Curator: Aviva Lev-Ari, PhD. RN
UPDATED on 11/2/2013
Curator and Reporter: Larry H. Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/10/11/new-data-dispute-calcium-cardiovascular-risk-in-both-sexes/
Minerals and Cardiovascular Risk
Modern diet contains high sodium to potassium ratio, low omega-3-polyunsaturated acid. (PUFAs) increased omega-6-polyunstaureted,
saturated fat and
Trans fatty acids these have lead to higher incidence of
cardiovascular disease, diabetes mellitus and hyperlipidemia.
|
Nutrient
|
Paleolithic diet
|
Modern diet
|
|
|
More than 10,000 mEq/day (256 Grm)
|
150mEq/day (6gram)
|
|
|
Less than 50 mmol/day 1.2 Grm
|
175 mmol/day (4Gram)
|
|
Na/K ratio
|
Less than 0.13 /day
|
More than 0.67/day
|
|
Fiber
|
More than 100gram/day
|
Less than 9 gram/day
|
|
Protein
|
37%
|
20%
|
|
Carbohydrate
|
41%
|
40-50%
|
|
Fat
|
22%
|
30-40%
|
|
Poly saturated to saturated ratio
|
1.4
|
0.4
|
Sodium
Increased intake of sodium is associated with hypertension and reduction of salt intake is associated with decrease in BP by 4-6/2-3mmhg in salt sensitive patients. Daily allowance of sodium is not more than 500mg/day.
Cardiovascular events are more common in salt sensitive patients than salt resistance patients, independent of BP reduction. Reduction of BP by salt restriction has benefit apart from BP reduction.
A balance of sodium with other nutrients is important not only for reduction of BP but also for reduction cardiovascular events.
Potassium
Increased intake of potassium is associated with BP reduction. Recommended daily intake of potassium is 650mEq/day with Na/k ratio of 5:1.
Supplements of 120 mEq/day of potassium reduce BP by 4.4/2.5mmhg in hypertensive patients.
Higher Na/K ratio reduces not only BP but also cardiovascular events.
Magnesium
Intake of 500mg/day to 1000mg/day reduces BP by 5.6/2.8mmhg. Reducing intracellular sodium and calcium and increasing intracellular magnesium and potassium improves BP response.
Insulin sensitivity,
LVH and dyslipidemia can be improved with magnesium supplementation.
Oral magnesium acts like natural calcium channel blocker, increases nitric oxide, and improves endothelial dysfunction, and induces vasodilatation.
Calcium
Studies show link between calcium and hypertension. But trials supplementing calcium do not show benefit. Below we present results of a recent study on Calcium supplementation citing >1400 mg/day been associated with increased cardiovascular risk and mortality.
Zinc
Low serum zinc levels are associated with hypertension.
Calcium levels in serum are under tight homeostatic control, and calcium intake is not normally correlated with calcium serum levels.
- Diets that are low or very high in calcium can, however, override normal homeostatic control causing changes in blood levels of calcium or calciotropic hormones.52
- Calcium enriched meals can reduce calcitriol, the active vitamin D metabolite, by inhibition of 1α hydroxylase53and also increase serum levels of fibroblast growth factor 23.54
- Higher levels of circulating fibroblast growth factor 23 are associated with an increased risk of cardiovascular events and all cause mortality.55 56 57 In addition,
- fibroblast growth factor 23 downregulates calcitriol levels.58
- Vitamin D suppression leads to an upregulation of the renin-angiotensin-aldosterone system and hypertension, higher levels of proinflammatory cytokines involved in the pathogenesis of atherosclerosis:
– increased carotid artery intima medial thickness,
– decreased endothelial function,
– hypertrophy of cardiac and vascular muscle cells, and a
– possible increase in serum triglycerides.59 Finally,
- high serum calcium levels can increase the risk of cardiovascular mortality60 by induction of a hypercoagulable state.61
Vascular calcification and plaque rupture
There are two types of vascular calcification, intimal calcification of atherosclerosis and medial calcification. Both are associated with increased incidence of ischemic heart disease. Plaque rupture is manly restricted to intimal plaques fibrous cap calcification. Calcification of this fibrous cap is associated with increased incidence of ischemic heart disease. Below discussion is about controversy associated with fibrous cap calcification.
Whether intimal calcification stabilizes the plaque or makes it prone for rupture is a matter debate. Calcified and fibrotic lesions are more hypo-cellular, they are stiffer than cellular lesions, and further more biomechanical data suggest calcification reduces the “stresses” in a plaque does not cause rupture. Plaques with heavily calcified are 5 times stiffer that non-calcified lesions.
