Hypertension and Calcium Deficiency

Also see:
Calcium Paradox
Blood Pressure Management with Calcium & Dairy
Calcium to Phosphorus Ratio, PTH, and Bone Health

Calcium deficiency, not sodium excess, is an overlooked link in hypertension (high blood pressure) likely due to overstimulation of parathyroid hormone (PTH). Don’t forget your dairy products and egg shells.

Hypertension 1980 Mar-Apr;2(2):162-8.
Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak.
McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S.
Recent reports, though, suggest that increased parathyroid gland function may be one of the more common endocrine disturbances associated with hypertension. Compared to a second age- and sex-matched normotensive population, the hypertensives demonstrated a significant (p less than 0.005) relative hypercalciuria. For any level of urinary sodium, hypertensives excreted more calcium. These preliminary data suggest that parathyroid gland function may be enhanced in essential hypertension.

Am J Med 1987 Jan 26;82(1B):27-33.
The calcium paradox of essential hypertension.
McCarron DA, Morris CD, Bukoski R.
Three disparate observations–that calcium mediates vascular smooth muscle contraction, that calcium channel blockers lower blood pressure, and that increased dietary calcium intake can also ameliorate hypertension–constitute somewhat of a paradox. This evidence, and the paradoxical therapeutic efficacy of both calcium channel blockers and supplemental dietary calcium, can be integrated into a single theoretic construct.

Science. 1984 Jun 29;224(4656):1392-8.
Blood pressure and nutrient intake in the United States.
McCarron DA, Morris CD, Henry HJ, Stanton JL.
A data base of the National Center for Health Statistics, Health and Nutrition Examination Survey I (HANES I), was used to perform a computer-assisted, comprehensive analysis of the relation of 17 nutrients to the blood pressure profile of adult Americans. Subjects were 10,372 individuals, 18 to 74 years of age, who denied a history of hypertension and intentional modification of their diet. Significant decreases in the consumption of calcium, potassium, vitamin A, and vitamin C were identified as the nutritional factors that distinguished hypertensive from normotensive subjects. Lower calcium intake was the most consistent factor in hypertensive individuals. Across the population, higher intakes of calcium, potassium, and sodium were associated with lower mean systolic blood pressure and lower absolute risk of hypertension. Increments of dietary calcium were also negatively correlated with body mass. Even though these correlations cannot be accepted as proof of causation, they have implications for future studies of the association of nutritional factors and dietary patterns with hypertension in America.

Am J Hypertens 1995 Oct;8(10 Pt 1):957-64.
Regulation of parathyroid hormone and vitamin D in essential hypertension.
Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA.
The maximal stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance.

Hypertension 1986 Jun;8(6):497-505.
Effects of calcium infusion on blood pressure in hypertensive and normotensive humans.
Ellison DH, Shneidman R, Morris C, McCarron DA.
Together, these data provide evidence for interactions between dietary sodium intake and the cardiovascular response to calcium. They confirm that hypertensive subjects exhibit enhanced parathyroid gland function even when dietary factors are controlled, and they suggest that these subjects are more sensitive to the cardiovascular effects of short-term calcium infusion.

Hypertension. 2000 May;35(5):1154-9.
Relation between low calcium intake, parathyroid hormone, and blood pressure.
Jorde R, Sundsfjord J, Haug E, Bonaa KH.
In a population health survey in 1995, serum parathyroid hormone (PTH) was measured in 1113 subjects, aged 30 to 79 years, and was found to be elevated (>6.9 pmol/L) in 118 subjects. In 1998, this group and 131 subjects with normal PTH levels were invited for reexamination, and 82 and 90 subjects from each respective group attended the follow-up. At the follow-up, 72 subjects had elevated and 100 had normal serum PTH levels. Those with elevated serum PTH levels (8 subjects with hyperparathyroidism were excluded) had significantly lower serum calcium levels and intake of calcium than those with normal PTH (2.24+/-0.09 and 2.29+/-0.10 mmol/L [mean+/-SD] and 400.3+/-227.3 and 592.1+/-459.6 mg/d, respectively; P<0.01). Serum levels or intake of vitamin D did not differ between the 2 groups. Subjects with elevated PTH in both 1995 and 1998 had significantly lower bone mineral content and bone mineral density in the lumbar spine than did those with persistently normal PTH levels (P<0.05). In the females, but not in the males, the systolic and diastolic blood pressures were significantly higher in those with elevated serum PTH (158.0+/-27.5 versus 141.5+/-19.2 mm Hg and 90. 5+/-13.6 versus 82.6+/-8.6 mm Hg, respectively; P<0.01). This difference was even more pronounced when those with persistently elevated PTH were considered separately. In conclusion, reduced intake of calcium is frequently associated with high levels of serum PTH. This is associated with moderately reduced bone mineral content and bone mineral density in the lumbar spine. In women, high levels of serum PTH are also associated with markedly increased blood pressure.

