Population based study on serum ionised calcium, serum parathyroid hormone, and blood pressure. The Tromsø study

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1 European Journal of Endocrinology (1999) ISSN CLINICAL STUDY Population based study on serum ionised calcium, serum parathyroid hormone, and blood pressure. The Tromsø study Rolf Jorde 1, Kaare H Bønaa 2 and Johan Sundsfjord 3 1 Department of Medicine and 3 Department of Clinical Chemistry, University Hospital of Tromsø, Tromsø, Norway, 2 Institute of Community Medicine, University of Tromsø, Tromsø, Norway and 1 Centre for Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health Sciences, University of Newcastle, Newcastle, Australia (Correspondence should be addressed to R Jorde, Department of Medicine, University Hospital of Tromsø, 9038 Tromsø, Norway; medrj@rito.no) Abstract Objective: To study associations between serum ionised calcium, serum parathyroid hormone (PTH) and blood pressure. Design: A population based, cross-sectional study was used. Methods: Blood pressure, body mass index, serum ionised calcium and serum PTH were measured in 460 males and 486 females in the Tromsø study in 1994/1995. None were on medication for hypertension. The data were analysed with a multiple linear regression model. Results: When looking at subjects with serum ionised calcium <1.39 mmol/l, there was a significant negative association (P < 0.01) between serum ionised calcium and PTH. There was no association between blood pressure and serum ionised calcium. In both sexes there was a significant positive association between age and serum PTH (P < 0.01). For women, but not for men, there was a significant positive association between serum PTH and systolic and diastolic blood pressure (P < 0.01). Within each age group there was a difference in both systolic and diastolic blood pressure of 3 10 mm Hg between the upper and lower serum PTH halves of the female population. Females with hypertension had significantly higher serum PTH levels than the normotensive females (P < 0.01). Conclusion: Serum PTH is strongly and positively associated with blood pressure in women. European Journal of Endocrinology Introduction The role of calcium in the development of hypertension has received much attention. Although not confirmed by all (1), most studies have found an association between low calcium intake and hypertension (2 4). Furthermore, calcium supplementation seems to give a small but significant lowering of the systolic blood pressure according to a recent meta-analysis (5). In patients with hypertension most (6 8), but not all (9) studies have demonstrated a lower serum ionised calcium in hypertensive subjects than in normal controls. If that were the case, one would expect a positive association between serum parathyroid hormone (PTH) levels and blood pressure, as even minor changes in serum ionised calcium result in large changes in serum PTH (10). There are, indeed, reports of increased PTH levels in hypertension (11 13). Thus, calcium metabolism seems to be involved in the regulation of blood pressure. However, the results are conflicting, and larger epidemiological studies are lacking. The Tromsø study was started in 1974 and is a health survey focusing on cardiovascular diseases (14). In the fourth and last study which took place in 1994 to 1995, serum ionised calcium and serum PTH were measured in 1113 subjects. Thus, a suitable database was created for investigating possible relationships between these variables and blood pressure. In addition, associations between anthropological data and life style factors and the serum levels of ionised calcium and PTH were studied. Methods Subjects In the Tromsø study in 1994 and 1995, a total of men and women participated. A subgroup 1999 Society of the European Journal of Endocrinology Online version via

2 EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Serum PTH and blood pressure 351 of 1113 consecutively examined subjects, aged 30 to 79 years, had blood samples taken for ionised serum calcium and serum PTH measurements in addition to the general examination. Those on medication for hypertension were excluded, leaving 460 males and 486 females for the present study. Questionnaires The letter of invitation included a questionnaire on the number of cigarettes smoked per day, cups of coffee drunk per day, hours of moderate and hard physical activity per week, and number of glasses of beer, wine and spirit (e.g. vodka) drunk per two weeks. The participants brought the questionnaire with them to the examination. From this questionnaire a physical activity score was made by adding the hours of moderate and hard physical activity together, giving the hours with hard activity double weight, and an alcohol intake score was made by adding together the number of glasses of beer, wine and spirit (assuming an equal amount of alcohol in one glass of each type). A second questionnaire on medical history and past and present medication was filled out at home and returned by mail. Measurements The examinations were performed between 0900 h and 1400 h. The participants were not requested to fast. Height and weight were measured in light clothing without shoes, and body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in metres. Blood pressure was measured with an automatic device (Dinamap Vital Signs Monitor 1846, Critikon Inc., USA) (15). The subjects were seated for 2 min, three recordings were made at 2-min intervals, and the mean of the last two were used in this report. Intact PTH was measured on Immulite (Diagnostic Products Corporation, Los Angeles, CA, USA) based on a two-site chemiluminescent immunometric assay. The reference range in our laboratory is pmol/l for those below the age of 50, and pmol/l for those 50 years or above, the between assay coefficient of variation (CV) being 6 8% in the actual range. Serum ionised calcium was measured with an