Calcium crystal have shown to aggravate inflammation
Above observation are contradictory to each other. If calcium induces inflammation than plaque should get destabilize?
Under mechanical stress produced by balloon angioplasty, calcified plaque is more likely to rupture than non-calcified plaque, and the rupture occurs along the interface between the calcium deposit and soft tissue. So this suggest that plaque rupture may occur at these week points
Conclusion
It has been stated that when entire plaque is calcified it protects against rupture unlike focal calcification
The ratio of surface area to volume in calcium deposits may determine whether they are harmful or protective
Lipoprotein a (Lp(a)) genetic variant doubles the causal risk of Aortic valvular calcification.
In the last 15 to 20 years our understanding of aortic valve calcification has changed from just simple degenerative disease to disease secondary to an active process involving endothelial dysfunction, lipid accumulation, an inflammatory infiltrate. With this understanding many potential therapeutic approach have been considered. Statins showed promise in prevention of calcification in retrospective trials but prospective trials did not show benfit. Rennin angiotensin inhibitors have given discordant results in retrospective trials and no randomized control trial is there to prove their efficacy.
Aortic Valvular Calcification
new potential therapeutic target for prevention aortic valve calcification i.e. Lp(a).Article published in NEJM Feb 7 2013 from Johns Hopkins, Harvard University, McGill University, the University of Iceland and the National Institutes of Health says, there is variant of Lp(a) which is associated with aortic valve calcification. In this publication genomewide association was evaluated for 6942 participants of aortic valvular calcification and 3795 participants of mitral valve calcification, detected by CT scanning.
Previous studies showed association of Lp(a) with calcification of aortic valve. Causal or just marker of calcification was not confirmed, present study shows causal relationship of Lp(a) and aortic valve calcification.
From this causal relationship one may think of targeting Lp(a) for preventing aortic valve calcification. Niacin reduces Lp(a) levels. Although HPS-2 THRIVE trial (with niacin/laropiprant) which was done for coronary artery disease did not show clinical benfit, still one may keep hope for prevention of aortic valve calcification. Time may tell about us this in future.
Types of Vascular Calcification
- Artery Medial Calcification (AMC) – Concentric Vessel – Stiffening
- Atherosclerotic Intimal Calcification (AIC)
Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study
BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f228 (Published 13 February 2013)
Cite this as: BMJ 2013;346:f228
- Karl Michaëlsson, professor1,
- Håkan Melhus, professor2,
- Eva Warensjö Lemming, researcher1,
- Alicja Wolk, professor3,
- Liisa Byberg, associate professor1
Author Affiliations
-
1Department of Surgical Sciences, Section of Orthopedics, Uppsala University, SE-751 85 Uppsala, Sweden
2Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, Sweden
3Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Correspondence to: K Michaëlsson karl.michaelsson@surgsci.uu.se
- Accepted 28 December 2012
Abstract
Objective To investigate the association between long term intake of dietary and supplemental calcium and death from all causes and cardiovascular disease.
Design Prospective longitudinal cohort study.
Setting Swedish mammography cohort, a population based cohort established in 1987-90.
Participants 61 433 women (born between 1914 and 1948) followed-up for a median of 19 years.
Main outcome measures Primary outcome measures, identified from registry data, were time to death from all causes (n=11 944) and cause specific cardiovascular disease (n=3862), ischaemic heart disease (n=1932), and stroke (n=1100). Diet was assessed by food frequency questionnaires at baseline and in 1997 for 38 984 women, and intakes of calcium were estimated. Total calcium intake was the sum of dietary and supplemental calcium.
Results The risk patterns with dietary calcium intake were non-linear, with higher rates concentrated around the highest intakes (≥1400 mg/day). Compared with intakes between 600 and 1000 mg/day, intakes above 1400 mg/day were associated with higher death rates from all causes (hazard ratio 1.40, 95% confidence interval 1.17 to 1.67), cardiovascular disease (1 49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09) but not from stroke (0.73, 0.33 to 1.65). After sensitivity analysis including marginal structural models, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average associated with all cause or cause specific mortality but among calcium tablet users with a dietary calcium intake above 1400 mg/day the hazard ratio for all cause mortality was 2.57 (95% confidence interval 1.19 to 5.55).
Conclusion High intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke.
