OPTIMIZING PEAK BONE mass accrual during childhood

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1 JOURNAL OF BONE AND MINERAL RESEARCH Volume 22, Supplement 2, 2007 doi: /JBMR.07S American Society for Bone and Mineral Research Vitamin D, Calcium Homeostasis, and Skeleton Accretion in Children Connie M Weaver ABSTRACT: Overt vitamin D deficiency early in life has classically been associated with the etiology of rickets. Recent interest has focused on vitamin D insufficiency and calcium homeostasis and bone health. A review of the literature suggests that the relationship between vitamin D status and calcium utilization has some important differences with life stage and race. In contrast to adults, serum 1,25-dihydroxyvitamin D, but not serum 25-hydroxyvitamin D, predicts calcium absorption in growing children. PTH suppression with increasing serum 25-hydroxyvitamin D varies with race in adolescents. A limitation of our understanding of vitamin D status on calcium homeostasis in children relates to the cross-sectional nature of the evidence and interventions that typically use too little vitamin D supplementation to affect status. Vitamin D status has predicted changes in BMD during growth, and higher doses have been associated with increased bone area and BMC of the hip in pubertal girls with low baseline vitamin D status. Bone accretion is related to calcium status, sexual maturity, race, and genetics. Current cross-sectional studies in children suggest that vitamin D status is less important for bone accrual than for bone health in adults. Intervention studies are needed to identify responsive groups. J Bone Miner Res 2007;22:S2;V45 V49. doi: /JBMR.07S201 Key words: vitamin D, pediatric, children, calcium, bone INTRODUCTION OPTIMIZING PEAK BONE mass accrual during childhood provides one of the most effective strategies for preventing age-related osteoporosis. (1) Two dietary nutrients that have been most associated with building optimal bone mass are vitamin D and calcium. The classical role of vitamin D has been through conversion to its active form, 1,25- dihydroxyvitamin D [1,25(OH) 2 D], in response to PTH release with low serum calcium levels, which results in increased calcium absorption, renal calcium reabsorption, and bone resorption. More recently, the indicator of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], has been associated with bone health in adults. Poor vitamin D status leads to elevated serum PTH, which increases bone remodeling and leads to increased fracture risk. (2 6) Low calcium fractional absorption was increased by 12% (p < 0.001) when serum 25(OH)D values were increased to 162 nm with oral 25 (OH)D supplementation in the elderly. (7) Calcium absorption efficiency increased with increasing serum 25(OH)D levels up to 80 nm, after which a plateau occurred in data compiled by Heaney. (8) A recent evaluation of randomized, controlled trials on the relationship of serum 25(OH)D and BMC measures of risk of falling and muscle weakness and relative risk of fracture led the authors to suggest that optimal levels of serum 25(OH)D levels in adults should be at least 75 nm, and improved health may occur with levels as high as 90 Dr Weaver has received grants from Delaveau and serves on the advisory boards of Wyeth Global Nutrition and Pharmavite. 100 nm. (9) The purpose of this review is to evaluate the evidence for similar biochemical relationships and the impact of vitamin D status on calcium metabolism and bone accrual in children. There are fewer studies in children than adults, and understanding the role of any nutrient on bone health during growth is complicated by the dominance of sexual maturity. Adolescence is a particularly relevant life stage to study because a major portion of peak bone mass is accrued during this period, which offers an important window for improving later bone health. VITAMIN D REQUIREMENTS Historically, requirements for vitamin D in infants were to prevent rickets. An intake of 100 IU is thought adequate to protect against rickets. (10,11) Serum 25(OH)D levels <27.5 nm are associated with vitamin D deficiency, which can lead to reduction in bone length and bone mass. (11) Vitamin D deficiency rickets has recently reappeared in temperate zones, associated with prolonged breast feeding by vitamin D deficient mothers and lack of vitamin D supplementation. (12,13) Vitamin D deficiency in mothers can be caused by reduced cutaneous production of vitamin D because of lack of exposure to UVB radiation or dark skin. Between 1986 and 2003, 166 cases of rickets in the United States were published. (13) The American Academy of Pediatrics recommended a minimal intake of 200 IU/d vitamin D for all infants beginning at 2 mo of life to address this growing problem. (14) The current dietary reference intakes (DRIs) for vitamin D in North America includes an adequate intake (AI) of Department of Foods and Nutrition, Purdue University, Lafayette, Indiana, USA. V45

