Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Technical Report Calcium deficiency worldwide: prevalence of inadequate intakes and associated health outcomes Julie Shlisky,1 Rubina Mandlik,2 Sufia Askari,3 Steven Abrams,4 Jose M. Belizan,5 Megan W. Bourassa,1 Gabriela Cormick,5 Amalia Driller-Colangelo,6 Filomena Gomes,1,7 Anuradha Khadilkar,2 Victor Owino,8 John M. Pettifor,9 Ziaul H. Rana,1 Daniel E. Roth,10 and Connie Weaver11 1The New York Academy of Sciences, New York, New York. 2Hirabai Cowasji Jehangir Medical Research Institute, Pune, India. 3Children’s Investment Fund Foundation, London, United Kingdom. 4University of Texas, Austin, Texas. 5Centro de Investigaciones en Epidemiología y Salud Pública (CIESP), Instituto de Efectividad Clínica y Sanitaria (IECS-CONICET), Buenos Aires, Argentina. 6Harvard University, Cambridge, Massachusetts. 7NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal. 8Division of Human Health, International Atomic Energy Agency, Vienna, Austria. 9Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa. 10The Hospital for Sick Children/University of Toronto, Toronto, Ontario, Canada. 11San Diego State University, San Diego, California Address for correspondence: Connie Weaver, San Diego State University, San Diego, CA 92182. cmweaver@sdsu.edu Dietary calciumdeficiency is considered to bewidespread globally, with published estimates suggesting that approx- imately half of the world’s population has inadequate access to dietary calcium. Calcium is essential for bone health, but inadequate intakes have also been linked to other health outcomes, including pregnancy complications, can- cers, and cardiovascular disease. Populations in low- and middle-income countries (LMICs) are at greatest risk of low calcium intakes, although many individuals in high-income countries (HICs) also do not meet recommenda- tions. Paradoxically, many LMICswith lower calcium intakes show lower rates of osteoporotic fracture as compared with HICs, though data are sparse. Calcium intake recommendations vary across agencies and may need to be cus- tomized based on other dietary factors, health-related behaviors, or the risk of calcium-related health outcomes. The lack of standard methods to assess the calcium status of an individual or population has challenged efforts to estimate the prevalence of calcium deficiency and the global burden of related adverse health consequences. This paper aims to consolidate available evidence related to the global prevalence of inadequate calcium intakes and associated health outcomes, with the goal of providing a foundation for developing policies and population-level interventions to safely improve calcium intake and status where necessary. Keywords: calcium; calcium deficiency; osteoporosis; calcium paradox Purpose In March and April 2021, the Nutrition Science Program of the New York Academy of Sciences, in partnership with the Children’s Investment Fund Foundation, convened a Calcium Task Force and hosted two virtual meetings. This task force is composed of experts in micronutrients, mal- nutrition, pediatrics, gynecology and obstetrics, biochemistry, public health, and strategies for supplementation and fortification. During these meetings, the task force assessed evidence on global calcium deficiency and its health consequences, calcium status indicators, calcium supplementation for pregnant women to improve pregnancy out- comes, and associated implementation challenges, as well as food-based interventions to improve the intake of this vital micronutrient, especially in populations with low calcium intake. The group identified research gaps and provided guidance doi: 10.1111/nyas.14758 10 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. https://orcid.org/0000-0002-4660-3013 https://orcid.org/0000-0003-1201-3397 https://orcid.org/0000-0001-7958-7358 https://orcid.org/0000-0003-1702-1433 https://orcid.org/0000-0002-3399-3235 https://orcid.org/0000-0003-4493-0501 https://orcid.org/0000-0003-1155-0334 https://orcid.org/0000-0001-7742-0925 https://orcid.org/0000-0002-5450-9609 http://creativecommons.org/licenses/by-nc/4.0/ Shlisky et al. Inadequate calcium intakes: prevalence and outcomes Table 1. Dietary calcium recommended intakes by life stage and region Region/organization Recommendation Infants Children Adolescent males Adolescent females Men Women Men 50+ Women 50+ Pregnancy Lactation United States/Canada (IOM)5 EAR (mg/day) – 500−800 1100 1100 800 800 800 1000 No change No change Europe (EFSA)6 AR (mg/day) – 390−680 960 960 860−750 860−750 750 750 No change No change United Kingdom (SACN)95 EAR (mg/day) 400 275−425 750 625 525 525 525 525 No change +550 India7 EAR (mg/day) 300 (AI) 400−650 800 800 800 800 800 1000 No change 1000 Southeast Asia96 RDA (mg/day) 300−400 500−700 1000 1000 700 700 1000 1000 1000 1000 Taiwan97 DRI (mg/day) – – – – 1000 1000 1000 1000 1000 1000 Mexico98 mg/day – – 1200 1200 800 800 800 800 1200 1200 South Africa99 mg/day – – 1000 1000 1000 1000 1000 – – – FAO/WHO100 EAR (mg/day) 240−300 440 1040 1040 840 840 840 840 940 1040 AI, adequate intake; AR, average requirement; DRI, dietary reference intake; EAR, estimated average requirement; EFSA, European Food Safety Authority; FAO/WHO, Food and Agriculture Organization/World Health Organization; IOM, Institute of Medicine; RDA, recommended dietary allowance; SACN, Scientific Advisory Committee on Nutrition. for interventions and policies based on available evidence. This paper describes discussions and conclusions on the global prevalence of inadequate calcium intakes and their related health outcomes. Dietary calcium requirements Calcium is an essential mineral with critical func- tions in the skeletal, cardiovascular, endocrine, and neurological systems. Approximately 99% of total body calcium is in bone, where it provides rigidity and structure to the skeletal system and acts as a calcium reservoir. The remaining frac- tion participates in metabolic processes, including vascular and muscle contraction, nervous system transmission, transmembrane transport, enzymatic activation, and hormonal function. The majority of studies of long-term consequences of inadequate calcium intake are related to bone health, especially rickets in children and fractures, osteopenia, and osteoporosis in older adults.1,2 A variety of methods have been used to esti- mate calcium requirements; most recent references for calcium intake were set for healthy individu- als based on evidence for bone health outcomes (Table 1). The Institute of Medicine/National Academy of Medicine (IOM/NAM) dietary refer- ence intake values for calcium in North America (United States and Canada) were published in 2011. Requirements were based on the effect of calcium intake on bone health, as evidence for the effect of calcium intake on cancer, cardiovascular dis- ease, diabetes, and autoimmune disorders was too inconsistent to inform nutritional requirements.3,4 However, future calcium panels may want to con- sider adding dietary reference intakes (i.e., for chronic disease risk reduction) to include some of the emerging data on calcium and these and other disease outcomes. Current requirements are intended to maximize bone accretion during the growth periods of child- hood and adolescence, and promote bone retention later