Trial Of Calcium Supplementation Research Articles

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy

(Abstracted from N Engl J Med 2024;390:143–53) Many maternal deaths globally are associated with hypertensive disorders of pregnancy, which include preeclampsia. Several interventions have been investigated as possible preventive measures, one of which is calcium supplementation.

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy

Effects of maternal calcium supplementation on offspring blood pressure and growth in childhood and adolescence in a population with a low-calcium intake: follow-up study of a randomized controlled trial

BackgroundThe World Health Organization recommends calcium supplementation (1500–2000 mg/d) during pregnancy for women with a low-calcium intake. ObjectivesThe purpose of this study was to investigate whether pregnancy calcium supplementation affects offspring blood pressure and growth in The Gambia where calcium intakes are low (300–400 mg/d). MethodsFollow-up of offspring born during a randomized controlled trial of pregnancy calcium supplementation (ISRCTN96502494, 1996–2000) in which mothers were randomly assigned to 1500 mg Ca/d (Ca) or placebo (P) from 20 wk pregnancy to delivery. Offspring were enrolled at age 3 y in studies where blood pressure and anthropometry were measured under standardized conditions at approximately 2-yearly intervals. Mean blood pressure and growth curves were fitted for females and males separately, using the longitudinal SuperImposition by Translation and Rotation (SITAR) mixed effects model. This generates 3 individual-specific random effects: size, timing, and intensity, reflecting differences in size, age at peak velocity, and peak velocity through puberty relative to the mean curve, respectively. ResultsFive hundred twenty-three singleton infants were born during the trial (maternal group assignment: Ca/P = 259/264). Four hundred ninety-one were enrolled as children (females: F-Ca/F-P = 122/129 and males: M-Ca/M-P = 119/121) and measured regularly from 3.0 y to mean age 18.4 y; 90% were measured on ≥8 occasions. SITAR revealed differences in the systolic blood pressure and height curves between pregnancy supplement groups in females, but not in males. F-Ca had lower systolic blood pressure than F-P at all ages (size = −2.1 ± SE 0.8 mmHg; P = 0.005) and lower peak height velocity (intensity = −2.9 ± SE 1.1%, P = 0.009). No significant pregnancy supplement effects were seen for other measures. ConclusionsThis study showed, in female offspring, that pregnancy calcium supplementation may lower systolic blood pressure and slow linear growth in childhood and adolescence, adding to evidence of offspring sexual dimorphism in responses to maternal supplementation. Further research is warranted on the long-term and intergenerational effects of antenatal supplementations.This trial was registered at ISRCTN Registry as ISRCTN96502494.

Longitudinal self-learning of individualized treatment rules in a nutrient supplementation trial with missing data.

Longitudinal outcomes are prevalent in clinical studies, where the presence of missing data may make the statistical learning of individualized treatment rules (ITRs) a much more challenging task. We analyzed a longitudinal calcium supplementation trial in the ELEMENT Project and established a novel ITR to reduce the risk of adverse outcomes of lead exposure on child growth and development. Lead exposure, particularly in the form of in utero exposure, can seriously impair children's health, especially their cognitive and neurobehavioral development, which necessitates clinical interventions such as calcium supplementation intake during pregnancy. Using the longitudinal outcomes from a randomized clinical trial of calcium supplementation, we developed a new ITR for daily calcium intake during pregnancy to mitigate persistent lead exposure in children at age 3 years. To overcome the technical challenges posed by missing data, we illustrate a new learning approach, termed longitudinal self-learning (LS-learning), that utilizes longitudinal measurements of child's blood lead concentration in the derivation of ITR. Our LS-learning method relies on a temporally weighted self-learning paradigm to synergize serially correlated training data sources. The resulting ITR is the first of this kind in precision nutrition that will contribute to the reduction of expected blood lead concentration in children aged 0-3 years should this ITR be implemented to the entire study population of pregnant women.

Calcium for pre-eclampsia prevention: A systematic review and network meta-analysis to guide personalised antenatal care.

