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Original Studies |
Institute of Clinical Osteology Gustav Pommer, Clinic der Fürstenhof, 31812 Bad Pyrmont; and Strathmann, Inc. (D.N., C.H.), 22459 Hamburg, Germany
Address all correspondence and requests for reprints to: Dr. Michael Pfeifer, Institute of Clinical Osteology Gustav Pommer, Clinic der Fürstenhof, 31812 Bad Pyrmont, Germany. E-mail: iko-pyrmont{at}t-online.de
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Abstract |
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The effects of 8 weeks of supplementation with vitamin D3 (cholecalciferol) and calcium on blood pressure and biochemical measures of bone metabolism were studied. The sample consisted of 148 women (mean ± SD age, 74 ± 1 yr) with a 25-hydroxycholecalciferol (25OHD3) level below 50 nmol/L. They received either 1200 mg calcium plus 800 IU vitamin D3 or 1200 mg calcium/day. We measured intact PTH, 25OHD3, 1,25-dihydroxyvitamin D3, blood pressure, and heart rate before and after treatment.
Compared with calcium, supplementation with vitamin D3 and calcium resulted in an increase in serum 25OHD3 of 72% (P < 0.01), a decrease in serum PTH of 17% (P = 0.04), a decrease in systolic blood pressure (SBP) of 9.3% (P = 0.02), and a decrease in heart rate of 5.4% (P = 0.02). Sixty subjects (81%) in the vitamin D3 and calcium group compared with 35 (47%) subjects in the calcium group showed a decrease in SBP of 5 mm Hg or more (P = 0.04). No statistically significant difference was observed in the diastolic blood pressures of the calcium-treated and calcium- plus vitamin D3-treated groups (P = 0.10). Pearson coefficients of correlation between the change in PTH and the change in SBP were 0.49 (P < 0.01) for the vitamin D3 plus calcium group and 0.23 (P < 0.01) for the calcium group.
A short-term supplementation with vitamin D3 and calcium is more effective in reducing SBP than calcium alone. Inadequate vitamin D3 and calcium intake could play a contributory role in the pathogenesis and progression of hypertension and cardiovascular disease in elderly women.
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Introduction |
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We have previously shown that short-term supplementation with vitamin D3 and calcium improves body sway and secondary hyperparathyroidism and therefore prevents falls and subsequent nonvertebral fractures in elderly women (18, 19). We have now extended our studies to the effects of short-term supplementation with vitamin D3 and calcium on blood pressure, as vascular smooth muscle is a target organ for vitamin D (20). The role of calcitropic hormones in the regulation of blood pressure is unclear (21, 22, 23). To our knowledge this is the first randomized, placebo-controlled, and double-blind clinical trial investigating the effects of calcium and vitamin D3 compared with calcium therapy on blood pressure in elderly women.
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Subjects and Methods |
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We studied ambulatory women 70 yr of age or older who were recruited through newspaper advertisements in our community. The inclusion criterion was a 25OHD3 serum level below 50 nmol/L, and the exclusion criteria included hypercalcemia or primary hyperparathyroidism; fractures of the extremities due to osteoporosis; therapy with thiazide, bisphosphonate, calcitonin, vitamin D3 and other vitamin D metabolites, estrogen, antiestrogen in the past 6 months, or fluoride in the past 2 yr; known intolerance to study medication; chronic renal failure (serum creatinine >20% of the upper limit of the reference range); history of drug or alcohol abuse; nicotine abuse (>20 cigarettes/day); more than seven cups of coffee daily; scheduled holiday along the geographic longitude during the study period, diabetes mellitus; and severe cardiovascular disease (e.g. myocardial infarction, stroke, and known hypertension with a systolic blood pressure of >180 mm Hg and a diastolic blood pressure of >95 mm Hg after 5 min of resting).
Two hundred and eight subjects were prescreened by a standardized telephone interview. One hundred and sixty-five (79%) were invited for screening, of whom 148 (71%) were finally enrolled. The protocol was approved by the responsible ethics committee, and written informed consent was obtained from each subject.
Study design and supplements
During an 8-week, double-blind, controlled trial, subjects were randomly assigned to either the calcium or the vitamin D3-calcium group. At study entry, a complete physical examination and assessment of each subject’s medical history, diet, and physical activity were performed. In addition, blood and urine were analyzed. The subjects were advised to maintain their usual diets and to avoid taking supplemental calcium and vitamin D on their own. The subjects took either one tablet containing 600 mg elemental calcium in the form of calcium carbonate or one tablet with 600 mg elemental calcium and 400 IU vitamin D3 at breakfast and dinner together with meals. The tablets of calcium or calcium plus vitamin D3 were identical.
