Calcium in Global Health and Nutrition Webinar

Global calcium deficiency: prevalence, impact and indicator

Connie Weaver gave the meeting’s first presentation, providing an overview of global calcium deficiency. While some countries have population-wide average calcium intakes above current dietary recommendations, many others, especially in parts of Africa and South Asia, fall well below those recommendations. The data also reveal the major source of calcium in many diets: “There’s a huge correlation between adequacy of calcium intake and availability of milk in the world,” said Weaver.

A closer look, however, reveals a complicated set of challenges. Even in wealthy countries with ample milk supplies, some sub-populations have low calcium intakes. Vegans, adolescents, and post-menopausal women, for example, are especially likely to be calcium-deficient by current standards. The standards themselves also need careful examination, though. As Weaver explained, calcium needs vary by age and sex, and may also differ from one region to another due to complex interactions of metabolism, diet, lifestyle, and genetics. As a result, she advocated combining data from multiple studies to develop new recommendations. “If you start with an estimated average requirement from the biology, then you might need to apply regional adjustments in these harmonized average requirements, to adjust for local diet effects like bioavailability,” said Weaver.

Analyses of different calcium-rich foods reveal significant differences in bioavailability, or how well someone absorbs the calcium once it’s ingested. Milk and calcium-set tofu both have highly bioavailable calcium, but calcium-rich spinach also contains oxalic acid, which inhibits calcium absorption. Diets high in salt can reduce calcium bioavailability, as can some genetic factors linked to race.

Insufficient calcium intake increases the risk of several serious medical problems, including hypertension, pre-eclampsia, and maternal morbidity. However, osteoporosis is one of the most common and serious outcomes of low calcium, especially in women. As Weaver explained, a woman’s ability to absorb calcium changes significantly throughout her life, and inadequate intake in adolescence can lead to insufficient bone mass later.

To assess the risk of osteoporosis, the World Health Organization (WHO) developed the Fracture Risk Assessment Tool (FRAX), which uses a short questionnaire to estimate ten-year fracture rates in adults. Despite the well-characterized link between calcium intake and osteoporosis, though, global FRAX data reveal a surprise. “You have countries in Africa … that have a low risk of lifetime fracture, despite having a very low calcium intake, [and] we don’t understand that yet,” said Weaver.

Addressing that and other outstanding questions about calcium biology will require new research tools. Weaver described how the Academy’s Calcium Task Force identified the field’s major research gaps and the most promising strategies for filling them. “We judged research gaps and priorities, the top one being a need for a good calcium status indicator that we can use to relate [calcium intakes] to health and disease risk,” said Weaver, adding that the Task Force compiled a list of requirements for such a biomarker, and investigated several existing options. Other priorities include gathering more complete data on calcium intakes in low- and middle- income countries, and gaining a more detailed understanding the link between calcium intake and fracture risk.

Calcium supplementation in pregnancy and preeclampsia

Justus Hofmeyr discussed the connection between inadequate calcium intake and a potentially deadly condition: preeclampsia. Characterized by high blood pressure and organ dysfunction in pregnancy, preeclampsia can lead to convulsions and a cascade of complications, usually late in the pregnancy. The rate of preeclampsia varies dramatically between different countries. “We need to look for biological reasons why women in poor countries are at such grossly increased risk of preeclampsia, compared with women in well-off countries,” said Hofmeyr.

Studies as far back as the 1950s have implied a connection between calcium intake and preeclampsia, but it wasn’t until a major multinational study at the beginning of the 21st century that scientists became convinced of the link. In that study, “we randomly allocated more than 8,000 pregnant women to supplementation with a gram and a half of calcium daily, or placebo,” said Hofmeyr. From those data, plus a comprehensive review of smaller studies, Hofmeyr and his colleagues concluded that calcium supplementation reduced preeclampsia significantly in countries where dietary calcium intake was inadequate. In countries with diets richer in calcium, the effect was not significant.

Most trials of calcium supplementation have used doses ranging from 1.5 to 2 grams daily, which led to the current WHO recommendation for pregnant women to take this amount of calcium daily. However, some smaller studies suggest that more modest doses can also reduce preeclampsia and other bad pregnancy outcomes, though perhaps not as dramatically. “In a resource-constrained setting, we need to consider that if we have limited funding for calcium … it may be more effective for the population to give a smaller dose to everyone than to give this big dose to a small number of women,” said Hofmeyr.

Next, Hofmeyr and his colleagues asked whether calcium supplementation at the earliest stages of pregnancy would work even better to prevent preeclampsia. To answer that question, “we recruited non-pregnant women who were not using contraception, and were at high risk because of previous preeclampsia,” Hofmeyr explained. The researchers randomized the women to take either a 500 mg daily calcium supplement or placebo and waited for them to become pregnant.