Introduction
Calcium is one of the most abundant minerals in the human body and plays a pivotal role in human physiology. The serum levels of calcium are strictly regulated and an insufficient calcium intake is met by a more efficient intestinal absorption and renal conservation of calcium. Calcium is also mobilised from the skeleton, which can lead to bone loss1 and subsequent risk of fractures. Consequently, to prevent fractures in elderly people previous and existing guidelines2 recommend avoidance of low calcium intake. Fractures are common, especially in women, and are associated with high disability, healthcare costs, and mortality.3 Insufficient calcium intakes might also lead to secondary hyperparathyroidism, which is associated with higher mortality.1 4 5 Supplemental use of calcium has become common, and more than 60% of middle aged and older women in the United States are regular users of calcium supplements.6 7 Worryingly, three recent reanalyses of randomised trials in women have indicated a higher risk of both ischemic heart disease and stroke with calcium supplements,8 9 10 a pattern not observed in a reanalysis of another randomised trial.11 Few cohort studies in women have examined the association between dietary and supplemental intake of calcium with risk of cardiovascular incidence and mortality; instead,12 13 14 15 16 the focus has been on the incidence of stroke, with both contrary and inconsistent findings.12 13 14 16
We hypothesised that long term intake of low or high calcium increases the risk of cardiovascular mortality. We investigated associations between long term dietary and supplemental intake of calcium with all cause mortality as well as with cardiovascular mortality in a large population based prospective study of Swedish women.
Methods
The Swedish mammography cohort
The Swedish mammography cohort was established in 1987-90. All women (n=90 303) residing in two Swedish counties (Uppsala and Västmanland) and born between 1914 and 1948 received a mailed invitation to a routine mammography screening. Enclosed with this invitation was a questionnaire covering diet (food frequency questionnaire) and lifestyle, which was completed by 74% of the women. In 1997, a second, expanded questionnaire was distributed to those who were still living in the study area (response rate 70%). The study sample with exclusions has been described previously.17 18 In all, 61 433 women with baseline data (1987-90) and 38 984 with data from 1997 were available for analysis in the present study (fig 1⇓).
Fig 1 Study samples in Swedish mammography cohort
Outcomes
Follow-up was through the Swedish cause of death registry. Complete linkage with the register is rendered by the personal identity number provided to all Swedish residents. Since 1952 the National Board of Health and Welfare has collected information on the causes of death for all Swedish residents in the cause of death registry. We used the underlying cause of death in the registry to define the outcomes of death from all causes, cardiovascular disease (international classification of diseases, ninth and 10th revisions; ICD-9 codes 390-459 or ICD-10 codes I00-I99), ischaemic heart disease (ICD-9 codes 410-414 or ICD-10 codes I20-I25), and stroke (ICD-9 codes 430-436 or ICD-10 codes I60-I64).
Dietary assessment
The food frequency questionnaires have been described previously.17 19 20 The participants reported their average frequency of consumption of up to 96 foods and beverages during the past year. For most food items, eight categories for frequency of consumption were provided, ranging from never to three or more times daily. For some commonly consumed foods such as milk, sour milk/yogurt, and cheese, participants could fill in the exact number of servings they consumed daily or weekly. We estimated nutrient intakes by multiplying the consumption frequency of each food item by the nutrient content of age specific portion sizes. Nutrient data were obtained from the Swedish National Food Administration database.21 We adjusted nutrient intakes for total energy intake (7.1 MJ or 1700 kcal, mean in the study population) using the residual method.22 To better account for changes in diet during follow-up and to better represent long term dietary intake we treated calcium intake as cumulative average intake.23 In the second questionnaire the lifetime use of dietary supplements and multivitamins was reported. In Sweden one calcium dose contains 500 mg if from calcium supplements and 120 mg if from multivitamins. Total calcium intake included supplemental calcium from any source. Even if supplement use was absent in the first food frequency questionnaire (baseline questionnaire), the frequency of calcium containing supplement use (with or without vitamin D) within the cohort during the first years of follow-up was low (6%),24 and this proportion was similar across the whole range of dietary calcium intake. Calcium intake in the 1997 food frequency questionnaire correlated well with estimates from 14 repeated 24 hour recalls over one year (r=0.77).25 Furthermore, a second validation of calcium intake was carried out with four seven day food records every third month in 104 of the women (r=0.72). Bland-Altman plots revealed only small systematic errors related to intake level between the methods, and the average difference with 95% confidence interval between the 1997 food frequency questionnaire and seven day food record was 56.4 mg/day (95% confidence interval −4.4 to 108.4 mg/day)—that is, as previously reported,25 a tendency of higher estimates for calcium intake with the food frequency method. Similar estimates were achieved for the baseline questionnaire.24
Comorbidity and other additional information
Lifestyle information was obtained from the questionnaires. This information included the use of postmenopausal oestrogen therapy and menopausal status, parity, weight and height, smoking habits, and leisure time physical activity during the past year, with five predefined levels ranging from one hour weekly to more than five hours weekly. Physical activity, collected in the 1997 questionnaire, is valid compared with activity records and accelerometer data.26 We divided educational level into four categories: up to 9 years, 10-12 years, more than 12 years, and other (such as vocational). Diagnosis codes were collated from the national patient registry (ICD codes 8, 9, and 10) to calculate Charlson comorbidity scores.27 28 The Charlson comorbidity index predicts the 10 year mortality for a patient who may have a range of comorbid conditions (up to 22 diseases). Each condition is assigned a score of 1 to 6 depending on the risk of dying associated with this condition.
