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Osteoporosis as a Pediatric Problem
0031-3955/95 $0.00
PEDIATRIC NUTRITION
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OSTEOPOROSIS AS A PEDIATRIC PROBLEM Anne-Lise Carrie Fassler, PhD, and Jean-Philippe Bonjour, MD
Because osteoporosis is a major cause of morbidity, mortality, and medical expense worldwide, it has become a concern of public health authorities. Variation in bone mass accumulation during childhood and adolescence is now recognized as an important determinant of the risk of sustaining osteoporotic fractures during adult life; therefore, recent investigations have focused on the prevention of the disease. Some findings suggest that maximizing bone mass during growth constitutes one of the best preventive strategies. A consensus development conference in 199p4 dearly defined osteoporosis as "a disease characterized by low bone mass and micro architectural deterioration of bony tissue, leading to enhanced bone fragility and a consequent increase in fracture risk." This definition has been accepted by the World Health Organization, which now considers osteoporosis a major health problem?5 Although osteoporosis occurs in both sexes, women are more often affected, with a fracture prevalence about six times greater than in men in most populationsY, 64 At present, the lifetime risk for a 50-year-old white woman to sustain an osteoporotic fracture is estimated between 30% to 40%,64 The observation in many countries of increasing agespecific fracture incidence52, 65 and the continuing rise in life expectancy suggest that the incidence of osteoporosis is likely to worsen in the future for both men and women. Research by the authors of this article is supported by the Swiss National Foundation (grant no. 32-32415.91) and Nestec Ltd. From the Department of Nutrition, Nestec Ltd. Research Center, Lausanne (ALC); and the Division of Clinical Pathophysiology, World Health Organization Collaborating Center for Osteoporosis and Bone Disease, Department of Medicine, University Hospital, Geneva (JPB), Switzerland
PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 42 • NUMBER 4 • AUGUST 1995
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Cross-sectional and longitudinal studies show that bone mass develops with age, increasing to a peak value attained in early adulthood, remaining stable for some years, and decreasing thereafter. 61 , 62, 76 Peak bone mass (PBM) and rate of bone loss are therefore important determinants of the risk of osteoporotic fracture in the elderly. Because none of the present treatments can significantly restore the amount of bone lost in severe osteoporosis, emphasis is on prevention through maximizing PBM reached at maturity and through reducing subsequent bone loss. Therefore, even though osteoporosis is considered a disease of the elderly, prevention should be focused not only on preventing the bone loss occurring from the sixth decade but also on achievement of optimal PBM during childhood and adolescence. Thus the adolescent period may be critical for the development of the disease later in life. Although building the greatest skeletal mass within genetic limits is considered the best approach in preventing osteoporotic fractures,44, 67 little is known about the mechanisms involved in the attainment of a maximal PBM. Although some factors influencing bone mass have already been identified (e.g., dietary calcium and exercise), a better understanding of the physiology of bone mass growth is essential to further define adequate strategies for achieving optimal PBM and preventing osteoporosis. LOW BONE MASS: A MAJOR DETERMINANT OF FRACTURE RISK
Fracture risk is determined by a number of factors, including low bone mass, skeletal microdamage, geometric properties, and traumaP' 21,40,69 Among these factors, bone mass is the main determinant because it can account for up to 80% of the variance in skeletal strength as determined in vitro. 5 , 38, 61 Bone mass resistance to mechanical stress depends on both bone density and bone volume or size. 34 This has been confirmed by several prospective or longitudinal studies showing that patients with fractures have lower bone mass at the fracture site than controls. 23, 40, 63 Furthermore, one standard deviation (1 SD) decrease in bone mass has been estimated to account for a 50% to 100% increase in the risk of nonspinal fractures/ 5, 41, 93 and a 1 SD decrease in bone mass at the femoral neck is associated with a 160% increase in risk of hip fracture. 16 Therefore, low bone mass constitutes the major factor for sustaining a fracture, and consequently optimal bone mass is essential for osteoporosis prevention. TECHNIQUES FOR BONE MASS MEASUREMENT
