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Does fetal exposure to vitamin D programme childhood bone mass?
Comment
Does fetal exposure to vitamin D programme childhood bone mass? Calcitriol, the active or hormonal form of vitamin D, has a crucial role in the regulation of calcium and bone metabolism in children and adults. In animals and people, severe vitamin D deficiency, inactivating mutations of the vitamin D receptor (VDR), or inactivating mutations of CYP27B1 (which synthesises calcitriol), share a common phenotype. Intestinal calcium absorption is reduced, which leads to secondary hyperparathyroidism, low serum calcium and phosphorus, skeletal resorption, and reduced mineralisation (rickets or osteomalacia). An enriched calcium diet or parenteral calcium infusions normalise mineral and bone metabolism, bypassing the intestinal abnormality.1 In mice, deletion of VDR solely from intestinal cells recapitulates the phenotype,2 while expression of VDR only in intestinal cells rescues global loss of vitamin D receptors.2,3 Overall, these findings confirm that calcitriol mainly acts indirectly on the skeleton through stimulation of intestinal calcium absorption. However, whether calcitriol is needed before birth is not clear. In animal models, fetal development is undisturbed by severe vitamin D deficiency, loss of vitamin D receptors, or genetic absence of calcitriol in the fetus;1 fetal calcium, phosphorus, and parathyroid hormone serum concentrations, and skeletal morphology and mineral content, are all normal. Active transport of calcium across the placenta—not the intestines—is the dominant route of calcium delivery, and this is not impaired by altered vitamin D physiology. Several clinical trials and observational studies have found no differences between babies born of vitamin D-deficient mothers versus vitamin D-replete mothers with regard to cord blood calcium, phosphorus, and parathyroid hormone concentrations, and radiographic or clinical signs of rickets.1 Even where severe vitamin D deficiency is endemic, its first manifestation in offspring is hypocalcaemia beginning 48 h or later after birth, and skeletal evidence of rickets develops more slowly with a peak incidence between 6–18 months.1 Similarly, children with inactivating mutations of VDR or CYP27B1 generally present with hypocalcaemia or rickets late in the first or second year.1 These findings suggest that vitamin D and calcitriol are not required for calcium or skeletal metabolism before birth.
A 2016 clinical trial (MAVIDOS)4 randomly assigned 1134 pregnant women to receive 1000 IU per day of vitamin D or placebo, and found no difference in offspring bone mineral content measured by 14 days of age (the primary outcome). However, an unadjusted subgroup analysis showed a nominally significant (p=0·04) positive effect of vitamin D supplementation on the bone mineral density of winter-born babies. However, autumn-born babies born of vitamin D-supplemented mothers had a similar magnitude of reduction in their bone mineral density compared with those born of non-supplemented mothers (p=0·07). The opposing finding in autumn-born versus winter-born babies does not make mechanistic sense, and might be a chance finding attributable to the small subgroups. Other exceptions to the fetal data are recent studies that investigated possible associations between maternal 25-hydroxyvitamin D (25[OH]D) concentrations during pregnancy and offspring bone mineral content. The first UK study of 198 motherand-child pairs reported that decreased maternal 25(OH)D concentrations during pregnancy were not associated with anthropometric parameters at birth or at age 9 months, but were associated with reduced bone mineral content at age 8·9 years.5 This study was highly publicised for seeming to confirm that fetal exposure to 25(OH)D programmes childhood bone mass. However, a subsequent UK study with 20 times the number of participants (n=3960), and eight times the number of participants with low 25(OH)D concentrations (220 vs 28), found no association between maternal 25(OH) D concentration during pregnancy and childhood bone mass at age 9·9 years.6 A study in The Lancet Diabetes & Endocrinology7 reports that decreased maternal and cord blood 25(OH)D concentrations in 5294 Dutch participants were associated with increased offspring bone mineral content at age 6 years (the opposite result of the first UK study); however, this association was eliminated after adjusting for 25(OH)D concentrations in the children themselves at the time of bone assessment. Strengths of the study include the large cohort, analysis of cord blood and childhood 25(OH)D concentrations,
www.thelancet.com/diabetes-endocrinology Published online March 1, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30067-0
Lancet Diabetes Endocrinol 2017 Published Online March 1, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30067-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(17)30064-5
