Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study
BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f228 (Published 13 February 2013) Cite this as: BMJ 2013;346:f228All rapid responses
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Dear Sir:
We read with great interest the excellent article by Michaëlsson et al.(1). Without doubt, this study provides valuable information about the relationship between calcium intake and all cause and cardiovascular mortality. However, in our opinion the article has several drawbacks and limitations and it should consider or include more data to conclude that calcium is responsible for the highest mortality observed in the studied sample.
This article has been widely discussed in several scientific forums, and these findings could lead to some professionals to consider the option to stop prescribing calcium supplements to women with osteoporosis for fear of increasing the risk of cardiovascular disease or other causes of mortality.
Our first concern is about the dietary assessment. Authors have applied a self-administered food frequency questionnaire (FFQ) which has some limitations such as the under/over reporting of the consumption of some foods or energy (2). Although dairy consumption has been quite rigorously controlled, it could be possible that some foods are consumed in larger (i.e. pastries) or less (i.e. fruits and vegetables) amounts by people who consume more milk and dairy products (or have higher intakes of calcium), which can influence the results to favor the occurrence of some diseases, such as cardiovascular diseases. In the present manuscript the authors do not mention the consumption of other foods or nutrients to eliminate the influence of these before stating their conclusions.
On the other hand, the mean energy intake indicated by the authors was 1700 kcal, and this is quite low in comparison to those recommended for this age group (3,4). It could indicate much underreport in the dietary method such as other authors have found (5-7), although authors do not shown this data.
A second concern is that the authors raise the potential adverse effect of high calcium intake on cardiovascular health; however many researchers have promoted calcium intake because of its proposed benefit on bone health, or different diseases related to cardiovascular mortality such as hypertension, hypercholesterolemia or weight loss (8-13), specially in those people with low calcium intakes.
In this sense, the Institute of Medicine (IOM)(14) has recently published the dietary reference intakes for calcium and vitamin D indicating that the recommended dietary allowance for calcium is 1000 mg/day for women and men from 19 to 50 years old and 1200 for those women who are in the range of 51-70 years old. As the authors indicate that having a 1400 mg/day, or higher, increases the risk of cardiovascular mortality, it would have been desirable that they have assessed the risks of low intakes as a starting point for establishing a dietary reference intake for calcium. Moreover, the dietary reference intakes for calcium are established in a range of 1000-1300 mg/day and the upper level for this mineral in a range of 2000-3000 mg/day depending on the age. So, are the authors questioning the method used to set this figures by the IOM? What is the recommended intake for calcium proposed by the authors?
Our third concern is that, bearing in mind the wide diffusion that can have this article, this type of message should be transmitted with a little more caution. It could be possible that those people more concerned about their diet, with a health problem or, even, with chewing problems are taken more calcium supplements o more dairy products, and this message could lead to a dramatically reduce intake of calcium only by the fear of increasing the risk of death from cardiovascular disease.
In our opinion, it would have been desirable some considerations by the authors about which could be the recommended calcium intake for general population, those at risk of osteoporosis and those with cardiovascular risk.
References:
1. Michaëlsson K, Melhus H, Waresjö 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.
2. Field AE, Peterson KE, Gortmaker SL, Cheung L, Rockett H, Fox MK, Colditz GA. Reproducibility and validity of a food frequency questionnaire among fourth to seventh grade inner-city school children: implications of age and day-to-day variation in dietary intake. Public Health Nutr 1999;2:293–300.
3. Ortega RM, Requejo AM, Navia B, López-Sobaler AM. Recommended daily intakes of energy and nutrients for the Spanish population. In: Food composition. A basic tool for assessing nutritional status. Editorial Complutense, Madrid, 2010. 82-4.
4. Institute of Medicine. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and aminoacids. National Academy Press, Washintong D.C., 2005.
5. Bedard D, Shatenstein B, Nadon S. Underreporting of energy intake from a self-administered food-frequency questionnaire completed by adults in Montreal. Public Health Nutr 2004;7:675-81.
