Sex-specific associations between cardiovascular risk factors and physical function: the Gambian Bone and Muscle Ageing Study.

BACKGROUND: In Sub-Saharan Africa, the prevalence of obesity, cardiovascular disease (CVD) and impaired physical function are increasing due to rapid urbanization. We investigated sex differences in associations between cardiac workload, arterial stiffness, peripheral vascular calcification (PVC) and physical function in Gambian adults. METHODS: A total of 488 Gambians aged 40-75+ years were recruited (men: 239; and women: 249). Supine blood pressure and heart rate were measured to calculate rate pressure product and pulse pressure. Presence of PVC was determined from tibia peripheral quantitative computed tomography scans. Physical function was assessed by chair rise test (CRT), single two-legged jump (s2LJ) and hand grip strength (HGS). Body composition was measured by dual-energy x-ray absorptiometry; body size corrections were used to calculate fat mass index (FMI) and appendicular lean mass index (ALMI). Estimated glomerular filtration rate (eGFR) was measured from fasting blood samples. The relationship between rate pressure product, pulse pressure or presence of PVC (independent variable) with physical function parameters (dependent variable) was tested using linear regression. Sex-interactions were tested (p-int) adjusting for age, eGFR and ALMI/FMI. Results were expressed as mean differences between men and women with 95% confidence intervals. Mediation analyses used ALMI/FMI as mediator. RESULTS: Women weighed less (54.7 kg ± 10.3 vs. 59.9 kg ± 10.3) and were shorter (157.8 cm ± 6.0 vs. 169.2 cm ± 7.0) compared with men (both P < 0.0001). Women had higher FMI (6.8 kg/m2  ± 2.9 vs. 2.9 kg/m2  ± 2.0, P < 0.0001) and eGFR (263.7 mL/min/1.73 m2  ± 133.1 vs. 237.6 mL/min/1.73 m2  ± 134.6), but lower ALMI (6.2 kg/m2  ± 0.7 vs. 8.02 kg/m2  ± 1.0, P < 0.0001) compared with men. There were significant mean differences between men and women in rate pressure product and s2LJ power (-1.08 [-1.21, -0.95]) and force (-0.57 [-0.63, -0.51]), only after adjusting for age, eGFR and FMI. There were significant mean differences in the associations between pulse pressure and CRT power (-0.28 [-0.31, -0.25]), s2LJ power (-1.07 [-1.20, -0.93]) and HGS (-11.94 [-13.35, -10.54]); these differences were greater after adjusting for age, eGFR and FMI, than ALMI. There were similar differences in the associations between PVC and physical function parameters. In men, FMI mediated the association between rate pressuree product and CRT power (P = 0.002), s2LJ force (P < 0.001) and s2LJ power (P = 0.001). ALMI did not mediate associations for either men or women. CONCLUSIONS: Multiple risk factors for CVD were associated with poorer physical function in men and were mediated by FMI. There is a need to identify strategies to slow/prevent the rising CVD burden and poor physical function in Sub-Saharan Africa.

A randomized trial to investigate the effects of pre-natal and infant nutritional supplementation on infant immune development in rural Gambia: the ENID trial: Early Nutrition and Immune Development.

BACKGROUND: Recent observational research indicates that immune development may be programmed by nutritional exposures early in life. Such findings require replication from trials specifically designed to assess the impact of nutritional intervention during pregnancy on infant immune development. The current trial seeks to establish: (a) which combination of protein-energy (PE) and multiple-micronutrient (MMN) supplements would be most effective; and (b) the most critical periods for intervention in pregnancy and infancy, for optimal immune development in infancy. METHODS/DESIGN: The ENID Trial is a 2 x 2 x 2 factorial randomized, partially blind trial to assess whether nutritional supplementation to pregnant women (from < 20 weeks gestation to term) and their infants (from 6 to 12 months of age) can enhance infant immune development. Eligible pregnant women from the West Kiang region of The Gambia (pregnancy dated by ultrasound examination) are randomized on entry to 4 intervention groups (Iron-folate (FeFol = standard care), multiple micronutrients (MMN), protein-energy (PE), PE + MMN). Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination, including ultrasound. At delivery, cord blood and placental samples are collected, with detailed infant anthropometry collected within 72 hours. Infants are visited weekly thereafter for a morbidity questionnaire. From 6 to 12 months of age, infants are further randomized to a lipid-based nutritional supplement, with or without additional MMN. The primary outcome measures of this study are thymic development during infancy, and antibody response to vaccination. Measures of cellular markers of immunity will be made in a selected sub-cohort. Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age. DISCUSSION: The proposed trial is designed to test whether nutritional repletion can enhance early immune development and, if so, to help determine the most efficacious form of nutritional support. Where there is evidence of benefit from a specific intervention/combination of interventions, future research should focus on refining the supplements to achieve the optimal, most cost-effective balance of interventions for improved health outcomes.

