis{at}HealthPartners.com
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Abstract |
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Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women’s Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI: –0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI: –0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI: 0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up.
Key Words: calcium supplementation • 25-hydroxyvitamin D • 1 • 25-dihydroxyvitamin D • blood pressure • hypertension • clinical trials
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Introduction |
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The role of calcium in the prevention and treatment of hypertension is controversial, despite decades of study. An overall healthy dietary pattern that is rich in calcium from low-fat dairy products, fruits, and vegetables has been shown to lower blood pressure substantially compared with a typical diet higher in fat and sodium and lower in calcium, magnesium, potassium, and fiber.1–4 However, meta-analyses5–12 and systematic reviews13 of the epidemiological and clinical trial evidence regarding dietary intake of calcium as a single nutrient have generally concluded that the effect on systolic blood pressure (BP) lowering is small, on the order of 2 mm Hg. The effect on diastolic BP, if any, may be even smaller. Nevertheless, at a population level, sustained BP lowering of this degree by calcium supplementation could have important benefits on cardiovascular disease.
Although the relation between vitamin D and BP has been less studied, 2 small, short-term intervention studies suggest that vitamin D, either as ultraviolet light exposure or as an oral supplement, may lower BP.14,15 In addition, the risk of incident hypertension was lower in a 4-year prospective study among men and women with higher plasma levels of 25(OH) vitamin D.16 Animal studies have also shown that oral supplementation with vitamin D lowered BP in hypertensive rats; in this model vitamin D inhibited renin expression in the juxtaglomerular apparatus and inhibited smooth muscle proliferation.17–20
Most individual trials of calcium supplementation (with or without vitamin D) have been relatively small, short in duration, or both. Meta-analyses and reviews have called for high-quality, long-term studies including subgroups that might have greater BP lowering from calcium supplementation, such as individuals with elevated BP or hypertension (especially low renin or "salt-sensitive" hypertension), black subjects, or those with habitual low intake of calcium or vitamin D.21–24 The Women’s Health Initiative (WHI) included a methodologically rigorous randomized, double-blind, placebo-controlled trial of dietary supplementation with calcium plus vitamin D supplementation and long-term follow-up. We examined the effect on BP and the incidence of hypertension in this study of 36 282 postmenopausal women. Because of the large size of the trial, we were able to examine subgroups that might have differing degrees of benefit.
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Methods |
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Study Population and Intervention
Between 1993 and 1998, postmenopausal women aged 50 to 79 years were recruited at 40 US clinical centers into the WHI randomized trials assessing the risks and benefits of hormone therapy and dietary modification.25 Participants enrolled in one or both trials were further invited to join the calcium plus vitamin D (CaD) trial at their first (n=33 070) or second (n=3212) annual follow-up visit.26 Women with <3 years of predicted survival, a history of kidney stone or hypercalcemia, current oral corticosteroid use, or current calcitriol use were excluded. The primary outcome for the CaD intervention trial was incident hip fracture, and the secondary outcome was colorectal cancer. Results of these analyses have been published.27,28 The study protocol was approved by the institutional review board at each participating institution, and written informed consent was granted by each participant before the random assignment into the CaD trial.
Participants were randomly assigned in a double-blind fashion to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo.26 Each active tablet provided 500 mg of calcium (as calcium carbonate) and 200 IU of vitamin D3 (provided by GlaxoSmithKline). Participants were instructed to take 2 tablets daily, preferably in divided doses with meals. Women in both the active supplement and placebo groups were allowed to continue their own open-label use of calcium and vitamin D supplements as long as nonstudy use of vitamin D did not exceed 600 IU daily. The upper limit of nonstudy vitamin D intake was raised to 1000 IU after the Institute of Medicine released its report on the tolerable upper limits of vitamin D intake.29 Adherence to study medication was assessed by weighing returned bottles.
