Low Dietary Ca Intake Research Articles

Male Lrp5A214V mice maintain high bone mass during dietary calcium restriction by altering the vitamin D endocrine system.

Environmental factors and genetic variation individually impact bone. However, it is not clear how these factors interact to influence peak bone mass accrual. Here we tested whether genetically programmed high bone formation driven by missense mutations in the Lrp5 gene (Lrp5A214V) altered the sensitivity of mice to an environment of inadequate dietary calcium (Ca) intake. Weanling male Lrp5A214V mice and wildtype littermates (control) were fed AIN-93G diets with 0.125%, 0.25%, 0.5% (reference, basal), or 1% Ca from weaning until 12 weeks of age (ie, during bone growth). Urinary Ca, serum Ca, Ca regulatory hormones (PTH, 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)), bone parameters (μCT, ash), and renal/intestinal gene expression were analyzed. As expected, low dietary Ca intake negatively impacted bones and Lrp5A214V mice had higher bone mass and ash content. Although bones of Lrp5A214V mice have more matrix to mineralize, their bones were not more susceptible to low dietary Ca intake. In control mice, low dietary Ca intake exerted expected effects on serum Ca (decreased), PTH (increased), and 1,25(OH)2D3 (increased) as well as their downstream actions (ie, reducing urinary Ca, increasing markers of intestinal Ca absorption). In contrast, Lrp5A214V mice had elevated serum Ca with a normal PTH response but a blunted 1,25(OH)2D3 response to low dietary Ca that was reflected in the renal 1,25(OH)2D3 producing/degrading enzymes, Cyp27b1 and Cyp24a1. Despite elevated serum Ca in Lrp5A214V mice, urinary Ca was not elevated. Despite an abnormal serum 1,25(OH)2D3 response to low dietary Ca, intestinal markers of Ca absorption (Trpv6, S100g mRNA) were elevated in Lrp5A214V mice and responded to low Ca intake. Collectively, our data indicate that the Lrp5A214V mutation induces changes in Ca homeostasis that permit mice to retain more Ca and support their high bone mass phenotype.

Dietary Calcium Intake and Osteoporosis Risk in Arab Adults.

Osteoporosis is a major public health concern in Saudi Arabia's aging population. There is particularly limited information on how diet affects bone loss in this ethnic group. The purpose of this study was to examine the association between dietary calcium (Ca) intake and osteoporosis risk in Saudi adults. A total of 1950 patients (416 males and 1534 females) with known risk factors for osteoporosis participated in this cross-sectional study. A short questionnaire (CaQ) was used to assess dietary Ca intakes in patients attending tertiary hospitals in Riyadh City. The prevalence of osteoporosis was 21.3% and was more common in females (93.5%). Patients with osteoporosis were older (p < 0.001) and had lower BMI (p < 0.001). Results showed that the overall mean Ca intake was only 445.1 mg/day (recommended dietary intake of 1300 mg/day). Tea intake (OR = 0.8 95%CI: 0.7-1.0; p = 0.02) and consumption of fish and eggs (OR = 0.9 95%CI: 0.8-1.0; p = 0.01) were significantly associated with a lower risk of osteoporosis. Furthermore, consumption of biscuits, cake and bread slices were significantly associated with higher incidence of osteoporosis (OR = 1.3 95%CI: 1.0-1.5; p = 0.02). In conclusion, extremely low dietary Ca intake was observed among Saudi adults already at risk of osteoporosis. A balanced diet including high amount of Ca, vitamin D and omega-3 fatty acids accompanied by limiting consumption of foods high in saturated fats and glycemic index may be helpful in reducing osteoporosis risk in the Saudi adult population.

Role of Calcium Supplementation on Pregnancy Induced Hypertension Outcomes

Background: Pregnancy induced hypertension (PIH), is an important cause of both maternal and perinatalmorbidity and mortality. Low dietary calcium (Ca) intake represents a factor associated with an increasedincidence of hypertensive disease in general and in pregnant population in most low and middle income countries.Ca supplementation has the potential to reduce adverse gestational outcomes of PIH.Aim: To assess the effects of low-dose Ca supplementation on PIH outcomes.Method: A single- blind, randomized controlled trial was conducted in January through March, 2021. A totalnumber of 66 pregnant women with PIH at their 20th week of gestation attended maternal care outpatient inBaghdad Medical City were assigned randomly in two groups those received Ca supplementation 500 mg/day vsnone and follow up both groups till delivery for outcomes.Results: A significant reduction in diastolic blood pressure mean (93.28 mmHg vs. 88.62 mmHg, P= 0.015) andalmost significant reduction in systolic blood pressure mean (149.65 mmHg vs. 142.58 mmHg, P= 0.051) in theparticipants after receiving Ca supplements. Pre eclampcia (10.3% vs. 45.9%, P = 0.002), Low birth weight (6.9%vs. 40.5%, P = 0.002), Pre term delivery (10.3% vs. 43.2%, P=0.003), and admissions to neonatal intensive care unit(10.3% vs. 45.9%, P = 0.002) were significantly lower in the intervention group.Conclusion: Ca supplementation of 500 mg daily started at 20th week of gestation associated with reduction ofmaternal blood pressure, pre-eclampcia, preterm delivery, low birth weight and admission to neonatal intensivecare unit especially in a low dietary Ca intake mothers.