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.

Sex-Specific Associations Between Cardiac Workload, Peripheral Vascular Calcification, and Bone Mineral Density: The Gambian Bone and Muscle Aging Study.

Noncommunicable diseases (NCD) are rapidly rising in Africa, with multimorbidity increasing the burden on health and social care. Osteoporosis and cardiovascular disease (CVD) share common risk factors; both often remain undiagnosed until a major life-threatening event occurs. We investigated the associations between cardiac workload, peripheral vascular calcification (PVC), and bone parameters in Gambian adults. The Gambian Bone and Muscle Aging Study (GamBAS) recruited 249 women and 239 men aged 40 to 75+ years. Body composition and areal bone mineral density (aBMD) were measured using dual-energy X-ray absorptiometry; peripheral quantitative computed tomography (pQCT) scans were performed at the radius and tibia. Supine blood pressure and heart rate were measured and used to calculate rate pressure product and pulse pressure. Presence of PVC was determined from tibia pQCT scans. Sex interactions were tested (denoted as p-int); adjustments were made for residuals of appendicular lean mass (ALM) and fat mass (FM). There were negative associations between rate pressure product and aBMD in women only, all p-int < .05; after adjustment for ALM residuals, for every 10% increase in rate pressure product, aBMD was lower at the whole body (-0.6% [-1.2, -0.1]), femoral neck (-0.9% [-1.8, -0.05]), L1 to L4 (-0.6% [-1.7, 0.5]), and radius (-1.9% [-2.8, -0.9]); there were similar associations when adjusted for FM residuals. Similar negative associations were found between pulse pressure and aBMD in women only. PVC were found in 26.6% men and 22.5% women; women but not men with calcification had poorer cardiac health and negative associations with aBMD (all sites p-int < .001). There were consistent associations with cardiac parameters and pQCT outcomes at the radius and tibia in women only. Multiple markers of cardiac health are associated with poorer bone health in Gambian women. In the context of epidemiological transition and changing NCD burden, there is a need to identify preventative strategies to slow/prevent the rising burden in CVD and osteoporosis in Sub-Saharan Africa. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Pregnancy-Related Change in pQCT and Bone Biochemistry in a Population With a Habitually Low Calcium Intake.

In pregnancy, changes in maternal calcium (Ca) economy occur to satisfy fetal Ca demand. It is unclear whether maternal mineral reserves facilitate these requirements and no data exist from sub-Saharan Africa. The aim was to determine skeletal changes with peripheral quantitative computed tomography (pQCT) and bone biochemistry between early second and third trimesters. Pregnant rural Gambians aged 18 to 45 years (n = 467) participating in a trial of antenatal nutritional supplements (ISRCTN49285450) had pQCT scans and blood collections at mean (SD) 14 (3) and 31 (1) weeks' gestation. Outcomes were pQCT: radius/tibia 4% total volumetric bone mineral density (vBMD), trabecular vBMD, total cross-sectional area (CSA), 33%/38% radius/tibia cortical vBMD, bone mineral content (BMC), total CSA; biochemistry: collagen type 1 cross-linked ß-C-telopeptide (ß-CTX), type 1 procollagen N-terminal (P1NP), parathyroid hormone (PTH), and 1,25(OH)2 D. Independent t tests tested whether pooled or within-group changes differed from 0. Multiple regression was performed adjusting for age. Data for change are expressed as mean (confidence interval [CI] 2.5, 97.5%). Radius trabecular vBMD, cortical vBMD, and BMC increased by 1.15 (0.55, 1.75)%, 0.41 (0.24, 0.58)%, and 0.47 (0.25, 0.69)%. Tibia total and trabecular vBMD increased by 0.34 (0.15, 0.54)% and 0.46 (0.17, 0.74)%, while tibia cortical vBMD, BMC, and cortical CSA increased by 0.35 (0.26, 0.44)%, 0.55 (0.41, 0.68)% and 0.20 (0.09, 0.31)%, respectively. CTX, PTH, and 1,25(OH)2 D increased by 23.0 (15.09, 29.29)%, 13.2 (8.44, 19.34)%, and 21.0 (17.67, 24.29)%, while P1NP decreased by 32.4 (-37.19, -28.17)%. No evidence of mobilization was observed in the peripheral skeleton. Resorption, although higher in late versus early gestation, was lower throughout pregnancy compared with non-pregnant non-lactating (NPNL) in the same community. Formation was lower in late pregnancy than in early, and below NPNL levels. This suggests a shift in the ratio of resorption to formation. Despite some evidence of change in bone metabolism, in this population, with habitually low Ca intakes, the peripheral skeleton was not mobilized as a Ca source for the fetus. © 2021 crown copyright . Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). The article published with the permission of the Controller of HMSO and the Queen's Printer of Scotland..