Statistical analysis
For each participant, follow-up time was accrued from baseline (1987-90) until the first date of death, date of leaving the study regions, or the end of the study period (31 December 2008), whichever occurred first. In secondary analyses we considered time to incidence of cardiovascular disease, ischaemic heart disease, and stroke. To improve the validity of our exposure estimate, we used a calibrated calcium intake obtained by usage of linear regression coefficients between food records (FR) and the food frequency questionnaire (FFQ): (RiFR=αFR+ βFR* FFQi, (R reported calcium in the food records, i in the individual)).29 Using Cox proportional hazards regression we estimated age adjusted and multivariable adjusted hazard ratios and their 95% confidence intervals for prespecified categories of calcium intake: <600, 600-999, 1000-1399, and ≥1400 mg/day. To facilitate comparisons of the estimates we used the same category cut-offs in the analysis of dietary and total calcium intake. We estimated the risk with use of calcium containing supplements from the date of the second questionnaire survey (from 1 January 1998). The proportional hazard assumptions in the Cox models were confirmed graphically by comparing Nelson-Aalen plots. Non-linear trends of risk were additionally analysed using restricted cubic-spline Cox regression. We used four “knots” placed at centiles 5, 35, 65, and 95 of the cumulative average calcium intake.30 The reference level was set to 800 mg of calcium, which corresponds to the recommended daily intake for Swedish women aged more than 50 years.31
To minimise potential bias we used the directed acyclical graph approach to identify a suitable multivariable model. The model included age, total energy and vitamin D intake, body mass index, height (all continuous), educational level (≤9, 10-12, >12 years, other), living alone (yes or no), use of supplements containing calcium (yes or no), a healthy dietary pattern (fifths), physical activity (five categories), smoking status (never, former, current), and score on the Charlson comorbidity index (continuous, 1-16).27 28 A healthy dietary pattern was defined by using a validated method.3233 Briefly, we used factor analysis to derive the dietary pattern empirically. Factor analysis reduces dietary data to a few composite factors (one being a healthy dietary pattern) that describe the eating pattern in the population. Other potential covariates (such as menopausal status; hormone replacement therapy; intakes of total fat, retinol, alcohol, potassium, phosphorous, and protein; nulliparity; and previous fracture of any type) in the multivariable models only marginally changed the relations and were therefore not included in the models. We treated covariates as cumulative averages.28 The Markov chain Monte Carlo multiple imputation method was used to impute covariates not assessed in the baseline questionnaire in 1987-90 (for example, smoking habits and physical activity). Restriction to non-missing data did not alter our interpretation of the results (data not shown). Moreover, in an attempt to examine whether calcium supplement use modified the association between dietary calcium intake and mortality, we performed stratified analysis by calcium supplement use (no use, use of any type of calcium containing supplements, and specific use of calcium tablets). Additionally, we estimated the synergy index between dietary calcium intake and calcium tablet use.34 We performed sensitivity analysis, limiting the analysis to baseline data using ordinary Cox’s regression without time updated information. In an attempt to validate the robustness of the Cox’s regression model using information updated over time, we used marginal structural modelling.35 The categorical exposure in the marginal structural models was treated as described previously.36 We calculated an additional inverse probability weight for having time varying data, and we gave a weight of zero to those without time varying data.
In addition to ultraviolet radiation and genes, vitamin D intake is a determinant of vitamin D status,37 38 39 and vitamin D insufficiency is related to cardiovascular disease mortality and incidence.40 We therefore investigated effect measure modification between dietary calcium and vitamin D intake by including a product interaction term in the multivariable models and performing likelihood ratio tests of its contribution in nested models. We further calculated the relative excess risk that is due to interaction.34 When analysing cause specific mortality, we considered the potential competing risk problem from other causes of mortality41 and cumulative incidence curves.42 The subhazard ratios were similar to the hazard ratios from the ordinary Cox regression, suggesting no major effect of competing risks, which is also the conclusion drawn after analysis of cumulative incidence curves (data not shown).
The statistical analyses were performed with STATA 11 and SAS, version 9.2.
