Letters
COMMENT & RESPONSE
Dietary and Supplemental Calcium Intake and Mortality To the Editor The study by Xiao et al1 demonstrating increased cardiovascular risk from dietary calcium supplementation highlights an important but underappreciated principle: the nontransitivity of clinical inference. In formal logic, if A implies B and B implies C, then it follows that A implies C. However, if calcium deficiency is associated with poor health outcomes and calcium supplementation can raise calcium levels, it does not necessarily follow that taking calcium supplements benefits health, intuitive as it may seem. As this study shows, intuitively appealing inferences can be not only false but even harmful, and when large populations are affected, the harm can be substantial. Among the most dramatic examples where an intuitive supposition proved harmful when finally tested in a randomized trial was the Cardiac Arrhythmia Suppression Trial (CAST) study of type 1 antiarrhythmic drugs,2 which found an increase in cardiac deaths despite decreasing premature ventricular contractions on the patient’s electrocardiograms, overturning many years of clinical practice. More recently, decades of practice were challenged as it became clear that although patients with asymptomatic bacteriuria were more likely to progress to symptomatic disease, and although the patient’s urine cultures and urinalyses could be improved by antibiotics, treating in the absence of symptoms does not decrease rates of future symptomatic disease.3 Particularly in an era with steep increases in antibiotic-associated Clostridium difficile colitis,4 the implications for overall patient health are profound. Both the intuitive psychological appeal and—given the complexity of biological systems—the medical limitations of assuming transitivity of clinical inference are straightforward to understand but all too easy to underestimate. The new prospective trial on calcium supplementation reminds us again to be circumspect in setting clinical practice on the basis of logical inference without direct verification from controlled trials. Primum non nocere applies to our reasoning as much as to our procedures. Robert Colgrove, MD Author Affiliation: Division of Infectious Diseases, Mount Auburn Hospital, Cambridge, Massachusetts. Corresponding Author: Robert Colgrove, MD, Division of Infectious Diseases, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA 02138 (robin@hms .harvard.edu). Conflict of Interest Disclosures: None reported. 1. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646. 2. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781-788. 3. Nicolle LE. Asymptomatic bacteriuria: review and discussion of the IDSA guidelines. Int J Antimicrob Agents. 2006;28(suppl 1):S42-S48. 4. Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359(18):1932-1940. 1840
To the Editor Several recent articles documented increased cardiovascular mortality associated with high calcium intake, in particular supplemental calcium.1 Most epidemiological studies of calcium intake and cardiovascular health have been conducted in white individuals with moderate to high calcium intake. Only a few specifically focused on cardiovascular mortality. Xiao et al2 reported that supplemental calcium was associated with elevated cardiovascular disease (CVD) mortality in men but not in women, whereas dietary calcium intake was unrelated to CVD death in either sex.2 In contrast, another female cohort study showed that dietary calcium intake above 1400 mg/d was associated with higher all-cause and CVD mortality compared with lower intakes. Interestingly, among women with dietary calcium intake exceeding 1400 mg/d, the addition of calcium supplements further increased risk of death in a dose-dependent manner.3 Results of both studies reveal that increasing calcium intake increases mortality, in particular CVD mortality, but the relationship is possibly dependent on habitual calcium intake.4,5 In a Chinese population with comparatively low habitual calcium intake, high calcium intake has a protective effect. In a cohort of Hong Kong Chinese men and women 65 years and older and free of stroke or CVD and without supplemental calcium use at baseline, we examined the association between dietary calcium intake and rates of all-cause mortality (n = 2704) and CVD mortality (n = 2332). Baseline energyadjusted dietary calcium intake assessed using a validated food frequency questionnaire was categorized into sex-specific quartiles (762 mg/d for men and 668 mg/d for women). Data on allcause and CVD mortality were ascertained using the official death registry. Cox regression models adjusted for demographic and lifestyle variables were used to estimate hazard ratios (HRs) and 95% confidence intervals. During a median of 9.2 years of follow-up, 477 all-cause deaths and 105 CVD deaths were identified. An inverse trend between dietary calcium intake and mortality was observed. Compared with the lowest quartile, the highest quartile of dietary calcium intake had a significantly reduced risk of all-cause mortality (HR, 0.69; 95% CI, 0.54-0.90 [P value for trend, .004]) but a nonsignificant decreased risk of CVD mortality (HR, 0.77; 95% CI, 0.451.32 [P value for trend, .29]). The association between calcium intake and mortality is likely U-shaped, with high intake being protective in populations with habitual low intake, while increasing risk in populations with higher intake. Recommendations regarding calcium supplementation should take into account individual population characteristics. Ruth Chan, PhD Jason Leung, MSc Jean Woo, MD Author Affiliations: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Chan, Woo); Jockey Club Centre for Osteoporosis Care and Control, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Leung). Corresponding Author: Ruth Chan, PhD, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 10/F Clinical Sciences Bldg, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region ([email protected]).
