Dietary Reference Intakes for Calcium and Vitamin D (2011) / Chapter Skim
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6 Tolerable Upper Intake Levels: Calcium and Vitamin D
6 Tolerable Upper Intake Levels: Calcium and Vitamin D
Pages 403-456
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From page 403... ...
and hazard characterization (intake–response assessment and reference value specification) , the first two steps of the general risk assessment approach for Dietary Reference Intake (DRI)
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The conditions associated with the intoxication syndrome for calcium and vitamin D are informative, but avoiding acute toxicity is not the ideal basis for a UL, a reference value with the larger purpose of public health protection over a life time of chronic intake. Although information concerning chronic excess intakes remains limited, data have emerged recently that may warrant caution about the levels of vitamin D that are consumed and raise questions about the long-term effects of high intakes that are less than those associated with toxicity and that may result in an increase in serum 25-hydroxyvitamin D (25OHD)
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Rather, excess intakes are more likely to be associated with the use of calcium supplements. However, the potential indicators for the adverse outcomes of excessive calcium intake are not characterized by a robust
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The "classic" toxicity state of hypercalcemia is seen with either calcium or vitamin D excess, although it appears that the symptoms of hypercalcemia are manifested at relatively lower intake of calcium compared with vitamin D, for which high intakes are required to reach a toxic state. In the discussions below, hypercalcemia, as well as, hypercalciuria is described first as general conditions associated with the toxicity of either nutrient, followed by a discussion of adverse outcomes associated with excess calcium intake.
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Available case reports tend to provide only serum calcium levels and do not specify calcium intakes per se, or serum phosphate, associated with the condition. As shown in Table 6-1, a number of recent case reports have been iden
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TABLE 6-1 Case Reports of Calcium-Alkali Syndrome 408 Patient Gender/Age Calcium Carbonate Serum Calcium Level Creatinine Level Reference (years) Intake (mg/day)
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Although nephrocalcinosis has been reported to be induced by calcium intake in rats (Peterson et al., 1996) , no data link calcium intake or the use of calcium supplements in humans to the onset of nephrocalcinosis.
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Associated with Calcium Supplements Calcification of vascular tissues has been reported with high calcium intake (Goodman et al., 2000; Asmus et al., 2005; Block et al., 2005; Raggi et al., 2005) ; however, the reports are based on individuals with compromised kidney function.
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. Hypercalciuria can be present in the absence of hypercalcemia and may reflect routine excretion of excess calcium intake.
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Therefore, it is reasonable to consider the possibility that total calcium intake of 2,100 mg per day were associated with increased kidney stones in this population. Although the kidney stone events were not adjudicated specifically, adjudication problems should be randomly distributed and thus not a contributing factor to the outcome.
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From page 413... ...
The most important evidence to date is from the WHI trial (Jackson et al., 2006) , which indicated that a mean calcium intake from foods and supplements that totaled about 2,150 mg/day -- plus a vitamin D supplement of 400 IU/day, a level low enough to avoid potential confounding effects for adverse events given the mean total vitamin D intake of approximately 750 IU/day -- resulted in a 17 percent increased incidence of kidney stones among postmenopausal women, regardless of whether the subjects had experienced previous clinical events related to urinary calculi formation.
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The mean calcium intake for infants receiving the supplemented formula was more than 4 times that of children in control groups at months 4 and 9, with a mean calcium intake of 1,563 ± 703 mg/day at 9 months. Although the focus of the study was lead absorption, the data demonstrated that total calcium intakes of about 1,550 to 1,750 mg/day did not affect urinary calcium excretion.
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(2006a) found a significantly increased risk for advanced prostate cancer associated with increasing total calcium intake and for fatal prostate cancer associated with supplemental calcium intakes of 401 mg/day and above.
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Overall, data in this area are at best emerging. Although observational studies suggest that total calcium intake of 2,000 mg/day or higher may be associated with increased risk for prostate cancer and particularly with advanced and metastatic cancer, these data are not sufficiently robust to serve as an indicator for a UL.
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However, as calcium intakes among this age group could be higher than those studied, there is little evidence to shed light on the larger issue. Excessive Calcium and Constipation Calcium supplement intake has long been associated with constipation.