Calcium supplementation reduces the risk of pre-eclampsia, but questions remain about the dosage to prescribe and who would benefit most. To evaluate the effectiveness of high (≥1g/day) and low (<1g/day) calcium dosing for pre-eclampsia prevention, according to baseline dietary calcium, pre-eclampsia risk and co-interventions, and intervention timing. CENTRAL, PubMed, Global Index Medicus and CINAHL, from inception to 2 February 2021, clinical trial registries, reference lists and expert input (CRD42018111239). Randomised controlled trials of calcium supplementation for pre-eclampsia prevention, for women before or during pregnancy. Network meta-analysis (NMA) also included trials of different calcium doses. Two independent reviewers extracted published data. The meta-analysis employed random-effects models and the NMA, a Bayesian random-effects model, to obtain direct and indirect effect estimates. The meta-analysis included 30 trials (N=20 445 women), and the NMA to evaluate calcium dosage included 25 trials (N=15 038). Calcium supplementation prevented pre-eclampsia similarly with a high dose (RR0.49, 95%CI 0.36-0.66) or a low dose (RR0.49, 95%CI 0.36-0.65). By NMA, high-dose (vs low-dose) calcium did not differ in effect (RR0.79, 95%CI 0.43-1.40). Calcium was similarly effective regardless of baseline pre-eclampsia risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake. Low- and high-dose calcium supplementation are effective for pre-eclampsia prevention in women with low calcium intake. This has implications for population-level implementation where dietary calcium is low, and targeted implementation where average intake is adequate. A network meta-analysis of 25 trials found that low-dose calcium supplementation (<1g/day) is as effective as high-dose calcium supplementation (≥1g/day) in halving the risk of pre-eclampsia when baseline calcium intake is low.

Participants’ Experience in a Clinical Trial of Calcium Supplementation in Pregnancy

This Patient Platform recalls the experience of four women who were enrolled in a clinical trial in Argentina 35 years ago. The patients reflect on their experience as described to the narrator and translator, Dr. José M. Belizán.

Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania

BackgroundHypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5 years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500–2000 mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (< 1000 mg elemental calcium/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy.Methods/designWe will conduct two independent trials in Bangalore, India (n = 11,000 pregnancies), and Dar es Salaam, Tanzania (n = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500 mg elemental calcium/day) as compared to standard high-dose calcium supplementation (1500 mg elemental calcium/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20 weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials’ secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death.DiscussionThe trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake.Trial registrationClinicalTrials.gov identifier: NCT03350516; registered on 22 November 2018. Clinical Trials Registry—India identifier: CTRI/2018/02/012119; registered on 23 February 2018.Tanzania Medicines and Medical Devices Authority Trials Registry identifier: TFDA0018/CTR/0010/5; registered on 20 December 2018.

Calcium supplementation commencing before or early in pregnancy, for preventing hypertensive disorders of pregnancy.