6. Neilann K Horner, Ruth E Patterson, Marian L Neuhouser, Johanna W Lampe, Shirley A Beresford, and Ross L Prentice. Participant characteristics associated with errors in self-reported energy intake from the Women’s Health Initiative food-frequency questionnaire. Am J Clin Nutr 2002;76:766–73.
7. Marks GC, Hughes MC, van der Pols JC. Relative validity of food intake estimates using a Food Frequency Questionnaire is associated with sex, age, and other personal characteristics. J Nutr 2006;136:459-65.
8. Varenna M, Manara M, Galli L, Binelli L, Zucchi F, Sinigaglia L. The association between osteoporosis and hypertension: the role of a low dairy intake. Calcif Tissue Int 2013;93:86-92.
9. Varenna M, Binelli L, Casari S, Zucchi F, Sinigaglia L. Effects of dietary calcium intake on body weight and prevalence of osteoporosis in early postmenopausal women. Am J Clin Nutr 2007;86:639-44.
10. Peterlik M, Kállay E, Cross HS. Calcium nutrition and extracellular calcium sensing: relevance for the pathogenesis of osteoporosis, cancer and cardiovascular diseases. Nutrients 2013;5:302-27.
11. Zemel MB, Shi H, Greer B, DiRienzo D, Zemel PC. Regulation of adiposity by dietary calcium. FASEB J 2000; 14:1132-8.
12. Zemel MB, Richards J, Mathis S, Milstead A, Gebhardt L, Silva E: Dairy augmentation of total and central fat loss in obese subjects. Int J Obesity 2005; 29:391-7.
13. Rodríguez-Rodríguez E, Bermejo L, Aparicio A, Perea JM, López-Sobaler AM, Ortega RM. Beneficios del consumo de productos lácteos sobre la pérdida de peso en mujeres con sobrepeso/obesidad que siguen dos tipos de dietas hipocalóricas. Nutr Hosp 2008;1:117.
14. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. National Academy Press, Washinton DC, 2010.
Competing interests: No competing interests
We thank Dr Grant for his interest in our study. He suspects that the results are not sustainable and we agree that observational studies should be interpreted with caution. The title wording “long term calcium intake” refers to the available repeatedly measured information on dietary habits enabling estimation dietary intake over a longer period, as is common in nutritional epidemiology. However, it is noteworthy that Dr. Grant presents an article by Heaney and colleagues (1) as an argument that a high calcium intake does not increase the risk of cardiovascular disease. Readers should be aware that this overview was initiated by the Council for Responsible Nutrition (CRN), the leading trade association representing the dietary supplement industry. This fact has been previously presented in BMJ by Reid and colleagues. (2) After publication of our study, the last author of the Heaney study (1), Dr Wallace (senior director, scientific and regulatory affairs of CRN), sent a press release from CRN (http://www.crnusa.org/CRNPR13-BMJCVD021213.html) criticizing our study on non-objective grounds, including claims that the results were confounded by estrogen therapy use, even though we clearly described in the article that this was not the case. In an e-mail correspondence with Dr. Wallace (February 15 2013), we have presented how our estimates change after adjustment for estrogen therapy, but despite this presentation to him, no retraction of his untrue statements has been made by CRN. The multivariable hazard ratios for total mortality of highest dietary calcium intake (>1400 mg/day) was, after addition of estrogen therapy use in the model, 1.41 (95% CI 1.18 to 1.68). The corresponding HR for IHD mortality was 2.15 (1.49 to 3.10). Both these values are marginally different from those presented without estrogen therapy adjustment.
