45 ng vitamin D may be enough (what about vitamin A)- Aug 2013

Calcium and Vitamin D Intake and Mortality: Results from the Canadian Multicentre Osteoporosis Study (CaMos)

Lisa Langsetmo, Claudie Berger, Nancy Kreiger, Christopher S. Kovacs, David A. Hanley, Sophie A. Jamal, Susan J. Whiting, Jacques Genest, Suzanne N. Morin, Anthony Hodsman, Jerilynn C. Prior, Brian Lentle, Millan S. Patel, Jacques P. Brown, Tassos Anastasiades, Tanveer Towheed, Robert G. Josse, Alexandra Papaioannou, Jonathan D. Adachi, William D. Leslie, K. Shawn Davison, David Goltzman, and the CaMos Group

Context: Calcium and vitamin D are recommended for bone health, but there are concerns about adverse risks. Some clinical studies suggest that calcium intake may be cardioprotective, whereas others report increased risk associated with calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have been associated with increased mortality.

Objective: The purpose of this study was to determine the association between total calcium and vitamin D intake and mortality and heterogeneity by source of intake.

Design: The Canadian Multicentre Osteoporosis Study cohort is a population-based longitudinal cohort with a 10-year follow-up (1995-2007).

Setting: This study included randomly selected community-dwelling men and women.

Participants: A total of 9033 participants with nonmissing calcium and vitamin D intake data and follow-up were studied.

Exposure:Total calcium intake (dairy, nondairyfood, and supplements) andtotal vitamin D intake (milk, yogurt, and supplements) were recorded.

Outcome: The outcome variable was all-cause mortality.

Results: There were 1160 deaths during the 10-year period. For women only, we found a possible benefit of higher total calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01) per 500-mg increase in daily calcium intake and no evidence of heterogeneity by source; use of calcium supplements was also associated with reduced mortality, with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs nonusers with statistically significant reductions remaining among those with doses up to 1000 mg/d. These associations were not modified by levels of concurrent vitamin D intake. No definitive associations were found among men.

Conclusions: Calcium supplements, up to 1000 mg/d, and increased dietary intake of calcium may be associated with reduced risk of mortality in women.
We found no evidence of mortality benefit or harm associated with vitamin D intake. (J Clin Endocrinol Metab 98: 3010-3018, 2013)

Images from attached PDF

Discussion

We assessed the association between total calcium intake, total vitamin D intake, and all-cause mortality, including possible heterogeneity by the nutrient source and effect modification by the other nutrient. Our analysis showed thattotalcalciumintakeamongwomenwasmorelikelyto be beneficial than harmful and that the same was true of calcium intake from dairy sources, nondairy sources, and supplements. In fact, we observed that supplemental calcium intake up to 1000 mg/d among women was associated with statistically significant decreased mortality, although the results were inconclusive for supplement intake exceeding 1000 mg/d. The lack of a demonstrable benefit observed for higher doses may be a threshold effect or a failure to determine effective intake, which is determined by variables that we did not measure (frequency, time of day, timing relative to meals, and formulation). Consequently, we cannot at this time advocate intakes in excess of this amount. We also found that the relationship between calcium and mortality was relatively consistent by strata of total vitamin D. Thus, in our data, there is no evidence of increased mortality risk associated specifically with calcium supplements at the typical intake levels of Canadian women.
Our results are concordant with findings from the Iowa Women's Health Study in which use of calcium supplements was associated with a lower risk of mortality in older women (21). In a subgroup analysis of the Women's Health Initiative (WHI), calcium supplementation was associated with increased risk of myocardial infarction (MI) and/or cardiovascular mortality among those not already taking personal calcium supplements at baseline; however, calcium supplementation was not associated with increased all-cause mortality in the same group (22). Furthermore, all-cause mortality was in fact lower in those receiving active treatment vs that in those receiving placebo among participants reporting personal calcium use, and, indeed, the original WHI report concluded that supplements may reduce mortality rates in postmenopausal women (23), consistent with results in the present study. A recent analysis of the WHI shows possible early risk for MI and coronary heart disease in selected subsets of participants, but, again, this was not associated with early mortality (24). Our results are partially consistent with results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg prospective cohort study in that moderately high dietary calcium intake was associated with a lower risk of MI, and the association differed by sex with attenuation of the protective effect in men (25). However, in contrast to our study, use of calcium supplements was associated with increased risk of MI (25).