Association of Dietary Calcium Intake with Dental, Skeletal and Non-Skeletal Fluorosis among Women in the Ethiopian Rift Valley.

Fluorosis is a major public health problem in the Rift Valley of Ethiopia. Low calcium (Ca) intake may worsen fluorosis symptoms. We assessed the occurrence of fluorosis symptoms among women living in high-fluoride (F) communities in South Ethiopia and their associations with dietary Ca intake. Women (n = 270) from two villages provided clinical and questionnaire data. Dental fluorosis examination was done using Dean’s Index, and skeletal and non-skeletal fluorosis assessment was carried out using physical tests and clinical symptoms. Daily Ca intake was estimated by a food frequency questionnaire. Food, drinking water and beverage samples were analyzed for F level. Many subjects (56.3%) exhibited dental fluorosis. One-third of the women were unable to perform the physical exercises indicative of skeletal fluorosis; about half had ≥2 symptoms of skeletal/non-skeletal fluorosis. The average F level in drinking water sources was ~5 mg/L. The F content in staple food samples varied from 0.8–13.6 mg/kg. Average Ca intake was 406 ± 97 mg/day. Women having ≤400 mg/day Ca intake had ~3 times greater odds of developing skeletal rigidity with joint pains [AOR = 2.8, 95%CI: 1.6, 5.0] and muscular weakness [AOR = 2.9, 95%CI: 1.3, 6.3] compared to those with higher intakes. No association of calcium intake was seen with dental fluorosis. As low dietary Ca intake was associated with symptoms related to skeletal and non-skeletal fluorosis, this warrants nutritional intervention on calcium intakes in this setting.

Intestinal responses to 1,25 dihydroxyvitamin D are not improved by higher intestinal VDR levels resulting from intestine-specific transgenic expression of VDR in mice

Intestinal calcium (Ca) absorption depends upon vitamin D signaling through the vitamin D receptor (VDR) in the proximal and distal intestine while lower VDR content causes intestinal resistance to 1,25 dihydroxyvitamin D (1,25(OH)2 D) action. We tested whether intestinal responsiveness to 1,25(OH)2 D is increased in mice with higher than normal VDR levels resulting from transgenic VDR expression in the whole intestine (villin promoter-human VDR transgene, HV2). Wild type (WT) and HV2 mice were treated with 0, 0.15, or 0.3 ng 1,25(OH)2 D/g body weight (BW) (n = 6/dose) for 6 h. 1,25(OH)2 D significantly induced Cyp24a1, Trpv6, and S100 g mRNA in duodenum (Dd) of WT mice but induction was not higher in HV2 mice. We next tested whether higher intestinal VDR could protect mice from the consequences of low dietary Ca intake. WT and HV2 mice were fed diets with 0.125, 0.25, 0.5 (reference), or 1% Ca from weaning to 3 months of age (n = 9/diet/genotype). Dietary Ca restriction caused a dose dependent increase in serum 1,25(OH)2 D, Dd TRPV6, and Dd S100 g mRNA in WT mice and the effect was greater in HV2 mice. While Ca absorption was increased by low Ca intake, there was no difference in Ca absorption between HV2 and WT mice. Similarly, while bone density and microstructure were reduced by low Ca intake in WT mice, high intestinal VDR in HV2 mice did not protect bone in mice fed low Ca diets. Thus, while intestinal VDR and vitamin D signaling are essential for normal Ca metabolism during growth, our data demonstrate that higher than normal intestinal VDR levels do not improve the intestinal response to either 1,25(OH)2 D injection or to elevated 1,25(OH)2 D levels resulting from the physiologic adaptation to low Ca diets.