The large, lengthy trial eventually revealed that the low-dose calcium supplement lowered women’s blood pressures and their risks of both preeclampsia and pregnancy loss. Though calcium’s exact role in pregnancy remains unclear, Hofmeyr hypothesizes that it may work primarily by improving oxygen supply to the placenta, preventing the hypoxia-induced release of placental toxins that can drive preeclampsia.

Unfortunately, most women in countries with low-calcium diets don’t visit doctors until later in their pregnancies. “The only intervention which would enable us to improve calcium intake before and in early pregnancy would be a population-based intervention, education or something like calcium fortification of staple foods,” said Hofmeyr. He added that while the data on calcium supplementation in pregnancy may not be as conclusive as some researchers would like, “we don’t really need more evidence on pregnant women, because there’s many other reasons … in terms of hypertension, bone health and so on … to improve access to calcium.”

Calcium supplementation in pregnancy: bone health and long-term offspring outcomes

Per Ashorn moved the discussion to the next stage of the life cycle, with an analysis (systematic review) of the effects of maternal calcium supplementation on women and their babies after delivery. In principle, calcium levels during pregnancy could have far-reaching impacts on both mother and child for years afterward. Calcium is essential for bone growth, so a deficiency could lead to low birth weight, developmental delay, and metabolic derangement in the baby. Meanwhile, pregnancy places immense demands on the mother’s metabolism, potentially causing bone or dental problems for her as well.

However, those risks, and the effect of calcium supplementation on them, were largely theoretical. To get a better sense of the available data, “we looked at what evidence there is from randomized controlled trials that antenatal calcium supplementation might reduce those adverse outcomes,” said Ashorn.

After a careful review of the literature, his team categorized published results based on the strength of the underlying studies, and the relative risk of various adverse pregnancy outcomes with or without calcium supplementation. Besides corroborating Hofmeyer’s conclusion that calcium supplementation likely reduces the risk of maternal hypertension, preeclampsia, and pregnancy-associated morbidity and mortality, Ashorn found that “there probably is also an impact on preterm birth … fetal growth restriction, stillbirth, and [neonatal intensive care unit] admissions.” The available papers don’t show any clear impact on infant death or low birth weight, though, largely due to a shortage of data.

Next, Ashorn and his colleagues conducted a systematic literature review to find studies on child outcomes. A search with predefined keywords revealed six randomized, controlled clinical trials that met the inclusion criteria, ranging in time from 1991 to 2013, and in size from 43 to 2000 participants. Most of the studies used high calcium doses started in mid-pregnancy. “There wasn’t much of a problem that we could see in terms of bias, but the one big thing was that when you follow up kids for five or ten years … the loss to follow-up tended to be rather high,” said Ashorn.

The results were mixed. Overall, the trials found no significant effect of maternal calcium supplementation on newborn weight or length, or children’s subsequent blood pressures or dental health. A trial conducted in The Gambia in 2017 yielded two perplexing findings, though.

First, girls born to women who had received calcium supplements grew more slowly than those born to controls, while the reverse happened in boys. “The authors hypothesized that this might be related to a postponement of puberty in the girls and advancement of it in the boys, but unfortunately they don’t have puberty data that they could actually look at,” said Ashorn. Second, the same trial found lower bone mass in treated mothers than controls when they were lactating. Neither finding has been reproduced.

“Putting it all together, what can be learned is that high dose calcium supplementation reduces the incidence of hypertension, preeclampsia, maternal mortality, preterm birth, and possibly low birth weight, [but there’s] very little data on other outcomes that we reviewed,” said Ashorn.

Food-based interventions to improve calcium intake

The meeting’s second session focused on potential interventions for improving calcium intake. Gabriela Cormick started the webinar with a presentation on calcium fortification of staple foods. Though well-controlled studies on the impact of food fortification are hard to perform, combining data from calcium supplementation trials with international and historical comparisons suggests that it has significant benefits, and few if any drawbacks.

For example, flour sold in the UK has been calcium fortified since 1943. A study modeling the impact of rescinding mandatory fortification there estimated that such a move would significantly increase the number of people with calcium-deficient diets, leading to a substantial rise in long-term health problems. “This impact would be greater in low socioeconomic groups, [and] it would increase the cost on the [National Health Service] and the social care costs,” said Cormick. Indeed, Denmark has already performed a natural experiment that backs up those findings. The country fortified flour from 1954-1987, and after mandatory fortification ended, the incidence of inadequate calcium intake rose from 6% to 22% among adults there.