Bone mass is generally estimated from measurements of bone mineral content (BMC) or bone mineral density (BMD) in the entire skeleton or at given sites. A number of noninvasive methods, with varying accuracy and precision depending on the skeletal region assessed,13, 14
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are currently available for bone mass measurements. Particularly in pediatrics, the most commonly used approach is dual X-ray absorptiometry. Mean volumetric mineral density (g hydroxyapatite/cm3 ) of bone can be determined by quantitative computed tomography (QCT). This technique can be used to measure the quantity of trabecular bone within fue vertebral bodyll; however, other densitometric techniques, including single- and dual-energy photon (spa, dpa) or x-ray (sXA, DXA) absorptiometry, which express BMC with respect to bone width (g/ cm) or bone area (g/cm2), are more useful in pediatrics. To estimate bone mass at the lumbar spine, femoral neck, or the total skeleton, the most commonly used technique at present is DXA, which provides areal BMD measurements (g/ cm2) that have been shown to be inversely related to bone strength and fue prevalence of osteoporotic fractures. 61 ,64 Because this measurement encompasses both volumetric mineral density and overall fuickness of scanned bone, it is particularly useful during puberty to assess bone mass changes, which are mostly due to increases in bone size. 7,88
OPTIMIZED PEAK BONE MASS FOR PREVENTION OF OSTEOPOROSIS
Adult bone mass at any time depends on both the amount achieved at skeletal maturity (Le., PBM) and the subsequent rate of bone 10ss.16, 41,76 Consequently, fue lower bone mass found in patients with fractures may be due to a lower PBM or to a greater bone 10ss.67, 80, 81 These two determinants may partly account for the sex differences in fue ageadjusted occurrence of osteoporotic fracture, because PBM is lower and subsequent rate of bone loss is greater in women fuan in men. Similarly, fue greater bone mass in black subjects fuan in white subjects may be attributed to the attainment of a greater PBM.27 The relative contribution of PBM and bone loss to fue development of fracture is difficult to evaluate, however, because of the time interval between fue attainment of PBM and fue occurrence of fractures. This issue has been addressed indirectly by studying fue premenopausal daughters of postmenopausal women wifu osteoporotic fractures; both mofuers and daughters were found to have lower spinal bone densities fuan could be predicted from age, menopausal status, height, and weight. 8o The influence of a low PBM in the development of osteoporosis was further supported by the finding that fuese daughters had reduced bone mass at fue lumbar spine and possibly at fue femoral neck compared wifu daughters of normal postmenopausal women. 81 The broad variability in bone mass observed in adults, particularly at sites such as the lumbar spine and fue femur,8 appears during adolescence, suggesting that fuese differences must occur during the rapid phase of bone mass accumulation at puberty.7, 8, 88 Uneven rates of bone loss after the
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menopause or with aging should also contribute to the bone mass variability observed in the elderly.
GREAT HETEROGENEITY IN SKELETAL DEVELOPMENT
Skeletal development is not linear throughout childhood and adolescence but varies according to sex, sexual maturation, and skeletal sites. Indeed, differences in skeletal development can be observed at several organization levels, for instance between axial and appendicular, or between proximal and distal limb segments, or between cortical and trabecular bone.