Calcium Supplementation for Preeclampsia Prevention: Estimated Risk of Excessive Intake in Ethiopian Women

The WHO recommends supplementation with 1.5–2.0 g/d elemental calcium (Ca) for pregnant women in settings with low dietary Ca intake, to help prevent preeclampsia. There is insufficient guidance on implementing this recommendation and avoiding risk of excessive Ca intake at the population level. We investigated usual dietary Ca intake of Ethiopian women of childbearing age and simulated the impact of different supplementation doses. In a nationally‐representative sample (n= 7834), 24‐hr dietary recall data was analyzed to estimate usual dietary Ca intake and the proportions of women below the estimated average requirement (EAR ) or above the upper tolerable limit (UL) at different supplementation dosages. An EAR of 1.1 and 0.8 g/d and UL of 3.0 and 2.5 g/d was used for women 15‐18 and 19‐45 y, respectively. Mean Ca intake was 506.4 mg/d ± 263.6; 96.6% of women 15‐18y and 88.4% overall had inadequate intake. In simulations, supplementing with 1.0, 1.5, and 2.0 g/d would allow &gt;99% of women to meet the EAR. The 1.5 and 2.0 g/d supplemental doses would result in intakes above the UL in 4.9% and 38.4% of all women, respectively. At 1.5g/d, only 0.6% of women aged 15‐18y would exceed the UL. At the 1.0g/d dose of Ca, the overall prevalence of excessive intake would be below the target of 2.5% (0.74%). Thus, with high adherence, a lower dose of 1.0 g/d would allow &gt;99 % of Ethiopian women meet the EAR and could be safer than the recommended 1.5‐2.0 g/d. Similar investigation of potential risks of Ca supplementation using 1.5‐2.0 g/d is warranted in countries considering this intervention. Funded by The Micronutrient Initiative.

Bioavailability of enteric‐coated microencapsulated calcium during pregnancy: a randomized crossover trial in Bangladesh (804.4)

Prenatal calcium (Ca) and iron (Fe) supplements are recommended in settings of low dietary Ca intake and high prevalence of anemia. However, concurrent Ca and Fe administration may inhibit Fe absorption. Therefore, we developed a multi‐micronutrient powder containing Fe (60 mg), folic acid (400 µg), and Ca (0.5, 1.0 or 1.5 g) in which calcium carbonate granules were microencapsulated with a pH‐sensitive enteric coating to delay intestinal release and limit Ca‐Fe interactions. To compare the fractional intestinal absorption (fAb) of Ca from enteric‐coated (EC) Ca granules versus uncoated (non‐EC) granules, we conducted a randomized crossover trial among pregnant women (n=49) in Dhaka. fAb was estimated by a dual stable isotope method (44Ca‐labeled granules and intravenous 42Ca), based on the relative recovery of 44Ca vs 42Ca in urine over 48 hours. Mean (±SD) fAb from EC Ca was significantly less than from non‐EC Ca (2.7±2.2 % vs. 16.5±10.0 %; p&lt;0.0001) at all 3 Ca doses. In conclusion, the pH‐sensitive enteric coating substantially reduced Ca absorption. Therefore, in its current formulation this novel enteric‐coated Ca‐Fe supplement is not suitable for clinical use.Grant Funding Source: Supported by Saving Lives at Birth

Estrogen deficiency-induced Ca balance impairment is associated with decrease in expression of epithelial Ca transport proteins in aged female rats

AimsThe study is designed to determine whether estrogen and vitamin D endocrine systems interact to regulate calcium (Ca) balance as well as changes in mRNA expression of epithelial Ca transport proteins involved in intestinal and renal Ca transport in aging animals in response to ovariectomy and low dietary Ca intake. Main methodsEleven-month-old female sham or ovariectomized (OVX) rats were divided into four groups and fed with either a low-Ca (LCD; 0.1% Ca, 0.65% P) or a high-Ca (HCD; 1.2% Ca, 0.65% P) diet for 12weeks. Ca balance and mRNA expression of Ca transport proteins in the intestine and kidney from rats were systematically studied. Key findingsOVX rats fed with LCD resulted in a negative Ca balance. LCD suppressed serum Ca in OVX but not sham rats, resulting in an induction of serum PTH and 1,25(OH)2D3 levels. The surge in serum 1,25(OH)2D3 levels in LCD-fed OVX rats was associated with an increase in mRNA expression of intestinal transient receptor potential cation channel (TRPV6) and calbindin D9k (CaBP9k) as well as renal vitamin D receptor (VDR), but such an induction was unable to restore Ca balance in vivo. In contrast, the negative Ca balance was associated with suppression of intestinal plasma membrane Ca pump (PMCA1b) and renal transient receptor potential cation channel (TRPV5), calbindin D28k (CaBP28k) and PMCA1b mRNA expression in aged OVX rats. SignificanceNegative Ca balance in aged female OVX rats is associated with estrogen-dependent and vitamin D-independent downregulation of epithelial Ca transport protein mRNA expression.