Background The hypertensive disorders of pregnancy include pre-eclampsia, gestational hypertension, chronic hypertension, and undefined hypertension. Pre-eclampsia is considerably more prevalent in low-income than in high-income countries. One possible explanation for this discrepancy is dietary differences, particularly calcium deficiency. Calcium supplementation in the second half of pregnancy reduces the serious consequences of pre-eclampsia, but has limited effect on the overall risk of pre-eclampsia. It is important to establish whether calcium supplementation before, and in early pregnancy (before 20 weeks' gestation) has added benefit. Such evidence could count towards justification of population-level interventions to improve dietary calcium intake, including fortification of staple foods with calcium, especially in contexts where dietary calcium intake is known to be inadequate. This is an update of a review first published in 2017. Objectives To determine the effect of calcium supplementation, given before or early in pregnancy and for at least the first half of pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, and fetal and neonatal outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Trials Register (31 July 2018), PubMed (13 July 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 31 July 2018), and reference lists of retrieved studies. Selection criteria Eligible studies were randomised controlled trials (RCT) of calcium supplementation, including women not yet pregnant, or women in early pregnancy. Cluster-RCTs, quasi-RCTs, and trials published as abstracts were eligible, but we did not identify any. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. They assessed the quality of the evidence for key outcomes using the GRADE approach. Main results Calcium versus placeboWe included one study (1355 women), which took place across multiple hospital sites in Argentina, South Africa, and Zimbabwe. Most analyses were conducted only on 633 women from this group who were known to have conceived, or on 579 who reached 20 weeks' gestation; the trial was at moderate risk of bias due to high attrition rates pre-conception. Non-pregnant women with previous pre-eclampsia received either calcium 500 mg daily or placebo, from enrolment until 20 weeks' gestation. All participants received calcium 1.5 g daily from 20 weeks until birth.Primary outcomes: calcium supplementation commencing before conception may make little or no difference to the risk of pre-eclampsia (69/296 versus 82/283, risk ratio (RR) 0.80, 95% confidence interval (CI) 0.61 to 1.06; low-quality evidence). For pre-eclampsia or pregnancy loss or stillbirth (or both) at any gestational age, calcium may slightly reduce the risk of this composite outcome, however the 95% CI met the line of no effect (RR 0.82, 95% CI 0.66 to 1.00; low-quality evidence). Supplementation may make little or no difference to the severe maternal morbidity and mortality index (RR 0.93, 95% CI 0.68 to 1.26; low-quality evidence), pregnancy loss or stillbirth at any gestational age (RR 0.83, 95% CI 0.61 to 1,14; low-quality evidence), or caesarean section (RR 1.11, 95% CI 0.96 to 1,28; low-quality evidence).Calcium supplementation may make little or no difference to the following secondary outcomes: birthweight 24h, or both (RR 1.11, 95% CI 0.77 to 1.60; low-quality evidence).It is unclear what impact calcium supplementation has on Apgar score 24 hours, maternal death, hospital stay > 7 days from birth, and pregnancy loss before 20 weeks' gestation. Authors' conclusions The single included study suggested that calcium supplementation before and early in pregnancy may reduce the risk of women experiencing the composite outcome pre-eclampsia or pregnancy loss at any gestational age, but the results are inconclusive for all other outcomes for women and babies. Therefore, current evidence neither supports nor refutes the routine use of calcium supplementation before conception and in early pregnancy.To determine the overall benefit of calcium supplementation commenced before or in early pregnancy, the effects found in the study of calcium supplementation limited to the first half of pregnancy need to be added to the known benefits of calcium supplementation in the second half of pregnancy.Further research is needed to confirm whether initiating calcium supplementation pre- or in early pregnancy is associated with a reduction in adverse pregnancy outcomes for mother and baby. Research could also address the acceptability of the intervention to women, which was not covered by this review update.

Aortic Calcification is Associated with Five-Year Decline in Handgrip Strength in Older Women.

The objective of the study was to determine the association between AAC and neuromuscular function over 5years. Participants in this study were ambulant women over 70years old residing in Perth, Western Australia who participated in the Calcium Intake Fracture Outcomes Study, a randomised controlled trial of calcium supplementation. 1046 women (mean age = 74.9 ± 2.6years; BMI = 27.1 ± 4.4kg/m2) were included. Lateral spine images captured during bone density testing were scored for AAC (AAC24; 0-24) at baseline. Severe AAC (AACsev) was defined using established cut points (AAC24 ≥ 6). At baseline and follow-up, isometric grip strength was assessed using a dynamometer. Mobility was assessed by the Timed-Up-and-Go (TUG) test. Using pre-defined criteria, muscle weakness was considered as grip strength < 22kg and poor mobility defined as TUG > 10.2s. A subset of women had appendicular lean mass (ALM) determined by dual-energy X-ray absorptiometry at baseline and follow-up (n = 261). AACsev was evident in 193 (18.5%) women. Average decline in grip strength after 5years was greater in those with AACsev than those without (3.6 ± 3.7 vs. 2.9 ± 4.2kg; p = 0.034). This remained significant after adjustment for age, treatment allocation, diabetes, smoking history, renal function, medical record-derived prevalent vascular disease, BMI and physical activity (β = - 0.184; 95% confidence interval: - 0.361, - 0.008; p = 0.040). AACsev was not associated with 5-year changes in TUG or ALM in univariable or multivariable analyses (all p > 0.05). In older women, severe aortic calcification was associated with greater 5-year decline in muscle strength, but not TUG or ALM. These findings support the concept that vascular disease may have an effect on the loss of muscular strength.

Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy.

Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy.