2 V46 WEAVER 200 IU/d for those 0 50 yr of age and a tolerable upper level (UL) of 1000 IU for infants 0 12 mo of age and 2000 IU/d for those 1 50 yr of age. (15) In 1997, the panel convened to set the DRIs for vitamin D used AIs because it was concluded there was insufficient evidence to set a recommended dietary allowance (RDA). The AI for vitamin D was set on the basis of serum 25(OH)D values observed in healthy populations. New evidence on vitamin D efficacy and safety has called into question the values for both the AI and UL for adults. (16 20) Dose response studies of vitamin D on which to base requirements or ULs in children are practically nonexistent. Nevertheless, there have been some cross-sectional and small intervention studies since the DRIs for vitamin D were released in 1997 that do provide some insights that will likely inform further requirements. VITAMIN D STATUS IN CHILDREN FIG. 1. Effect of low (A) vs. high (B) dietary calcium on calcium homeostasis. Calcium absorption is dominated by vitamin D regulated homeostasis at low calcium intakes, but unregulated, paracellular absorption is increasingly more important at high calcium intakes. The dashed lines pose the question of how vitamin D status regulates calcium absorption and bone resorption. Prevalence figures of vitamin D deficiency in children are sparse or incomplete in most countries. A longitudinal study in 83 girls 4 8 yr of age in Georgia showed that serum 25(OH)D values decreased with increasing age (p 0.02), explained by increasing fat-free soft tissue mass. (21) White girls had higher serum 25(OH)D values than black girls, especially after summer months. This study showed that youth can exhibit seasonal changes and compromised vitamin D status even in southern latitudes. In Maine, 48% of girls 9 11 yr of age studied over 3 yr fell below 50 nm serum 25(OH)D at least once. (22) In adolescents in the United States, serum 25(OH)D levels averaged 78.6 nm for boys and 64.9 nm for girls living at lower latitudes in winter and 89.5 nm for boys and 80.5 nm for girls living in higher latitudes in summer in the Third National Health and Nutrition Examination Survey (NHANES III ). (23) Only 5% of southern adolescents during winter and <2% of northern adolescents during summer had serum 25(OH)D levels <25 nm, but 17% and 8%, respectively, were 37.5 nm, or 72% and 49%, respectively, were 62.5 nm, with a higher incidence in black adolescents. An estimation of the vitamin D intakes needed to bring females yr of age from these levels was 297 IU/d for white women and 2154 IU/d for black women using response data in adults. (16) Similar estimates for white males were 0 for white men and 1714 IU/d for black men. In a cohort of 307 adolescents in Boston, 24.1% had serum 25(OH)D levels 37.5 nm, but 42% had serum 25(OH) D levels 50 nm. (24) Predictors of serum 25(OH)D levels included ethnicity, season, body mass index, milk (positive) and juice (negative) consumption, and physical activity. In winter/spring, milk consumption made a 13% (absolute) difference (95% CI, ) in serum 25(OH)D level. This reflects that vitamin D fortified dairy products are the main dietary source of the vitamin in older children and adolescents in the United States. Reports of vitamin D status in children outside the United States suggest that vitamin D insufficiency is a global problem. (25 27) In a summary of studies around the world, (27) levels of serum 25(OH)D ranged from 13 to 142 nm. The range is wide and not necessarily related to latitude. Even in countries near the equator, vitamin D status may be poor because of dark skin or clothing and sunscreen habits. (28) VITAMIN D AND CALCIUM HOMEOSTASIS The homeostatic response to dietary calcium is shown in Fig. 1. Under conditions of low dietary calcium, PTH is released, which stimulates conversion of 25(OH)D to 1,25(OH) 2 D in the kidney. This active form of the vitamin binds to the vitamin D receptor (VDR) and leads to synthesis of calcium-binding proteins and to increased transcellular calcium absorption. Calcium renal tubular reabsorption in the kidney is also increased, as is bone resorption. The question being addressed here is whether serum 25(OH)D levels also influence calcium homeostasis. Higher dietary calcium levels are thought to increase calcium absorbed through the paracellular route, which is not regulated by vitamin D. This would have the effect of suppressing PTH release and would have a negative feedback on vitamin D regulated calcium absorption at the intestine, tubular reabsorption at the kidney, and bone resorption. In a state of sufficiently high dietary calcium, serum 25(OH)D levels would play a less important role. This may be why Abrams et al. (29) found no relationship between serum 25(OH)D and fractional calcium absorption in 93 adolescents estimated to be consuming 906 ± 280 mg calcium/d and serum 25(OH) levels of 50 ± 20 nm. Calcium absorption was related to serum 1,25(OH) 2 D levels (r 0.35, p 0.001). In adolescents, increasing calcium intakes to above the recommended level of calcium of 1300 mg/d compared with average usual intakes of 900 mg/d resulted in increased calcium absorption and suppressed bone resorption, with no change in serum PTH or vitamin D metabolites. (29) At these high calcium intakes, the vitamin D PTH homeostatic control mechanism was likely not activated.