High renal calcium (Ca) excretion does not reduce femur bone density in mice fed adequate or low dietary Ca

Active vitamin D, 1,25(OH)2D3 (1,25D) regulates intestinal Ca absorption (Ca Abs) under low dietary Ca intake by inducing gene expression through the vitamin D receptor (VDR). Vitamin D‐regulated Ca Abs is greatest in the proximal small intestine but VDR is highest in the large intestine. We generated transgenic (TG) mice using a CDX2P9.5 promoter‐Cre transgene to drive deletion of floxed VDR alleles from the lower bowel to test whether this disrupts whole body Ca metabolism. Weanling, male TG and control mice were fed diets with low (0.25%) or normal (0.5%) Ca levels until 10 wks of age. Transgene expression was seen in the distal ileum, cecum, and colon as well as the kidney, a 1,25D target tissue. Serum 1,25D was not different between genotypes and serum Ca was normal in all groups. TG mice had low serum PTH (p&lt;0.001) which explains the 10‐fold higher urinary Ca/creatinine ratio (p&lt;0.001) we observed. However, no genotype effects were found in femur cancellous or cortical bone density. These data show that while Ca metabolism is disturbed in TG mice, high renal Ca excretion does not negatively affect bone density or adaption to restricted Ca intake.Grant Funding Source: NIH award DK54111 (JCF)

Genetic control of serum 1,25 dihydroxyvitamin D (1,25D) level under normal and low dietary calcium (Ca) conditions

Low dietary Ca intake increases renal conversion of 25 hydroxyvitamin D (25D) to 1,25D. This adaptation protects bone under periods of dietary Ca stress. We conducted two studies to characterize the genetic controls on serum 25D and 1,25D levels in mice. Male mice from 11 inbred lines (Study 1) and 51 BXD recombinant inbred lines (Study 2) were placed on diets containing 200 IU vitamin D and either normal (0.5%) or low (0.25%) Ca from 4–12 wks of age. Study 1 revealed significant variation in serum 25D, serum 1,25D, and adaptation of serum 1,25D to low dietary Ca intake among the 11 lines. In Study 2, narrow sense heritability (h2) of 25D and 1,25D on the 0.5% Ca diet was 0.40 and 0.66, respectively. Quantitative trait loci (QTL) were located using composite interval mapping (CIM) and a Bayesian method. Five loci were in common between metabolites. Twelve QTL affecting 25D were identified and included the candidate genes VDR, Cdh3, and FGF23 located near the QTL on chr 6, 8, and 15. Nineteen QTL accounting for 52% of the genetic variance in 1,25D were identified, including 3 diet interaction loci. Previously identified candidate genes are near 5 loci, including the VDR gene. Our results show serum vitamin D metabolite levels are controlled by multiple genetic factors that, in some cases, interact with the dietary environment.Supported by NIH awards ES019103 to JCF and USDA NIFA award 2012–67011‐19963 to RAR

Calcium economy in human pregnancy and lactation

Pregnancy and lactation are times of additional demand for Ca. Ca is transferred across the placenta for fetal skeletal mineralisation, and supplied to the mammary gland for secretion into breast milk. In theory, these additional maternal requirements could be met through mobilisation of Ca from the skeleton, increased intestinal Ca absorption efficiency, enhanced renal Ca retention or greater dietary Ca intake. The extent to which any or all of these apply, the underpinning biological mechanisms and the possible consequences for maternal and infant bone health in the short and long term are the focus of the present review. The complexities in the methodological aspects of interpreting the literature in this area are highlighted and the inter-individual variation in the response to pregnancy and lactation is reviewed. In summary, human pregnancy and lactation are associated with changes in Ca and bone metabolism that support the transfer of Ca between mother and child. The changes generally appear to be independent of maternal Ca supply in populations where Ca intakes are close to current recommendations. Evidence suggests that the processes are physiological in humans and that they provide sufficient Ca for fetal growth and breast-milk production, without relying on an increase in dietary Ca intake or compromising long-term maternal bone health. Further research is needed to determine the limitations of the maternal response to the Ca demands of pregnancy and lactation, especially among mothers with marginal and low dietary Ca intake, and to define vitamin D adequacy for reproductive women.