Evidence for a downward secular trend in age of menarche in a rural Gambian population.

Menarcheal age is a key indicator of female maturity and development. Studies in many countries have reported a downward secular trend in age of menarche over the past century. This study presents data gained using the 'status quo' method and interval regression to estimate median menarcheal age of girls in a rural Gambian community. Cross-sectional studies carried out in 1989, 2000 and 2008 revealed a median menarcheal age of 16.06 (95% CI 15.67-16.45), 15.03 (95% CI 14.76-15.30) and 14.90 (95% CI 14.52-15.28), respectively. The average rate of decline of median age of menarche was amongst the most rapid yet reported, at 0.65 years of age per decade (p < 0.00001). There was no evidence for a change in the rate of decline over the two decades studied. These results probably reflect ongoing socio-economic development within the region.

Vitamin D Deficiency and Its Health Consequences in Africa.

Africa is heterogeneous in latitude, geography, climate, food availability, religious and cultural practices, and skin pigmentation. It is expected, therefore, that prevalence of vitamin D deficiency varies widely, in line with influences on skin exposure to UVB sunshine. Furthermore, low calcium intakes and heavy burden of infectious disease common in many countries may increase vitamin D utilization and turnover. Studies of plasma 25OHD concentration indicate a spectrum from clinical deficiency to values at the high end of the physiological range; however, data are limited. Representative studies of status in different countries, using comparable analytical techniques, and of relationships between vitamin D status and risk of infectious and chronic diseases relevant to the African context are needed. Public health measures to secure vitamin D adequacy cannot encompass the whole continent and need to be developed locally.

The prevalence of sarcopenia and relationships between muscle and bone in ageing West-African Gambian men and women.

BACKGROUND: The rapidly rising ageing population in low and middle-income countries (LMIC) will lead to a concurrent increase in musculoskeletal diseases. Sarcopenia is a disease caused by progressive loss of skeletal muscle mass and strength, leading to adverse outcomes including frailty, falls, fractures, and premature mortality. We investigated the prevalence of sarcopenia, assessed the suitability of current diagnostic guidelines and explored muscle-bone relationships in ageing men and women from rural Gambia. METHODS: A total of 249 women and 239 men aged 40-75+ years were recruited. Body composition was measured using dual energy X-ray absorptiometry. Comparisons of the Foundations for the National Institutes of Health (FNIH) and European Working Group On Sarcopenia (EWGSOP) definitions of sarcopenia to define prevalence and to identify poor physical capability were determined. Functional ability was assessed by jumping mechanography to calculate lower limb muscle force and power; grip strength was assessed by a hand dynamometer. Peripheral quantitative computed tomography was used to assess muscle-bone relationships. RESULTS: The prevalence of sarcopenia in Gambian men and women significantly varied depending on the definition used; in men 20% and 19% and in women 45% and 10% for FNIH and EWGSOP, respectively. The FNIH appendicular lean mass cut-off had greatest sensitivity and specificity in identifying low functional ability in Gambian adults. Muscle force was positively associated with measures of tibial bone size, strength, and mineral content. CONCLUSIONS: The variation in the prevalence of sarcopenia depends on the definition used and highlights the importance of measuring functional capability across ethnic populations.

Corrigendum: The Gambian Bone and Muscle Ageing Study: Baseline Data From a Prospective Observational African Sub-Saharan Study.