Results
Table 1⇓ lists the characteristics of the study participants by categories of calcium intake. The average total cumulative calcium intake in the lowest category was 572 mg/day and in the highest was 2137 mg/day. With increasing categories of energy standardised calcium intake, the reported intake for most other nutrients also increased, although alcohol intake tended to decrease. There were small differences in calcium supplement use, comorbidity, educational level, smoking status, and physical activity level between categories of calcium intake.
Vitamin D intake did not significantly modify the associations between calcium intake and the rate of deaths from all causes, cardiovascular disease, or ischaemic heart disease (results not shown).
Discussion
In this study of women in the Swedish mammography cohort, a high calcium intake (>1400 mg/day) was associated with an increased rate of mortality, including death from cardiovascular disease. The increase was moderate with a high dietary calcium intake without supplement use, but the combination of a high dietary calcium intake and calcium tablet use resulted in a more pronounced increase in mortality. For most women with lower intakes we observed only modest differences in risk.
Strengths and weaknesses of the study
Strengths of our study include the population based prospective design, study size, and repeated measurements of calcium intake, as well as a large number of potential covariates. Date and cause of death were traced through national healthcare registries and deterministic record linkage, permitting complete ascertainment of the outcomes. The accuracy of classification of causes of death in the cause of death registry and diagnoses in the national patient registry are high.43 Furthermore, we adjusted for several important covariates (for example, smoking, socioeconomic status, physical activity, nutrients other than calcium, educational level, and comorbidity), but residual confounding remains a possible limitation. The lower age adjusted rates of death from all causes and cardiovascular disease among women with a high total calcium intake were largely explained by their use of dietary supplements (table 2), a variable considered in the multivariable models. Other health related covariates, including a healthy diet and level of physical activity contributed to a lesser degree. People who use dietary supplements have, on average, a healthier lifestyle and a lower risk factor profile for cardiovascular disease44 and not considering this might distort the risk estimates. Moreover, the low proportion of women who took prescription calcium tablets (6%), containing a four times higher dose of calcium than in regular multivitamin dietary supplements, made it difficult to detect modestly strong associations with calcium tablet use specifically. Dietary assessment methods are prone to several limitations, affecting both the precision and accuracy of the measurement. In larger studies, a food frequency questionnaire is used to assess the habitual intake of diet, and a recent review concluded that it was a valid method for assessing dietary mineral intake, particularly for calcium.45 The food frequency questionnaire may, to some extent, overestimate calcium intake,25 which was also indicated by our validation. A further limitation in our study is the use of age standardised portion sizes and not actual individual portion sizes. By use of our calibrated analysis of calcium intake, we none the less tried to avoid some misclassification of study participants. By using repeated measurements on dietary intake we increased the accuracy of the measurement but may also have introduced bias using time dependent Cox regression models. Indeed, after using only baseline data and also after performing the marginal structural model analyses, we no longer observed an increased mortality for women with low calcium intakes or a high total calcium intake. Without being causally linked to death, a low calcium intake could therefore be viewed as a marker of frailty or a less healthy behaviour associated with a higher mortality. There are, however, also theoretical drawbacks of our causal inference model. It is sensitive to correct model specifications and indeed renders estimates with lower precision than ordinary Cox’s regression.46 47 It is worth emphasising that traditionally obtained estimates, such as those from Cox’s regression, would not generally agree with estimates from marginal structural models even when there is no confounding.48 Irrespective of analytical approach, the observational study design precludes conclusions about causality, and cautious interpretations of the results are therefore recommended. The results for women with a high calcium intake are, however, compatible with results from previous randomised studies,8 9 10 and by fitting the marginal structural model we obtained similar risk estimates although with wider confidence intervals. Our results might also not apply to people of different ethnic origins or to men.
Strengths and weaknesses in relation to other studies
Calcium intake in adulthood and all cause mortality in women has not been previously investigated. In an analysis including 387 deaths within the Iowa Women’s Health Study cohort15 a total calcium intake below 700 mg/day but not above 1400 mg/day was associated with higher mortality from ischaemic heart disease. Furthermore, a recent reanalysis of the same cohort showed that use of calcium supplements was inversely related to the total and cardiovascular mortality rate, although the benefit was lost at the highest doses of dietary calcium intake.49In contrast, use of calcium supplements in a Finnish cohort increased the risk of cardiovascular disease.50 Intriguingly, three reanalyses of randomised trials have consistently shown a higher rate of both myocardial infarction and stroke by 25% to 30% and by 15% to 20%, respectively, with calcium supplementation.8 9 10These results were not confirmed in a reanalysis of another randomised trial using a broad composite endpoint of different cardiovascular events.11 Interestingly, the higher risk of cardiovascular events with calcium supplements in a meta-analysis8was only observed in women with a dietary calcium intake higher than 800 mg/day and not in women with lower intake levels.