1
Comment
and the rigorous liquid chromatography-tandem mass spectrometry methodology used. Taken in context with the previous observational studies, it seems likely that there is no real association between 25(OH)D measures at or before birth and childhood bone mass. As Audry Garcia and colleagues suggest, childhood 25(OH) D concentration is probably more relevant than cord blood 25(OH)D concentration in determining childhood bone mass. Such observational studies can be fraught with residual confounding. Decreased maternal 25(OH)D concentration during pregnancy is predicted by poor maternal nutrition, maternal obesity, lower socioeconomic status, etc.8 These maternal factors might affect fetal development without invoking a direct effect through 25(OH)D. Furthermore, some factors that determine maternal 25(OH)D concentration might be shared with the child after birth, thereby affecting childhood skeletal development independent of an effect of 25(OH)D exposure before birth. Overall, the bulk of available data suggest that vitamin D and calcitriol are not needed to regulate calcium homoeostasis or skeletal development before birth. Nevertheless, vitamin D sufficiency should be maintained during pregnancy because calcitriol
2
becomes important soon after birth when the intestines become the dominant route of calcium delivery. Christopher S Kovacs Health Sciences Centre, Faculty of Medicine, Endocrinology, Memorial University of Newfoundland, St John’s, Newfoundland, NL A1B 3V6, Canada [email protected] I declare no competing interests. 1 2 3 4
5 6 7
8
Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev 2014; 94: 1143–218. Lieben L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122: 1803–15. Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 2009; 136: 1317–27. Cooper C, Harvey NC, Bishop NJ, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 2016; 4: 393–402. Javaid MK, Crozier SR, Harvey NC, et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006; 367: 36–43. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study. Lancet 2013; 381: 2176–83. Garcia AH, Erler NS, Jaddoe VWV, et al. 25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study. Lancet Diabetes Endocrinol 2017; published online March 1. http://dx.doi.org/10.1016/S22138587(17)30064-5. Kovacs CS. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev 2016; 96: 449–547.
www.thelancet.com/diabetes-endocrinology Published online March 1, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30067-0
Does fetal exposure to vitamin D programme childhood bone mass? Calcitriol, the active or hormonal form of vitamin D, has a crucial role in the regulation of calcium and bone metabolism in children and adults. In animals and people, severe vitamin D deficiency, inactivating mutations of the vitamin D receptor (VDR), or inactivating mutations of CYP27B1 (which synthesises calcitriol), share a common phenotype. Intestinal calcium absorption is reduced, which leads to secondary hyperparathyroidism, low serum calcium and phosphorus, skeletal resorption, and reduced mineralisation (rickets or osteomalacia). An enriched calcium diet or parenteral calcium infusions normalise mineral and bone metabolism, bypassing the intestinal abnormality.1 In mice, deletion of VDR solely from intestinal cells recapitulates the phenotype,2 while expression of VDR only in intestinal cells rescues global loss of vitamin D receptors.2,3 Overall, these findings confirm that calcitriol mainly acts indirectly on the skeleton through stimulation of intestinal calcium absorption. However, whether calcitriol is needed before birth is not clear. In animal models, fetal development is undisturbed by severe vitamin D deficiency, loss of vitamin D receptors, or genetic absence of calcitriol in the fetus;1 fetal calcium, phosphorus, and parathyroid hormone serum concentrations, and skeletal morphology and mineral content, are all normal. Active transport of calcium across the placenta—not the intestines—is the dominant route of calcium delivery, and this is not impaired by altered vitamin D physiology. Several clinical trials and observational studies have found no differences between babies born of vitamin D-deficient mothers versus vitamin D-replete mothers with regard to cord blood calcium, phosphorus, and parathyroid hormone concentrations, and radiographic or clinical signs of rickets.1 Even where severe vitamin D deficiency is endemic, its first manifestation in offspring is hypocalcaemia beginning 48 h or later after birth, and skeletal evidence of rickets develops more slowly with a peak incidence between 6–18 months.1 Similarly, children with inactivating mutations of VDR or CYP27B1 generally present with hypocalcaemia or rickets late in the first or second year.1 These findings suggest that vitamin D and calcitriol are not required for calcium or skeletal metabolism before birth.