ion-selective electrode (Ciba Corning 288, Chiron Diagnostic Corporation, USA). The measurements were carried out in serum samples collected anaerobically, the samples being centrifuged and analysed within one hour. The actual measured ionised calcium levels, without ph adjustments, have been used in the present investigation. The reference range in our laboratory is mmol/l, the between assay CV being % in the actual range. Statistical analyses Linear trends were evaluated by Pearson correlation coefficients. A sex-specific multiple linear regression model was used to control for confounding factors and included serum ionised calcium, serum PTH, age, BMI, alcohol and coffee consumption, number of cigarettes smoked, and physical activity as potential predictors. The regression coefficient was calculated as a standardised beta coefficient (b) (the coefficient of the independent variables when all variables are expressed in standardised (Z score) form). For serum ionised calcium and serum PTH levels, comparison between males and females, and between subjects with and without hypertension, was carried out with linear regression using serum ionised calcium or PTH as dependent variable, gender or blood pressure status as fixed factor, and independent variables as in the multiple linear regression model. Systolic hypertension was arbitrarily defined as blood pressure >160 mm Hg, and diastolic hypertension as blood pressure >100 mm Hg. In addition, the subjects were also grouped according to systolic blood pressure >140 and diastolic blood pressure >90 mm Hg, and evaluated as above. The influence of gender on the relation between PTH and blood pressure was evaluated with linear regression using blood pressure as dependent variable, gender and PTH (grouped in quartiles) as fixed factors, and independent variables as in the multiple linear regression model. The influence of age and BMI on the relation between PTH and blood pressure in females was evaluated with linear regression using blood pressure as dependent variable, age, BMI and PTH groups as fixed factors (see results for definition), and independent variables as in the multiple linear regression model. All tests were two-sided, and P < 0.05 was considered statistically significant. The data were analysed with the SPSS statistical package for Windows version 8.0 (SPSS Inc, Chicago, IL, USA). Ethics The study was approved by the Regional ethics committee, and all subjects gave their written informed consent to participate. Results Study population The distributions of serum ionised calcium, serum PTH, and BMI in relation to age and sex are given in Table 1. Eight of the females and six of the males probably had primary hyperparathyroidism (serum ionised calcium >1.34 mmol/l together with serum PTH >6.8 pmol/l). Regarding blood pressure, they did not differ significantly from the rest of the study population, and were included in the following analyses.

3 352 R Jorde and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Table 1 Distribution of serum ionised calcium, serum PTH and BMI (means S.D.) in relation to sex and age. Ionised calcium PTH BMI Sex Age group n (mmol/l) (pmol/l) (kg/m 2 ) Male Female Serum ionised calcium Mean serum ionised calcium was significantly higher in males than in females ( and mmol/l respectively, P < 0.01). There was no association between serum ionised calcium and age or any of the other variables tested except for serum PTH (Tables 2 4). When looking at all subjects there was no significant zero-order association between serum ionised calcium and serum PTH (Table 2), nor after correcting for the other variables in the multiple regression analysis (Tables 3 and 4). However, the relation between serum ionised calcium and PTH was not linear as serum PTH had a nadir at a serum ionised calcium of 1:39 mmol/l. If subjects with a serum ionised calcium below 1.39 mmol/l were looked at separately there was a highly significant negative correlation between PTH and serum ionised calcium (Tables 2 4). Serum PTH Mean serum PTH was similar in males and females ( and pmol/l respectively). In both sexes there was a significant positive association between age and PTH (P < 0.01) (Tables 2 4). In males there was a negative association with physical activity (P < 0.05) (Tables 2 and 3) and in females a positive association with BMI (P < 0.01) (Tables 2 and 4). Blood pressure In both sexes there was a significant correlation between age, BMI and systolic and diastolic blood pressure after correcting for the other variables (P < 0.01). In addition, alcohol consumption in males had a significant positive association with diastolic blood pressure (P < 0.01) (Tables 2 and 3). In neither males nor females were there any significant associations between blood pressure and serum ionised calcium (Tables 2, 3, and 4). There were no significant differences in serum ionised calcium between hypertensive and normotensive subjects (Table 5). There was a significant effect of gender on the relation between PTH and systolic as well as diastolic blood pressure (P < 0.05 and P < 0.01 respectively). Table 2 Pearson correlation coefficient between serum PTH, systolic and diastolic blood pressure (BP) and the rest of the variables in 460 males and 486 females. Males Females PTH Systolic BP Diastolic BP PTH Systolic BP Diastolic BP Ionised calcium ¹0.091 a ¹0.051 ¹0.036 ¹0.039 a ¹0.029 ¹0.041 PTH ** 0.218** Systolic BP ** 0.225** 0.757** Diastolic BP ** 0.218** 0.757** Age 0.221** 0.287** 0.170** 0.151** 0.349** 0.183** BMI * 0.160** 0.129** 0.319** 0.303** Alcohol ¹0.097* * ¹0.064 ¹0.105* ¹0.081 Smoking ¹0.100* ¹0.100* ¹0.070 ¹0.053 ¹0.095* ¹0.060 Coffee ¹0.057 ¹ ¹0.046 ¹0.052 Physical activity ¹0.162** ¹0.034 ¹0.029 ¹0.021 ¹0.113* ¹0.061 a The correlation coefficient was ¹0.120 (P < 0:01) and ¹0.195 (P < 0:01) in males and females respectively, who had serum ionised calcium <1.39 mmol/l. * P < 0:05, **P < 0:01.