The results from the few prospective cohort studies that have examined the relation between calcium intake and incidence of cardiovascular disease in women are contradictory or not conclusive. In the Nurses’ Health Study cohort there was a higher risk of stroke in women with a calcium intake below 600 mg/day.12 Similarly, in a Japanese setting with a comparably low average calcium intake, women with an intake below about 500 mg/day had a higher rate of stroke but not of coronary heart disease.13 14 None the less, calcium intake was not related to stroke incidence in a previous analysis in our cohort,16 concordant with the results of the present investigation. We have recently shown that calcium intakes above 700 mg/day do not further reduce the risk of fracture and osteoporosis.18
Vitamin D enhances, directly or indirectly, renal conservation and intestinal absorption of calcium.51 Our results suggest that vitamin D intake did not modify the association of calcium intake and mortality rate. In comparison with exposure to ultraviolet radiation and genetic constitution, vitamin D intake contributes only modestly to vitamin D status,37 38 39 which is determined by serum calcidiol levels, a metabolite not measured in the present investigation.
Possible explanations and implications
Calcium levels in serum are under tight homeostatic control, and calcium intake is not normally correlated with calcium serum levels. Diets that are low or very high in calcium can, however, override normal homeostatic control causing changes in blood levels of calcium or calciotropic hormones.52 Calcium enriched meals can reduce calcitriol, the active vitamin D metabolite, by inhibition of 1α hydroxylase53and also increase serum levels of fibroblast growth factor 23.54 Higher levels of circulating fibroblast growth factor 23 are associated with an increased risk of cardiovascular events and all cause mortality.55 56 57 In addition, fibroblast growth factor 23 downregulates calcitriol levels.58 Vitamin D suppression leads to an upregulation of the renin-angiotensin-aldosterone system and hypertension, higher levels of proinflammatory cytokines involved in the pathogenesis of atherosclerosis, increased carotid artery intima medial thickness, decreased endothelial function, hypertrophy of cardiac and vascular muscle cells, and a possible increase in serum triglycerides.59 Finally, high serum calcium levels can increase the risk of cardiovascular mortality60 by induction of a hypercoagulable state.61
Our present data together with previous observations suggest that for the prevention of fractures in elderly people18 and simultaneous avoidance of possible serious adverse events related to a high calcium intake (such as higher risk of hip fracture,18 62 cardiovascular disease,63 renal stones,64 and, as observed in the current study, mortality) emphasis should be placed on people with a low intake of calcium rather than increasing the intake of those already consuming satisfactory amounts.
Conclusion
When looking at the totality of our data, high calcium intakes were associated with higher rates of death from all causes and cardiovascular disease. Mortality was not increased between 600 and 1400 mg/day of total calcium intake, the most customary levels of intake in this setting. The suggestion of an increased risk of mortality by a low calcium intake in our study seemed to be biased by time varying confounding factors.
What is already known on this topic
- A low calcium intake is associated with higher fracture rates in elderly people and a higher risk of stroke and fatal ischaemic heart disease
- Meta-analyses of some randomised studies have, however, shown a higher risk of incident ischaemic heart disease and stroke with calcium supplement use
- In observational studies, use of calcium supplements has been associated with both lower overall and cardiovascular mortality rate, as well as higher incidence of cardiovascular disease
What this study adds
- In this Swedish cohort study of women, high intakes of calcium (>1400 mg/day) were associated with higher mortality
- The increase was moderate with a high dietary calcium intake without supplement use, but more pronounced with a high dietary calcium intake with calcium tablet use
- For most women with lower calcium intakes only modest differences in risk were observed
REFERENCES
- ↵
Fraser WD. Hyperparathyroidism. Lancet2009;374:145-58.
- ↵
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab2011;96:53-8.
- ↵
Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet2011;377:1276-87.
- ↵
Hagstrom E, Hellman P, Larsson TE, Ingelsson E, Berglund L, Sundstrom J, et al. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation2009;119:2765-71.
- ↵
Peiris AN, Youssef D, Grant WB. Secondary hyperparathyroidism: benign bystander or culpable contributor to adverse health outcomes? South Med J2012;105:36-42.
- ↵
Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief Apr(61):1-8.
- ↵
Mangano KM, Walsh SJ, Insogna KL, Kenny AM, Kerstetter JE. Calcium intake in the United States from dietary and supplemental sources across adult age groups: new estimates from the National Health and Nutrition Examination Survey 2003-2006. J Am Diet Assoc2011;111:687-95.
- ↵
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341:c3691.
- ↵
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ2010;342:d2040.