Flour types and intakes vary between countries, though, so Cormick’s team investigated fortifying a more ubiquitous and uniform product: water. “Water has some advantages, it is universally consumed as part of a healthy diet, it’s free … and water is usually consumed spread out during the day, [which] improves calcium absorption,” said Cormick. Unfortunately, water isn’t included in most dietary recommendations, and details such as the most common sources of water aren’t recorded even in studies that ask about its consumption, leaving substantial gaps in the available data. Researchers will need to gather all of that information in order to design effective fortification strategies.

To begin tackling that problem, Cormick and her colleagues reviewed available data on water sources and calcium levels in countries around the world, and classified them based on how feasible it would be to add calcium to those sources. Modeling those data showed that 59 of the 71 countries examined could fortify the water supplies of at least half of their households.

In developed countries, water fortification could lead some groups to exceed established maximum doses for recommended calcium intakes, but in countries with less available dietary calcium, that wasn’t a problem. The model shows that at least 9 countries could deliver at least 650 mg of calcium supplementation per person per day through fortified water, without exceeding recommended limits in any sub-population. Stressing that the analysis had many limitations, Cormick characterized it as a first approximation of water fortification’s potential.

Cormick and her colleagues also tested the taste of water fortified with different amounts and types of fortification. In a group of 59 subjects, they found that adding calcium gluconate had no effect on flavor at concentrations up to 500 mg per liter. Calcium chloride, however, conferred a noticeable flavor at levels less than 200 mg per liter, suggesting that the specific type of fortificant could affect its acceptance. The team is also investigating the capacity and limitations of different fortification systems, using either a hydraulic venturi device or a bed of calcite or calcium-impregnated zeolite.

Feasibility studies for fortification with calcium

Victor Taleon described a new approach to food improvement. Fortification has traditionally been implemented solely as a way to add nutrients to staple foods, which adds cost to the fortified products without conferring any obvious advantages beyond nutrition. Taleon and his colleagues wondered whether they could do more. “By having calcium as a functional ingredient, we wanted to see if [we could] not only provide calcium, but … provide benefits to processors or consumers, so the adoption could be easier,” said Taleon.

To investigate that, his team developed, produced, and test-marketed four calcium-fortified products in different countries. Two of the products were designed to improve only nutritive value, while the other two provided additional benefits.

In South Asia, producers often parboil rice, which reduces pest damage and also allows the rice to be milled longer, making the grains longer and whiter. The additional milling decreases the rice’s nutrient content, though. Taleon found that by adding calcium to the parboiling water, he could raise the calcium content of the rice significantly, while producing whiter rice with a given amount of milling.

Taking the calcium-whitened rice to markets in Bangladesh yielded mixed results. “We noticed that in several markets, there was a premium in the willingness to pay for the rice, up to 10% in some cases, although we also saw some areas where they didn’t like it … not due to the color but due to the other attributes, in some cases flavor,” said Taleon. Nonetheless, in South Asian nations where people eat a lot of rice, he projects that a fortified product with additional market appeal could go a long way toward boosting calcium intakes.

In many African countries, corn is a much bigger component of diets than rice, so for that continent, the researchers tried transplanting an ancient maize processing technique from South America: nixtamalization. By treating maize with calcium hydroxide, or lime, nixtamalization simultaneously boosts the resulting corn flour’s calcium content and improves its dough-making characteristics. However, in Nigeria, where corn flour is used for different recipes than in South America, the team encountered difficulties. “Unfortunately, the consumers didn’t like [the nixtamalized maize] much, just because they’re not used to the textures, meaning we have to explore better ways to process it or understand better the markets before introducing this technology, but still it has potential,” said Taleon.

Pursuing a more traditional fortification strategy focused solely on nutrient content, the investigators tested two strategies for adding calcium to wheat flour, using either calcium salts or finger millet. Calcium salt treatment yielded a high-calcium product that at least a subset of consumers in India found acceptable for chapati, or unleavened flatbreads. Blending wheat with finger millet, a grain with inherently high calcium levels, produced an all-natural biofortified flour that Indian consumers accepted as equivalent to the unfortified product for most uses. “The final additional cost will be around 1-2% … for these flours, and now because there is no additional functionality, that will be pretty much just cost,” said Taleon.

Improving dietary calcium intake through fortification of maize and rice in Nigeria and Bangladesh

In an effort to extend Taleon’s work, Keith Lividini investigated how much impact fortified maize and rice could make on calcium insufficiency if deployed widely. He began by building a detailed model of current calcium intakes in two countries: Nigeria and Bangladesh.