in life, particularly among postmenopausal women.5 Requirements peak in adolescence to sup- port the period of rapid growth and then decrease in adulthood. Guidelines recommend calcium intakes between 700 and 1200 mg/day for individuals >19 years of age, with some authorities recommending an increase during lactation. Recommendations rise again for women following menopause and in populations >70 years of age, as calcium bioavail- ability decreases with age.5 Average requirements established by the European Food Safety Authority (EFSA) in 2015 are generally slightly lower than those recommended by the IOM/NAM, and EFSA emphasized the inconsistency of the available evidence to support causal relationships between calcium intake and health outcomes, including bone health.6 Some low- and middle-income coun- tries (LMICs) have calcium recommendations that are specific to their populations, and several agencies have reference values for calcium that were developed some time ago (Table 1).7 The IOM/NAM established a tolerable upper intake level for calcium as the highest average daily intake likely to pose no risk of adverse effects for nearly all persons in the general population and it was set at a calcium intake of 2500 mg/day for adults 19–50 years of age and 2000 mg/day for adults >50 years of age. More recently, EFSA set an upper limit of 2500 mg/day for all adults, includ- ing during pregnancy and lactation, based on evi- dence from existing randomized controlled trials 11Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. (RCTs) that showed an absence of adverse effects at the specified intake levels. IOM/NAM upper intake levels for children and adolescents range from 1000 mg/day (birth to 6 months) to 3000 mg/day (9–18 years). Conversely, EFSA did not establish a calcium upper limit for infants, children, and adolescents due to insufficient information for these age groups. Adverse effects of calcium supplementation have also been systematically investigated and are cov- ered in greater detail elsewhere in this special issue.8 Factors influencing calcium requirements Dietary factors Several nutrients are known to influence calcium requirements. Plant nutrient and antinutrient fac- tor composition and soil properties (pH, water content, and microbial activity) in which foods are grown, vitamin D intake, and the presence of phytic acid and oxalic acid can all influence calcium available through the diet.9 Phytates and oxalates inhibit calcium absorption as they bind calcium to form unabsorbable salts.9 Dietary sodium intake has been shown to increase urinary calcium loss, thus resulting in increased calcium requirements among individuals with high sodium intakes.2 Previously, high protein intakes were thought to negatively affect calcium balance by increasing uri- nary calcium excretion;10 however, recent studies have shown that diets rich in protein may increase intestinal calcium absorption leading to calcinuria but without affecting calcium balance.11 Dietary cofactors that influence calcium bioavailability will be covered in detail elsewhere in a related paper on food-based interventions in this special issue.12 Vitamin D is essential for intestinal calcium absorption by the active, transcellular pathway and is involved in maintaining normocalcemia and thus bone mineralization; therefore, dietary calcium requirements depend, in part, on vitamin D status.2 In most adult populations, vitamin D deficiency is unlikely to be a rate-limiting constraint on calcium absorption, as only very low concentrations of 25-hydroxyvitamin D (25(OH)D) are associated with impaired calcium absorption.13,14 The effect of vitamin D on calcium absorption in children is not clearly established.15 Calcium retention is higher in children than adults, especially during periods of rapid growth when bone mineral accretion is high. Fractional intestinal calcium absorption is higher in children than adults, possibly due their higher 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. Thus, vitamin D may play a more important role in maintaining calcium homeostasis in children, especially when calcium intakes are low.16 Vitamin D and calcium interact in the regulation of parathyroid hormone (PTH), such that sup- pression of PTH to low (normal) concentrations depends on the adequacy of calcium intake and vitamin D status, indicated by the serum 25(OH)D concentration. Vitamin D–deficient populations may have higher PTH and, therefore, higher bone turnover and calcium requirements. In South Korea, where average calcium intakes are low (∼485 mg/day), the 2009–2010 Korea National Health and Nutrition Examination Survey found that PTH levels were inversely associated with calcium intakes at both lower (<50 nmol/L) and higher (>75 nmol/L) 25(OH)D levels.13 In Iceland, where calcium intakes are higher, a cross-sectional study of 944 healthy participants with a mean calcium intake of >1000 mg/day found that cal- cium intakes of <800 mg/day were significantly associated with higher serum PTH compared with calcium intakes of >1200 mg/day in people with low 25(OH)D (<25 nmol/L). However, in people without vitamin D deficiency, calcium intake was not related to PTH.14 These are representative find- ings in that observational studies generally show an inverse relationship between calcium intake and PTH when calcium intakes are low, particularly in the context of low vitamin D status, but the relationship is attenuated at higher calcium intake levels and/or when vitamin D status is adequate.15 Physical activity Weight-bearing exercises (e.g., walking and run- ning) and resistance exercise support bone health. As IOM/NAM dietary reference values for calcium intake are based on maximizing calcium retention for bone health independent of exercise, the level and type of physical activity of a population may affect bone health and is, therefore, relevant to recommendations for calcium intake.17 In children, a synergistic effect of dietary calcium intake and exercise on bone mass has been reported.17 How- ever, in a study of adolescent gymnasts, calcium supplements had no effect on bone mass, possibly because they were already taking sufficient dietary calcium prior to the supplementation.18 12 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes 0 5 10 15 20 25 30 Sweden South Africa (White) Denmark France China (Hong Kong) USA (White) Canada United Kingdom Germany Portugal Finland Spain Singapore (Indian) South Africa (Indian) Russia Romania South Africa (Coloured) USA (Black) South Africa (African) Morocco Botswana Tunisia Life�me risk (%) of femoral neck fracture in men and women over 50 years of age living in selected countries Co un tr y Men Women Figure 1. Lifetime risk (%) of femoral neck fracture in men and women over 50 years of age living in selected countries. Based on data compiled by Ref. 25. Population-level variations in calcium requirements Some studies have shown racial and ethnic dif- ferences in calcium retention and bone mineral density (BMD). Among American adolescents, Black female adolescents have higher calcium retention, more efficient absorption, and lower urinary calcium excretion than white male and female adolescents, a trend that persists into adulthood.19,20 Some Black African populations may have lower bone mass compared