[This corrects the article on p. 219 in vol. 8, PMID: 28912754.].

The Gambian Bone and Muscle Ageing Study: Baseline Data from a Prospective Observational African Sub-Saharan Study.

The Gambian Bone and Muscle Ageing Study is a prospective observational study investigating bone and muscle ageing in men and women from a poor, subsistence farming community of The Gambia, West Africa. Musculoskeletal diseases, including osteoporosis and sarcopenia, form a major part of the current global non-communicable disease burden. By 2050, the vast majority of the world's ageing population will live in low- and middle-income countries with an estimated two-fold rise in osteoporotic fracture. The study design was to characterise change in bone and muscle outcomes and to identify possible preventative strategies for fracture and sarcopenia in the increasing ageing population. Men and women aged ≥40 years from the Kiang West region of The Gambia were recruited with stratified sampling by sex and age. Baseline measurements were completed in 488 participants in 2012 who were randomly assigned to follow-up between 1.5 and 2 years later. Follow-up measurements were performed on 465 participants approximately 1.7 years after baseline measurements. The data set comprises a wide range of measurements on bone, muscle strength, anthropometry, biochemistry, and dietary intake. Questionnaires were used to obtain information on health, lifestyle, musculoskeletal pain, and reproductive status. Baseline cross-sectional data show preliminary evidence for bone mineral density and muscle loss with age. Men had greater negative differences in total body lean mass with age than women following adjustments for body size. From peripheral quantitative computed tomography scans, greater negative associations between bone outcomes and age at the radius and tibia were shown in women than in men. Ultimately, the findings from The Gambian Bone and Muscle Ageing Study will contribute to the understanding of musculoskeletal health in a transitioning population and better characterise fracture and sarcopenia incidence in The Gambia with an aim to the development of preventative strategies against both.

Randomized, placebo-controlled, calcium supplementation study in pregnant Gambian women: effects on breast-milk calcium concentrations and infant birth weight, growth, and bone mineral accretion in the first year of life.

BACKGROUND: Growth and bone mineral accretion in Gambian infants are poorer than those in Western populations. The calcium intake of Gambian women is low, typically 300-400 mg Ca/d, and they have low breast-milk calcium concentrations, which result in low calcium intakes for their breastfed infants. A low maternal calcium supply in pregnancy may limit fetal mineral accretion and breast-milk calcium concentrations and thereby affect infant growth and bone mineral accretion. OBJECTIVE: We investigated the effects of calcium supplementation in Gambian women during pregnancy on breast-milk calcium concentrations and infant birth weight, growth, and bone mineral accretion. DESIGN: A randomized, double-blind, placebo-controlled supplementation study was conducted in 125 Gambian women who received 1500 mg Ca/d (as calcium carbonate) or placebo from 20 wk of gestation until delivery. Infant birth weight and gestational age were recorded. Breast milk was collected, and infant anthropometric and bone measurements were performed at 2, 13, and 52 wk after delivery. Infant bone mineral status was assessed by using single-photon absorptiometry of the radius and whole-body dual-energy X-ray absorptiometry. RESULTS: Compliance with the supplement was high. No significant differences were detected between the groups in breast-milk calcium concentration, infant birth weight, or growth or bone mineral status during the first year of life. A slower rate of increase in infant whole-body bone mineral content and bone area was found in the supplement group than in the placebo group (group x time interaction: P = 0.03 and 0.02, respectively). CONCLUSION: Calcium supplementation of pregnant Gambian women had no significant benefit for breast-milk calcium concentrations or infant birth weight, growth, or bone mineral status in the first year of life.

Randomized, placebo-controlled, calcium supplementation trial in pregnant Gambian women accustomed to a low calcium intake: effects on maternal blood pressure and infant growth.