4 EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Serum PTH and blood pressure 353 Table 3 Standardised beta coefficients (b) and t values from the multiple regression analysis in the males. Dependent variables PTH Systolic BP Diastolic BP Independent variables b t b t b t Ionised calcium ¹0.07 a ¹1.45 b ¹0.03 ¹0.67 ¹0.01 ¹0.27 PTH Age BMI Alcohol ¹0.05 ¹ Smoking ¹0.07 ¹1.25 ¹0.03 ¹0.49 ¹0.03 ¹0.60 Coffee ¹0.01 ¹0.13 ¹0.00 ¹ Physical activity 0.11 ¹ Adjusted R a b ¼¹0:10 and b t ¼¹1:94 in those with serum ionised calcium <1.39 mmol/l. t values > 1.96, > 2.58 and > 3.29 correspond to P < 0:05, P < 0:01 and P < 0:001 respectively. BP, blood pressure. Thus, in males there was no association between serum PTH levels and blood pressure, either when looking at zero-order correlation (Table 2), or when correcting for the other variables (Table 3). There was no significant difference between serum PTH levels in males with and without hypertension (Table 5). On the other hand, for females there was a highly significant association between serum PTH and systolic and diastolic blood pressure (Table 2), which was also present when corrected for age and the other variables (P < 0.01) (Tables 2 and 4). In females with systolic or diastolic hypertension serum PTH was significantly higher than in the normotensive subjects, regardless of definition of hypertension (P < 0.01) (Table 5). The relationship between serum PTH and blood pressure was further demonstrated in two stratified analyses. First, as age was an important determinant not only for blood pressure but also for serum PTH, the subjects were grouped according to PTH quartile (serum PTH <2.6, , , and >4.9 pmol/l), and the corresponding systolic and diastolic blood pressures in these subgroups for ages years, years, and years are shown in Fig. 1. Within each age-group there was an increase in systolic and diastolic blood pressure with increasing PTH levels in females, whereas this was not seen in males. Secondly, as BMI was a strong predictor of both blood pressure and PTH in females (but not in males), the females were grouped according to BMI quartiles (BMI <22.6, , , and >28.1 (kg/m 2 )) and to serum PTH <3.8 or >3.8 pmol/l. The corresponding systolic and diastolic blood pressures in these subgroups in relation to age are shown in Fig. 2. Except for diastolic blood pressure in females years old in the third BMI quartile, all subgroups with PTH >3.80 pmol/l had higher mean blood pressure than those with PTH <3.8 pmol/l. Using linear regression and the above grouping of age, BMI, and PTH, there was no significant Table 4 Standardised beta coefficients (b) and t values from the multiple regression analysis in the females. Dependent variables PTH Systolic BP Diastolic BP Independent variables b t b t b t Ionised calcium ¹0.04 a ¹0.81 b ¹0.04 ¹0.86 ¹0.05 ¹1.15 PTH Age BMI Alcohol ¹0.03 ¹ ¹0.02 ¹0.41 Smoking Coffee ¹0.05 ¹0.96 Physical activity Adjusted R a b ¼¹0:20 and b t ¼¹3:94 in those with serum ionised calcium <1.39 mmol/l. t values > 1.96, > 2.58 and > 3.29 correspond to P < 0:05, P < 0:01 and P < 0:001 respectively. BP, blood pressure.