JAMA Internal Medicine October 28, 2013 Volume 173, Number 19
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 05/17/2015
jamainternalmedicine.com
Letters
Conflict of Interest Disclosures: None reported. 1. Reid IR, Bolland MJ. Calcium supplements: bad for the heart? Heart. 2012;98(12):895-896.
clearly increases the calcium load of the body and may need optimal control of calcium homeostasis.
2. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park YY. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646.
Elke Theuwissen, PhD Vladimir Badmaev, MD, PhD Cees Vermeer, PhD
3. Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all-cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013;346:f228.
Author Affiliations: VitaK, Maastricht University, the Netherlands (Theuwissen, Vermeer); NattoPharma ASA, Oslo, Norway (Badmaev).
4. Larsson SC, Orsini N, Wolk A. Dietary calcium intake and risk of stroke: a dose-response meta-analysis. Am J Clin Nutr. 2013;97(5):951-957.
Corresponding Author: Elke Theuwissen, PhD, VitaK, Biopartner Building Maastricht, Oxfordlaan 70, 6229 EV Maastricht, the Netherlands (e.theuwissen @vitak.com).
5. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
Conflict of Interest Disclosures: Dr Badmaev is Head R&D at NattoPharma ASA, Oslo, Norway. No other conflicts of interests were reported.
To the Editor In a recent report, Xiao et al1 discuss the outcome of the National Institutes of Health (NIH)–AARP Diet and Health Study, which evaluated the role of calcium intake on cardiovascular health. The outcome of the study revealed that intake of 1000 mg/d of supplemental calcium was associated with significant increase in cardiovascular mortality in men but not in women. Arterial calcification is an actively regulated process with a key function for the vitamin K–dependent matrix Gla protein (MGP).2 Mature MGP is a powerful inhibitor of soft-tissue calcification and is abundantly expressed by vascular smooth muscle cells. The vitamin K–dependent step in MGP synthesis is the carboxylation of 5 glutamate residues into γ-carboxyglutamate (Gla), which are essential for MGP’s calcification inhibitory activity. In healthy adults, at least 20% of plasma MGP occurs in the uncarboxylated, inactive form. Conformationspecific assays have demonstrated that circulating uncarboxylated MGP has a high predictive value for cardiovascular and overall mortality.2,3 Moreover, several independent populationbased studies have shown that dietary vitamin K2 intake is inversely associated with cardiovascular disease and mortality. Calcium supplements have been widely used for the prevention and treatment of osteoporosis. However, when nutritional vitamin K intake is low, the vitamin K–dependent proteins involved in calcium homeostasis are only partly activated resulting in suboptimal control of tissue mineralization; one of the consequences thereof may be excessive mineralization of the arteries. Recent studies have demonstrated that MGP carboxylation can be improved significantly with supplemental vitamin K2 (menaquinone), thus eliminating uncarboxylated MGP, which is now recognized as an independent risk factor for cardiovascular mortality.4 Although the study by Xiao et al1 indicates that supplemental calcium may adversely affect cardiovascular health in men only, other studies indicate that supplemental calcium intake puts women at cardiovascular risk as well.5 To further underpin the crucial importance of vitamin K in the prevention of arterial calcification, we recommend that vitamin K intake or MGP carboxylation is included as potential confounder when analyzing the association between calcium intake and cardiovascular disease. Epidemiological findings and clinical intervention studies suggest that guidelines for calcium supplements may have to be revised; the use of calcium and vitamin D supplements
1. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646. 2. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012;3(2):166-173. 3. Cranenburg EC, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. 2010;104(4):811-822. 4. Westenfeld R, Krueger T, Schlieper G, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012;59(2):186-195. 5. 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. BMJ. 2011;342:d2040.