J Hypertens. 2005 Sep;23(9):1639-44.
Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men.
Jorde R, Svartberg J, Sundsfjord J.
In cross-sectional studies there appears to be a link between calcium metabolism and blood pressure, and most studies have found a positive association between serum parathyroid hormone (PTH) and hypertension.
To determine the prognostic value of serum PTH regarding a future increase in blood pressure.
A prospective cohort study.
A total of 1784 individuals who had measurements of PTH in serum samples from both the fourth (1994) and fifth (2001) Tromsø studies, who did not use blood pressure medication during the observation period, and had serum calcium less than 2.61 mmol/l, were included.
Delta blood pressure (blood pressure from 2001 minus blood pressure from 1994).
The mean delta systolic blood pressure in the men and women during these 7 years was 5.8 and 8.1 mmHg, respectively. In a sex-specific linear regression model correcting for age, body mass index (BMI), and smoking status, serum PTH from 1994 was a significant predictor of delta systolic blood pressure in men (P < 0.01), but not in women. The difference in delta systolic blood pressure between those in the highest and those in the lowest PTH quartile was 3.5 mmHg. Similarly, delta serum PTH (serum PTH from 2001 minus serum PTH from 1994) was a significant predictor of delta systolic blood pressure in men (P < 0.05).
Although these findings do not prove a causal relationship between PTH and blood pressure, it adds to the growing number of indications that PTH is involved in the development of hypertension.

Am J Hypertens. 1990 Aug;3(8 Pt 2):161S-166S.
Calcium regulating hormones in essential hypertension. Importance of gender.
Young EW, McCarron DA, Morris CD.
Alterations of calcium metabolism have been described in human essential hypertension and experimental hypertension. We investigated the interrelationship of parathyroid hormone (PTH) and 1,25(OH)2-vitamin D (1,25(OH)2D) in patients with untreated essential hypertension as compared to normotensive controls. The hypertensive subjects (n = 75; 43 men, 32 women) had a mean blood pressure of 138 +/- 8/95 +/- 5 mm Hg as compared with 120 +/- 11/80 +/- 8 in the normotensive group (n = 40; 22 men, 18 women). Serum PTH was measured with an intact molecule immunochemiluminometric assay and 1,25(OH)2D was measured with radioimmunoassay after HPLC separation. Hypertensive men had PTH levels that were 36% higher than normotensive men (5.3 +/- 2.9 v 3.9 +/- 0.8 pmol/L, P = .005). When blood pressure was analyzed as a continuous variable, there was a direct correlation between it and serum PTH in men (r = .31, P = .004). In women, by contrast, there was no difference in serum PTH between hypertensive and normotensive subjects and no relationship between blood pressure and the serum PTH concentration. Blood pressure was inversely correlated with serum phosphorus levels in both sexes (r = -0.20, P = .04). In men, the elevated serum PTH levels and depressed serum phosphorus levels would have predicted that serum 1,25(OH)2D would be higher in the hypertensive subjects. However, that was not observed, as serum 1,25(OH)2D was slightly lower in hypertensive (38.3 +/- 15.2 pg/mL) than normotensive men (42.7 +/- 11.3, P = .21).