with Black Americans, perhaps owing to lower calcium intakes.21,22 Although we do not know the distri- butions of bone mass or fracture incidence rates across Africa, available studies suggest that there is a relatively low incidence of osteoporotic fractures among Black Africans (Fig. 1).23–25 A lower inci- dence of fracture may be an adaptative response to low calcium intake, ultraviolet sun exposure, or genetic differences in calcium absorption.26,27 Numerous studies have identified single nucleotide polymorphisms associated with 13Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. calcium homeostasis. Differences in polymor- phism expression showed changes in calcium levels or renal excretion of calcium, and, therefore, may be relevant if calcium requirements depend on the genotypes expressed. Understanding the frequency of these different genotypes in various populations and if they can be used to guide dietary calcium recommendations requires further research.28 Additional cross-national studies are necessary to provide convincing evidence of racial or geographic differences in bone health, including fracture risks. Risk factors for inadequate calcium intake Global distribution of calcium intake and prevalence of inadequate intake Due to the lack of a reliable biomarker of calcium intake or status in population surveys, calcium intake data are often used to assess calcium ade- quacy at the population level. Dietary reference guidelines set by several agencies are used to mea- sure the prevalence of inadequate calcium intake in a population comparing the calcium intake with the age-specific estimated average requirement.2,6 However, it may be problematic to assume inad- equacy in one population using dietary reference standards established in another population, where calcium needs may vary due to the aforementioned factors. Where calcium intake data are unavailable, risk of calcium intake inadequacy may be estimated from national food balance sheets.29 Food balance sheets provide the available foods for consumption in a population from which the average amount of calcium available for that population can be derived.30 The risk of inadequate calcium intake is then estimated considering calcium available and age-specific requirements for that population. This information usually underestimates the risk of inadequate intake as it does not consider house- hold waste or inter and intrahousehold variation in food intake.29 Moreover, calcium availability is estimated per capita without considering inequities in food access or distribution. Despite these limi- tations, available data suggest substantial variabil- ity in calcium intake worldwide.29,31 A major rea- son low calcium intakes are widespread globally is the low availability of or preference for dairy prod- ucts in many regions of the world, particularly in LMICs, as well as the limited number of countries in which commercial food products are calcium fortified.31 For example, wheat flour, breakfast cere- als, and fruit juices are fortified with calcium in some high income countries (HICs), but less fre- quently in LMICs.32 More information on calcium- fortified foods can be found in a related paper on food-based interventions in this special issue.12 Low- and middle-income countries. Of the 3.5 billion people at risk of inadequate calcium intake, approximately 90% live in Africa and Asia.29 Many countries in South and East Asia, including India, have average dietary calcium intakes that are far lower than those in Western nations, and some are <500 mg/day,31 although recommendations are similar (Table 1).7 For example, calcium intake in Malaysian adolescents has been reported as low as 377 mg/day, a third of the IOM/NAM recom- mended daily intake for this age group.33 Though most countries in Africa do not have calcium intake data available, those with data have average dietary calcium intakes of between 400 and 700 mg/day.31 A systematic review of global calcium intake dur- ing pregnancy showed that calcium intakes <800 mg/day were reported in 5 (29%) HICs and in 14 (82%) LMICs studied.34 Mean calcium intake was 622 mg/day in Latin America (10 studies), 653 mg/day forAsia Pacific (32 studies), and 566mg/day in African countries (5 studies). This systematic review highlighted that many LMICs do not have estimates of calcium intake during pregnancy.34 High-income countries. Although overall aver- age calcium intake is greater in HICs compared with LMICs,1 numerous subgroups in HICs are at high risk of insufficient calcium intake, including adolescents, postmenopausal women, women with amenorrhea, women involved in high-performance athletics, individuals with lactose intolerance or cow’s milk allergy, and people who maintain a vegan diet.2 In the United States, at-risk age groups include boys and girls 9–13 years of age, girls 14–18 years of age, women 51–70 years of age, and both men andwomen≥70 years of age.2 Still, those living in the United States havemean total calcium intakes from food and supplements ranging from 918 to 1296 mg/day,2 and Northern European countries have national calcium intakes >1000 mg/day.31 Outcomes of inadequate calcium intake Since the most recent systematic review of calcium- related health outcomes, published in 2009, was 14 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes basedmainly on bone health,35 new evidence on the effect of adequate calcium intake on other health outcomes has been published.1 One of the most well-documented benefits of calcium supplementa- tion beyond bone health is a significant reduction in the risk of preeclampsia and maternal morbidity in pregnant women and preterm birth. This topic is, therefore, discussed in detail elsewhere in this special issue.8 In nonpregnant adults, calcium supplementa- tion may have a small effect in reducing blood pressure, especially in young adults,36,37 but the broader public health impact on the prevalence of hypertension is unclear. Calcium supplementation has also been associated with favorable changes in cholesterol metabolism, including a reduc- tion in low-density lipoprotein and increase in high-density lipoprotein.38 Although less studied, unabsorbed calcium in the intestinal lumen may bind and impair absorption of oxalates, thereby reducing the risk of renal stones, and bind to triglyc- erides and bile acids, whichmay reduce low-density lipoprotein cholesterol concentrations.39 The same mechanisms have been postulated to reduce the risk of recurrent colorectal adenomas by reducing bile-induced mucosal damage.40 These studies are described in greater detail in Table 2. Bone outcomes Bone increases in size and mass during periods of growth, with peak bonemass achieved by around 30 years of age. Osteopenia (low bonemass) and osteo- porosis characterized by porous, fragile bones is a public health problem in most parts of the world. When calcium intake is low or when calcium is poorly absorbed, bone resorption occurs since the stored calcium in bone is used to maintain normal biological functions. Bone loss is part of the nor- mal aging process, particularly in postmenopausal women with reduced circulating estrogen. Other factors that increase the risk of developing osteo- porosis include inactivity, smoking, drinking exces- sive alcohol, and a family