Long-term effects of maternal calcium supplementation on childhood growth differ between males and females in a population accustomed to a low calcium intake

The importance of adequate calcium intakes for healthy growth and bone development has long been recognised. Recent evidence suggests that calcium supplementation may have sex-specific effects on bone growth in childhood. The aim was to describe the long-term effects of calcium supplementation in pregnant Gambian women with a low calcium intake (ISCRTN96502494) on offspring height, weight, bone and body composition in childhood, and whether the effects differ by sex.Children of mothers who participated in the original calcium supplementation trial were measured at age 8–12years using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Linear models tested for sex*supplement interactions before and after adjusting for current age and size in early life.447 children, aged 9.2(SD 0.9) years, were measured. Significant sex*supplement interactions (p<0.05) were observed for many of the anthropometric and bone outcomes, Females whose mothers received calcium (F-Ca) were shorter, lighter with smaller bones and less bone mineral than those whose mothers received placebo (F-P), differences (SE) ranged from height=−1.0 (0.5)% to hip BMC −5.5 (2.3)%. Males from mothers in the calcium group (M-Ca) had greater mid-upper arm circumference (MUAC) (+2.0 (1.0)%, p=0.05) and fat mass (+11.6 (5.1)%, p=0.02) and tended towards greater BMC and size than those whose mothers were in the placebo group (M-P). The differences in anthropometry and body composition were robust to adjustment for current height and weight, whereas all bone differences became non-significant. F-P were taller with more BMC than M-P, whereas F-Ca had similar sized bones and mineral content to M-Ca.Calcium supplementation of pregnant women with low calcium intakes altered the childhood trajectories of growth and bone and body composition development of their offspring in a sex-specific manner, resulting in slower growth among females compared to placebo and accelerated growth among males by age 8–12years.

Calcium and Cardiovascular Disease.

Circulating calcium is a risk factor for vascular disease, a conclusion arising from prospective studies involving hundreds of thousands of participants and extending over periods of up to 30 years. These associations may be partially mediated by other cardiovascular risk factors such as circulating lipid levels, blood pressure, and body mass index, but there appears to be a residual independent effect of serum calcium. Polymorphisms of the calcium-sensing receptor associated with small elevations of serum calcium are also associated with cardiovascular disease, suggesting that calcium plays a causative role. Trials of calcium supplements in patients on dialysis and those with less severe renal failure demonstrate increased mortality and/or acceleration of vascular disease, and meta-analyses of trials in those without overt renal disease suggest a similar adverse effect. Interpretation of the latter trials is complicated by a significant interaction between baseline use of calcium supplements and the effect of randomisation to calcium in the largest trial. Restriction of analysis to those who are calcium-naive demonstrates a consistent adverse effect. Observational studies of dietary calcium do not demonstrate a consistent adverse effect on cardiovascular health, though very high or very low intakes may be deleterious. Thus, obtaining calcium from the diet rather than supplements is to be encouraged.

Calcium supplements for the management of osteoporosis

It seems quite impossible that a worldwide accepted ‘dogma’ like the recommendation of calcium supplementation for the prevention of osteoporotic fractures is still debated in the most important medical journals. In fact it was about 30 years ago that the first consensus statement on osteoporosis recommended a daily calcium intake of 1500 mg in postmenopausal women [1], followed about 10 years later by the recommendation of vitamin D supplementation in older adults [2], although the latter was based on extrapolation of the results obtained in very old institutionalized women to the general population [3]. The recommended intake cannot easily be achieved through diet alone, and consequently middle-aged and older women worldwide are taking calcium plus vitamin D supplements. In fact, by the early 2000s, routine supplementation to reach at least 1200 mg calcium and 800 IU vitamin D daily was a common recommendation in medical practice for the prevention of osteoporotic fractures in women aged >50, supported also by the guidelines of different influential organizations, such as the US National Osteoporosis Foundation and the Europe-based International Osteoporosis Foundation. Thus the recent publication of two systematic reviews raising serious doubts about the efficacy of calcium intake from dietary sources or calcium supplements opened a heated debate on the matter. In the first paper, Tai and colleagues [4] reported a systematic review and meta-analysis of randomized controlled trials of dietary or supplemental calcium in women and men aged over 50: 15 trials studied dietary sources of calcium (n=1533) and 51 calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased total hip and total body bone mineral density (BMD) by 0.6–1.0% , with no further gains beyond the first year. This limited improvement in BMD was similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus calcium+vitamin D, in trials with calcium doses of ≥1000 versus 500 mg/day, and in trials where the baseline dietary calcium intake was 1000 participants) randomized trials of calcium supplements, vitamin D supplements, or their combination, published to the end of 2010: • three reported a reduction in fracture risk, • nine reported no effect, and • two reported an increased fracture risk. Grey and Bolland also examined why calcium and vitamin D

C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study.