Am J Hypertens. 1995 Oct;8(10 Pt 1):957-64.
Regulation of parathyroid hormone and vitamin D in essential hypertension.
Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA.
Patients with essential hypertension have been reported to have a higher serum concentration of parathyroid hormone (PTH) than normotensive individuals although this finding is not universal among studies. To further characterize the status of the calcium regulating hormones in essential hypertension, we measured the parathyroid gland response to acute EDTA-induced hypocalcemia and the renal response of 1,25(OH)2-vitamin D to dietary calcium deprivation in 16 hypertensive (H) and 15 normotensive (N) men. The average mean arterial blood pressure once all antihypertensive medications were discontinued was 108 +/- 7 mm Hg for the hypertensive group and 89 +/- 4 mm Hg for the normotensive group (P < .01). There were no group differences in baseline serum concentrations of ionized calcium, creatinine, intact PTH, and 1,25(OH)2-vitamin D, urinary calcium excretion, and creatinine clearance. After a 1-h infusion of EDTA at 12.5 mg/kg/h, the serum concentration of ionized calcium fell (H: 1.25 +/- .03 to 1.17 +/- .04 mmol/L, N: 1.26 +/- .04 to 1.18 +/- .04 mmol/L, P = NS) and PTH increased (H: 36 +/- 9 to 91 +/- 30 pg/mL, N: 40 +/- 14 to 85 +/- 28 pg/mL, P = NS). With an additional hour of EDTA at a dose of 25 mg/kg/h, serum ionized calcium concentration fell further (H: 1.01 +/- .05 mmol/L, N: 1.03 +/- .06 mmol/L, P = NS) and PTH increased to 150 +/- 58 pg/ml in patients and 130 +/- 32 pg/ml in controls (P < .001). The response suggested an increased maximal parathyroid gland secretory capacity in the hypertensive patients relative to the controls. There was no group difference in the serum concentration of 1,25(OH)2-vitamin D at baseline (H: 32 +/- 6 pg/ml, N: 32 +/- 8 pg/ml, P < .90) and following dietary calcium deprivation for three days (H 50 +/- 12, N 48 +/- 14 P < 0.76). The maximal stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance. These findings suggest an intrinsic alteration of PTH regulation in patients with essential hypertension, manifest as increased parathyroid gland secretory capacity.

Blood Press. 1996 Mar;5(2):121-7.
Effect of low dietary calcium intake on blood pressure and pressure natriuresis response in rats: a possible role of the renin-angiotensin system.
Yuasa S, Sumikura T, Yura T, Takahashi N, Shoji T, Uchida K, Fujioka H, Miki S, Matsuo H, Takamitsu Y.
Dietary Ca is an important modulator of blood pressure in humans and rats. Since the kidney plays a key role in the pathogenesis of hypertension, the effects of a low Ca diet (0.01% Ca) on blood pressure and pressure natriuresis response were studied in normotensive Sprague-Dawley rats. In addition, a possible role of the renin-angiotensin system in the development of hypertension and an altered pressure natriuresis response resulting from low dietary Ca intake was examined. In the low Ca diet group, systolic blood pressure measured by the tail-cuff method was significantly higher than in the normal Ca diet group (1,1% Ca) 1 week after the diet (1 13.0 +/- 7.1 vs. 105.0 +/- 9.5mmHg, p < 0.05). After 4 weeks, the hypertension was more pronounced. Low dietary Ca intake significantly inhibited the water and sodium excretory responses to acute elevation of renal perfusion pressure by tightening an infrarenal aortic constriction. Treatment with an inhibitor of angiotensin-converting enzyme, captopril (30 mg/kg/day), completely abolished the elevation of blood pressure and attenuated the reduced pressure natriuresis response observed in Ca-deficient rats. Although plasma renin activity was not different between the low and normal Ca diet groups after the 2-week dietary regimen, the pressor response to angiotensin II was enhanced by 30% in the low Ca diet group and there was a significant difference in the pressor response between the two groups. These results suggest a possible involvement of the renin-angiotensin system in the development of hypertension and an inhibitory effect on the pressure natriuresis response caused by low dietary Ca intake, via an enhanced sensitivity to angiotensin II.