BP Measurement and Ascertainment of Hypertension
BP was measured by certified staff using standardized procedures and instruments, in the right arm, with a conventional mercury sphygmomanometer and an appropriately sized cuff, after the participant was seated and resting for 5 minutes.30 Two measurements, obtained 
30 seconds apart, were performed at the WHI enrollment visit and at each subsequent annual visit, including the CaD enrollment visit. The average of the 2 measurements was used for analyses. At enrollment, participants were asked whether they had been diagnosed by a physician with high BP or hypertension and whether they were taking medications for hypertension. Then, at each semiannual contact, participants were asked, "Since the date given on the front of this form, has a doctor prescribed any of the following pills or treatments?" The choices included "pills for hypertension." Medication inventories were conducted at WHI enrollment, and at the first, third, sixth, and ninth annual visits. The product or generic name of the medications on the label was entered into the study database and matched to the corresponding item in a pharmacy database (Master Drug Data Base, Medi-Span). Drugs from the following classes were considered to be antihypertensive agents: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, centrally acting antihypertensive agents, vasodilators, and combinations of these medications. At enrollment in the WHI study, 94% of women with self-reported hypertension treatment had an antihypertensive agent in the baseline drug inventory, and 79% with incident self-reported hypertension treatment during the first year of the trial brought an antihypertensive medication to the year 1 drug inventory.
Covariates
Demographic and health history data were self-reported at WHI baseline. Dietary data were collected using a validated food frequency questionnaire.31 Total calcium and vitamin D intakes included both dietary and supplement sources determined from the medication and supplement inventory. Metabolic equivalent task scores were calculated from the frequency and duration of recreational physical activity.32 Baseline 25-hydroxyvitamin D levels were measured using the DiaSorin Liaison chemiluminescent immunoassay system in a subset of CaD trial participants as part of nested case-control studies examining fractures, breast cancer, and colorectal cancer.27,28 Only participants selected as control subjects were included in these biomarker analyses (n=2029).
Statistical Methods
Of 36 282 postmenopausal women enrolled in the CaD trial, 36 189 had either a systolic or diastolic BP measurement at random assignment. The primary outcome measure was BP change (annual BP measurements collected through 7 years of follow-up minus the BP at the CaD randomization visit). All of the participants with 1 BP change measurement were included in the intent-to-treat analysis using linear repeated-measures regression modeling with an unstructured covariance matrix (using SAS PROC MIXED 9.1, SAS Institute). Repeated-measures regression allows for correlations among responses within an individual and allows for missing response data. This procedure does not impute missing data or carry the last observation forward but allows the inclusion of available data from individuals with missing responses by using a maximum likelihood approach that gives valid results under missing-at-random assumptions. Plots of longitudinal data are based on fitted means from these models where both treatment assignment and time are modeled as class variables, and treatment effect is allowed to vary over time (saturated model).
The effect of treatment on incident hypertension was examined using Cox proportional hazards models stratified by age and randomization status for other WHI trials. Incident hypertension was defined as self-report of medication prescribed for hypertension or any BP 140/90 mm Hg during 7 years of follow-up among 17 122 women who did not have hypertension at CaD enrollment (no self-report of hypertension treatment, no antihypertensive medications in inventory, and BP at all visits <140/90 mm Hg before random assignment). We also examined the effect of treatment on incident prehypertension (1 visit with BP 120 to 139/80 to 89 mm Hg with no self-report of medication prescribed for hypertension) or hypertension during follow-up among 9416 normotensive women at CaD enrollment (no self-report of hypertension treatment, no antihypertensive medications in inventory, and BP <120/80 mm Hg at all prerandomization visits). For all of the analyses of incident hypertension, women were considered at risk from entry into the CaD trial until the date at which hypertension was determined or until the last date during the follow-up period that outcome data were available. Women who were normotensive at CaD enrollment were considered at risk for prehypertension or hypertension from date of entry into the CaD trial until the first annual visit with BP 120/80 mm Hg, a self-report of medication prescribed for hypertension, or the last date that outcome data were available.