5 354 R Jorde and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Table 5 Serum PTH and ionised calcium (means S.D.) in the male and female subjects, according to blood pressure (BP) status. Males Females PTH Ionised calcium PTH Ionised calcium Blood pressure n (pmol/l) (mmol/l) n (pmol/l) (mmol/l) Systolic BP < 160 mm Hg mm Hg a < 140 mm Hg mm Hg b Diastolic BP < 100 mm Hg mm Hg c < 90 mm Hg mm Hg d P < 0:01 versus a systolic BP < 160 mm Hg, b systolic blood pressure < 140 mm Hg, c diastolic BP < 100 mm Hg, d diastolic BP < 90 mm Hg. interaction between either age or BMI on the relation between PTH and blood pressure in the females. Discussion In the present study we have demonstrated a significant association between serum ionised calcium and serum PTH, and in women, but not in men, a highly significant positive association between serum PTH and blood pressure. It is therefore tempting to speculate on a sequence of events starting with a reduced intake or absorption of calcium, and a compensatory increase in the PTH secretion together with an increase in blood pressure. However, before doing so, we will compare our results with those reported by others. First, we did not find any association between serum ionised calcium and blood pressure. Admittedly, the serum ionised calcium levels were lower in the females with hypertension, but the difference was not significant, regardless of how hypertension was defined. This is contrary to that reported by McCarron (6), Hvarfner et al. (7) and Brickman et al. (8) of a four percent lower serum ionised calcium in hypertensive subjects. However, Folsom et al. (9) found only a non-significant difference in serum ionised calcium, and Resnick et al. (16) found that ionised calcium in hypertension mainly reflected the renin status, with low renin hypertension associated with low serum ionised calcium values, and high renin hypertension with high serum ionised calcium levels. However, the above were all small casecontrol studies, in contrast to our population based approach. The discrepancy could therefore reflect selection of study groups. Furthermore, our study was carried out in non-fasting subjects, which might Figure 1 Mean systolic and diastolic blood pressure (mm Hg) in males and females in relation to age and PTH quartiles (PTH < 2.6 (1), (2), (3), and > 4.9 (4) pmol/l).

6 EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Serum PTH and blood pressure 355 Figure 2 Mean systolic and diastolic blood pressure (mm Hg) in females in relation to age, serum PTH level, and BMI quartiles (BMI <22.6 (1), (2), (3), and >28.1 (4) kg/m 2 ). possibly have influenced both the ionised calcium as well as the PTH levels. We found no association between serum ionised calcium and age. Although there are reports of an increase (17) as well as a decrease (18) with age, most studies (16, 19, 20) are in agreement with our observation. On the other hand, we did find that the serum ionised calcium levels were significantly lower in females than in males, which is in agreement with the studies by Endres et al. (17) and Rudnicki et al. (21), although the difference was not significant in the latter study. For serum PTH, however, there is general agreement that there is an increase with age (17 19, 22 24). The cause of this is most likely related to vitamin D status. Thus, there is a reverse relationship between serum levels of 25-hydroxyvitamin D and PTH (25, 26), and relative vitamin D deficiency has repeatedly been described in the elderly (25, 27). Moreover, a reduced capacity of the skin to produce vitamin D, a lack of exposure to sunlight (26, 27), as well as a decreased intestinal responsiveness to vitamin D with age (29) could also contribute to the high serum PTH levels in our older subjects. However, an alternative explanation could be the gradual reduction in glomerular filtration rate which occurs with advancing age. In addition to the relationship with age, we also found a highly significant relationship between BMI and serum PTH in the females. This persisted after controlling for all other covariables included in the analysis, and confirms the observation by Landin-Wilhelmsen et al. (30). In a similar manner as for age, most studies (8, 11 13) have found a positive association between serum PTH and blood pressure, although in a few, the association did not persist after controlling for other variables (30, 31). In our study there was a strong association between serum PTH and blood pressure, but in females only. This persisted after correcting for age, BMI and all the other variables in the study. Thus, when stratified for the most important covariables, age and BMI, the difference between the upper and lower serum PTH halves of the female population was from 3 to 10 mm Hg for both systolic and diastolic blood pressure. Furthermore, as an indication of relative importance, the standardised beta coefficient from the multiple regression analysis showed that the association with diastolic blood pressure was as strong for PTH as for age. The lack of association between serum PTH and blood pressure in males in our study is puzzling, and contrary to that described by Young et al. (13). In their study on 75 hypertensive subjects, elevated PTH levels were only seen in the