In Reply In their study of a Hong Kong Chinese population, whose calcium intake is substantially lower than the Western population, Chan et al reported there was a protective effect of dietary calcium intake on total mortality and cardiovascular mortality. The lower cutoff of their highest intake category (>762 mg/d for men and >668 mg/d for women) are around the median intake values (739 mg/d for men and 648 mg/d for women) found in our US cohort. As shown in Figure 2 of our article,1 we observed a nonlinear association between total calcium intake and total cardiovascular disease mortality in men: risk decreased at a calcium intake up to approximately 1200 mg/d, but started to increase at an intake of 1500 mg/d and higher. Therefore, a study with population that has relatively low calcium intake and narrow range of intake is likely to observe an inverse association between calcium intake and mortality, especially cardiovascular disease mortality. In addition, the source of calcium may also play a role. In Western diet, dairy products are usually the major contributing source of dietary calcium.2 However, dairy consumption among populations in East Asia is generally much lower,3 and the primary sources of calcium are plant-based foods such as vegetables, grains, and soy foods.4,5 Different foods contain different nutrients other than calcium, and these nutrients may interact with calcium or act independently to affect cardiovascular health. Therefore, the different relationship between calcium intake and certain health outcomes observed in different studies may also be partially attributed to different dietary patterns of the study populations. When evaluating the effect of certain nutrients on health, it is important to investigate wide range of intake and the source of the nutrient in various populations.
jamainternalmedicine.com
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 05/17/2015
JAMA Internal Medicine October 28, 2013 Volume 173, Number 19
1841
Letters
In their letter, Theuwissen et al raised an interesting point that intake of vitamin K may confound the association between calcium intake and cardiovascular disease and mortality. To explore this possibility, we estimated dietary vitamin K intake in our study population. We found that vitamin K intake was weakly and positively correlated with both dietary (correlation coefficient, 0.11 in men and 0.10 in women) and supplemental (correlation coefficient, 0.05 in men and 0.05 in women) calcium intake (all P < .001). When we further adjusted for vitamin K intake in the multivariate model used in our study,1 we observed a negligible change (
COMMENT & RESPONSE
Dietary and Supplemental Calcium Intake and Mortality To the Editor The study by Xiao et al1 demonstrating increased cardiovascular risk from dietary calcium supplementation highlights an important but underappreciated principle: the nontransitivity of clinical inference. In formal logic, if A implies B and B implies C, then it follows that A implies C. However, if calcium deficiency is associated with poor health outcomes and calcium supplementation can raise calcium levels, it does not necessarily follow that taking calcium supplements benefits health, intuitive as it may seem. As this study shows, intuitively appealing inferences can be not only false but even harmful, and when large populations are affected, the harm can be substantial. Among the most dramatic examples where an intuitive supposition proved harmful when finally tested in a randomized trial was the Cardiac Arrhythmia Suppression Trial (CAST) study of type 1 antiarrhythmic drugs,2 which found an increase in cardiac deaths despite decreasing premature ventricular contractions on the patient’s electrocardiograms, overturning many years of clinical practice. More recently, decades of practice were challenged as it became clear that although patients with asymptomatic bacteriuria were more likely to progress to symptomatic disease, and although the patient’s urine cultures and urinalyses could be improved by antibiotics, treating in the absence of symptoms does not decrease rates of future symptomatic disease.3 Particularly in an era with steep increases in antibiotic-associated Clostridium difficile colitis,4 the implications for overall patient health are profound. Both the intuitive psychological appeal and—given the complexity of biological systems—the medical limitations of assuming transitivity of clinical inference are straightforward to understand but all too easy to underestimate. The new prospective trial on calcium supplementation reminds us again to be circumspect in setting clinical practice on the basis of logical inference without direct verification from controlled trials. Primum non nocere applies to our reasoning as much as to our procedures. Robert Colgrove, MD Author Affiliation: Division of Infectious Diseases, Mount Auburn Hospital, Cambridge, Massachusetts. Corresponding Author: Robert Colgrove, MD, Division of Infectious Diseases, Mount Auburn Hospital, 330 Mt Auburn St, Cambridge, MA 02138 (robin@hms .harvard.edu). Conflict of Interest Disclosures: None reported. 1. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646. 2. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781-788. 3. Nicolle LE. Asymptomatic bacteriuria: review and discussion of the IDSA guidelines. Int J Antimicrob Agents. 2006;28(suppl 1):S42-S48. 4. Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359(18):1932-1940. 1840