BACKGROUND: Dietary calcium intake in rural Gambian women is very low (∼350 mg/d) compared with international recommendations. Studies have suggested that calcium supplementation of women receiving low-calcium diets significantly reduces risk of pregnancy hypertension. OBJECTIVE: We tested the effects on blood pressure (BP) of calcium carbonate supplementation (1500 mg Ca/d) in pregnant, rural Gambian women. DESIGN: The study was a randomized, double-blind, parallel, placebo-controlled supplementation trial from 20 wk of gestation (P20) until delivery (calcium: n = 330; placebo; n = 332). BP and anthropometric measures were taken at P20 and then 4 weekly until 36 wk of gestation (P36), and infant anthropometric measures were taken at 2, 13, and 52 wk postdelivery. RESULTS: A total of 525 (calcium: n = 260; placebo: n = 265) women had BP measured at P36 and subsequently delivered a healthy term singleton infant. Mean compliance was 97%, and urinary calcium measures confirmed the group allocation. At P20, the mean (±SD) systolic blood pressure (SBP) was 101.2 ± 9.0 and 102.1 ± 9.3 mm Hg, and diastolic blood pressure (DBP) was 54.5 ± 7.3 and 55.8 ± 7.8 mm Hg, in the calcium and placebo groups, respectively. The intention-to-treat analysis that was adjusted for confounders showed no significant effect of calcium supplementation on the change between P20 and P36 (calcium compared with placebo; mean ± SEM) in SBP (-0.64 ± 0.65%; P = 0.3) or DBP (-0.22 ± 1.15%; P = 0.8). There was no significant effect of supplementation on BP, pregnancy weight gain, weight postpartum, or infant weight, length, and other measures of growth. However, the comparability of the original randomly assigned groups may have been compromised by the exclusion of 20.7% of women from the final analysis. CONCLUSIONS: Calcium supplementation did not affect BP in pregnancy. This result may have been because the Gambian women were adapted to a low dietary calcium intake, and/or obesity, high gestational weight gain, high underlying BP, tobacco use, alcohol consumption, and sedentary lifestyles were rare. This trial was registered at the International Standard Randomized Controlled Trial Register (www.controlled-trials.com/mrct/) as ISRCTN96502494.

Critical windows for nutritional interventions against stunting.

An analysis of early growth patterns in children from 54 resource-poor countries in Africa and Southeast Asia shows a rapid falloff in the height-for-age z score during the first 2 y of life and no recovery until ≥5 y of age. This finding has focused attention on the period -9 to 24 mo as a window of opportunity for interventions against stunting and has garnered considerable political backing for investment targeted at the first 1000 d. These important initiatives should not be undermined, but the objective of this study was to counteract the growing impression that interventions outside of this period cannot be effective. We illustrate our arguments using longitudinal data from the Consortium of Health Oriented Research in Transitioning collaboration (Brazil, Guatemala, India, Philippines, and South Africa) and our own cross-sectional and longitudinal growth data from rural Gambia. We show that substantial height catch-up occurs between 24 mo and midchildhood and again between midchildhood and adulthood, even in the absence of any interventions. Longitudinal growth data from rural Gambia also illustrate that an extended pubertal growth phase allows very considerable height recovery, especially in girls during adolescence. In light of the critical importance of maternal stature to her children's health, our arguments are a reminder of the importance of the more comprehensive UNICEF/Sub-Committee on Nutrition Through the Life-Cycle approach. In particular, we argue that adolescence represents an additional window of opportunity during which substantial life cycle and intergenerational effects can be accrued. The regulation of such growth is complex and may be affected by nutritional interventions imposed many years previously.

Unexpected long-term effects of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake: a follow-up study.

BACKGROUND: Calcium supplementation of pregnant Gambian women with a low calcium intake results in lower maternal bone mineral content in the subsequent lactation. OBJECTIVE: The objective was to investigate whether the lower bone mineral content persists long term. DESIGN: All women in the calcium supplementation trial (International Trial Registry ISRCTN96502494) who had been scanned with dual-energy X-ray absorptiometry at 52 wk of lactation (L52; n = 79) were invited for follow-up when neither pregnant nor lactating for ≥3 mo (NPNL) or at 52 wk postpartum in a future lactation (F52). Bone scans and anthropometric and dietary assessments were conducted. RESULTS: Sixty-eight women participated (35 at both NPNL and F52 and 33 at only one time point): n = 59 NPNL (n = 31 calcium, n = 28 placebo) and n = 44 F52 (n = 24 calcium, n = 20 placebo). The mean (±SD) time from L52 was 4.9 ± 1.9 y for NPNL and 5.0 ± 1.3 y for F52. Size-adjusted bone mineral content (SA-BMC) was greater at NPNL than at L52 in the placebo group (P ≤ 0.001) but not in the calcium group (P for time-by-group interaction: lumbar spine, 0.002; total hip, 0.03; whole body, 0.03). No significant changes in SA-BMC from L52 to F52 were observed in either group. Consequently, the lower SA-BMC in the calcium group at L52 persisted at NPNL and F52 (P ≤ 0.001): NPNL (lumbar spine, -7.5 ± 0.7%; total hip, -10.5 ± 1.0%; whole body, -3.6 ± 0.5%) and F52 (lumbar spine, -6.2 ± 0.9%; total hip, -10.3 ± 1.4%; whole body, -3.2 ± 0.6%). CONCLUSION: In rural Gambian women with a low-calcium diet, a calcium supplement of 1500 mg/d during pregnancy resulted in lower maternal bone mineral content in the subsequent lactation that persisted long term. This trial was registered at www/controlled-trials.com/mrct/ as ISRCTN96502494.