history of osteoporosis.41 The calcium paradox Despite lower calcium intakes in most LMICs, osteoporotic fracture rates are also lower in some LMICs, from which data are available for compar- ison to North America and Europe (Fig. 1). This has been described as the calcium paradox.42 In the following sections, we review data from three general regions to explore the relationship between calcium intakes and bone outcomes. These data are summarized in Table 3 and at the end of this section. There are limitations in assuming an ecological association between average calcium intake and prevalence of osteoporosis or fracture. There are limited high-quality, relevant datasets, including both dietary calcium intake and bone health param- eters. Moreover, data related to osteoporosis are more likely to be available in well-resourced health systems located in HICs, which also typically have higher proportions of older adults. Regional sources of calciummay differ, and dietary calcium estimates do not take bioavailability and other dietary factors into account, whichmay influence calciumbioavail- ability or metabolism. Similarly, other factors, such as physical activity and genetics, may modify rela- tionships between calcium intake and osteoporosis. Lastly, it is important to consider associations that may be real at the individual level but might not be apparent—or even be reversed—at the group level. Regional considerations. High-income countries. Osteoporosis is a public health issue for greater than 10 million U.S. adults, of whom 80% are women. An estimated 1.5 million fractures occur yearly due to osteoporosis,43 with most occurring in the hip, vertebrae, wrist, pelvis, and ribs.44 The Centers for Disease Control and Prevention reports that 4.2% of men and 18.8% of women ≥50 years of age have osteoporosis of the femoral neck or lumbar spine, as defined by BMDmeasurements.45 Supplementationwith calcium and vitaminDhas been effective in reducing fractures and falls in insti- tutionalized women >50 years of age.46 However, among community-dwelling older adults>50 years of age, the benefits of calcium supplementation for reducing fracture rates are less clear. A systematic review of 26 RCTs published in 2015 found that calcium supplements (most studies used a dose of ≥1000 mg/day) modestly, though significantly, reduced the risk of total and vertebral fractures, but not hip or forearm fractures.47 When the analysis was limited to the four trials with the lowest risk of bias, involving 44,505 individuals, it showed no effect of calcium supplementation on risk of frac- ture at any site. Another meta-analysis assessing the effect of calcium intake on BMD (with 51 studies and 12,257 individuals) found supplementation produced only a small increase (0.7–1.8%) in BMD, 15Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. Table 2. Effect of calcium intake on health outcomes Health outcomes Outcome Population group Research evidence Effect size Hypertensive disorders of pregnancy Preeclampsia Pregnant women Meta-analysis Calcium supplementation compared to placebo reduced the risk of preeclampsia, RR = 0.45 (95% CI: 0.31–0.65)101 Pregnant women with low basal calcium intake Meta-analysis Calcium supplementation compared to placebo reduced the risk of preeclampsia, RR = 0.36 (95% CI: 0.20–0.65)101 High blood pressure Pregnant women Meta-analysis Calcium supplementation compared to placebo reduced the high blood pressure RR to 0.65 (95% CI: 0.530.81)101 Blood pressure Blood pressure Normotensive adults Meta-analysis Calcium supplementation reduced SBP in adults by 1.14 mmHg (95% CI: −2.01 to −0.27) with doses of calcium 1000–1500 mg/day and by 2.79 mmHg (95% CI: −4.71 to −0.86) with doses of calcium equal to or over 1500 mg/day. Calcium supplementation had the greatest effect in young adults of less than 35 years as their SBP was reduced by 2.11 mmHg (95% CI: −3.58 to −0.64)102 Blood pressure Hypertensive adults Calcium supplementation reduced SBP by −1.86 mmHg (95% CI: −2.91 to −0.81) and DBP by −0.99 mmHg (95% CI: −1.61 to −0.37)37 Blood pressure Hypertensive adults with low basal calcium intake In people with relatively low calcium intake (≤800 mg/day) calcium supplementation reduced SBP by −2.63 (95% CI: −4.03 to −1.24) and DBP by −1.30 (95% CI: −2.13 to −0.47)37 Blood pressure Hypertensive adults Calcium supplementation as compared to control induced a statistically significant reduction in SBP (mean difference: −2.5 mmHg, 95% CI: −4.5 to −0.6, I(2)= 42%) but not DBP (mean difference: −0.8 mmHg, 95% CI: −2.1 to 0.4, I(2) = 48%)103 Progeny blood pressure High blood pressure Pregnant women/children RCT Calcium supplementation showed that children whose mothers received calcium supplementation had, at 7 years of age, a reduction in the risk of high blood pressure (above the 90th percentile) in comparison with children whose mothers were in the placebo group (RR = 0.59; 95% CI: 0.39–0.90)36 Cholesterol LDL and HDL cholesterol Adults Meta-analysis Calcium supplementation reduced low-density lipoprotein (LDL) cholesterol (−0.12 mmol/L (95% CI: −0.22 to −0.02)) and increased high-density lipoprotein (HDL) cholesterol (0.05 mmol/L (95% CI: 0.00–0.10))104 Colorectal adenomas Recurrent colorectal adenomas Adults with previous adenomas Meta-analysis Calcium supplementation with doses from 1200 to 2000 mg/day and treatment duration from 36 to 60 months reduced the risk of recurrent colorectal adenomas, RR = 0.89 (95%CI: 0.82−0.96)105 Bone health Bone mineral density Children Meta-analysis Calcium supplementation had a small effect on total body bone mineral content (standardized mean difference = 0.14, 95% CI: 0.01–0.27) and upper limb bone mineral density (0.14, 95% CI: 0.04–0.24), and this effect persisted after the end of supplementation only in the upper limb (0.14, 95% CI: 0.01–0.28)106 Renal stones Urolithiasis Individuals with osteoporosis Meta-analysis Calcium supplementation compared to placebo, RR = 0.66 [95% CI 0.19, 2.34]; five studies in postmenopausal or elderly women, including 2038 subjects107 Urolithiasis Pregnant women Meta-analysis Calcium supplementation during pregnancy did not increase the risk of urolithiasis, RR = 1.52 [95% CI: 0.06, 40.67] or renal colic, RR = 1.75 [95% CI; 0.51, 5.99] in two studies with 12,901 women108 Note: Evidence from randomized controlled trials (RCTs) and systematic reviews of RCTs. Table taken from Ref. 1, with permission of the authors. CI, confidence interval; DBP, diastolic blood pressure; RR, relative risk; SBP, systolic blood pressure. with little additional effect after a year, which is unlikely to produce a clinically significant reduc- tion in fracture risk. According to the authors of this systematic review, increases in BMD by 1–2% due to increased calcium intake would be predicted to produce a relatively small reduction of 5–10% in fracture risk.48 In 2013, the U.S. Preventive Services Task Force concluded that therewas insufficient evi- dence to assess the balance of benefits and harms of combined vitamin D and calcium supplementation to prevent bone fractures in premenopausal women and men.49 16 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes Table 3. Data summary of SouthAsian andAfrican regions exploring the relationship between calcium intakes and bone