Longitudinal Growth and Rates of Bone Mass Accumulation
During the first years of life, the appendicular skeleton grows faster than the axial skeleton. During puberty, the axial skeleton growth is accelerated while appendicular skeleton growth remains linear.87 This heterogeneity in longitudinal bone growth could be the consequence of site-specific differential responses to various growth factors, including the growth hormone-insulin-like growth factor 1 (IGFl) system. 42, 87, 89 Similarly, distal limb segments' growth precedes growth of the proximal limb segments of the appendicular skeleton.lO In addition, heterogeneity in rates of bone mass accrual has been shown according to sites. 22 In this study, regional BMC from 8 years of age onward are reported as a percentage of regional peak BMC obtained at 15 years of age. At 8 years of age the skull bone density was 70% of its peak, whereas other sites were only about 30% of their peak. Bone mass is largely independent of height in adults, but in children there is a close relationship between bone mass and height, which disappears during puberty. This has been observed in a number of cross-sectional and longitudinal studies that showed a dissociation in rates of bone growth velocity and bone mass gain. 7,48, 88 Therefore, some determinants of bone mass accumulation during puberty at some sites of the skeleton must be independent from those responsible for gain in height. Bone mass accrual follows longitudinal growth, and the greatest disparity between height gain and bone mass accumulation rate is observed when growth velocity is at its maximum, that is from 11 to 12 years of age in girls and 13 to 14 years of age in boys?' 88 This asynchrony may result in transient bone fragility during adolescence that could explain the peak of fracture incidence reported at these ages, which has usually been attributed to risk-taking behavior. 1, 31
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Sex Differences Expressed During Pubertal Changes
During puberty, increases in bone mass gain do not occur at all skeletal sites at the same rate. In a longitudinal study using DXA, bone mass in both the lumbar spine (L5) and the femoral neck (FN) increased four- to sixfold in girls between 11 to 14 years of age and in boys 13 to 17 years of age. 88 In contrast, only a twofold increase in bone mass was observed at the midfemoral shaft, during the same period in both sexes. 88 It is well-known that bone mass at adulthood is greater in men than in women, with a significant sex difference in size and cortical thickness of most axial and appendicular bones. This gender difference develops during puberty; no consistent differences are observed in bone mass between male and female prepubertal children.?' 39, 48 In contrast, volumetric bone density is similar in both males and females from childhood to young adulthood. 2o,26 Thus, the greater bone mass, expressed in BMD jBMC as measured by DXA, accumulated during puberty in male adolescents as compared with female adolescents seems to result from a greater increase in bone size and cortical thickness.? Moreover, the increase in BMC at the lumbar spine during puberty is about tenfold greater than the corresponding mean increase in the volumetric trabecular density of the vertebrae, in both male and female adolescents. This suggests that a large part of bone mass increment observed during puberty results from an increase in size that is associated, at least at several axial and appendicular sites, with an increased thickness of the cortical shell. Both components are usually greater in male than in female adolescents. 8 As mentioned above, bone mass accrual accelerates at 11 years of age and 13 years of age in girls and boys, respectively, and BMD increases at a high rate for 3 consecutive years in girls as compared with 4 years in boys7, 88; however, BMD increments at the L5, the midfemoral shaft, and the FN slow sharply after 16 years of age in girls and virtually cease from 17 to 20 years of age (or 2 years after menarche). The gain in BMD is maintained in boys at the L5 and the midfemoral shaft but not at the FN up to 20 years of age. 88 Hence, these studies suggest that the greater bone mass in young adult males may be due to a longer pubertal maturation rather than to a greater rate of bone mass gain, and possibly to a greater "consolidation period" in duration or magnitude in boys than in girls. 8 The 2 years of additional prepubertal growth in boys may also be an important determinant of the sex difference in bone mass. 29 As previously mentioned, puberty is also the period during which the broad variability in bone mass observed in adults develops. The greatest increases in the variability of bone mass are found at the L5 and FN, two sites particularly susceptible to osteoporotic fractures, whereas the variability remains constant at the midfemoral shaft,?, 88 These differential changes in bone mass variability according to sites are not understood. They seem to result from a broader range of the variability in bone size rather than in volumetric bone mineral density.