To examine the effect of nonadherence to the active CaD supplements or placebo, sensitivity analyses were conducted in which participants were censored after their first visit at which nonadherence was detected, defined as use of <80% of the study pills.
To assess whether the effect of CaD supplementation on BP and incident hypertension varied according to baseline risk factors, the same models were extended, and formal tests of interactions were performed. These factors included demographic characteristics; other risk factors for hypertension (baseline BP, presence of hypertension, body mass index, and physical activity); baseline intake of sodium, calcium, and vitamin D; and randomization status in the hormone therapy and dietary modification trials. Because 16 interactions with baseline characteristics were investigated, chance alone would be expected to produce 
1 statistically significant interaction test at the 0.05 level of significance.
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Results |
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Baseline Characteristics, Retention, and Adherence
Between 1995 and 2000, 36 282 women were randomly assigned into the CaD trial: 18 176 were assigned to the active CaD supplementation and 18 106 to placebo. Mean (SD) follow-up time was 7.0 years (1.4 years). Participant characteristics, described in detail in Table 1
, did not differ by CaD treatment assignment. The mean age at enrollment in the WHI Trial of women included in this study was 62±7 years; 83% described themselves as non-Hispanic white, 9% black, 4% Hispanic, <1% American Indian, and 2% Asian/Pacific Islander. Mean BP was 126/75 mm Hg, and 46% of the participants had evidence of hypertension (28% with self-reported antihypertensive treatment and 18% with 1 visit BP 140/90 mm Hg).
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Mean (SD) dietary calcium intake was 825 mg/d (438 mg/d), total calcium intake was 1150 mg/d (656 mg/d), dietary vitamin D intake was 175 IU/d (117 IU/d), and mean total vitamin D intake was 367 IU/d (266 IU/d). The mean intake of dairy products was 1.5 servings per day, and 52% of the participants reported the use of calcium supplements. At CaD enrollment, 40% of women met the current recommendation for 1200 mg/d of calcium intake from supplements and diet combined.
At the termination of the trial, 1551 participants (4.3%) had died, and 2.7% percent had withdrawn or been lost to follow-up. In year 1, the proportion taking 80% of study medication was 60% overall and remained stable through year 7, ranging between 56% and 63%, with small differences between treatment groups. The mean dose of open-label supplemental calcium increased by <100 mg/d during the trial from 325 mg/d at enrollment and was similar across both treatment groups.
BP Change
From baseline to the end of follow-up, systolic BP declined by 1 mm Hg during follow-up, whereas diastolic BP declined by 4 mm Hg. There was no difference in the change in either systolic BP (Figure 1A) or diastolic BP (Figure 1B) between women randomly assigned to the active versus placebo CaD supplements. In sensitivity analyses accounting for nonadherence, the results were similar (data not shown). The overall mean difference in change in systolic BP was 0.22 mm Hg (95% CI: –0.05 to 0.49 mm Hg) and in diastolic BP was 0.11 mm Hg (95% CI: –0.04 to 0.27 mm Hg), with a positive mean difference indicating that BP was lowered less in the active group than the placebo group, although differences were not significant (Table 2).
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There were no subgroups based on demographic characteristics, hypertension risk factors, calcium/vitamin D intake, or measured serum 25-hydroxy vitamin D that appeared to derive BP benefits from the supplements (Table 2
). In addition to our a priori subgroups of approximate tertiles of baseline calcium intake (data not shown), we further subdivided the lowest tertile of the level of intake to attempt to identify a group with extremely low intake (<400 mg/d of dietary calcium [14th percentile] and <600 mg/d of total calcium [20th percentile]) that might benefit from the supplements. In each subgroup, the mean BP differences were very close to 0, and none of the tertile or posthoc subgroups showed statistically significant treatment group differences either individually or overall. There were also no differences in BPs between treatment groups in the subgroup of women with joint intake of dietary calcium <400 IU/d and total vitamin D intake <200 IU/d (data not shown).