- ↵
Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ2008;336:262-6.
- ↵
Lewis JR, Calver J, Zhu K, Flicker L, Prince RL. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. J Bone Miner Res2011;26:35-41.
- ↵
Iso H, Stampfer MJ, Manson JE, Rexrode K, Hennekens CH, Colditz GA, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke1999;30:1772-9.
- ↵
Umesawa M, Iso H, Date C, Yamamoto A, Toyoshima H, Watanabe Y, et al. Dietary intake of calcium in relation to mortality from cardiovascular disease: the JACC Study. Stroke2006;37:20-6.
- ↵
Umesawa M, Iso H, Ishihara J, Saito I, Kokubo Y, Inoue M, et al. Dietary calcium intake and risks of stroke, its subtypes, and coronary heart disease in Japanese: the JPHC Study Cohort I. Stroke2008;39:2449-56.
- ↵
Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol1999;149:151-61.
- ↵
Larsson SC, Virtamo J, Wolk A. Potassium, calcium, and magnesium intakes and risk of stroke in women. Am J Epidemiol2011;174:35-43.
- ↵
Larsson SC, Bergkvist L, Wolk A. Long-term dietary calcium intake and breast cancer risk in a prospective cohort of women. Am J Clin Nutr2009;89:277-82.
- ↵
Warensjo E, Byberg L, Melhus H, Gedeborg R, Mallmin H, Wolk A, et al. Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ2011;342:d1473.
- ↵
Larsson SC, Bergkvist L, Wolk A. Long-term meat intake and risk of breast cancer by oestrogen and progesterone receptor status in a cohort of Swedish women. Eur J Cancer2009;45:3042-6.
- ↵
Larsson SC, Bergkvist L, Wolk A. Conjugated linoleic acid intake and breast cancer risk in a prospective cohort of Swedish women. Am J Clin Nutr2009;90:556-60.
- ↵
Bergström L, Kylberg E, Hagman U, Erikson H, Bruce Å. The food composition database KOST: the National Administration’s information system for nutritive values of food. [In Swedish]. Vår Föda1991;43:439-47.
- ↵
Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr1997;65(4 Suppl):S1220-8; discussion S29-31.
- ↵
Hu FB, Stampfer MJ, Rimm E, Ascherio A, Rosner BA, Spiegelman D, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol1999;149:531-40.
- ↵
Michaëlsson K, Melhus H, Bellocco R, Wolk A. Dietary calcium and vitamin D intake in relation to osteoporotic fracture risk. Bone2003;32:694-703.
- ↵
Messerer M, Johansson SE, Wolk A. The validity of questionnaire-based micronutrient intake estimates is increased by including dietary supplement use in Swedish men. J Nutr2004;134:1800-5.
- ↵
Orsini N, Bellocco R, Bottai M, Hagstromer M, Sjostrom M, Pagano M, et al. Validity of self-reported total physical activity questionnaire among older women. Eur J Epidemiol2008;23:661-7.
- ↵
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis1987;40:373-83.
- ↵
Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi J, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care2005;43:1130-9.
- ↵
Kaaks R, Ferrari P, Ciampi A, Plummer M, Riboli E. Uses and limitations of statistical accounting for random error correlations, in the validation of dietary questionnaire assessments. Public Health Nutr2002;5(6A):969-76.
- ↵
STATA. Stata reference manual, release 11. In: Stata Corporation, ed. Stata Press, 2009.
- ↵
Anon. Nordic Nutrition Recommendadtions 2004. Integrating nutrition and physical activity. 4th ed. Nordic Council of Ministers, 2004.
- ↵
Newby PK, Tucker KL. Empirically derived eating patterns using factor or cluster analysis: a review. Nutr Rev2004;62:177-203.
- ↵
Newby PK, Weismayer C, Akesson A, Tucker KL, Wolk A. Long-term stability of food patterns identified by use of factor analysis among Swedish women. J Nutr2006;136:626-33.
- ↵
Andersson T, Alfredsson L, Kallberg H, Zdravkovic S, Ahlbom A. Calculating measures of biological interaction. Eur J Epidemiol2005;20:575-9.
- ↵
Fewell Z, Hernán MA, Wolfe F, Tilling K, Choi H, Sterne JAC. Controlling for time-dependent confounding using marginal structural models. Stata J2004;4:402-20.
- ↵
Nandi A, Glymour MM, Kawachi I, VanderWeele TJ. Using marginal structural models to estimate the direct effect of adverse childhood social conditions on onset of heart disease, diabetes, and stroke. Epidemiology2012;23:223-32.
- ↵
Snellman G, Melhus H, Gedeborg R, Olofsson S, Wolk A, Pedersen NL, et al. Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study. PLoS One2009;4:e7747.