males, and were related to their low serum concentrations of 1,25-dihydroxyvitamin D. On the other hand, the hypertensive females had normal serum vitamin D and PTH levels. One explanation for the discrepancy between their study and ours could therefore be a difference in vitamin D status, and possibly also a difference in the dietary intake of calcium. What then is the cause and importance of the association between PTH and blood pressure? The main regulator of PTH secretion is the serum ionised calcium level, as shown in the subjects with ionised calcium values below 1.39 mmol/l. Thus, minute changes in serum ionised calcium prompt large reciprocal changes in serum PTH, as demonstrated by Ljunghall et al. (10). In their study a 0.02 mmol/l lowering of the serum ionised calcium by an EDTA infusion more than doubled serum PTH levels. Accordingly, changes in serum ionised calcium are more easily detected by the compensatory larger increases in serum PTH. Therefore, the most likely reason for the increased PTH level in our hypertensive

7 356 R Jorde and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 females was a minute lowering of the serum ionised calcium that went undetected by us. One explanation of a lower serum ionised calcium in hypertensive subjects could be a reduced intake of calcium, which has frequently been described in this group (2 4). In addition, there appears to be an increased renal excretion of calcium in hypertension (32), which, if not compensated for by an increased calcium intake, would trigger PTH secretion. This could also link hypertension to the development of osteoporosis which has been suggested in humans (33) and supported by animal studies (34). Whether the increased PTH levels further aggravate or reduce the hypertension is uncertain. Thus, Hulter et al. (35) found that a 12-day chronic PTH infusion in normal subjects caused hypertension, an effect however, that could also be the result of the accompanying hypercalcaemia. On the other hand, in the elegant study by Jespersen et al. (36), serum ionised calcium level was kept constant by a clamping technique, and a 120-min infusion with PTH caused a reduction in mean arterial blood pressure in hypertensive men. This obviously needs further study, and could possibly have therapeutic implications. In conclusion, there was a positive association between serum PTH and blood pressure in women that was not related to changes in serum ionised calcium. However, the most likely cause of the increased PTH levels were minute changes in serum ionised calcium that were not detected by us. Acknowledgements This study was supported by a grant from the Norwegian Research Council. The expert technical assistance of Eva Kramvik and Monika Larsen with the serum ionised calcium measurements is greatly appreciated. References 1 Gruchow HW, Sobocinski KA & Barboriak JJ. Alcohol, nutrient intake, and hypertension in US adults. 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8 EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Serum PTH and blood pressure Dawson-Hughes B, Harris SS & Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. American Journal of Clinical Nutrition van der Wielen RP, Löwik MRH, van den Berg H, de Groot CPGM, Haller J, Moreiras O et al. Serum vitamin D concentrations among elderly people in Europe. The Lancet Jacques PF, Felson DT, Tucker KL, Mahnken B, Wilson PWF, Rosenberg IH et al. Plasma 25-hydroxyvitamin D and its determinants in an elderly population sample. American Journal of Clinical Nutrition Ebling PR, Sandgren ME, DiMagno EP, Lane AW, DeLuca HF & Riggs BL. Evidence of and age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25- dihydroxyvitamin D 3 and intestinal vitamin D receptor concentration in normal women. Journal of Clinical Endocrinology and Metabolism Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosén T, Lindstedt G, Lundberg PA et al. Serum intact parathyroid hormone in a random population sample of men and women: relationship to anthropometry, life-style factors, blood pressure, and vitamin D. Calcified Tissue International Hvarfner A, Ljunghall S, Morlin C, Wide L & Bergström R. Indices of mineral metabolism in relation to blood pressure in a sample of a healthy population. Acta Medica Scandinavica Young EW, Morris CD & McCarron DA. Urinary calcium excretion in essential hypertension. Journal of Laboratory and Clinical Medicine MacGregor GA & Cappuccio FP. The kidney and essential hypertension: a link to osteoporosis? Journal of Hypertension Fukuda S, Tsuchikura S, Iida H, Ikeda K, Nara Y & Yamori Y. Intestinal calcium absorption and response of calcium regulating hormones in the stroke-prone spontaneously hypertensive rat as a model of osteoporosis. Clinical and Experimental Pharmacology and Physiology (Suppl 1) S240 S Hulter HN, Melby JC, Peterson JC & Cooke CR. Chronic continuous PTH infusion results in hypertension in normal subjects. Journal of Clinical Hypertension Jespersen B, Randløv A, Abrahamsen J, Fogh-Andersen N & Kanstrup IL. Effects of PTH(1 34) on blood pressure, renal function, and hormones in essential hypertension. The altered pattern of reactivity may counteract raised blood pressure. American Journal of Hypertension Received 19 March 1999 Accepted 7 July 1999