Moreover, Dr. Grant also refers to a previous study from our group which demonstrated a U-shaped relationship between serum 25-hydroxyvitamin D levels and death from cancer and with cancer incidence.3 For cardiovascular death, there was an increased risk only at low levels of 25-OH-D. The link between high serum vitamin D and all-cause mortality was driven thus by an increased risk of cancer death. Dr Grant does not explain this detail even though he is well aware of the study's content. Grant now also claims that our research group is the only one who found the U-shaped relationship but this is not correct.4-9 There are, however, a number of studies that have not found similar correlations. Several explanations for these discrepancies may exist such as genetic constitution, differences in exposure range of serum 25-hydroxyvitamin D, differences in precision and accuracy of assays, outcome information bias, statistical approach and mere statistical power, as also discussed in the article.3 Dr. Grant's one-sided view that "more is better" when it comes to vitamin D and calcium should be supported by proper evidence. As long as there is a remaining uncertainty of benefits to supplement those who already have a good nutritional status, a precautionary principle is prudent to prevail. I would also remind Dr. Grant, that the number of hip fractures increase with supplementation with calcium10 - a fact not widely recognized. Results that do not suit one’s purposes should not be swept under the carpet but should be viewed with interest - no one benefits in the long run of a one-sided reporting of research results, not even Dr. Grant's Sunlight, Nutrition and Health Research Center (SUNARC).
Dr Gupta discusses the seemingly contradictory results of the cross-sectional study INTERSALT displaying that a low calcium intake in Japan was associated with increased risk of high blood pressure and our study results which showed a U-shaped relationship between calcium intake and death, particularly cardiovascular death. We do not see that there is a contradiction. In our study, we also noted an increased risk of death at a low calcium intake, although this risk was largely biased according to results from our marginal structural model.
Dr Gada correctly notes that the calcium in combination with vitamin D may have a different effect than calcium alone. This fact made us to consider vitamin D intake in an interaction analysis, as presented in the article. No such effect modification was found. Unfortunately, we had not the possibility to measure serum 25-hydroxyvitamin D levels in our cohort, considered to best reflect vitamin D status.
Dr Pena Pradel makes two observations. First, we fully agree that with an observational study you can definitely not be sure of a causal relation. However, the prospects for managing comorbidity are relatively good with our Swedish national patient registers. (11) We were able to take diseases both before baseline and until the second questionnaire into account, rather than excluding women with cardiovascular disease. Nevertheless, we cannot be certain that our estimates are correct and our study may be viewed as a puzzle piece among others. Second, we could not separate prescribed supplements from over-the-counter supplements in our data and it is therefore unclear to us what the actual indication the women in our cohort had with their supplement use. General screening for osteoporosis do not occur in Sweden. It is possible that a previous fracture caused individuals starting out with supplementation. When we took previous fractures into account in our multivariable model - as we described in the article - the estimates remained unchanged. Since Dr. Pena Pradel seems to be of the opinion that supplementation with calcium is of importance to prevent osteoporotic fractures, we want to make clear that the evidence for this claim is thin and that supplementation with calcium leads to an increased risk of hip fractures,10 the fracture in the elderly with most devastating consequences and also associated with a significantly increased mortality.12 The recent US Preventive Services Task Force (USPSTF) opinion on combined vitamin D and calcium supplementation to prevent fractures in adults is that there is at present insufficient evidence to recommend daily supplementation to non-institutionalized postmenopausal women. (13)
We agree with Dr Naneria that calcium is probably over-prescribed to individuals with an already good nutritional status. At the same time, we want to stress that if you suffer a hip fracture it may have serious implications. Premature mortality following hip fracture is well recognized and despite improved hospital care, there is no trend of decreasing mortality after hip fracture. (14)
Prof Katan argues that our relationship between calcium intake and death can be explained by a high intake of saturated fat. In the article, we reported only that our estimates did not change after adjustment for total fat intake. Anyhow, he calls for estimates after adjustment for saturated fat. In our Table 2 it can be noted that a calcium intake greater than 1400 mg per day was associated with a multivariable-adjusted HR of 1.40 (95% CI 1.17 to 1.67) for all-cause mortality and an HR of 2.14 (95% CI 1:48 to 3:09) for IHD mortality. After adjustment for saturated fat intake, these estimates were changed to 1.45 (95% CI 1.24 to 1.47) and 2.32 (95% CI 1.60 to 3.36), respectively. Thus, the associations do not appear to be explained by the saturated fat intake.