- ↵
Burgaz A, Akesson A, Oster A, Michaelsson K, Wolk A. Associations of diet, supplement use, and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter. Am J Clin Nutr2007;86:1399-404.
- ↵
McCullough ML, Weinstein SJ, Freedman DM, Helzlsouer K, Flanders WD, Koenig K, et al. Correlates of circulating 25-hydroxyvitamin D: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol2010;172:21-35.
- ↵
Swales HH, Wang TJ. Vitamin D and cardiovascular disease risk: emerging evidence. Curr Opin Cardiol2010;25:513-7.
- ↵
Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc1999;94:496-509.
- ↵
Lin DY. Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med1997;16:901-10.
- ↵
Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation1994;90:583-612.
- ↵
Rautiainen S, Åkesson A, Levitan EB, Morgenstern R, Mittleman MA, Wolk A. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. Am J Clin Nutr2010;92:1251-6.
- ↵
Serra-Majem L, Pfrimer K, Doreste-Alonso J, Ribas-Barba L, Sanchez-Villegas A, Ortiz-Andrellucchi A, et al. Dietary assessment methods for intakes of iron, calcium, selenium, zinc and iodine. Br J Nutr2009;102(Suppl 1):S38-55.
- ↵
Suarez D, Borras R, Basagana X. Differences between marginal structural models and conventional models in their exposure effect estimates: a systematic review. Epidemiology2011;22:586-8.
- ↵
Cole SR, Hernan MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol2008;168:656-64.
- ↵
Kaufman JS. Marginalia: comparing adjusted effect measures. Epidemiology2010;21:490-3.
- ↵
Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women’s Health Study. Arch Intern Med2011;171:1625-33.
- ↵
Pentti K, Tuppurainen MT, Honkanen R, Sandini L, Kroger H, Alhava E, et al. Use of calcium supplements and the risk of coronary heart disease in 52-62-year-old women: the Kuopio Osteoporosis Risk Factor and Prevention Study. Maturitas2009;63:73-8.
- ↵
Cashman KD. Diet, nutrition, and bone health. J Nutr2007;137(11 Suppl):S2507-12.
- ↵
Schwartz GG. Is serum calcium a biomarker of fatal prostate cancer? Future Oncol2009;5:577-80.
- ↵
Bushinsky DA, Riera GS, Favus MJ, Coe FL. Evidence that blood ionized calcium can regulate serum 1,25(OH)2D3 independently of parathyroid hormone and phosphorus in the rat. J Clin Invest1985;76:1599-604.
- ↵
Vervloet MG, van Ittersum FJ, Buttler RM, Heijboer AC, Blankenstein MA, ter Wee PM. Effects of dietary phosphate and calcium intake on fibroblast growth factor-23. Clin J Am Soc Nephrol2011;6:383-9.
- ↵
Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol2011;22:1913-22.
- ↵
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest2011;121:4393-408.
- ↵
Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis2009;207:546-51.
- ↵
John GB, Cheng CY, Kuro-o M. Role of Klotho in aging, phosphate metabolism, and CKD. Am J Kidney Dis2011;58:127-34.
- ↵
Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol2008;52:1949-56.
- ↵
Leifsson BG, Ahren B. Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab1996;81:2149-53.
- ↵
Reid IR, Bolland MJ, Avenell A, Grey A. Cardiovascular effects of calcium supplementation. Osteoporos Int2011;22:1649-58.
- ↵
Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, Burckhardt P, Li R, Spiegelman D, et al. Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr2007;86:1780-90.
- ↵
Reid IR, Bolland MJ, Sambrook PN, Grey A. Calcium supplementation: balancing the cardiovascular risks. Maturitas2011;69:289-95.
- ↵
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med2006;354:669-83.
Other related articles published on this Open Access Online Scientific Journal include the following:
Like this:
Like Loading...
Read Full Post »
2012pharmaceutical
Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
alexcrystal6
anamikasarkar
apreconasia
aviralvatsa
David Orchard-Webb, PhD
danutdaagmailcom
Demet Sag, Ph.D., CRA, GCP
Dror Nir
dsmolyar
Ethan Coomber
evelinacohn
Gail S Thornton
Irina Robu
jayzmit48
jdpmd
jshertok
kellyperlman
Ed Kislauskis
larryhbern
Madison Davis
marzankhan
megbaker58
ofermar2020
Dr. Pati
pkandala
ritusaxena
Rick Mandahl
sjwilliamspa
Srinivas Sriram
stuartlpbi
Dr. Sudipta Saha
tildabarliya
vaishnavee24
zraviv06
zs22