Semin Nephrol. 1995 Nov;15(6):593-602.
Mechanisms of calcium’s effects on blood pressure.
Hatton DC, Yue Q, McCarron DA
Manipulations of dietary calcium have been repeatedly shown to alter blood pressure in animal models of human essential hypertension. Supplemental dietary calcium lowers blood pressure, whereas restricted calcium diets tend to elevate blood pressure. The mechanisms responsible have not been identified, but numerous possibilities have been proposed. Many of the proposals have attempted to relate dietary calcium to calcium metabolism in vascular smooth muscle and altered vascular tone. Other proposals have focused on neural, hormonal, and renal effects of dietary calcium. In this article, mechanisms through which elevations in extracellular calcium levels might influence intracellular calcium levels are explored. Also examined are the potential roles of calcium regulating hormones, sympathetic nervous system, and electrolyte interactions in modifying blood pressure.

J Lab Clin Med. 1989 Oct;114(4):338-48.
Calcium and hypertension.
Sowers JR, Zemel MB, Standley PR, Zemel PC.
A possible relationship between dietary calcium intake and blood pressure has been the focus of considerable recent observational and experimental research. To provide a current perspective, we have reviewed and summarized the epidemiologic data, evidence suggesting abnormalities in calcium metabolism in human hypertension, studies evaluating calcium supplementation in various hypertension populations, and data that may help elucidate possible blood pressure-lowering mechanisms of calcium supplementation. An important relationship between “calcium metabolism” and “salt-sensitivity” is emerging and appears to be providing insights into potential mechanisms that account for the antihypertensive properties of dietary calcium in certain individuals. More experimental work needs to be performed to further define the individuals with hypertension who demonstrate a blood pressure-lowering response to dietary calcium supplementation.

Science 16 July 1982: Vol. 217 no. 4556 pp. 267-269
Dietary calcium in human hypertension
DA McCarron, CD Morris, C Cole
A pilot survey was made of the dietary calcium intake of normotensive and hypertensive individuals. Compared to 44 normotensive controls, 46 subjects with essential hypertension reported significantly less daily calcium ingestion (668 +/- 55 milligrams compared to 886 +/- 89 milligrams). The intake of other nutrients, including sodium and potassium, was very similar in the two groups. The hypertensives differed from the controls primarily in their consumption of nonfluid dairy products. The data suggest that inadequate calcium intake may be a previously unrecognized factor in the development of hypertension.

J Am Coll Nutr February 1998 vol. 17 no. 1 97-98
Importance of Dietary Calcuim in Hypertension
David A. McCarron, MD
For decades dietary factors have been postulated as being important in the pathogenesis and treatment of arterial hypertension. Almost to the exclusion of other nutrients, sodium has dominated both the clinical arena and research paradigm. In recent years emphasis has also been placed on weight control and alcohol moderation as nutrition-related, life-style factors that might favorably influence blood pressure. Fifteen years ago in a paper in Science [1] we reported that in contrast to commonly held notions, a diet deficient in calcium from dairy products was the dietary pattern that predicted an elevated arterial pressure. In that study cohort there was no evidence of an impact of dietary sodium on blood pressure.

In 1984 we published a second paper in Science [2] which reported the results of an analysis of the first NHANES. Again we observed that as reported dietary calcium and potassium intake decreased, arterial pressure and the risk of being hypertensive increased. Further we reported that a diet low in dairy products and fresh fruits and vegetables were the two dietary patterns most predictive of hypertension in the United States. Besides confirming our 1982 paper, the 1984 Science paper raised the disturbing possibility that a lower sodium intake might actually be associated with an increased risk of hypertension. In spite of these intriguing findings, the extensive data base that emerged to support the calcium deficiency hypothesis [3,4], and the significant disagreement that exists among experts regarding sodium’s role in arterial pressure control [5,6], public health policy continues to emphasize sodium reduction as its principle recommendation [7,8].

Two potentially landmark studies [9,10], both funded by the National Heart Lung and Blood Institute, and published in April should finally redirect our emphasis towards the dietary patterns that will benefit the millions of Americans with high blood pressure. The Trials of Hypertension Prevention II (TOHP II) [9] was the largest and longest randomized controlled trial of sodium reduction in a population at high risk of developing hypertension. Over the 48 months of observation there was no evidence that the primary end-point, diastolic blood pressure, was improved by consumption of a reduced sodium chloride diet. Systolic blood pressure was lowered by 0.6 mm Hg, but the reduction in blood pressure could not be related to the level of dietary sodium restriction. Furthermore, there was little evidence that reduced dietary sodium lowers the incidence of new cases of hypertension. As Dr. Pickering noted in his accompanying editorial [11], it is time to move on from recommending sodium restriction as a population-wide strategy to reduce the prevalence of hypertension.