outcomes Bone health data Calcium intake data Region and population type Study year Number of partici- pants Age (years) Sex Method of bone assessment Bone health outcome (%) Ca intake data available, or other source used for Ca intake data. (Ref. #) Method of calcium intake assessment Population (#, age, sex, and population type) Calcium intake (mg/day) India, Mumbai; urban109 2002− 2003 200 >40 Females DXA, PF, and spine OP - 0.34 OS - 0.08 Ref. 31 24-h diet recall 306,329; ≥18 years; male and female 429 India, Hyderabad; urban, slum-dwelling63 nd 289 30−60 Females Hologic DXA, LS, hip, and total body OP - 0.52 OS - 0.29 Available 24-h diet recall and FFQ n/a 270 ± 54 India, Jammu; urban110 2004− 2005 158 25−65 Females Calcaneal QUS OP - 0.37 OS - 0.20 India, Delhi, low SES (55), high SES (250); and rural Haryana (125)111 nd 430 60−80 Females Hologic DXA, hip, and LS OP - 0.29 OS - 0.62 India, Vellore; urban65 nd 150 ≥50 PostM females Hologic DXA, LS, and PF OP: LS - 0.35, PF - 0.57; OS: LS - 0.48, PF - 0.17 Available Oral semiquan- titative FFQ n/a 398.8 ± 190.13 India, Kerala; rural112 2005− 2007 609 >18 Males (71) Females (538) QUS and distal radius OP: M - 0.37, F - 0.44; OS: M - 0.28, F - 0.44 India, Pune; urban113 2008 105 40−72 Females DXA lunar and LS OP - 0.31 OS - 0.14 India, Pune; urban64 2008 172 40−75 Females PreM: 80 PostM: 92 Lunar DXA, LS, and dual femurs OP, PreM: LS-0.44, PF-0.46, TH-0.27 OP, PostM: LS-0.48, PF-0.62, TH-0.45 OS, PreM: LS-0.08, OS, PostM: LS-0.26, PF-0.09, TH-0.02 Available 24-h diet recall n/a PreM: 416 + 154 PostM: 434 + 160 India, Chandigarh; urban114 nd 200 >45 Females Lunar DXA and LS OP/OS: 0.53 Available 24-h diet recall n/a 516.8 ± 208.9 India, Delhi; urban115 nd 1600 >50 Males (792) Females (808) Lunar DXA, LS, femur, and forearm OP: M-0.54, F-0.45 OS: M-0.25, F-0.43 India, Pune; urban low SES (54), high SES (58)116 2008 112 39−70 Females Lunar DXA, LS, and total femur OP, Low-SES: LS-0.33, femur-0.11 OP, high-SES: LS-0.12, femur-0.0 Available 3-day diet recall with 2 weekdays and a Sunday n/a Low SES: 231.4 ± 120.9 High SES: 342.2 ± 128.3 India; urban117 2010 158 >35 Females Calcaneal QUS OP - 0.48 OS - 0.13 India, Varanasi; urban118 2010− 2011 200 50−84 Males Lunar DXA and right PF OP: FN-0.42, PF-0.37, Hip-0.41 OS: FN-0.09, PF-0.08 India, Vellore; urban119 nd 250 51−74 Males Hologic DXA, LS, and PF OP - 0.58 OS - 0.20 Delhi; urban58 nd 760 >50 Males (345) Females (415) Lateral X-rays of the LS and thoracic spine, Genant’s semiquantitative method for fracture assessment Vertebral fracture: M: 0.19 F: 0.17 Bangladesh, Dhaka; urban66 2010− 2011 500 16−65 Females DXA, LS, and PF OP: LS - 0.41, FN - 0.21; OS: LS - 0.03, FN - 0.04 Ref. 120 National household diet survey 31,066; <5 to >80 years; male and female; urban and rural 529 Nepal, Kathmandu; urban67 2017− 2018 169 >50 Males (38) Females (131) Lunar Prodigy DXA, LS, and femur OP: M-0.45, F-0.37 OS: M-0.24, F-0.41 Assessed 24-h diet recall n/a 520.4 ± 297.0 India, Bharatpur, Pokhara, and Bhairahawa; urban68 2018 465 >20 Males (201) Females (264) Calcaneal QUS OP: M-0.59, F-0.62 OS: M-0.24, F-0.22 Continued 17Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. Table 3. (Continued) Bone health data Calcium intake data Region and population type Study year Number of partici- pants Age (years) Sex Method of bone assessment Bone health outcome (%) Ca intake data available, or other source used for Ca intake data. (Ref. #) Method of calcium intake assessment Population (#, age, sex, and population type) Calcium intake (mg/day) Pakistan, Quetta; urban121 2007 334 >20 Females Calcaneal QUS OS: 0.43, OP:0.13 Ref. 122 24-h diet recall and FFQ 144; ≥18 years; female; urban 462 ± 176 Pakistan, Karachi; urban123 2004 925 >35 Females Heel ultrasound OS: 0.32, OP:0.07 Pakistan, Karachi; urban124 2009 170 18−80 Females Calcaneal QUS OS: 0.52, OP:0.11 Pakistan, Nahaqi; rural125 nd 107 40−65 PostM females Broadband ultrasound attenuation of the calcaneus OS: 0.43, OP:0.27 Available 24-h diet recall n/a 360.9 ± 74.2 Pakistan, Karachi; urban126 2013 203 40−60 PostM Females Hologic DXA, LS, hip, and femur OS: 0.49, OP:0.29 Sri Lanka, Gampaha district, near Colombo; urban72 2007 700 35−64 Males (279) Females (421) AccuDexa scanner peripheral DXA, middle phalanx of the middle finger of the nondominant hand OS: M-0.06, F-0.20 Sri Lanka, seven different provinces; urban (1150), rural (492)74 2004− 2005 1642 56.5 ± 6.8 PostM females AccuDEXA scanner BMD and BMC of the middle phalanx of the middle finger of the nondominant hand OS: 0.45 Sri Lanka, seven different provinces; urban and rural73 2004− 2005 1147 50−84 Males AccuDEXA scanner, middle phalanx of the middle finger of the nondominant hand OS: 0.06 Sri Lanka, Galle75 2017− 2018 355 20−70 Females Hologic DXA, LS, and femur OS: PostM - 0.37 using manufacturer’s Asian reference data; 0.17 using local reference data South Africa, Baragwanath, Hillbrow, and Johannesburg; urban21 nd 367 20−64 Female Hologic QDR 1000 DXA, spine, and femur. Single-photon absorptiometry using a Norland densitometer, radial bone at distal third radius on nondominant side Spinal bone density: Black- 0.94, White- 0.97; femoral bone density Black-0.74, White-0.90 Ref. 127 24-h diet recall 3231; ≥15 years; male and female 479 Botswana, two private hospitals in the capital city; three tertiary-level public hospitals in southern, central, and northern parts of the country; three private insurance companies25 2009− 2011 435 ≥40 Males (196) Females (239) Used retrospective patient chart, including radiology reports, digital radiology files, surgical ward notes, postoperative theater notes, and discharge summaries. FRAX used to calculate fracture probabilities Hip fracture: M-0.03, F-0.03 Ref. 128 24-h diet recall and FFQ 79; 18−75 years; male and female 588 Uganda, Kampala and Zimbabwe, Harare, Chitungwiza; urban76 2009− 2012 518 18−45 PreM women DXA, TH, and LS OP: LS-0.35, TH-0.10 Ref. 129 24-h diet recall and FFQ 173; male and female; local 238 Continued 18 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes Table 3. (Continued) Bone health data Calcium intake data Region and population type Study year Number of partici- pants Age (years) Sex Method of bone assessment Bone health outcome (%) Ca intake data available, or other source used for Ca intake data. (Ref. #) Method of calcium intake assessment Population (#, age, sex, and population type) Calcium intake (mg/day) South Africa, Bantu; urban81 1960 117 ≥30 Male and female Radiographic examination of the pelvis with a portable unit Hip fracture: 0.03; osteoarthrtis of the hip: 0.13 Nigeria, Ibadan and UK, Southampton and Newcastle; urban82 1988− 1989 746,700 ≥50 Male (385,200) Female (361,500) All fractures were radiologically confirmed Hip fracture: Nigeria-0.003, UK-0.131 Ref. 130 FFQ 13,142; all ages; male and female 636 South Africa, Durban; urban and rural83 1966− 1967 300 50−90 Female Lateral X-ray films of LS OS: 0.06 South Africa, Cape Town; urban84 nd 189 ≥40 Female DXA, LS, and PF; postero-anterior standing radiographs of the thoracic and LS were assessed Vertebral fracture: White-0.05, Black-0.09 hip fracture: White-0.01 South Africa, Durban; urban85 2010− 2013 197 ≥60 Male and female DXA, hip, and spine OP: hip-0.45, spine-0.38 OS: hip-0.16, spine-0.21 