Iron status and fibroblast growth factor-23 in Gambian children.

A relationship between iron and fibroblast growth factor-23 (FGF23) metabolic pathways has been proposed. Iron deficiency anaemia is prevalent in The Gambia and concentrations of fibroblast growth factor-23 FGF23 are elevated in a large percentage of Gambian children with rickets-like bone deformity. We speculate that low iron status may be involved in the aetiology of Gambian rickets. The aim of this study was to determine if there was a relationship between haemoglobin, as a marker of iron status, and FGF23 in samples from children with and without a history of rickets-like bone deformities in The Gambia. We conducted a retrospective analysis of studies carried out from 2006 to 2008 in children from a rural community in The Gambia where iron deficiency anaemia is endemic and where elevated circulating concentrations of FGF23 have been found. To investigate the relationship between circulating FGF23 and haemoglobin concentrations we used an age-adjusted linear regression model on data from children <18y of age with a family or personal history of rickets-like bone deformity (BD) (n=108) and from the local community (LC) (n=382). We found that circulating concentration of FGF23 was inversely correlated with haemoglobin concentration. This effect was more pronounced in BD children compared with LC children (interaction: P≤0.0001). Anaemia and elevated FGF23 were more prevalent in BD children compared to LC children (P=0.0003 and P=0.0001 respectively). In conclusion, there is a stronger relationship between FGF23 and haemoglobin in Gambian children with a history of rickets compared to local community children. This study provides support for the contention that iron may be involved in FGF23 metabolic pathways.

Follow-up study of Gambian children with rickets-like bone deformities and elevated plasma FGF23: possible aetiological factors.

We have previously reported on a case-series of children (n=46) with suspected calcium-deficiency rickets who presented in The Gambia with rickets-like bone deformities. Biochemical analyses discounted vitamin D-deficiency as an aetiological factor but indicated a perturbation of Ca-P metabolism involving low plasma phosphate and high circulating fibroblast growth factor-23 (FGF23) concentrations. A follow-up study was conducted 5 years after presentation to investigate possible associated factors and characterise recovery. 35 children were investigated at follow-up (RFU). Clinical assessment of bone deformities, overnight fasted 2 h urine and blood samples, 2-day weighed dietary records and 24 h urine collections were obtained. Age- and season-matched data from children from the local community (LC) were used to calculate standard deviation scores (SDS) for RFU children. None of the RFU children had radiological signs of active rickets. However, over half had residual leg deformities consistent with rickets. Dietary Ca intake (SDS-Ca=-0.52 (0.98) p=0.04), dietary Ca/P ratio (SDS-Ca/P=-0.80 (0.82) p=0.0008) and TmP:GFR (SDS-TmP:GFR=-0.48 (0.81) p=0.04) were significantly lower in RFU children compared with LC children and circulating FGF23 concentration was elevated in 19% of RFU children. Furthermore an inverse relationship was seen between haemoglobin and FGF23 (R(2)=25.8, p=0.004). This study has shown differences in biochemical and dietary profiles between Gambian children with a history of rickets-like bone deformities and children from the local community. This study provided evidence in support of the calcium deficiency hypothesis leading to urinary phosphate wasting and rickets and identified glomerular filtration rate and iron status as possible modulators of FGF23 metabolic pathways.

Nutritional supplementation during pregnancy and offspring cardiovascular disease risk in The Gambia.