Serum C-reactive protein (CRP) is a sensitive marker of systemic inflammation. Because there is a well-recognized relationship between local inflammation and colorectal cancer, we aimed to evaluate whether serum CRP levels were associated with the occurrence of colorectal adenomas and serrated polyps using data from a large adenoma prevention trial. A total of 930 participants with a history of colorectal adenomas were enrolled in a randomized trial of calcium supplementation (1,200 mg/day) for the prevention of colorectal adenomas. Outcomes in this analysis are metachronous adenomas (and advanced neoplasms specifically), and serrated polyps at follow-up colonoscopy. High-sensitivity CRP levels were measured 1 year following baseline colonoscopy. Multivariate analysis was performed to estimate risk ratios (RR) using Poisson regression, controlling for potential confounders. We measured serum CRP levels in 689 participants (mean CRP, 3.62 ± 5.72 mg/L). There was no difference in CRP levels with respect to calcium versus placebo treatment assignment (P = 0.99). After adjustment for potential confounders, we found no association between CRP level and risk of recurrent adenoma or advanced lesion [quartile 4 vs. quartile 1: RR, 95% confidence interval (CI) = 0.99 (0.73-1.34) and 0.92 (0.49-1.75), respectively]. Similarly, no association was seen between CRP levels and risk of serrated polyps or proximal serrated polyps [quartile 4 vs. quartile 1: RR (95% CI) = 1.32 (0.85-2.03) and 1.19 (0.54-2.58), respectively]. In conclusion, this large prospective colorectal adenoma chemoprevention study found no significant relationship between CRP levels and occurrence of adenomas, advanced neoplasms, or serrated polyps.

Abstract 2132: Personalized prevention of colorectal rectal trial (PPCCT)

Abstract We previously reported from the Tennessee Colorectal Polyp Study that high total intakes of calcium or magnesium may only be related to a reduced risk of colorectal adenoma or hyperplastic polyp when the calcium/magnesium intake ratio was below 2.8. Furthermore, we found that calcium/magnesium intake ratio significantly interacted with the common Thr1482Ile polymorphism (rs8042919, GA) in the TRPM7 gene, in relation to both adenomas and hyperplastic polyps. The TRPM7 gene is involved in magnesium and calcium re(absorption) and homeostasis. Compared to those with the GG genotype, we found that people who carry A allele(s) were at 60% and 85% increased risks of adenoma and hyperplastic polyp, respectively, if they also consumed diets with calcium/magnesium intake ratio &amp;gt;2.8; and the corresponding risks increased by 345% and 1500% among those with the AA genotype. The risk was not increased among those who carried the A allele(s) if they consumed diets low in calcium/magnesium ratio (&amp;lt;2.8). In a recent report from the Calcium Polyp Prevention Study, a large-scale randomized clinical trial of calcium supplementation, it was found that calcium treatment only significantly reduced colorectal adenoma recurrence risk when the baseline dietary calcium/magnesium intake ratio was under 2.6 and this effect modification by the calcium/magnesium ratio cannot solely be attributed to the baseline dietary intake in calcium or magnesium. It is possible for those with a high calcium/magnesium ratio, reducing the calcium/magnesium intake ratio may be helpful. We are funded by NCI (R01CA149633) to conduct a personalized intervention trial clinical trial among 240 colorectal polyp patients with a high calcium/magnesium intake ratio. We are testing 1) if reducing the calcium/magnesium through magnesium supplementation affects biomarkers related to colorectal carcinogenesis in rectal tissues; and 2) if the effects differ by TRPM7 genotype. As of November 16, 2013, we have enrolled at least 160 participants and we plan to complete the trial by the end of January, 2015. Thus the uniqueness of the trial includes 1) only target colorectal polyp patients with a high calcium/magnesium ratio through nutritional screening using multiple 24-hour dietary recalls; 2) personalized doses are based on and used to reduce the current calcium/magnesium intake ratios; and finally, 3) the participants are also randomized by the TRPM7 genotype. We have conducted immunohistochemical assays to measure expressions of carcinogenesis biomarkers, including apoptosis, cell proliferation, COX2 and TRPM7, in normal rectal tissues collected at baseline and the end of the intervention for 40 participants who first completed the trial. We have also measured lipid profile and blood pressure. We have obtained very promising preliminary findings. We will report updated findings in the presentation. The results from our study may ultimately help to develop personalized strategies to prevent the colorectal cancer. Citation Format: Qi Dai, Martha J. Shrubsole, Xinqing Deng, Xiangzhu Zhu, Eugene Shubin, Tiffany McCray, Wei Zheng, Harvey Murff, Douglas Seidner, Reid M. Ness, Chang Yu. Personalized prevention of colorectal rectal trial (PPCCT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2132. doi:10.1158/1538-7445.AM2014-2132