We agree that it may look odd that the estimate for the highest category of calcium intake change from an estimate below (1) in an age-adjusted model to a heightened risk after multivariable adjustment for supplement use. One fact we have to consider is that the supplement users in our setting, on average, are healthier than the general population. Again, this is due to the fact that we cannot separate prescription supplement use from over-the-counter supplement use. The latter users are healthier and more health conscious compared to the general population. (15) This bias has to be considered in our observational study. Ideally, however, the effect of supplementation itself is best investigated in randomized trials while large-scale dietary intervention studies are difficult to implement. We want to stress that even among those who did not report use of supplements we noted an increased mortality at a high calcium intake through diet (See figure).
Mr Farrar has misunderstood the conditions for epidemiological research in Sweden. Although some cohort members no longer lived within the catchment area, we can still track them until they die by using the individual's personal identity number provided to all Swedish citizens, combined with our national mortality registries. (11) Thus, the information lost pertains to updated information on nutrients and other questionnaire data, not follow-up on outcomes. Implausible energy intake was defined as an energy intake lower or higher than 3 SDs from the mean value for loge-transformed energy intake, which is a standardized criterion for also many other large cohort studies. This is described in the article’s references 17 and 18. The majority of women which were excluded based on this criterion in our cohort had reported low dietary intakes, not high.
References
1. Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Advances in nutrition 2012;3(6):763-71.
2. Bolland MJ, Grey A, Reid IR. An inappropriate response? BMJ 2013;346:f942.
3. Michaelsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundstrom J, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr;92(4):841-8.
4. Dror Y, Giveon S, Hoshen M, Feldhamer I, Balicer R, Feldman B. Vitamin D Levels for Preventing Acute Coronary Syndrome and Mortality: Evidence of a Non-Linear Association. J Clin Endocrinol Metab 2013.
5. Durup D, Jorgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab 2012;97(8):2644-52.
6. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168(15):1629-37.
7. Meyer HE, Robsahm TE, Bjorge T, Brustad M, Blomhoff R. Vitamin D, season, and risk of prostate cancer: a nested case-control study within Norwegian health studies. Am J Clin Nutr 2013;97(1):147-54.
8. Albanes D, Mondul AM, Yu K, Parisi D, Horst RL, Virtamo J, et al. Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 2011;20(9):1850-60.
9. Tuohimaa P, Lou YR. Optimal serum calcidiol concentration for cancer prevention. Anticancer Res 2012;32(1):373-81.
10. 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 Nutr 2007;86(6):1780-90.
11. Calltorp J, Adami HO, Astrom H, Fryklund L, Rossner S, Trolle Y, et al. Country profile: Sweden. Lancet 1996;347(9001):587-94.
12. Haentjens P, Magaziner J, Colon-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 2010;152(6):380-90.
13. Moyer VA, on behalf of the USPSTF. Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2013.
14. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip fractures in the United States. JAMA 2009;302(14):1573-9.
15. Rautiainen S, Akesson 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 Nutr 2010;92(5):1251-6.
Competing interests: No competing interests
A few issues:
1. The authors sent out two questionnaires to Swedish women born between 1914 and 1948 residing in two counties. The first was between 1987-1990 alongside an invitation to routine mammography screening. The second in 1997 to those women still living in the area. The questionnaire requested various details about the participants diet and lifestyle. It can therefore be said that the authors made every effort to include a fair representative of the population. However, the second questionnaire was only sent out to participants that were still living in the area. This introduces migration bias, which has potential to be largely significant; a total of 5403 of the participants sent the original questionnaire were not sent the second one, as they were no longer living in the area.