vertebral fracture: M-0.13, F-0.24 Available Calcium intake diary n/a 474.1 (reported) Congo,Kinshasa; urban86 2011− 2016 430 47–87 PostM black women Computerized tomography scanners Vertebral fracture - 0.69 Gambia, Keneba, Kanton Kunda, and Manduar; rural79 nd 195 >44 Female Dual-photon absorptiometer bone mineral status at LS and PF LS-0.29, midshaft of the radius-0.35, PF-0.30, distal radius-0.60 BMD, bone mineral density; DXA, dual X-ray absorptiometry; FFQ, food frequency questionnaire; LS, lumbar spine; OP, osteopenia; OS, osteoporosis; PF, proximal femur; PostM, postmenopausal; PreM, premenopausal; QUS, qualitative ultrasound; SES, socioeco- nomic status; TH, total hip; UK, United Kingdom. South Asia. Among the important factors contributing to low calcium intakes are a lack in availability of calcium-rich foods, traditional dietary habits, food insecurity, and gender discrimination.50,51 There is considerable dis- parity among Southeast Asians with regard to dairy consumption, but principally dairy consumption is low due to traditional dietary practices. While East Asians do not consume much dairy due to tra- ditional dietary customs,51 South Asians consume some dairy products like curd, buttermilk, and clarified butter, but the practice of milk drinking is uncommon among South Asians, with milk con- sumption limited to that added to tea or coffee.52,53 Many Indians consume very little dairy and follow a vegetarian diet, which often includes cereals and vegetables with significant phytate and oxalate levels, known to inhibit calcium absorption. Food insecurity and poor purchasing power also limit milk and milk product consumption by most of the population in LMICs.52 This is compounded by gender discrimination in many communities, resulting in girls and women being at a disadvan- tage for being allocated milk and milk products for consumption in their households.50,54 While osteoporosis is an important public health concern globally, the overwhelming burden of malnutrition and infectious diseases overshadows its importance in South Asian countries. Data on osteoporosis prevalence come from studies con- ducted in small groups across the region as there are no national data from any South Asian country (Table 3). In 2013, approximately 50 million Indians were estimated to have osteopenia or osteoporosis.55 Prevalence of osteoporosis among Indian women >25 years of age was reported as 8–62%.56 Studies among Indian men ≥50 years of age report osteo- porosis prevalence rates of 8.5–25%.57 Vertebral fractures are commonly reported among Indians, 19Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. with a prevalence of at least one reported among 15–20% of urban adults ≥50 years of age.55 For example, the Delhi Vertebral Osteoporosis Study reported a prevalence of 17.9% of vertebral frac- tures in older adults.58 These rates are similar to those reported among whites worldwide, though osteoporotic fracture rates among Indian men were highest.58 Crude incidence of hip fractures among Indians from Rohtak, North India was reported as 105 and 159/100,000 in men and women, respec- tively, >50 years of age, with an increasing trend in rates noted with increasing age in both sexes.59 Population prevalence of low trauma hip, spine, and wrist fractures in a questionnaire-based study was reported as 34.3/100,000.55 Multiple reports show that while hip fracture rates have stabilized or decreased inHICs, they have been steadily increasing in LMICs.60 Projections on incidence of hip fractures in India indicated that by 2050, there would be a 2.39-fold increase in the total number of hip fractures compared with 2018.60 However, increased rates may be attributed to increased life expectancy among Asians. Com- pared with other Asian populations, Indian women (≥45 years) residing in Singapore have higher hip BMD thanChinese women.61 Zengin et al. reported that South Asian and white men residing in the UK have lower areal BMD compared with Black men. While there are no differences in areal BMD between white and South Asian men, South Asian men had thinner radial and tibial cortices than white men; despite this, no differences were noted in bone strength between these two groups.62 Few studies have reported determinants of low BMD or osteoporosis among Indians. Of slum- dwelling women 30–60 years of age from Hyder- abad, India, 29% had osteoporosis and calcium intake was significantly and positively associated with hip BMD.63 A positive correlation of calcium intake with BMD at lumbar spine, femoral neck, and total hip, and a positive, yet weak, association of serum vitamin D with BMD at all three sites was reported in urban Indian women >40 years of age living in Pune, India.64 Paul et al. reported a positive correlation between vitamin D and femoral neck BMD, but failed to find a correlation between dietary calcium intake and BMD, which they attributed to overall inadequate calcium con- sumption among their sample of 150 ambulatory postmenopausal South Indian women ≥50 years of age.65 Begum et al. reported among urban and sub- urban Bangladeshi women 16–45 years of age attending a tertiary care public hospital that preva- lence of osteopenia was 43.6% and osteoporosis was 5.5%. Among women 46–65 years of age attending the same hospital, 40.7% had osteopenia and 41.8% had osteoporosis.66 Limited reports from Nepal indicate considerable prevalence of osteopenia and osteoporosis among the population. In a hospital-based study in Kathmandu, 23.7% of men and 41.2% of women had osteoporosis as assessed by dual-X-ray absorptiometry (DXA) scans; daily calcium intake was inversely associ- ated with osteoporosis67 In a cross-sectional study among residents of three major metropolitan cities of Nepal, the prevalence of osteopenia and osteo- porosis, assessed by calcaneal ultrasound in 465 participants ≥20 years of age, was reported to be 60.6% and 22.4%, respectively.68 In Pakistan, data on the prevalence of osteoporo- sis are available from hospital-based studies using heel ultrasound; DXA data are scarce. Limited data suggest a prevalence of osteoporosis ranging from 5.6% to 17.8% in women who are premenopausal and 20–49.3% in those who are postmenopausal, mostly from urban areas.69 Furthermore, in a ret- rospective study on patients with low impact hip fractures admitted to a tertiary care center in Pak- istan, health providers rarely evaluated patients for osteoporosis despite typical presentations.70 Data are also lacking on osteoporosis prevalence in Sri Lanka. While the Galle Prospective Osteoporosis survey reported that 61.5% of women >50 years of age were found to be osteoporotic based on DXA assessments,71 a study using a peripheral DXA found that 27% of women and 7% of men >50 years of age had osteoporosis.72 Another study in men ≥50 years of age living in Sri Lanka reported that 5.8% had osteoporosis based on phalangeal BMD.73 In postmenopausal Sri Lankan women, one report indicates that osteoporosis is likely to be prevalent among 45% of the participants via phalangeal BMD,74 while more recently, a study of trabecular bone score of the lumbar spine via DXA found osteoporosis in approximately 33% using the Asian reference data provided by the manufacturer, and approximately 20% using local reference data.75 20 