The study took place in Bad Pyrmont and Hameln, two neighborhood cities in Lower Saxony, Germany (latitude, 52°N). It commenced in March (when vitamin D levels are known to be at their lowest level) 1997 and terminated in May 1997.
Status of subjects and compliance
During the trial one subject in the calcium group was excluded from the study due to noncompliance. She refused to undergo the measurements. One subject in the vitamin D3-calcium group and another in the calcium group discontinued for personal reasons (loss of interest and decision to go on holiday). One hundred and forty-five subjects were examined at their final visit and included in the intention to treat analyses. The mean ± SD rate of compliance with treatment, assessed on the basis of pill counts, was 95 ± 12% for the calcium tablets and 96 ± 10% for the vitamin D3-calcium tablets.
Measurements
The calcium, vitamin D, and salt intakes of the subjects were assessed semiquantitatively by a food frequency questionnaire. Physical activity as well as consumption of alcohol and nicotine were also determined by questionnaires. Height was measured with a stadiometer, and weight was determined with a digital scale. Concomitant medication was classified according to Anatomical Therapeutic Chemical groups and anatomical regions depending on the active compound and the indication (Anatomical Therapeutic Chemical classification index 1994) (24). Blood pressure and pulse rate were measured after at least 5 min of supine rest in a quiet room using a sphygmomanometer with an appropriate cuff. Systolic and diastolic blood pressures were taken at Korotkov sounds I and V.
Laboratory analyses
Blood was drawn between 0800–0900 h after the subjects had
fasted for at least 8 h. Urine measurements were made in overnight
collections, taken between 0000–0700 h. Serum
25OHD3, and
1,25-(OH)2D3 were measured
by RIA (Nichols Institute Diagnostics, San Juan
Capistrano, CA), serum PTH by immunometric assay (Nichols Institute Diagnostics), serum ionized calcium and urinary
calcium by the kresolphtalein method, serum creatinine and urinary
creatinine by the Jaffé method, total bilirubin by the
dichlorphenyldiazo method, 
-glutamyl-transferase by the Szasz
method, and albumin by the bromkresolgreen method. Erythrocytes,
leukocytes, and platelets were counted by an electronic counter;
hemoglobin was determined by the cyanhemoglobin method; and hematocrit
and mean corpuscular volume were calculated. The coefficients of
variation for the assays ranged from 5.5–7.9%. All samples, except
for the screening samples and the hematological samples, were frozen at
-80 C and analyzed at the same time.
Statistical analyses
The biostatistical evaluation was carried out using the statistical software package SAS for Windows (version 6.10) and NCSS (version 6.0.21, CCDRD, Berlin, Germany). For determination of sample size, the software package NCSS-PASS 1.0 was used. The expected difference between both therapy groups was estimated at 40–60% of the SD. To detect a difference of 50% of the SD with a power of 80%, 74 subjects/group were needed. A normal distribution could be assumed for the pre-post differences. A 2-sided t test for independent samples could be applied. If a significant deviation from normality was found, the Mann-Whitney U test was used. In addition, Pearson coefficients of correlation were calculated between the changes in PTH and the changes in blood pressure.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Both treatment groups were
comparable concerning age, height, weight, physical activity,
concomitant diseases, and concomitant medication. Forty-seven percent
in the calcium group and 53% in the vitamin
D3-calcium group used cardiovascular drugs
(according to the Anatomical Therapeutic Chemical classification index)
for the treatment of hypertension. There were no changes in these
medications during the study. In addition, there were no group
differences with regard to dietary calcium, vitamin D, and salt intake
(data not shown).
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. All parameters were
within the normal reference range and did not change significantly
during the course of the study. However, we observed a tendency for a
lower platelet count and a lower serum albumin in both treatment
groups.
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The changes in blood pressure and heart rate are documented in Tables 4 and 5.
Compared with baseline, significant decreases were found in systolic
blood pressure (SBP) and diastolic blood pressure (DBP) in both
treatment groups. Concerning heart rate, a significant decrease was
found only in the vitamin D3-calcium group.
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Sixty subjects (81%) in the vitamin D3-calcium group compared with 35 (47%) subjects in the calcium group showed a decrease in SBP of 5 mm Hg or more (P = 0.04). In contrast, only 8 subjects (11%) in the vitamin D3-calcium group compared with 29 subjects (39%) in the calcium group showed an increase in SBP of 5 mm Hg or more (P = 0.04).