Using available diet survey data, Lividini and his colleagues constructed food composition tables for both countries, combined those with population data, and calculated calcium consumption per person. People’s calcium needs and food consumption vary by age and sex, though, so Lividini normalized the data to one specific group, a common technique in nutrition research. “We determined absolute intake using the adult male equivalent method, [so] we used the adult male at age 18 to 30 as the reference, but it’s important to note that any reference can be used,” said Lividini. The normalized data allowed him to apply correction factors to account for likely and recommended calcium intakes for different members of a household.

Using those data, Lividini ran computer simulations of calcium intake changes if maize nixtamalization became standard in Nigeria, and two simulations of rice fortification in Bangladesh, one with the fortification strategy Taleon found was best accepted in the market, and one with the approach that yielded the highest calcium levels in the rice.

In Nigeria, people consume widely divergent amounts of maize in different regions and at different times of the year. “Households in north zones consume higher average quantities of maize compared to households in other zones in Nigeria, [and] we see that households in rural areas consume higher average quantities of maize than urban areas, and we see that households in the lowest [income] quintile consume higher average quantities of maize in the harvest period,” said Lividini. Those patterns led to a similar divergence in the impact of maize nixtamalization in the model. Nonetheless, the researchers found that fortified maize could boost calcium intakes substantially in specific situations, especially in northern areas after the planting season.

Regional and demographic differences also affect rice consumption in Bangladesh, and culinary preferences vary as well. “We do see large differences in consumption of different rice types across Bangladesh, which does have implications for industrial fortification … if certain rice types are more amenable to fortification,” said Lividini. However, the model shows that calcium-fortified rice could fill 24-50% of the shortfall in calcium needs in different settings across the country, depending on the type of fortification and local consumption habits.

Having shown the potential benefits of fortification, Lividini advocated scrutinizing the hurdles to implementing it. “The coverage of nixtamalization through industrial processes really needs to be more closely looked at, [and] the coverage of rice fortification through industrial parboiling, meaning which varieties are most amenable to that, needs to be closely examined,” he said. In addition, researchers need to analyze the capital and ongoing costs of such a fundamental change to the food supply.

In both Nigeria and Bangladesh, the models showed that while widespread uptake of fortified staple foods could boost calcium intakes significantly, fortification alone wouldn’t eliminate calcium inadequacy for most of the population. As a result, Lividini advocates combining fortification with other strategies, such as supplements.

Optifood modeling to improve calcium intake

Frances Knight gave the meeting’s final presentation, which addressed three of the major questions asked by the Calcium Task Force. “We really wanted to know if you could meet recommended calcium intakes using local foods … and then using those local food types that were found to be good food sources of calcium, could you develop food-based recommendations to improve calcium intake, and to what extent could they help to improve that intake for the most nutritionally vulnerable groups?” asked Knight.

To answer those questions, Knight and her colleagues modeled food consumption and calcium intakes in Bangladesh, Uganda, and Guatemala, picking two regions in each country to analyze, and including both urban and rural areas. The researchers focused on four target groups for whom calcium is especially critical, ranging from children to adult women, and used the same normalization technique Lividini described, expressing calcium intakes and needs in terms of adult male equivalent units. They then fed all of those parameters into a computer model called Optifood, which uses linear programming to model the range of acceptable diets in a population based on food survey data.

The Optifood models showed that it’s possible for adult women, at least, to get more than 100% of their recommended calcium intakes from foods available in the modeled areas. “However, for the younger target groups … even the diets with the maximum possible content of calcium would still not meet 100% of the nutrient requirement for calcium,” said Knight. Looking at the food subgroups that contributed the most calcium, her team found that dairy, fish, and leafy vegetables stood out. Unfortunately, many populations in Uganda and Guatemala don’t have sufficient access to those foods.

Next, the investigators tested various food recommendations in the Optifood models, based on diets that at least some people likely eat already in each population. Because people will adopt recommendations to varying degrees, the goal was to move the overall distribution of diets so that even those consuming the least calcium would still meet recommended intakes. “We ended up with between three and six food-based recommendations per target group per area” that could meet the requirements for most of the population, said Knight. However, some groups, including adolescent girls and young children, didn’t reach recommended intakes. “This really indicates that we might need some sort of additional change to be able to improve calcium intake for these groups,” said Knight.

Because accessing calcium-rich foods stood out as a major problem in two of the countries, Knight has added a fourth question to her list to investigate: “to what extent could we improve access to new local nutritious foods, or add new calcium-rich foods to food systems, and whether they would help to improve calcium intakes further for those nutritionally-vulnerable target groups,” she said. Knight added that the computer modeling also needs to be confirmed through real-world testing of different recommendations.

Though no single intervention discussed at the meeting is likely to solve global calcium insufficiency, speakers broadly agreed that a combination of practical approaches could improve intakes substantially, with far-reaching impacts on public health.