Benefits of Calcium Supplements Are Too Small for Clinical Equipoise to Exist

In his article “The Calcium Supplement Controversy: Now What?” Dr Bauer suggests that there is clinical equipoise regarding the use of calcium supplements and that more clinical trials are needed.1 We think both these views are questionable. Clinical equipoise implies uncertainty as to whether the benefits of calcium outweigh the risks. The benefits of calcium have been clearly defined in a number of large clinical trials with fracture as a primary endpoint. Pooled analyses of these trials suggest a 12% reduction in total fractures with calcium2 but no reduction, and possibly an increase, in hip fracture risk in community-dwelling individuals.3, 4 A 12% reduction in relative risk translates into a very small absolute benefit for people at low-moderate risk of fracture. For a population with an average 10-year fracture risk of 20%, 10 in 100 people would sustain a fracture within 5 years. By taking calcium supplements for 5 years, the proportion with fracture would reduce to 8.8 in 100 people, so that about 1 in 100 people benefit from taking calcium. If the average 10-year fracture risk is 10%, about 1 in 200 people benefit from taking calcium for 5 years. Because the absolute benefit of calcium in preventing fractures is so small, the risks must also be very small for clinical equipoise to exist. However, many people experience adverse effects from taking calcium. At least 10% to 20% experience gastrointestinal side effects, such as constipation, which cause a significant number to stop the supplements. Less common side effects include hospital admissions for acute gastrointestinal symptoms,5 renal stones,6 myocardial infarction (MI),7, 8 stroke,8 and, rarely, hypercalcemia.9 In the study by Prince and colleagues, there were 24 more women with a hospitalization for acute gastrointestinal symptoms in the calcium group than in the placebo group, and 16 fewer women with a fracture.5, 10 In the Women's Health Initiative, there were 68 more women with a kidney stone in the calcium group, and 56 fewer women with a fracture.6 In our two meta-analyses, the cardiovascular risks of calcium were similar to7 or exceeded8 the benefits of calcium on fracture prevention. Thus, available evidence suggests that the small risk of significant side effects coupled with the moderate risk of minor side effects outweighs any small benefits on fracture prevention. Even if clinical equipoise does exist, further clinical trials are both difficult to justify and unlikely to be feasible. The effect on fracture risk is already known, so the main purpose of future trials would be to define the risk of adverse events such as cardiovascular events. Based on the incidence of events in our previous individual patient data meta-analyses (mean age 74 years, 77% female),7 a 5-year study with 90% power to detect a 20% increase in MI, allowing for 20% loss to follow-up, would need about 27,000 participants and 45,000 participants to detect a 15% increase in stroke. Using data from a younger cohort at lower risk (mean age 67 years, 93% female),8 the respective numbers would be 56,000 for MI and 108,000 for stroke. Depending on the study design, these numbers are likely conservative estimates. Such trials would be extremely expensive and logistically challenging. Furthermore, obtaining ethical approval and recruiting participants is likely to be difficult given that the primary purpose would be to define the risks of an intervention with very small absolute benefits. For these reasons, we think that further large clinical trials of calcium supplements are unlikely to be undertaken. Clinical practice must, therefore, be guided by the data from existing clinical trials, with all their limitations. All authors state that they have no conflicts of interest.

The Calcium Supplement Controversy: Now What?

The Calcium Supplement Controversy: Now What?