The second study, published in the New England Journal of Medicine, was the Dietary Approaches to Stop Hypertension (DASH) [10]. In stark contrast to the results in TOHP II, DASH demonstrated a significantly beneficial effect of a diet replete in low fat dairy products and fruits and vegetables on systolic (5 to 6 mm Hg) and diastolic (2 to 3 mm Hg) blood pressure in the general population. Weight and sodium intake were held constant and thus were not a factor in the blood pressure reductions observed. In the DASH participants with mild hypertension, the reductions were comparable (systolic 11 to 12 mm Hg and diastolic 5 to 6 mm Hg reductions) to those observed with monotherapy (single drug) regimens. The DASH authors also noted that their results were generalizable to the entire US population since the blood pressure reductions did not stratify based upon age, gender, weight or race.

The DASH diet was also reflective of current nutritional recommendations to reduce the risk of dyslipidemia, osteoporosis, and cancer. Thus, we have compelling additional reasons to promote dietary patterns that emphasize low fat dairy products and fruits and vegetables as the dietary pattern that will most likely reduce the risk of hypertensive heart disease and its attendant complications: coronary heart disease and stroke. It is imperative that the nutrition community—researchers, practitioners, and leaders—accept the challenge of focusing of our preventive and public health programs on the nutritional factors that are most likely to benefit us all [12].

J Am Coll Nutr October 1999 vol. 18 no. suppl 5398S-405S
Finding Consensus in the Dietary Calcium-Blood Pressure Debate
David A. McCarron, MD and Molly E. Reusser, BA
No single study or avenue of investigation can resolve the scientific controversies that entangle efforts to determine the effects of specific nutrients on medical conditions. To reach consensus in this area requires a substantial body of plausible, reproducible and consistent data from various investigative approaches—such as the data that now exist regarding the relationship between dietary calcium and blood pressure. In this paper we describe the plethora of epidemiological and clinical studies and analyses that have been published in the last two years and which cumulatively reveal the consistency of the available data regarding the influence of dietary calcium on blood pressure regulation. Nearly 20 years of investigation in this area has culminated in remarkable and compelling agreement in the data, confirming the need for and benefit of regular consumption of the recommended daily levels of dietary calcium.

Key teaching points:
After nearly 20 years of controversy, the relationship between dietary calcium and blood pressure is being confirmed by a large body of recently published data consistently reporting a blood pressure-lowering effect of adequate calcium intake.

• Meta-analyses of 23 observational studies and of 42 randomized controlled trials have identified statistically significant reductions in hypertension risk and in blood pressure levels.

The impact of calcium on blood pressure appears to be greatest in persons consuming regularly low levels of dietary calcium, the primary source of which is dairy products.

The health benefits of adequate calcium, including lower risk of osteoporosis and colon cancer as well as hypertension, can be realized by simply consuming the recommended dietary calcium levels for an individual’s age and gender (1000 to 1500 mg/day).

J Bone Miner Metab (2000) 18:234–236.
Calcium paradox: consequences of calcium deficiency manifested by a wide variety of diseases.
Takuo Fujita
Calcium deficiency is a global problem, especially in the aging population. Among various nutrients, calcium is one of the few that is still deficient in industrialized countries such as Japan and many Western countries. Calcium deficiency is readily connected with osteoporosis, which is a decrease of bone calcium content. Less well known is the calcium outflow from bone that occurs to prevent decrease of blood calcium in calcium deficiency caused by the parathyroid hormone, with consequent calcium overflow into soft tissues and the intracellular compartment. Such intracellular paradoxical Ca overload as a consequence of nutritional calcium deficiency may give rise to a number of diseases common in old age: hypertension, arteriosclerosis, diabetes mellitus, neurodegenerative diseases, malignancy, and degenerative joint disease.

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