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes Africa. Few studies have addressed the preva- lence of osteoporosis in Africa, particularly among populations in the sub-Saharan region (Table 3). Though osteoporosis and fragility fractures are widely considered to be uncommon among Black African communities despite low calcium intakes, extensive data to support this hypothesis are lack- ing. In South Africa, BMD at the lumbar spine in pre and postmenopausal Black women was simi- lar or lower to that in South African whites after adjusting for differences in anthropometry, while femoral neck BMD was greater in Black women than in their white counterparts.21 Similar findings were reported fromZimbabwe, where Black women have lower lumbar spine BMD than U.S. Blacks and whites, but similar or higher femoral neck BMD to U.S. whites.76 The latter study suggests that much of the difference could be explained by differences in weight and body mass index.77 A recent study from Kampala, Uganda, in East Africa, comparing the BMD of premenopausal Blackwomenwith theNHANES reference database, found that mean lumbar spine BMD was 1.2 SD below the mean for U.S. Black women and 0.8 SD below that of U.S. white women, while at the femoral neck, the BMD was 0.4 SD below that of U.S. Black women but 0.1 SD above that of U.S. white women.78 In West Africa, a study of pre and postmenopausal Gambian women revealed that after correcting for age, weight, and height, bone mineral content at the lumbar spine was on average 24% lower than that of white women in the UK. The reduction in bone mineral content increased to 42% in those >64 years of age.79 Somali women who had immigrated to Swe- den from Africa were found to have lumbar spine BMD almost 1 SD below that of U.S. white women, although the hip BMD was similar. Com- pared with U.S. Black women, both lumbar spine and hip BMDs were between 0.9 and 1.6 SD below Black reference means, respectively. A small study in the United States found that immigrant Somali women had lower lumbar spine BMD (4%) than white women, but higher femoral neck BMD (11%).80 The incidence of femoral neck and vertebral frac- tures in Africa has also been infrequently studied. In 1968, Solomon calculated the femoral neck frac- ture rates for African Blacks in Johannesburg at 4.5 and 4.2/100,000 formen andwomen, respectively.81 The rate for women in Malmö, Sweden at that time was more than 10-fold higher at 46.9/100,000. A more recent study confirmed lower incidence of hip fractures in South African Black men and women compared with their white, Indian, and mixed-race compatriots (Fig. 2).24 In Nigeria, hip and forearm fracture incidences in adults >50 years of age were studied in Ibadan. As in other sub-Saharan African countries, calculated incidence varied between 1.5 and 8/100,000, substantially lower than rates found in Southampton and Newcastle in the UK.82 A study from Botswana confirmed the low risk of hip fracture in Black Africans living there (Fig. 1).25 Countries with the lowest risk of hip fracture for local adults include Tunisia, Botswana, Morocco, South Africa (Black Africans), Ukraine, and the United States (African Americans). Less information is available about the inci- dence of osteoporotic vertebral fractures in African countries, but like hip fractures, they are thought to be uncommon. In 1968, Dent reported the low prevalence of lumbar vertebral fractures in radiographs of African patients >50 years of age compared with similarly aged white patients from the same Durban, South Africa, hospital.83 More recently, however, a small study of thoraco-lumbar radiographs in a convenience sample of 189 women (47% Black) >40 years of age found similar preva- lence of radiographic vertebral fractures in Black and white women living in Western Cape, South Africa.84 Both studies suffer from small numbers and lack of random sampling. In a study of 197 study volunteers >60 years of age living in Durban, South Africa, 20.8% had morphometric vertebral fractures on thoraco-lumbar radiographs. There was no statistical difference in fracture prevalence between Black and Indian subjects in that study.85 In a cohort of 430 postmenopausal women living in Kinshasa, Democratic Republic of Congo, who complained of back pain, vertebral fractures were diagnosed in 11% of the thoraco-lumbar vertebrae; the prevalence of fractures rose with age.86 In the Gambia, a cross-sectional study of 488 healthy men and women >40 years of age from Kiang West were found to have a prevalence of 9% moderate or severe vertebral fractures on DXA.62 Regional considerations summary. Evidence is mixed in North America and other HICs that calcium supplementation is beneficial for the pre- vention of bone fractures in premenopausal women 21Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. Figure 2. Ten-year probability of hip fracture in South African men and women by ethnic group. Reproduced from Ref. 24. and men. In postmenopausal women, the benefits of supplementation on fracture rate are also still unclear. Reports from South Asian countries suggest a significant prevalence of osteopenia and osteo- porosis, with women being investigated more com- monly than men. However, data are primarily from hospital-based studies or small community studies and are unlikely to be representative of the broad population. Moreover, assessment methods for BMDdiffer, with few reports usingDXA; as fracture data are inadequately captured, current incidence ratesmay be an under-representation of the prevail- ing incidence. Still, reports from South Asian coun- tries indicate poor calcium intake, with low con- sumption of dairy. Together, these data suggest that the prevalence of osteoporosis among South Asians is similar to those of North Americans and Euro- peans despite lower calcium intakes. Further studies investigating community prevalence of low BMDor osteoporosis, using standard assessment methods, and fractures among South Asian populations are required. In African populations, there is increasing evidence that BMD in Black women living in sub-Saharan Africa is lower than that of Black American women, but hip BMD Z-scores are consistently higher than lumbar spine Z-scores. Lumbar spine BMD in African Black women is well below that of U.S. Blacks and more approximate to that of U.S. or UK whites (except for Gambian women who had lower bone mineral content than UK white women), while femoral neck BMD is above that of U.S. whites but below that of U.S. Black women.22 Notably, hip fracture rates among Black Africans are among the lowest in the world, but information on vertebral fractures, although limited, suggests that the difference in rates between Black Africans and whites is less marked. Further studies are needed from more African countries to confirm these findings and more information is needed on men in these populations. Consistently lower dietary calcium intakes in Black Africans than the recommended allowances in the face of low femoral neck fracture rates suggest that other factors, such as physical activity and genotype, may play important roles in maintaining bone health. Rickets Nutritional rickets is the most frequent cause of pediatric bone disease in theworld and ismost com- mon in LMICs, especially in India, Africa, and the Middle