BACKGROUND: Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring. OBJECTIVE: The objective was to follow up the offspring in 2 randomized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease (CVD) risk in offspring. DESIGN: We recruited offspring born during 2 trials in The Gambia, West Africa. One trial provided protein-energy-dense food supplements (1015 kcal and 22 g protein/d) to pregnant (intervention, from 20 wk gestation until delivery) or lactating (control, for 20 wk from birth) women and was randomized at the village level. The second was a double-blind, individually randomized, placebo-controlled trial of calcium supplementation (1.5 g/d), which was also provided from 20 wk gestation until delivery. RESULTS: Sixty-two percent (n = 1267) of children (aged 11-17 y) born during the protein-energy trial were recruited and included in the analysis, and 64% (n = 350) of children (aged 5-10 y) born during the calcium trial were recruited and included in the analysis. Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group (adjusted mean difference: -0.05 mmol/L; 95% CI: -0.10, -0.001 mmol/L). There were no other differences in CVD risk factors, including blood pressure, body composition, and cholesterol, between children born to intervention and control women from the protein-energy trial. Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure. CONCLUSION: These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring, at least in this setting and at the ages studied here. This trial was registered at www.controlled-trials.com as ISRCTN96502494.

Effect of maternal calcium supplementation on offspring blood pressure in 5- to 10-y-old rural Gambian children.

BACKGROUND: Evidence suggests that increased maternal calcium intake during pregnancy may result in lower offspring blood pressure, prompting calls for more robust data in this field, particularly in settings of habitually low calcium intake. OBJECTIVE: The objective was to investigate the effect of maternal calcium supplementation on blood pressure in offspring by recruiting children born after a randomized, double-blind, placebo-controlled trial of calcium supplementation during pregnancy. DESIGN: Children (n = 389) from a rural area of The Gambia (mean age: 7.4 ± 1.2 y; range: 5-10 y), whose mothers received a calcium supplement (1500 mg Ca/d from 20 wk of gestation until delivery) or placebo, were followed up in West Africa. Blood pressure was assessed under standardized conditions with use of the Omron 705IT automated oscillometric device (Morton Medical Ltd, London, United Kingdom), and anthropometric and body composition (bioelectrical impedance) measurements were also made. RESULTS: The analysis was restricted to 350 children born at term, which represented 64% of original trial births. There was no difference in systolic (adjusted mean difference: -0.04 mm Hg; 95% CI: -1.78, 1.69 mm Hg) or diastolic (adjusted mean difference: 0.25 mm Hg; 95% CI: -1.27, 1.77 mm Hg) blood pressure between children whose mothers had received calcium and those who received placebo. No interaction between childhood body mass index (in kg/m(2); mean: 14.0) and maternal calcium supplementation was observed in this study. CONCLUSION: Calcium supplementation in the second half of pregnancy in Gambian women with very low habitual calcium intakes may not result in lower offspring blood pressure at 5-10 y of age.

Effect of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake.

BACKGROUND: Mobilization of maternal bone mineral partly supplies calcium for fetal and neonatal bone growth and development. OBJECTIVE: We investigated whether pregnant women with low calcium intakes may have a more extensive skeletal response postpartum that may compromise their short- or long-term bone health. DESIGN: In a subset of participants (n = 125) in a double-blind, randomized, placebo-controlled trial (International Trial Registry: ISRCTN96502494) in pregnant women in The Gambia, West Africa, with low calcium intakes (approximately 350 mg Ca/d), we measured bone mineral status of the whole body, lumbar spine, and hip by using dual-energy X-ray absorptiometry and measured bone mineral status of the forearm by using single-photon absorptiometry at 2, 13, and 52 wk lactation. We collected blood and urine from the subjects at 20 wk gestation and at 13 wk postpartum. Participants received calcium carbonate (1500 mg Ca/d) or a matching placebo from 20 wk gestation to parturition; participants did not consume supplements during lactation. RESULTS: Women who received the calcium supplement in pregnancy had significantly lower bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) at the hip throughout 12 mo lactation (mean +/- SE difference: BMC = -10.7 +/- 3.7%, P = 0.005; BA = -3.8 +/- 1.9%, P = 0.05; BMD = -6.9 +/- 2.6%, P = 0.01). The women also experienced greater decreases in bone mineral during lactation at the lumbar spine and distal radius and had biochemical changes consistent with greater bone mineral mobilization. CONCLUSIONS: Calcium supplementation in pregnant women with low calcium intakes may disrupt metabolic adaptation and may not benefit maternal bone health. Further study is required to determine if such effects persist long term or elicit compensatory changes in bone structure.