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Time of Peak Bone Mass Attainment
Some cross-sectional and longitudinal studies have suggested that PBM at various skeletal sites in both men and women is attained in the mid-30s,24, 50, 74, 78 whereas others failed to show an increase in bone mass during the third decade, or even indicated a decreased bone mass during the same period. 25, 30, 39, 40, 77 Some investigations favor the conclusion that PBM in both the spine and the proximal femur is almost reached at 16 years of age in female adolescents?, 88 In addition, BMD at these sites was independent of age in a cohort of young adults from 20 to 35 years of age, and changes in bone mass at both the LS and the FN were not significant at a 1 year interval in either sex. 84 These longitudinal and cross-sectional studies are consistent with other published data reporting that bone mass gain ceased in the late teens. 28, 39, 51 This, however, does not mean that bone mass cannot be positively influenced by some appropriate lifestyle changes later in life. Skeletal development is therefore heterogeneous. Longitudinal growth and bone mass accumulation are sex-, pubertal stage-, and sitespecific in both rates and duration. Hence, exposure to protective or detrimental factors during growth may produce generalized and sitespecific effects that could influence the fracture risk later in life. INFLUENCE OF ENVIRONMENTAL FACTORS ON THE A ITAINMENT OF PBM
Many factors, including heredity, sex, diet, body weight, physical activity, hormonal status, and exposure to risk factors, are thought to influence bone mass accumulation during growth. IS, 33, 49, 68 It has been proposed from twin studies that the level of PBM achieved at maturity is largely dependent on genetic factors influencing both the overall growth pattern and the osteotropic endocrine system.72, 82, 85 Among these genetic factors, allelic variation in the vitamin D gene receptor may play a major role?3, 90 Some lifestyle factors, namely exercise and dietary calcium, are obviously of interest because they are susceptible to intervention. It is generally accepted that moderate physical activity positively influences bone mass development, especially at weight-bearing sites, during childhood and adolescencel9, 32,46, 92; however, any additional bone mass gain that possibly could be obtained with moderately increased levels of physical activity remains to be determined in wellcontrolled prospective longitudinal studies during growth. Such information is essential in order to provide credible public health recommendations. Importance of Calcium Metabolism for Bone Health
Calcium is an essential dietary nutrient not only as a major constituent of bone mineral (99% of body calcium is found in the skeleton),
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but also because of its involvement in numerous fundamental cellular mechanisms. To safeguard these essential functions when calcium intake is reduced, plasma calcium is maintained constant by effective regulatory mechanisms involving increased intestinal calcium absorption and renal tubular reabsorption capacities, and increased calcium mobilization from the skeletal pool. This regulation is achieved through increased production of parathyroid hormone (PTH) and 1,25 (OHh vitamin D (calcitriol, the active hormonal form of vitamin D). PTH acts primarily at the kidney level by enhancing the tubular reabsorption of calcium and stimulating the formation of calcitriol, but also at the skeletal level by mobilizing or storing calcium. Calcitriol stimulates intestinal calcium absorption, affects bone turnover, and down-regulates its own formation and the synthesis of PTH. The precursor of calcitriol is vitamin D, which therefore plays a central role in plasma calcium homeostasis. This vitamin is derived mainly from the skin, where it is synthesized from 7-dehydrocholesterol by ultraviolet light irradiation, and from the diet. Vitamin D deficiency may be present in individuals not exposed to sunlight, leading to defective mineralization with osteomalacia and rickets as a consequence 71 ; however, individuals with adequate vitamin D status metabolize vitamin D in the liver to form 25-hydroxyvitamin D, the storage form of the vitamin. Further metabolism to calcitriol is controlled in the kidney by PTH, IGFl, and plasma concentrations of calcium and phosphate. 59 Phosphate is as important as calcium for bone health because it contributes to about 50% of bone mineral weight. Both calcium and phosphate levels should be present in adequate quantities in the diet to ensure proper bone mass development. Low dietary phosphate levels are unusual in the United States because almost all foods contain phosphates as organic or inorganic phosphates; however, concern has arisen over a possible detrimental effect of excessive phosphate intakes on bone mass, because diets high in phosphates and low in calcium have been shown to increase serum PTH level,2,9 Although information is available about the phosphate effect on calcium-regulating hormones, consequences for bone mass development have not yet been shown. Recommended dietary allowances (RDA) for phosphorus levels are arbitrarily set to be identical to calcium RDAs, but the calcium-to-phosphorus ratio is considered less important than adequate calcium intake, as mentioned in a report of the Life Science Research Office. 53 Two other nutrients, sodium and protein, are reported to increase urinary calcium excretion; however, so far no study indicates that large intakes of either sodium or proteins would exert a deleterious effect on bone mass acquisition during growth. Whether variations within the "normal" range in the protein intake in well-nourished children and adolescents, independently of changes in energy supply, can influence skeletal growth and thereby modulate the genetic potential in PBM attainment is not known. This question is interesting because the protein intake can affect the growth hormone-IGFI system and thereby could modulate the rate of skeletal growth. 6