To the Editor Several recent articles documented increased cardiovascular mortality associated with high calcium intake, in particular supplemental calcium.1 Most epidemiological studies of calcium intake and cardiovascular health have been conducted in white individuals with moderate to high calcium intake. Only a few specifically focused on cardiovascular mortality. Xiao et al2 reported that supplemental calcium was associated with elevated cardiovascular disease (CVD) mortality in men but not in women, whereas dietary calcium intake was unrelated to CVD death in either sex.2 In contrast, another female cohort study showed that dietary calcium intake above 1400 mg/d was associated with higher all-cause and CVD mortality compared with lower intakes. Interestingly, among women with dietary calcium intake exceeding 1400 mg/d, the addition of calcium supplements further increased risk of death in a dose-dependent manner.3 Results of both studies reveal that increasing calcium intake increases mortality, in particular CVD mortality, but the relationship is possibly dependent on habitual calcium intake.4,5 In a Chinese population with comparatively low habitual calcium intake, high calcium intake has a protective effect. In a cohort of Hong Kong Chinese men and women 65 years and older and free of stroke or CVD and without supplemental calcium use at baseline, we examined the association between dietary calcium intake and rates of all-cause mortality (n = 2704) and CVD mortality (n = 2332). Baseline energyadjusted dietary calcium intake assessed using a validated food frequency questionnaire was categorized into sex-specific quartiles (762 mg/d for men and 668 mg/d for women). Data on allcause and CVD mortality were ascertained using the official death registry. Cox regression models adjusted for demographic and lifestyle variables were used to estimate hazard ratios (HRs) and 95% confidence intervals. During a median of 9.2 years of follow-up, 477 all-cause deaths and 105 CVD deaths were identified. An inverse trend between dietary calcium intake and mortality was observed. Compared with the lowest quartile, the highest quartile of dietary calcium intake had a significantly reduced risk of all-cause mortality (HR, 0.69; 95% CI, 0.54-0.90 [P value for trend, .004]) but a nonsignificant decreased risk of CVD mortality (HR, 0.77; 95% CI, 0.451.32 [P value for trend, .29]). The association between calcium intake and mortality is likely U-shaped, with high intake being protective in populations with habitual low intake, while increasing risk in populations with higher intake. Recommendations regarding calcium supplementation should take into account individual population characteristics. Ruth Chan, PhD Jason Leung, MSc Jean Woo, MD Author Affiliations: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Chan, Woo); Jockey Club Centre for Osteoporosis Care and Control, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (Leung). Corresponding Author: Ruth Chan, PhD, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 10/F Clinical Sciences Bldg, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region ([email protected]).
JAMA Internal Medicine October 28, 2013 Volume 173, Number 19
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 05/17/2015
jamainternalmedicine.com
Letters
Conflict of Interest Disclosures: None reported. 1. Reid IR, Bolland MJ. Calcium supplements: bad for the heart? Heart. 2012;98(12):895-896.
clearly increases the calcium load of the body and may need optimal control of calcium homeostasis.
2. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park YY. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646.
Elke Theuwissen, PhD Vladimir Badmaev, MD, PhD Cees Vermeer, PhD
3. Michaëlsson K, Melhus H, Warensjö Lemming E, Wolk A, Byberg L. Long term calcium intake and rates of all-cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013;346:f228.
Author Affiliations: VitaK, Maastricht University, the Netherlands (Theuwissen, Vermeer); NattoPharma ASA, Oslo, Norway (Badmaev).
4. Larsson SC, Orsini N, Wolk A. Dietary calcium intake and risk of stroke: a dose-response meta-analysis. Am J Clin Nutr. 2013;97(5):951-957.
Corresponding Author: Elke Theuwissen, PhD, VitaK, Biopartner Building Maastricht, Oxfordlaan 70, 6229 EV Maastricht, the Netherlands (e.theuwissen @vitak.com).
5. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
Conflict of Interest Disclosures: Dr Badmaev is Head R&D at NattoPharma ASA, Oslo, Norway. No other conflicts of interests were reported.