A decrease in heart rate of 5 beats/min or more was observed in 38 subjects (51%) during treatment with vitamin D3-calcium compared with 13 subjects (18%) treated with calcium alone (P = 0.02). On the other hand, we observed an increase in heart rate of 5 beats/min or more in only 7 subjects (9%) in the vitamin D3-calcium group compared with 23 subjects (31%) in the calcium group (P < 0.01).
Pearson coefficients of correlation between the change in PTH and the
change in SBP were 0.49 (P < 0.01) for the vitamin
D3 plus calcium group and 0.23 (P
< 0.01) for the calcium group (Table 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These results are in accordance with a publication by Krause et al. (25), who demonstrated that ultraviolet B irradiation and increased circulating levels of 25OHD were related to a decrease in both SBP and DBP.
Two meta-analyses of controlled trials of blood pressure and calcium levels in 2412 adults and 2459 pregnant women provide compelling evidence that both normotensive and hypertensive individuals may experience reductions in blood pressure when calcium intake is increased (6, 7). However, the absolute change in SBP in the 2412 adults was only 1.3 mm Hg, and the change in DBP was 0.2 mm Hg. In the present study we observed substantially bigger changes in SBP, which may be due at least in part to the underlying hypovitaminosis D associated with elevated PTH levels. Calcium requirements vary across the life span (15). When calcium needs are increased, the relationship between calcium intake and biological responses may be amplified. Elderly people may require greater calcium intake (15) due to malabsorption and vitamin D deficiency (16, 17), and old age is also a period associated with an increased risk of elevated blood pressure (26).
In a cross-sectional study (11) an inverse association between serum 1,25-(OH)2D3 level and blood pressure was described in normotensive men. St. John et al. (27) investigated the relationship between calcitropic hormones and blood pressure in 583 elderly subjects who were untreated for hypertension, but who were not vitamin D deficient. Univariate analysis demonstrated that serum PTH and 1,25-(OH)2D3 were correlated significantly with mean blood pressure. The coefficients of correlation, however, were rather low (r = 0.15 and 0.10, respectively). Multivariate analysis in the same study demonstrated that PTH and 1,25-(OH)2D3 were both significant independent determinants of the mean blood pressure. In summary, the study by John et al. (27) showed a weak, but significant, relationship between blood pressure and calcitropic hormones in a group of elderly people. The researchers concluded that hypertension may be due in part to calcium deficiency. This conclusion could be supported by Hvarfer et al. (28), who showed a statistically significant inverse relationship between mean blood pressure and plasma ionized calcium in 97 healthy subjects, aged 16–82 yr (28).
Hyperparathyroidism has been associated with hypertension (29), and it increases calcium uptake in human cells (30). Parathyroidectomy after primary hyperparathyroidism improves blood pressure and arterial smooth muscle (31, 32). Chronic PTH infusion results in hypertension in normal subjects (33). Thus, if the beneficial effect of calcium supplementation is mediated by a reduction in PTH secretion, it is likely that it occurs by a restoration of parathyroid gland function to normal. In our study we found a positive significant correlation between the change in PTH and the change in SBP in the vitamin D3 plus calcium group (r = 0.49) and the calcium group (r = 0.18). These results are in accordance with the study by Brickman et al. (34), who demonstrated a similar positive correlation between intact PTH and SBP (r = 0.41; P < 0.01) in a group of 91 normotensive subjects. When multiple regression analysis was performed using mean arterial pressure as the dependent variable, PTH maintained a significant correlation with mean arterial pressure (34). Together, these results suggest that PTH is associated with blood pressure regulation in normotensive subjects.
High salt intake has been associated with reduced peak bone mass in young girls, aged 8–13 yr (35), and with a higher rate of bone mineral loss in postmenopausal women (36). High salt intake causes an increase in urinary calcium excretion (37), and a decrease in dietary intake should promote a positive calcium balance and lower blood pressure. Decreased salt intake should therefore lessen the risk of osteoporosis and hip fractures in elderly people and also have a blood pressure-lowering effect (38).
Our study demonstrates that short-term supplementation with vitamin D3 and calcium is more effective in reducing SBP than calcium alone, and this effect is most likely to be due to the restoration of parathyroid gland function to normal. Inadequate vitamin D3 and calcium intake are not only a risk for osteoporosis, but they could play a contributory role in the pathogenesis and progression of hypertension and cardiovascular disease, particularly in elderly people with vitamin D deficiency and secondary hyperparathyroidism. Consequently, our results are also consistent with the inverse association among bone mineral density (13), stroke incidence (39), and cardiovascular mortality (40).
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Acknowledgments |
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Footnotes |
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Received July 19, 2000.
Revised November 9, 2000.
Accepted December 19, 2000.
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