Incident Hypertension and Prehypertension
Over a mean follow-up time of 7 years, of 17 122 initially nonhypertensive women, 4429 (2131 assigned to active CaD and 2098 assigned to placebo) reported being prescribed medication for hypertension. Including participants who developed BP 140/90 mm Hg in the definition, 6692 women (3377 assigned to active CaD and 3315 assigned to placebo) developed incident hypertension. The risk of hypertension did not differ by CaD treatment assignment (Figure 2). The hazard ratio for incident hypertension, defined as newly prescribed antihypertensive medication or elevated measured BP, was 1.01 (95% CI: 0.96 to 1.06.) In the subsample of participants with measured 25-hydroxy vitamin D, those with lower levels had a higher risk of incident hypertension. No other subgroup interactions were observed.
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Among 9416 normotensive women, prehypertension or hypertension developed during follow-up in 6636. Treatment with CaD did not lower the risk of incident prehypertension or hypertension either overall or in any subgroup (hazard ratio: 1.01; 95% CI: 0.97 to 1.06; data not shown).
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Discussion |
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Calcium plus vitamin D3 supplementation (1000 mg plus 400 IU daily, respectively) did not reduce BP over 7 years of follow-up or the risk of developing prehypertension or hypertension in the WHI CaD randomized, placebo-controlled trial. This null result was robust in intention-to-treat analyses, analyses among adherent participants, and subgroup analyses. With the hazard ratio for incident hypertension of 1.01, comparing supplementation with placebo, and a narrow 95% CI (0.96 to 1.06), a clinically significant benefit for this calcium supplementation with regard to lowering BP or preventing hypertension is unlikely among generally healthy postmenopausal women.
A recent meta-analysis by van Mierlo et al10 of randomized, controlled trials of calcium supplementation or dietary intervention with a duration of 2 weeks included 40 trials and 2492 nonpregnant adults. The duration ranged from 3 to 208 weeks (median: 9.5 weeks) and daily calcium dose from 335 to 2000 mg (median: 1055 mg). The weighted estimate of the effect of calcium supplementation on BP was –2 mm Hg for systolic BP and –1 mm Hg for diastolic BP. The effect on systolic BP (–3 mm Hg) was slightly larger in populations with calcium intake 
800 mg/d. The BP-lowering effect was substantially larger (–10/5 mm Hg) in 4 trials in Asian populations, composed of 154 subjects, mostly with habitual calcium intakes <600 mg/d. A second recent meta-analysis included only randomized, controlled trials of duration 8 weeks in nonpregnant adults with BP 140/85 mm Hg. In this study of 13 trials that enrolled 484 subjects, the BP-lowering effect of calcium supplements was similar to that observed in the meta-analysis by van Mierlo et al10: –2.5 mm Hg for systolic BP and –0.8 mm Hg for diastolic BP.
Several authors have argued that previous clinical trials and meta-analyses masked considerable heterogeneity of the effect of BP response to calcium supplementation.22,33 The present study did not detect any heterogeneity of effect by age, ethnicity, baseline BP, sodium intake, or calcium/vitamin D intake. The WHI CaD trial enrolled >10-fold the number of participants included in previous meta-analyses of randomized trials of calcium supplementation and included large numbers of women in these potentially more responsive subgroups. The lower bound of the 95% CI overall and in each of these subgroups excludes a BP-lowering effect of calcium supplementation of clinical or public health importance.
The WHI CaD trial intervention included supplementation with 400 IU of vitamin D3. Although data from large prospective studies have not shown that higher vitamin D intake lowered the incidence of hypertension, participants in these studies with plasma levels of 25-hydroxy vitamin D in the deficient range had an increase in the risk of incident hypertension (6-fold in men and 3-fold in women).16 In the present study, we did not find evidence of lower BP in women who received the active vitamin D3–containing supplement in the lowest quartile of measured 25-hydroxy vitamin D, which fell into the range generally considered deficient. In fact, there was a trend toward an increased risk of hypertension with supplementation in women with lower vitamin D levels. This was not statistically significant for hypertension defined only by antihypertensive treatment prescription. Because of the number of subgroup interactions that we examined, this finding may be attributable to chance.