To the Editor In a recent report, Xiao et al1 discuss the outcome of the National Institutes of Health (NIH)–AARP Diet and Health Study, which evaluated the role of calcium intake on cardiovascular health. The outcome of the study revealed that intake of 1000 mg/d of supplemental calcium was associated with significant increase in cardiovascular mortality in men but not in women. Arterial calcification is an actively regulated process with a key function for the vitamin K–dependent matrix Gla protein (MGP).2 Mature MGP is a powerful inhibitor of soft-tissue calcification and is abundantly expressed by vascular smooth muscle cells. The vitamin K–dependent step in MGP synthesis is the carboxylation of 5 glutamate residues into γ-carboxyglutamate (Gla), which are essential for MGP’s calcification inhibitory activity. In healthy adults, at least 20% of plasma MGP occurs in the uncarboxylated, inactive form. Conformationspecific assays have demonstrated that circulating uncarboxylated MGP has a high predictive value for cardiovascular and overall mortality.2,3 Moreover, several independent populationbased studies have shown that dietary vitamin K2 intake is inversely associated with cardiovascular disease and mortality. Calcium supplements have been widely used for the prevention and treatment of osteoporosis. However, when nutritional vitamin K intake is low, the vitamin K–dependent proteins involved in calcium homeostasis are only partly activated resulting in suboptimal control of tissue mineralization; one of the consequences thereof may be excessive mineralization of the arteries. Recent studies have demonstrated that MGP carboxylation can be improved significantly with supplemental vitamin K2 (menaquinone), thus eliminating uncarboxylated MGP, which is now recognized as an independent risk factor for cardiovascular mortality.4 Although the study by Xiao et al1 indicates that supplemental calcium may adversely affect cardiovascular health in men only, other studies indicate that supplemental calcium intake puts women at cardiovascular risk as well.5 To further underpin the crucial importance of vitamin K in the prevention of arterial calcification, we recommend that vitamin K intake or MGP carboxylation is included as potential confounder when analyzing the association between calcium intake and cardiovascular disease. Epidemiological findings and clinical intervention studies suggest that guidelines for calcium supplements may have to be revised; the use of calcium and vitamin D supplements
1. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health–AARP Diet and Health Study. JAMA Intern Med. 2013;173(8):639-646. 2. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012;3(2):166-173. 3. Cranenburg EC, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost. 2010;104(4):811-822. 4. Westenfeld R, Krueger T, Schlieper G, et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012;59(2):186-195. 5. 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. BMJ. 2011;342:d2040.
In Reply In their study of a Hong Kong Chinese population, whose calcium intake is substantially lower than the Western population, Chan et al reported there was a protective effect of dietary calcium intake on total mortality and cardiovascular mortality. The lower cutoff of their highest intake category (>762 mg/d for men and >668 mg/d for women) are around the median intake values (739 mg/d for men and 648 mg/d for women) found in our US cohort. As shown in Figure 2 of our article,1 we observed a nonlinear association between total calcium intake and total cardiovascular disease mortality in men: risk decreased at a calcium intake up to approximately 1200 mg/d, but started to increase at an intake of 1500 mg/d and higher. Therefore, a study with population that has relatively low calcium intake and narrow range of intake is likely to observe an inverse association between calcium intake and mortality, especially cardiovascular disease mortality. In addition, the source of calcium may also play a role. In Western diet, dairy products are usually the major contributing source of dietary calcium.2 However, dairy consumption among populations in East Asia is generally much lower,3 and the primary sources of calcium are plant-based foods such as vegetables, grains, and soy foods.4,5 Different foods contain different nutrients other than calcium, and these nutrients may interact with calcium or act independently to affect cardiovascular health. Therefore, the different relationship between calcium intake and certain health outcomes observed in different studies may also be partially attributed to different dietary patterns of the study populations. When evaluating the effect of certain nutrients on health, it is important to investigate wide range of intake and the source of the nutrient in various populations.
jamainternalmedicine.com
Downloaded From: http://archinte.jamanetwork.com/ by a Fudan University User on 05/17/2015
JAMA Internal Medicine October 28, 2013 Volume 173, Number 19
1841
Letters
In their letter, Theuwissen et al raised an interesting point that intake of vitamin K may confound the association between calcium intake and cardiovascular disease and mortality. To explore this possibility, we estimated dietary vitamin K intake in our study population. We found that vitamin K intake was weakly and positively correlated with both dietary (correlation coefficient, 0.11 in men and 0.10 in women) and supplemental (correlation coefficient, 0.05 in men and 0.05 in women) calcium intake (all P < .001). When we further adjusted for vitamin K intake in the multivariate model used in our study,1 we observed a negligible change (