East.87 Calcium intake along with vitamin D status influence the risk of developing nutritional rickets (Fig. 3). Risk of rickets appears to be highest for children with both low vitamin D levels and cal- cium intake,15 but a severe deficiency of either nutri- ent can also lead to rickets. Evidence suggests that as calcium intakes decrease, there is a greater neces- sity for a child to meet vitamin D requirements to maintain normal calcium homeostasis. This inter- action between calcium and vitamin D is central to both vitamin D–deficiency rickets and calcium– deficiency rickets.88 Young children with vitamin D–deficiency rickets are most likely to be those born prematurely or with very low birth weight 22 Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Shlisky et al. Inadequate calcium intakes: prevalence and outcomes 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 O dd s of N ut rit io na l R ic ke ts 20 30 40 50 60 Serum 25-Hydroxyvitamin D [nmol/L] Dietary Calcium 130 mg/d Dietary Calcium 200 mg/d Dietary Calcium 300 mg/d Figure 3. Synergistic effects of dietary calcium intake and serum 25-hydroxyvitamin D concentrations on the odds of having rickets in young Nigerian children. Reproduced from Ref. 15. and those who were exclusively breastfed infants or toddlers with low endogenous vitamin D produc- tion due to dark skin pigmentation or insufficient sunlight exposure. As infants are generally weaned onto the same foods consumed by the whole family, dietary calcium deficiency becomes a greater con- tributor to the pathogenesis of nutritional rickets.87 Beyond early infancy, calcium-deficiency rickets mainly afflicts children and teenagers with normal or slightly low vitamin D levels and extremely low calcium intakes (<300 mg/day). Extended breast- feeding without sufficient vitamin D and com- plementary food sources of calcium, as well as extremely restrictive diets, including vegan diets, also increase the risk of nutritional rickets.87 Research efforts are ongoing to elucidate poten- tial links between dietary factors for rickets and other risk factors, including genetic and environ- mental influences.89 A study of Nigerian children revealed a nearly 15% incidence of family history of rickets among a cohort of rachitic children, compared with 3% in the control group.90 Similarly, mothers who had previously had a child with rick- ets had lower calcium concentration in breastmilk than control mothers.91 Whether these findings are the result of a genetic difference in calcium homeostasis in mothers of rachitic children or some other predisposing factor remains to be seen. Additionally, preterm birth prevents optimal newborn calcium accrual in utero because calcium and phosphorus accrual peak during the third trimester. As a result, preterm babies, especially those born at <28 weeks gestation and weighing <1500 g, have the highest incidence of rickets worldwide. Rickets in this population is distinct etiologically from the disease in toddlers and young children, the former being the result of both dietary phosphorus and calcium deficiency needed for rapid bone mineralization rather than isolated calcium and/or vitamin D deficiency. Babies who are small for gestational age, approximately a third of babies born in LMICs, are also at elevated risk for rickets, as in utero growth failure is associated with a decreased transfer of boneminerals to the fetus.92,93 Challenges and limitations There is no global consensus on the definitions of low calcium intake or calcium deficiency. At a population level, the prevalence of low calcium intake can be estimated by comparing calcium intake or calcium availability in a population with age-specific dietary requirements provided by dif- ferent agencies. Information is needed on calcium intake from dairy and nondairy sources, namely, in LMICs where data are limited or of poor quality. Evidence from HICs suggests that intakes below 800 mg/day in adults are suboptimal, although most populations in LMICs have intakes closer to 400–500 mg/day without strong evidence that these levels cause adverse bone outcomes. Since much of the information on the effects of calcium on bone health comes from observational studies, more evidence from RCTs is necessary. As calcium effects on bone health are more likely to be evident in the long term, it would be desirable to start these trials in a variety of age groups. Prox- ies of bone health, such as BMD and bone status biomarkers, could be measured. Likewise, it would be desirable that existing RCTs of calcium intake follow up the randomized individuals for evaluation of long-term outcomes, such as fracture rates. Options for assessing calcium status are lim- ited by the absence of a well-validated, specific biomarker of calcium status that is field-friendly, and therefore, feasible at population level and priced for use in LMICs. Several emerging methodologies may hold promise in this area, but more research is needed. Research gaps and priorities Questions remain not just regarding the true global prevalence of inadequate calcium intakes, but 23Ann. N.Y. Acad. Sci. 1512 (2022) 10–28 © 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences. Inadequate calcium intakes: prevalence and outcomes Shlisky et al. also on what should be considered related health outcomes when making dietary goals and recom- mendations. More complete and consistent data for global calcium intake or status, specifically in LMICs where these data are especially lacking, are necessary to review a benefit to these populations. Evidence on the effects of calcium on bone health in understudied regions thought to be inadequate in calcium intake must be obtained from RCTs. This could begin within the populations outlined above when describing the calcium paradox. Research to determine a potential mechanism of low fracture rates and adequate BMD in the face of low calcium intakes within these populations is also needed. Ultimately, better clarity on these questions would inform and support development of policies and population-level interventions to safely improve calcium intake and status where necessary. Finally, the absence of a standard calcium status indicator has long hampered efforts to define the population burden of inadequate calcium intake and its associated health effects. Concentrations of total and ionized calcium in circulation are tightly regulated and do not accurately reflect calcium intake or physiological status.26,94 Meanwhile, as calcium is just one determinant of bone health and is associated with many other aspects of health beyond bone, no single biomarker or health out- come offers a perfect indicator of calcium status. The quest for both sensitive and specific markers of calcium status, which are also field-friendly, remains. Acknowledgments Development of this paper, its open access, and the assembly of andmeetings of the CalciumTask Force were supported by funding from The Children’s Investment Fund Foundation to the Nutrition Science Program of the New York Academy of Sciences. Competing interests The authors declare no competing interests. References 1. Cormick, G. & J.M. Belizán. 2019. Calcium intake and health. Nutrients 11: E1606. 2. Office of Dietary Supplements - Calcium. 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