Most recently, Michaelsson et al (26) found a U-shaped relationship between dietary calcium intake and mortality and between total intake and mortality, consistent with our finding that low calcium intake increases the risk of mortality. Our results differ with respect to high intake; a possible reason for the discrepancy is the different distribution of calcium intake, in particular with regard to dairy intake and supplement use. The strong attenuation of effect noted for their model using only baseline covariates could also be attributable to exposure misclassification, because their study lasted more than 20 years and there were time trends in calcium intake.

There are several plausible causal mechanisms for an apparent protective association. Supplemental calcium has been associated with lower plasma lipoprotein levels, a better lipid profile, and a lower risk of hypertension (27). Supplemental calcium will also protect against the potential adverse effects of low calcium intake, such as secondary hyperparathyroidism (28) and high serum PTH levels, which may accelerate bone turnover and mobilize bone calcium, resulting in bone loss, cause cardiovascular effects due to calcification of blood vessels (29), and be associated with increased mortality risk (30, 31). Calcium may also bind fatty acids in the colon and thus inhibit epithelial proliferation, and calcium supplementation has been associated with a lower risk of recurrent colorectal adenomatous polyps (32). Potential noncausal explanations include the indirect association of calcium intake from food with a healthy diet, including dairy products, whole grains, fish, and legumes, all of which are considered nutrient-dense foods and may have health effects unrelated to their calcium content (33,34). Similarly, dietary calcium intake is related to total energy intake. Low energy intake may be a surrogate marker for frailty in women and associated with increased mortality. Some attenuation of real effects might also occur because of various calcium-containing compounds, dose distribution over the day, and cointake of nutrients interfering with calcium absorption (eg, oxalates and phytates). Finally, use of calcium supplements may be associated with unmeasured risk factors such as socioeconomic status and thus there may be residual confounding.
The relationship between vitamin D intake for milk and supplements and mortality was inconclusive in both men and women. We considered the main source of dietary vitamin D variation as well as a crude assessment of sunlight exposure, but there are certainly other exogenous and endogenous sources affecting overall vitamin D status that were not assessed. We found that after adjustment for all risk factors including concurrent use of calcium supplements, vitamin D supplements were not associated with reduced mortality risk in women. Thus, neither major vitamin source studied (milk and supplements) was associated with mortality. This result is consistent with a recent meta-analysis of calcium and vitamin D supplement trials, which found reduced mortality with calcium and vitamin D supplements combined but not with vitamin D supplements alone (35).

Both higher (15) and lower (36) levels of serum 25(OH)D (a clinical correlate of low vitamin D intake) have been associated with increased mortality. If the observed associations between 25(OH)D levels and mortality are attributable to variations in intake, then lower and higher intakes ought to be associated with higher mortality, which we did not observe. It is possible that, with regard to milk intake as a source of vitamin D, other milk constituents may dilute the association attributable to vitamin D, leading to a null association. Furthermore, the prevalence of inadequate vitamin D intake may not match the associated prevalence of inadequate 25(OH)D (37), thus demonstrating the potential importance of cutaneous sources of vitamin D, as we found previously (18) and the likelihood that this source may counteract the effects of low intake. In addition, serum 25(OH)D is also influenced by other factors, such as PTH, BMI, and age-related decline in renal function (17). Finally, the association between 25(OH)D and mortality may not in fact be causal at all, but due to an unidentified pathophysiologic factor that influences both 25(OH)D concentrations and mortality independently.

The US Preventive Services Task Force recently released recommendations against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutional-ized postmenopausal women on the basis of evidence of no net benefit (38). The IOM found that calcium and vitamin D are necessary for skeletal growth and maintenance and recommended dietary reference intakes based on this premise (15). If calcium and vitamin D supplementation are indeed required to ensure adequate intake levels for bone health, then our study provides assurance that, in community-dwelling individuals, there is no increased mortality associated with ingestion of modest amounts of supplemental calcium and vitamin D and that there may in fact be a mortality benefit.