Association of renal failure with poor response to PTH treatment in osteoporosis

Association of renal failure with poor response to PTH treatment in osteoporosis

The effects of a 30-month dietary intervention on bone mineral density: The Postmenopausal Health Study

Low dietary Ca intake and vitamin D insufficiency have been implicated as part of the aetiology leading to osteoporosis. The aim of the present study was to examine the effects of a 30-month dietary intervention that combined supplementation of dairy products fortified with Ca and vitamin D3 and lifestyle and nutrition counselling sessions on bone mineral density (BMD) of postmenopausal women. Sixty-six postmenopausal women (aged 55-65 years) were randomised into a dietary group (DG; n 35), receiving daily and for the first 12 months 1200 mg Ca and 7.5 microg vitamin D3, while for the next 18 months of intervention 1200 mg Ca and 22.5 microg vitamin D3 through fortified dairy products, and a control group (CG; n 31) receiving neither counselling nor dairy products. The DG was found to have more favourable changes in arms (P < 0.001), total spine (P = 0.001) and total body BMD (P < 0.001) compared with the CG. Furthermore, a significant increase was observed for the DG in lumbar spine BMD (0.056; 95 % CI 0.009, 0.103), which was not found to differentiate significantly compared with the change observed in the CG (P = 0.075). In conclusion, the present study showed that intakes of vitamin D of about 22.5 microg/d and of Ca close to the recommended level of 1200 mg from fortified dairy foods for 30 months, with compliance ensured by lifestyle and nutrition counselling sessions, can induce favourable changes in arms, total spine and total body BMD of postmenopausal women.

Effect of low dietary calcium intake on blood pressure and pressure natriuresis response in rats: a possible role of the renin-angiotensin system.

Dietary Ca is an important modulator of blood pressure in humans and rats. Since the kidney plays a key role in the pathogenesis of hypertension, the effects of a low Ca diet (0.01% Ca) on blood pressure and pressure natriuresis response were studied in normotensive Sprague-Dawley rats. In addition, a possible role of the renin-angiotensin system in the development of hypertension and an altered pressure natriuresis response resulting from low dietary Ca intake was examined. In the low Ca diet group, systolic blood pressure measured by the tail-cuff method was significantly higher than in the normal Ca diet group (1,1% Ca) 1 week after the diet (1 13.0 +/- 7.1 vs. 105.0 +/- 9.5mmHg, p < 0.05). After 4 weeks, the hypertension was more pronounced. Low dietary Ca intake significantly inhibited the water and sodium excretory responses to acute elevation of renal perfusion pressure by tightening an infrarenal aortic constriction. Treatment with an inhibitor of angiotensin-converting enzyme, captopril (30 mg/kg/day), completely abolished the elevation of blood pressure and attenuated the reduced pressure natriuresis response observed in Ca-deficient rats. Although plasma renin activity was not different between the low and normal Ca diet groups after the 2-week dietary regimen, the pressor response to angiotensin II was enhanced by 30% in the low Ca diet group and there was a significant difference in the pressor response between the two groups. These results suggest a possible involvement of the renin-angiotensin system in the development of hypertension and an inhibitory effect on the pressure natriuresis response caused by low dietary Ca intake, via an enhanced sensitivity to angiotensin II.

Effects of ovariectomy on duodenal calcium transport in the rat: altered ability to adapt to low-calcium diet.

Studies were undertaken to determine whether ovariectomy (ovx) would alter the ability of female rats to adapt to low dietary Ca intake by exhibiting an in duodenal active Ca transport. Intact and ovx female rats were fed diets containing 1.5, 0.50, or 0.02% Ca prior to measuring active Ca transport using everted duodenal sacs in vitro. In some experiments, ovx animals were pair-fed to intact animals of the same age consuming the same diet. When ovx animals were allowed to eat ad lib, we found that both growth rate and duodenal active Ca transport increased relative to age-matched, intact controls. However, when growth of ovx animals was maintained at the control rate by pair-feeding, ovx per se did not affect intestinal active Ca transport. Ovx did not alter circulating levels of 1,25-dihydroxyvitamin D (1,25(OH)2D). We found that intact females responded to the low-Ca (0.02%) diet with increased circulating 1,25(OH)2D levels and increased intestinal active Ca transport. Ovx animals exhibited the same increase in circulating concentrations of 1,25(OH)2D in response to low-Ca diet, but did not demonstrate increased duodenal active Ca transport. When ovx animals consumed the diet ad lib, they became larger and exhibited higher Ca transport rates than intact animals fed the high-Ca diet, but there was no difference in Ca transport between ovx animals fed diets containing different Ca contents. The results of these experiments demonstrate that in female rats, the ability to adapt to altered dietary Ca intake is dependent on intact ovarian function and is not necessarily directly related to circulating concentrations of 1,25(OH)2D.