A 2016 clinical trial (MAVIDOS)4 randomly assigned 1134 pregnant women to receive 1000 IU per day of vitamin D or placebo, and found no difference in offspring bone mineral content measured by 14 days of age (the primary outcome). However, an unadjusted subgroup analysis showed a nominally significant (p=0·04) positive effect of vitamin D supplementation on the bone mineral density of winter-born babies. However, autumn-born babies born of vitamin D-supplemented mothers had a similar magnitude of reduction in their bone mineral density compared with those born of non-supplemented mothers (p=0·07). The opposing finding in autumn-born versus winter-born babies does not make mechanistic sense, and might be a chance finding attributable to the small subgroups. Other exceptions to the fetal data are recent studies that investigated possible associations between maternal 25-hydroxyvitamin D (25[OH]D) concentrations during pregnancy and offspring bone mineral content. The first UK study of 198 motherand-child pairs reported that decreased maternal 25(OH)D concentrations during pregnancy were not associated with anthropometric parameters at birth or at age 9 months, but were associated with reduced bone mineral content at age 8·9 years.5 This study was highly publicised for seeming to confirm that fetal exposure to 25(OH)D programmes childhood bone mass. However, a subsequent UK study with 20 times the number of participants (n=3960), and eight times the number of participants with low 25(OH)D concentrations (220 vs 28), found no association between maternal 25(OH) D concentration during pregnancy and childhood bone mass at age 9·9 years.6 A study in The Lancet Diabetes & Endocrinology7 reports that decreased maternal and cord blood 25(OH)D concentrations in 5294 Dutch participants were associated with increased offspring bone mineral content at age 6 years (the opposite result of the first UK study); however, this association was eliminated after adjusting for 25(OH)D concentrations in the children themselves at the time of bone assessment. Strengths of the study include the large cohort, analysis of cord blood and childhood 25(OH)D concentrations,
www.thelancet.com/diabetes-endocrinology Published online March 1, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30067-0
Lancet Diabetes Endocrinol 2017 Published Online March 1, 2017 http://dx.doi.org/10.1016/ S2213-8587(17)30067-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(17)30064-5
1
Comment
and the rigorous liquid chromatography-tandem mass spectrometry methodology used. Taken in context with the previous observational studies, it seems likely that there is no real association between 25(OH)D measures at or before birth and childhood bone mass. As Audry Garcia and colleagues suggest, childhood 25(OH) D concentration is probably more relevant than cord blood 25(OH)D concentration in determining childhood bone mass. Such observational studies can be fraught with residual confounding. Decreased maternal 25(OH)D concentration during pregnancy is predicted by poor maternal nutrition, maternal obesity, lower socioeconomic status, etc.8 These maternal factors might affect fetal development without invoking a direct effect through 25(OH)D. Furthermore, some factors that determine maternal 25(OH)D concentration might be shared with the child after birth, thereby affecting childhood skeletal development independent of an effect of 25(OH)D exposure before birth. Overall, the bulk of available data suggest that vitamin D and calcitriol are not needed to regulate calcium homoeostasis or skeletal development before birth. Nevertheless, vitamin D sufficiency should be maintained during pregnancy because calcitriol
2
becomes important soon after birth when the intestines become the dominant route of calcium delivery. Christopher S Kovacs Health Sciences Centre, Faculty of Medicine, Endocrinology, Memorial University of Newfoundland, St John’s, Newfoundland, NL A1B 3V6, Canada [email protected] I declare no competing interests. 1 2 3 4
5 6 7
8
Kovacs CS. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev 2014; 94: 1143–218. Lieben L, Masuyama R, Torrekens S, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 2012; 122: 1803–15. Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 2009; 136: 1317–27. Cooper C, Harvey NC, Bishop NJ, et al. Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial. Lancet Diabetes Endocrinol 2016; 4: 393–402. Javaid MK, Crozier SR, Harvey NC, et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006; 367: 36–43. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study. Lancet 2013; 381: 2176–83. Garcia AH, Erler NS, Jaddoe VWV, et al. 25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study. Lancet Diabetes Endocrinol 2017; published online March 1. http://dx.doi.org/10.1016/S22138587(17)30064-5. Kovacs CS. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev 2016; 96: 449–547.
www.thelancet.com/diabetes-endocrinology Published online March 1, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30067-0