2. If the participants weren't giving the authors an accurate picture about what they are eating, then a reliable estimate for correct calcium intake cant be made. However, there is no mention of how the authors defined “implausible”. We presume that this is a subjective measurement. If this is the case, there is a slight possibility that the authors are introducing a small amount of selection bias by removing participants whose diet they see as implausible (there were over 700 of them), and then not explaining how they defined implausible.
Competing interests: No competing interests
This study is a valuable addition to the literature on the effects of high calcium intake. However, I have reservations about the conclusions.
1. Confounding by saturated fat intake
An intake of more than 1400 mg of calcium per day suggests a high intake of saturated fat from dairy, especially from cheese. The apparent effect of calcium may therefore be due to a high intake of dairy fat. Can the authors provide the intakes of various fatty acids and dietary cholesterol by calcium intake, and the estimated impact of these on plasma cholesterol and on heart disease risk?
2. Overcorrection for health effects of supplements
The hazard ratio for total mortality was actually lowest in the group with the highest total calcium intake, namely 0.72 (Table 2). The hazard ratio for heart disease also went down continuously from the lowest to the highest calcium intake. These hazard ratios only became greater than 1 after statistical correction for the use of dietary supplements. However, dietary supplements do not reduce mortality and may even increase it.
The authors’ reasoning seems to be: people who take supplements have a healthy lifestyle, therefore their true hazard ratio should have been even lower than 0.72, so their calcium supplements must have brought the hazard back up to 0.72.
I find this argument unconvincing. More generally, numbers become less persuasive if they go one way in the original data and the other way after additional statistical analyses.
Competing interests: Between 1986 and 2001 I have received research grants from various food industries, including dairy industries, for research into nutrition and heart disease
How can a well treated fracture be a cause of mortality? This is over emphasized.It is some thing like all hypertensive patients are dying due to cerebral stroke or all myocardial ischemia are dying of myocardial infarc. Fracture of a hip in a case of osteoporosis is an incidence and not the end result of osteoporosis. I firmly believe that Calcium is over prescribed in all age group without even calculating the amount of calcium a person is taking in his normal diet.
Competing interests: No competing interests
This is an interesting article, but these things should be pointed out:
1. Were all patients free of cardiovascular risk diseases? To find and describe another cause of cardiovascular risk, it is necessary to rule out and have one hundred per cent certainty that there are no other contributing factors.
2. Why were these patients taking calcium? What was the underlying pathology behind it?
Overlapping statistics: it is known that osteoporosis by itself (and more if complicated by a fracture, i.e, of the hip) conveys a high index of mortality. The five year term in patients with osteoporosis and a fractured hip carries a high level of mortality.
More data are needed before recommending that high risk patients with osteoporosis stop taking calcium, since mortality related to osteoporosis complications is very high.
Competing interests: No competing interests
It might help to clarify that majority of the calcium supplement dispensed in this country is in conjugation with vitamin-D. This study is mainly covering unopposed calcium.
Competing interests: No competing interests
To investigate the association of calcium intake independently of other nutrients already known as predictors of hypertension, a cross-sectional study was carried out on the same population in Japan as used for the INTERSALT study. Dietary calcium intake was estimated from a 1-day 24-h recall. Sodium and potassium intakes were evaluated by 24-h urinary excretion. Data from 476 subjects aged 20-59 years, 230 men and 246 women, were analysed.
The mean dietary calcium intake ranged from 557 to 608 mg/day among men, and from 528 to 639 mg/day among women. A significant negative association of calcium intake with blood pressure was observed among the subjects in Osaka.
This study suggested that increased calcium intake may provide a benefit of lowering blood pressure independently of other minerals such as sodium and potassium1. On the other hand, high intakes of calcium in women are associated with higher death rates from all causes and cardiovascular disease but not from stroke in the present study 2.
To top it all, biological pausibility also explains that Ca2+ channel blockers which will reduce muscular contraction in blood vessels would reduce the Blood Pressure and hence reduce CVA. Therefore it is very perplexing how to explain all this evidence biologically.