There are a number of potential limitations to this study. First, only postmenopausal women were included, so our results may not apply to men or younger women, although there is little basis to believe that these populations would respond differently to calcium supplementation.10 Second, nonadherence may have biased results toward the null; however, sensitivity analyses accounting for this suggested that the study result was robust. Third, the baseline level of dietary calcium intake was higher in the WHI CaD trial than average for older women in the United States (825 versus 660 mg/d), and many women took supplemental calcium and vitamin D at baseline and as open-label supplements during the trial. However, because of the large size of the study, subgroup analyses included substantial numbers of participants with low intake of these nutrients, and a clinically important BP effect was also excluded in these subgroups. Fourth, different results might have been observed with a different formulation or dose of calcium or a higher dose of vitamin D3. The dose of 400 IU of vitamin D in particular has been questioned as being inadequate to reduce the incidence of hip fracture and colorectal cancer, the main end points of the trial.27,28 The lack of any degree of BP lowering even in subgroups with low intakes of calcium or vitamin D or in women with low vitamin D levels argues against this possibility, however. In addition, meta-analyses have not shown differences in BP lowering with higher (>1000 to 1200 mg/d) versus lower doses of calcium supplements.34,35 Finally, it is possible that combining calcium with other nutrients or other minerals or simultaneous dietary intervention focused on calcium and vitamin D rich foods might have led to different results. However, a meta-analysis of 3 trials of combinations of calcium, magnesium, and potassium supplementation in 277 participants did not find a significant effect on BP.36 Although 1 meta-analysis suggested the possibility of a trend toward a greater BP-lowering effect of dietary versus nondietary provision of calcium,9 unequivocally effective dietary interventions to lower BP have generally included sodium restriction and manipulation of multiple foods groups, macronutrients, and minerals.11
This study also has important strengths. The large size of the study allowed us to examine subgroups that had been hypothesized to have potential for greater benefit: blacks, Asians, hypertensive subjects, women with low habitual intake of calcium, and women with low serum levels of vitamin D. The study methodology was double blind and included adequate concealment of treatment assignment. The study was longer than any trial reported previously, and there was little loss to follow-up.
In conclusion, in postmenopausal women over 7 years of follow-up, calcium plus vitamin D3 supplementation did not reduce either BP or the risk of developing hypertension. There was no subgroup that appeared to benefit from CaD supplementation, and the precision of this study excludes a BP-lowering effect of calcium supplementation of clinical or public health importance.
Perspectives
Calcium supplementation, and, to a lesser extent, vitamin D supplementation have long been hypothesized to lower BP and delay the onset of hypertension. The results of previous calcium supplementation trials have been mixed but in general have shown a small BP–lowering benefit. The WHI CaD supplementation trial provides the most definitive answer to the question: no benefit was seen overall or in any subgroup of postmenopausal women. Although the dose of both supplements was modest, particularly the vitamin D, the lack of benefit in women with low intake of these nutrients or low levels of vitamin D argues against a different result had dosages been higher. Because the WHI trial did not include younger women or men, no firm conclusions can be drawn about the effect of calcium or vitamin D on BP in these groups. This study also did not address the question of BP lowering by dietary calcium intake or dairy foods, but it suggests that short cuts with dietary supplements cannot be substituted for encouraging people to adopt dietary patterns that have been shown to lower BP and decrease the risk of hypertension.
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Acknowledgments |
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Sources of Funding
The Women’s Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-32102, 32105-32106, 32108-32109, 32111-32113, 32115, 32118-32119, 32122, 42107-42126, 42129-42132, and 44221.
Disclosures
None.
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Footnotes |
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Please see http://hyper.ahajournals.org for a short list of the Women’s Health Initiative investigators.
Received April 28, 2008; first decision May 26, 2008; accepted September 2, 2008.
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