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The calcium excretion data provide information for a group for which no data were available in 1997. The newer data on kidney stone formation form a basis for a UL that is more akin to conditions experienced by the normal, healthy population than is calcium-alkali syndrome, although the cautions expressed by Patel and Goldfarb (2010)
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This 1999 report has provided the ability to estimate a NOAEL for calcium intake for infants based on calcium excretion. Within the confines of the limitations of the data, they suggest that infants can tolerate approximately 1,750 mg of calcium per day with no noted adverse effects.
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The NOAEL of 1,750 mg/day -- which is derived from one study within the age range of 3 to 9 months (Sargent et al., 1999) -- is reduced by an uncertainty factor of 2 to adjust for this weight difference and rounded to 1,000 mg of calcium per day to serve as the UL for this life stage group.
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. At that time, it was noted that the safety of excess calcium intake in children and adolescents had not been studied.
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The levels of calcium intake that may cause kidney stones within a normal population cannot be specified with certainty and are known to be variable depending upon a number of factors, including baseline renal function, pre-existing disease conditions, and interactions with drugs. Based on the findings of Jackson et al.
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There is no apparent reason to conclude that men in this age group are more sensitive than women. Although one 1993 observational study does not support the potential for increased kidney stone formation with supplement use among men, public health protection warrants caution for this older group.
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Consequently, excess intakes of calcium during pregnancy will aggravate hypercalciuria and possibly increase the risk of kidney stones. During lactation, the serum calcium (both ionized and albumin-corrected total calcium)
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The 2007 AHRQ analysis (Cranney et al., 2007; hereafter referred to as AHRQ-Ottawa) concluded that few adverse outcomes could be identified for intakes "above current recommended levels," but it raised concerns about potential previously unrecognized adverse effects, including an increased risk of pancreatic cancer.
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From page 426... ...
The function and activity of the parathyroid–kidney–bone axis have thus emerged as contributors to the "set point" for toxicity of excess vitamin D and calcium. Decreased renal function simultaneously increases CVD risk and impairs calciuric responses and calcium phosphate homeostasis.
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Table 6-3 contains case reports from the past 35 years in which the data are supported by vitamin D dose administered, serum calcium levels, and serum 25OHD levels. Also provided are data from several month-long studies with a range of vitamin D supplements in which fully documented vitamin D intoxication was not identified.
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From page 428... ...
GFR) Reference Vitamin D supplementation studies without documented hypercalcemia 800 4–6 mo NCaa 60–105b -- -- Byrne et al., 1995e 1,800 3 mo NCa 65, 80c -- -- Byrne et al., 1995e 1,800 3 mo NCa 57–86 82.4–3.8 -- Honkanen et al., 1990f 2,000 6 mo NCa -- -- -- Johnson et al., 1980g 10,000 4 wk -- 105d -- -- Stamp et al., 1977 10,000 10 wk -- 110d -- -- Davie et al., 1982 20,000 4 wk -- 150d -- -- Stamp et al., 1977 Vitamin D supplementation studies reporting hypercalcemia 50,000 6 wk 15.0 320 388 -- Schwartzman and Franck, 1987 50,000 15 y 12.5 560 -- -- Davies and Adams, 1978 100,000 10 y 12.8 865 215 0.508 Selby et al., 1995 200,000 2y 15.1 1,202 207 -- Selby et al., 1995 300,000 6y 13.2 1,692 184 0.432 Rizzoli et al., 1994 300,000 3 wk 11.3 800 339 0.065 Rizzoli et al., 1994 Accidental vitamin D intoxication ~ 1,131,840; -- 15.0 1,171 265 -- Klontz and vitamin D Acheson, overdose 2007
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(1990) measured serum 25OHD levels but observed no side effects of the vitamin D or calcium supplements.
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(1984) study, serum calcium levels in humans (with and without tuberculosis)
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Although increased serum calcium levels are of concern, the Narang et al.
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Other Adverse Effects of Excess Vitamin D: Mortality, Chronic Disease, Falls and Fractures The committee reviewed the evidence emerging from observational/ association studies and a limited number of clinical trials related to vitamin D intake and a diverse set of health outcomes, ranging from breast cancer to falls and fractures. The purpose was not to determine that certain levels of intake definitively cause harm, but rather to decide whether the emerging data were sufficiently compelling to warrant caution relative to vitamin D intakes and associated serum 25OHD concentrations that may be less than those associated with the more widely known acute toxicity but still associated with adverse effects that may occur as a result of chronic intake.