3 VITAMIN D AND CHILDREN TABLE 1. CONFOUNDERS OF ESTIMATING THE ROLE OF VITAMIN D STATUS IN BONE MASS ACCRETION DURING GROWTH Sexual maturity Race/skin color Genetics Lean mass Diet Calcium Salt Proteins Season We lack vitamin D intervention studies that relate change in status to biochemical indicators of calcium homeostasis. Cross-sectional data over wide ranges of vitamin D status show an inverse relationship between serum 25(OH)D and PTH. (24,26,29) In a study of French adolescent boys (25) with sufficient data points for serum 25(OH)D <20 nm, an inflection point of 83 nm for maximal suppression of PTH was determined. The border between summer and winter values of 25(OH)D in that study was 30 nm. In pooled data of black and white adolescents, serum PTH was inversely related to 25(OH)D in white, but not black, adolescents. (30) Optimal values for serum PTH, especially by race, are unknown in children. BARRIERS TO DETERMINING THE ROLE OF VITAMIN D STATUS ON SKELETAL ACCRETION DURING GROWTH There are many barriers to determining the role of vitamin D status in bone accretion during growth. All factors that influence either vitamin D status or bone accretion can increase their variance. Some of the potential confounders are listed in Table 1. Many of these are dominant and could easily mask a role of vitamin D. Too often, these factors are not fully considered in studies attempting to determine the relationship of vitamin D status on bone accretion. The longitudinal study of Canadian children through puberty clearly showed a large peak of BMC accretion that occurs during the pubertal growth spurt. (31) Approximately 25% of adult peak bone mass is acquired over a narrow age range of 2 yr. Thus, any study of calcium retention or bone accretion during this period has to consider the context of state of sexual maturity to accurately determine the influence of any lifestyle factor on bone mass accrual. Calcium absorption, calcium deposition in bone, and calcium retention in girls peak just before or during onset of menarche. (32 34) At that time, bone calcium deposition rate is approximately five times that of adulthood. To the extent postmenarcheal age can be accurately remembered, this is potentially a good covariate for assessing relationships between vitamin D status and bone accretion in girls. Tanner scores for sexual maturity (35) have also been used for both sexes, but upper body and lower body scores can differ, and confidence in accurate estimates for sexual maturity in terms of relative peak BMC velocity is uncertain. Race can influence both bone mass accretion and vitamin D status. Black adolescents retain more calcium at the same V47 level of intake than white adolescents through increased absorption, decreased urinary excretion, and greater bone formation rates relative to bone resorption rates. (36) Black children have lower serum 25(OH)D levels than white children, as previously discussed. In children 4 16 yr of age, the higher bone mass in black boys and girls was largely explained by differences in size and serum 25(OH)D and 1,25(OH) 2 D levels. (37) Dietary factors that influence bone accretion through perturbing calcium absorption, calcium excretion, or bone turnover rates would be potential confounders in determining a relationship between vitamin D status and bone mass accretion. Top dietary candidates include calcium, salt, and protein. The effect of calcium intake on perturbing calcium homeostasis was discussed earlier in the context of Fig. 1. In carefully controlled feeding studies on a range of calcium intakes in 182 observations in 121 girls yr of age, calcium intake and race explained 28% of skeletal calcium accretion and postmenarcheal age explained an additional 3.9% of the variance in this rather narrow age range. (38) Thus, any studies that do not account for these major determinants of skeletal accretion have little chance of determining the role of other predictors accurately. Estimating calcium intake by usual dietary histories or questionnaires would have very large associated variance, but it would reflect the very large differences in calcium intake from typical Asian children (39) and white children in the United States. (29) Genetics plays a yet undefined role in the relationship of vitamin D status to skeletal calcium accretion or each component. Vitamin D receptor Fok1 polymorphisms are significantly related to calcium absorption and whole body BMC in adolescents. (40) Race may be a crude indicator of genes that regulate body size, but habitual calcium intake and skin color may also be indicators in some cohorts. Dietary salt decreases calcium retention in adolescents through increased urinary calcium loss. (41) The effect was greater in black than white adolescents. (41) Dietary protein effects on the calcium economy in children has received little attention. Measurement of quantitative effects of such dietary constituents on bone accretion during growth is best done through controlled feeding studies. OBSERVATIONS ON VITAMIN D STATUS AND BONE ACCRUAL The few vitamin D intervention studies that have been reported on bone mass accrual in children have generally used doses too low to bring serum 25(OH)D levels up to ranges observed in healthy children during the summer. (26,41) In Finnish girls 9 15 yr of age, vitamin D 2 supplementation at 10 g (400 IU) vitamin D/d for 2 yr did not change serum 25(OH)D, and during the next 6 mo, supplementation with 20 g (800 IU) vitamin D 2 /d significantly increased serum 25(OH)D levels, but not to levels observed during the summer. (42) Only baseline serum 25(OH)D levels predicted the 3-yr change in BMD at the spine (r 0.35, p < 0.001) and femoral neck (r 0.32, p < 0.001). BMC and bone area were not reported, which are preferred measures during growth. In a dose response study using doses

4 V48 equivalent to 200 IU and 2000 IU/d in 10- to 17-yr-old Lebanese girls with baseline 25(OH)D levels of 35 ± 20 nm, total hip BMC increments were increased by supplementation, as was total hip area, but in the highest dose group only. (27) The relationship between vitamin D status was weakened when lean mass was used as a covariate in the regression model. Lean mass increased significantly with vitamin D supplementation. Vitamin D supplementation had no significant benefit on bone area or BMC of the femoral neck, trochanter, or total body. There has been no significant correlations between serum 25(OH)D and biochemical markers of bone turnover in the few studies that have studied these relationships. (26,43) CONCLUSIONS Current evidence suggests little effect of increased serum 25(OH)D levels on improving skeletal calcium accretion in children where calcium intake and vitamin D status are not optimal but not overtly deficient. 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