Effect of Calcium Supplements on Risk of Myocardial Infarction and Cardiovascular Events: Meta-analysis

ABSTRACT Objective To investigate whether calcium supplements increase the risk of cardiovascular events. Design Patient level and trial level meta-analyses. Data Sources Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), reference lists of meta-analyses of calcium supplements, and two clinical trial registries. Initial searches were carried out in November 2007, with electronic database searches repeated in March 2010. Study Selection Eligible studies were randomized, placebo controlled trials of calcium supplements (. 500 mg/day), with 100 or more participants of mean age more than 40 years and study duration more than 1 year. The lead authors of eligible trials supplied data. Cardiovascular outcomes were obtained from self-reports, hospital admissions and death certificates. Results Fifteen trials were eligible for inclusion, five with patient level data (8,151 participants, median follow-up 3.6 years, interquartile range 2.7-4.3 years) and 11 with trial level data (11,921 participants, mean duration 4.0 years). In the five studies contributing patient level data, 143 people allocated to calcium had a myocardial infarction compared with 111 allocated to placebo (hazard ratio 1.31, 95% confidence interval 1.02-1.67, p = 0.035). Nonsignificant increases occurred in the incidence of stroke (1.20, 0.96-1.50, p = 0.11), the composite end point of myocardial infarction, stroke, or sudden death (1.18, 1.00 to 1.39, p = 0.057), and death (1.09, 0.96-1.23, p = 0.18). The meta-analysis of trial level data showed similar results: 296 people had a myocardial infarction (166 allocated to calcium, 130 to placebo), with an increased incidence of myocardial infarction in those allocated to calcium (pooled relative risk 1.27, 95% confidence interval 1.01-1.59, p = 0.038). Conclusion Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

Vitamin D Supplements Don't Prevent Respiratory Infections

Vitamin D deficiency has been associated with many medical problems, but whether repletion improves clinical outcomes is still largely unclear. U.S. researchers who were conducting a large blinded trial of vitamin D3 and calcium supplementation for preventing large bowel adenomas included a …

The Effects of 3 Years of Calcium Supplementation on Common Carotid Artery Intimal Medial Thickness and Carotid Atherosclerosis in Older Women: An Ancillary Study of the CAIFOS Randomized Controlled Trial

Calcium is an essential nutrient for skeletal health; however, it has been suggested that supplemental calcium may be associated with adverse cardiovascular effects, raising widespread concern about their use. One suggested mechanism is via increasing carotid atherosclerosis, however few randomized controlled trials (RCT) of calcium supplements have assessed these mechanisms. The calcium intake fracture outcome study (CAIFOS) was a 5-year RCT (1998 to 2003) of 1.2 g of elemental calcium in the form of calcium carbonate in 1460 elderly women. An ancillary study of 1103 women assessed common carotid artery intimal medial thickness (CCA-IMT) and carotid atherosclerosis at year 3 (2001). The effects of supplementation were studied in intention-to-treat (ITT) and per-protocol (PP) analyses before and after adjustment for baseline cardiovascular risk factors. The mean age of participants at baseline was 75.2 ± 2.7 years. In ITT analyses, women randomized to calcium supplementation had no difference in multivariable-adjusted mean CCA-IMT (calcium 0.778 ± 0.006 mm, placebo 0.783 ± 0.006 mm, p = 0.491) and maximum CCA-IMT (calcium 0.921 ± 0.007 mm, placebo 0.929 ± 0.006 mm, p = 0.404). Women randomized to calcium did not have increased carotid atherosclerosis (calcium 47.2%, placebo 52.7%, p = 0.066). However, in women taking at least 80% of the supplements, a significant reduction in carotid atherosclerosis was observed in unadjusted but not in multivariate-adjusted models (p = 0.033 and p = 0.064, respectively). Participants in the highest tertile of total calcium (diet and supplements) had reduced carotid atherosclerosis in unadjusted and multivariable-adjusted analyses compared with participants in the lowest tertile (odds ratio [OR] = 0.67 [95% confidence interval (CI) 0.50-0.90], p = 0.008, and OR = 0.70 [95% CI 0.51-0.96], p = 0.028, respectively). In conclusion, these findings do not support the hypothesis that calcium supplementation increases carotid artery intimal medial thickness or carotid atherosclerosis, and high calcium intake may reduce this surrogate cardiovascular risk factor.