The strengths of the present analysis include assessment of calcium and vitamin D intake from food and supplements in a large population-based sample. In particular, our assessment of calcium and vitamin D supplement use was derived from a complete inventory of all medications and supplements and does not rely on recall to determine ingredients and/or doses. The baseline interviewer-administered questionnaire had detailed lifestyle and demographic information and we used measured height and weight to determine BMI.

Limitations of the study include a low response rate (42%), which could result in selection bias. CaMos investigators have previously addressed potential selection bias and found limited nonresponse bias, except perhaps in the oldest age groups (>80 years) (39). We used an abbreviated FFQ, which captures most calcium intake at 2 discrete time points, but only included foods supplemented with vitamin D. Potential causal pathways to all-cause mortality could only be hypothesized because of the observational nature of the study and lack of information concerning the cause of death. The cohort size and mortality rate may have limited our ability to detect significant relationships between calcium or vitamin D intake and mortality. Finally, death ascertainment may be incomplete and although we used a time-to-event analysis, it assumes that the censoring mechanism is noninformative.

In summary, we found that use of calcium supplements up to 1000 mg/d in women was associated with reduced mortality. This association was consistent with potential associations between overall calcium intake and mortality as well as calcium intake from dairy and nondairy food and mortality. We did not find any significant independent association between vitamin D intake and mortality nor did vitamin D intake affect the association noted between calcium and mortality. Thus, our recommendation is to assess dietary intake to meet calcium and vitamin D requirements for bone health and to consider supplementation necessary to meet the requirements.

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Letter to editor by Dr. Cannell - Vitamin A: rejected by publisher

The article by Sempos et al (1) on 25(OH)D levels and total mortality concerns us for several reasons. The shape is described as a “reverse J.“ Of note, >99% of the population is in the range where the association is inverse to level. The upward blip occurs in the most extreme 1% of the population. When a reverse J with 25(OH)D has been observed, it is typically in the very top one or few percentage of the distribution of the population. One explanation would be that higher 25(OH)D levels due to high intake or sun exposure in otherwise healthy people causes an increase in mortality, and this inflection point is fortuitously captured at the top few percentiles of these populations. Of note, in indigenous populations in East Africa with high sun exposure the majority of individuals would fall into this putatively “toxic” range (e.g. >100 nmol/L. (2) Alternatively, the top one or two percent in the range of 25(OH)D might be selecting for characteristics such as genetic variants, reduced conversion of 25(OH)D to its active form, and supplementation by individuals with diseases. Of note, the increased risk at the top 1% was not statistically significant when controlled for existing diseases. We offer here an additional potential reason, confounding by preformed vitamin A (i.e., not including provitamin A carotenoids).

A 2008 Cochrane meta-analysis of randomized trials found a 16% excess mortality in individuals who take vitamin A supplements. (3) Last year, Cheng and Neuhouser, using serum retinyl esters, reported that 29% of NHANES III participants had vitamin A excess as defined by serum retinyl esters > 7.0 ug/dL or the ratio of serum retinyl esters to retinol > 0.08. (4) They also found high retinyl ester levels masked vitamin D's otherwise favorable association with the incidence of lung cancer.

The same confounding of vitamin A with vitamin D appears to be true in overall survival in melanoma.(5) Also, higher total retinol intake appeared to mask the otherwise favorable association of higher vitamin D levels with lower rates of pancreatic cancer.(6)

The biological plausibility of these findings is sound; there is good experimental evidence of antagonism of vitamin D by excessive amounts of retinol. (7) It may be that vitamin A's toxicity is partially via its interaction with vitamin D. Although the exact mechanism is unknown, retinoic acid antagonizes the action of vitamin D and its active metabolite. (8) This may be because while vitamin D and vitamin A signal through common cofactors, they may compete for each other's function. In humans, even the vitamin A in a single serving of liver impairs vitamin D's rapid intestinal calcium response. (9)