References:
1. Morikawa Y, Nakagawa H, Okayama A, Mikawa K, Sakata K, Miura K, Ishizaki M, Yoshita K, Naruse Y, Kagamimori S, Hashimoto T, Ueshima H. A cross-sectional study on association of calcium intake with blood pressure in Japanese population. J Hum Hypertens. 2002;16(2):105-10.
2. BMJ 2013;346:f228
Competing interests: No competing interests
The paper by Michaëlsson and colleagues reported that community dwelling women in Sweden who had greater than 1400 mg/d calcium intake had significantly increased hazard ratios for all-cause, cardiovascular disease (CVD), and ischaemic heart disease mortality rates during a 19-year follow-up study of 61,433 women [1]. Possible explanations were given for the findings. However, given what is known about the role of calcium in human health, there is the question of whether the finding is really related to long-term calcium intake as indicated in the title.
A review of calcium supplementation and risk of CVD by Heaney and colleagues found no evidence that calcium intake is a risk factor for CVD [2]. This paper was published in November 2012, which is prior to the acceptance date of Ref. 1 [28 December 2012], so should have been known to the authors, reviewers, and editors. The review examined some of the studies references in Ref. 1 as showing support for the hypothesis that higher calcium intake increases the risk of CVD [3,4]. The review pointed out that the meta-analysis in Ref. 3 appeared to have some shortcomings, and that bias and confounding could not be ruled out as an explanation for their findings. The review also examined the calcium-CVD hypothesis with respect to four of A. Bradford Hill’s criteria for causality in a biological system: strength of association; consistency; dose-response; and biological plausibility [5]. It found that the meta-analysis [3] failed in all four criteria. They also presented the findings from four randomized controlled trials and eight observational studies not included in the meta-analysis. While most of the studies included in the review were based on less than 1400 mg/d, one randomized controlled trial used 1450 mg/d calcium along with 1100 IU/d vitamin D3 on postmenopausal women for a year and found 4.76 CVD events/1000 person years in the calcium treatment group compared to 6.94 CVD events/1000 person years in the placebo group [6].
The finding in Ref. 1 is similar to the finding by the same group for all-cause and cancer mortality rates but not cardiovascular mortality rates as a function of serum 25-hydroxyvitamin D [25(OH)D] concentrations [7]. Their finding of a non-significant increased hazard ratio for all-cause mortality rate is in general disagreement with ten other observational studies included in a recent meta-analysis of all-cause mortality rate [8].
An alternate explanation for their findings is that those participants with higher calcium intake or 25(OH)D concentrations started taking calcium or vitamin D supplements late in life due to a diagnosis of a vitamin D- or calcium-deficiency disease such as osteoporosis. Support for this explanation is provided in two studies of the association of frailty with serum 25(OH)D concentrations in the United States: older women had a U-shaped relation between 25(OH)D concentration and frailty status [9], while men had a linear inverse relation [10]. In the United States, women are much more likely to be diagnosed with low bone mass density and advised to take extra vitamin D and calcium supplementation. These two papers suggest that taking vitamin D late in life cannot overcome the adverse health effects of low 25(OH)D concentrations earlier in life.
A way to investigate this explanation is to review the medical records of some of the 1241 participants in the study to see what their health status was prior to the time they were identified as taking more than 1400 mg/d calcium and whether such status may have resulted in increased supplement use.
References
1.Michaëlsson K, Melhus H, Lemming EW, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013;346:1228.
2. Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr. 2012;3:763-71.
3. 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. 2010;341:c3691.
4. 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.
5. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295-300.
6. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91.
7. Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010;92:841-8.
8. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: A meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95:91-100.
9. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-73.
10. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59:101-6.
Competing interests: I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven) and have received funding from the UV Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).
Re: Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study
Are bisphosphonates still recommended for the treatment of osteoporosis?
Competing interests: No competing interests