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(2008) , using data from the Third National Health and Nutrition Examination Survey (NHANES III)
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. NOTE: Model 1 is adjusted for gender, age, and education; model 2 is adjusted for model 1 and for chronic disease, serum creatinine concentration, cognitive status, and depressive symptoms; model 3 is adjusted for model 2 and for lifestyle variables including body mass index, smoking status, alcohol consumption, and physical activity; model 4 is adjusted for model 3 and for frailty indicators: mobility performance, low serum albumin concentration, and low serum total cholesterol concentration.
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. NOTE: Model 1 is unadjusted; model 2 is adjusted for age, gender, race, and sea son; model 3 is adjusted for age, gender, race, season, hypertension, history of prior cardiovascular disease, diabetes, smoking, high-density lipoprotein cholesterol, to tal cholesterol, use of cholesterol medications, estimated glomerular filtration rate categories, serum albumin, log (albumin-creatinine ratio)
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Cancer Screening Trial, the same investigators found no association between higher serum 25OHD level and increased pancreatic cancer risk as an outcome (Stolzenberg-Solomon, 2009)
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, and participants whose blood was collected in summer months. Thus, a pooled analysis of large cohort studies suggests an association for increased risk of pancreatic cancer with serum 25OHD levels greater than 100 nmol/L that is not consistently seen in analyses of individual large cohorts.
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The results were similar after adjustment for baseline calcium intake.…" The non-physiological nature of a large one-time dose cannot be readily extrapolated to the situation in which smaller daily doses are provided. However, in view of a number of studies in the literature (e.g., Trivedi et al., 2003)
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. Another common feature was that calcium supplements were not given.
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the emerging data concerning other adverse effects at intakes lower than those associated with acute toxicity and at serum 25OHD levels previously considered to be at the high end of physiological values. Taken as a whole, the body of evidence suggests that there is reason to proceed cautiously in assuming that higher levels of vitamin D intake below those expected to cause hypervitaminosis D are harmless, especially in the absence of data to demonstrate benefit at such intake levels.
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(1966) forms the starting point for these life stage group, as it did in the 1997 IOM report (IOM, 1997)
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suggested that a serum calcium level obtained from a study in Glasgow of infants with hypercalcemia ages 3 weeks to 11 months was associated with an estimated vitamin D intake of 1,320 IU/day. Overall, on balance, 1,800 IU/day is reasonable as a NOAEL and offers an appropriate starting point.
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From page 443... ...
The emerging data related to all-cause mortality, chronic disease risk, and falls would appear to suggest that adverse events may occur with serum 25OHD levels of approximately 75 nmol/L or above (Visser et al., 2006; Ginde et al., 2009) , but ranging up to approximately 125 nmol/L (Melamed et al., 2008)
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From page 444... ...
More specifically, the evidence from the studies that focused on all-cause mortality, chronic disease, falls and fractures suggested that serum 25OHD levels between 75 nmol/L and approximately 120 nmol/L were associated with the adverse effect. There is considerable uncertainty surrounding such values, and -- using information on the serum levels achieved during maximal sun exposure and to avoid being unnecessarily restrictive given the uncertainties -- the committee determined that for the purposes of the UL, concern would be for levels above approximately 125 to 150 nmol/L.
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This value is greater than that set in 1997 by the previous IOM committee. A UL of 4,000 IU/day is still, however, a reference value that reflects the interest in providing public health protection, especially when existing data do not support benefit above such intakes.
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American Journal of Clinical Nutrition 87(6)
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2001. Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study.
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1997. Compari son of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women.
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American Journal of Clinical Nutrition 77(1)
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1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper In take Levels for Nutrients.
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2008. Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men.
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2010. Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case–control study.
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2003. Time trends in reported prevalence of kidney stones in the United States: 1976-1994.
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2009. Adverse health effects of excessive vitamin D and calcium intake: consid erations relevant to cardiovascular disease and nephrocalcinosis.
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2009. Dietary reference intakes for vitamin D: jus tification for a review of the 1997 values.
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