Examining dietary intakes in the Nurses' Health Study, Oh et al found that women in the highest quintile of vitamin D intake also took the most vitamin A, averaging about 10,000 IU/day. (10) That is, about 10% of the nurses took more than the current safe upper limit. As with lung cancer and melanoma, Oh et al found that high retinol intakes thwarted vitamin D's otherwise favorable association with the incidence of colorectal adenoma. Likewise, higher intake of vitamin A appeared to mask the inverse association between serum 25(OH) concentrations and colorectal cancers, with significantly lower rates of cancer in those with high vitamin D intake and low retinol intake, as compared to high intakes of both vitamin D and retinol. (11)
If vitamin A excess does contribute to excess mortality in developed countries, and as those with higher vitamin D levels also have the highest retinol intake and serum levels, we suggest that confounding may be occurring in cohort studies of vitamin D and total mortality. The excess mortality at high 25(OH)D levels, as described by Sempos et al may be due to excess vitamin A intake at these higher levels of vitamin D since higher intakes of the two vitamins co-occur due to the use of supplements containing both, liver, or fish liver oils such as cod liver oil. Have the authors examined the impact of vitamin A status on the vitamin D-mortality association?
References:

• 1.Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, Yetley EA, Looker AC, Schleicher RL, Cao G, Burt V, Kramer H, Bailey RL, Dwyer JT, Zhang X, Gahche J, Coates PM, Picciano MF Is There a Reverse J-Shaped Association Between 25-Hydroxyvitamin D and All-Cause Mortality? Results from the U.S. Nationally Representative NHANES. J Clin Endocrinol Metab. 2013 Jul;98(7):3001-9.
• 2. Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA.T raditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Nov 14;108(9):1557-61
• 3. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007176.
• 4. Cheng TY, Neuhouser ML. Serum 25-hydroxyvitamin D, vitamin A, and lung cancer mortality in the US population: a potential nutrient-nutrient interaction. Cancer Causes Control. 2012 Sep;23(9):1557-65. Epub 2012 Jul 25.
• 5. Field S, Elliott F, Randerson-Moor J, Kukalizch K, Barrett JH, Bishop DT, Newton-Bishop JA. Do vitamin A serum levels moderate outcome or the protective effect of vitamin D on outcome from malignant melanoma? Clin Nutr. 2013 Apr 13.
• 6. Bao Y, Ng K, Wolpin BM, Michaud DS, Giovannucci E, Fuchs CS (2010) Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies. Br J Cancer 102:1422-1427.
• 7.Rohde CM, Manatt M, Clagett-Dame M, DeLuca HF. Vitamin A antagonizes the action of vitamin D in rats. J Nutr. 1999 Dec;129(12):2246-50.
• 8. Rohde CM, DeLuca HF. All-trans retinoic acid antagonizes the action of calciferol and its active metabolite, 1,25-dihydroxycholecalciferol, in rats. J Nutr. 2005 Jul;135(7):1647-52.
• 9.Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001 Oct;16(10):1899-905.
• 10. Oh K, Willett WC, Wu K, Fuchs CS, Giovannucci EL Calcium and vitamin D intakes in relation to risk of distal colorectal adenoma in women. Am J Epidemiol. 2007 May 15;165(10):1178-86.
• 11. .Jenab M, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ. 2010 Jan 21.

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See also at VitaminDWiki

Is 50 ng of vitamin D too high, just right, or not enough
Mortality increased with highest levels of vitamin D – article and 4 letters Aug 2012
Search VitaminDWiki j-shaped OR U-shaped 255 items as of April 2014
Take vitamin D3 daily or weekly which has the following notional chart for >50 ng
 

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See also at VitaminDWiki - too much Vitamin A

7 X more likely to get hip fracture if have highest level of vitamin A – Jan 2003
Less Lung Cancer if take more than 800 IU of vitamin D and never smoke or low vitamin A – Oct 2013 <1000 μg/d of Retinol
Vitamin A serum levels of more than 2.2 micromols may interfere with vitamin D – April 2013
8X higher Osteoporosis risk if high level of vitamin A, vitamin D important too – Feb 2013
All items in category Vitamin A and Vitamin D You do not have the permission that is needed to use this feature items
Response to high dose vitamin D is limited by vitamin A - July 2013
response to vitamin D decreases if there is a lot of vitamin A and the vitamin D level i higher than 50 ng
 

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