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Dietary Calcium and Peak Bone Mass
The earliest data suggesting an influence of dietary calcium on the achievement of PBM found a difference in bone mass and fracture rate in two Croatian populations with substantially different calcium intakes. 58 Although this study does not demonstrate a causal relationship between calcium intake and bone mass, the difference in bone mass was already present at 30 years of age, suggesting that the greatest effect of dietary calcium probably occurred during growth rather than at adulthood. Additional evidence for a positive effect of increased calcium intake on bone mass development was obtained in recent intervention and longitudinal studies. 45, 54, 74 Bone mass has been reported to be positively correlated with calcium and protein intake, and increased self-selected calcium intake was positively correlated with increased spinal bone mass in a cohort of young adult women. 74 A 3-year intervention study was conducted in 45 pairs of monozygotic twins, 6 to 14 years old at entry, whose usual calcium intake was about 900 mg/d. 45 One of each twin pair received supplemental calcium raising overall daily calcium intake to 1600 mg. No significant differences in BMD were found in subjects having already entered puberty; however, in the prepubertal twins taking 1600 mg calcium daily, midradius bone density gains were significantly greater from 6 months up to 3 years of supplementation. The authors suggested that calcium supplementation may have been beneficial in the older children, but its effect on bone mass accumulation was possibly masked by more potent factors expressed during puberty (e.g., growth hormone and sex steroids); however, in the prepubertal children, the observed benefit was not sustained 1 year after the supplementation at the level of the forearm. 83 Calcium supplementation during growth is proposed to exert its effect by a reduction in bone turnover and remodeling; the transient effect of calcium after cessation of the supplementation could result from a rapid return to normal bone turnover. Therefore, a continued high calcium intake throughout childhood and adolescence may be required for the achievement of a maximal PBM, as has been suggested from a number of retrospective studies. 66,70, 79, 86 Interestingly, calcium deficiency during growth may be a greater risk factor for hip fractures than spine fractures. 37, 66, 94 Recker and colleagues 74 have estimated that the risk of fracture at 70 years of age could be doubled by low calcium intakes in the first 30 years of age . . It remains intriguing that some studies have failed to show a relationship between calcium intake and bone mass. 3,92 These negative observations are usually explained by the possible interaction of confounding factors, such as other nutritional factors or physical activity differences, or due to too-small differences in calcium intakes between the groups studied. 4, 19, 36, 89 Indeed, there may be a threshold in calcium intake below which calcium balance increases with additional calcium but above which no further beneficial effects can be observed (e.g., up to 2.5 g of calcium intake daily).56 For PBM to be achieved within the
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genetic potential, the fraction of dietary calcium absorbed by the intestine must be sufficient to cover both skeletal demand during growth and obligatory losses (i.e., fecal, urinary, and dermal). The magnitude of positive balance required for optimal PBM is unknown. Calcium requirements have been reported to be greatest during infancy and adolescence. 55 For infants with adequate vitamin D status, RDAs are set at 400 mg/ d for up to 6 months and 600 mg/ d from 6 to 12 months. These calcium needs are assumed to be fully covered with breast- or bottle-feeding. Prematurity seems to impair further skeletal development and mineralization, but any long-term effect on PBM has not been yet established. During childhood, dietary intakes of approximately 800 mg/ d, the current RDA, may allow sufficient calcium retention to cover the skeletal requirement of about 100 mg calcium/ d. 55 Increasing calcium levels up to approximately 1400 mg/ d in short-term balance studies permitted greater retention, suggesting that optimal bone mass may not be achieved at current RDA.55 During the accelerated skeletal growth of adolescence, calcium retention has been estimated to range from 360 to 400 mg/ d,35 which would be achieved with intakes of 1200 mg, corresponding to the RDA for this age group55; however, Heaney5 has suggested that a greater RDA for this age group should be considered in view of the unchanged urinary calcium excretion with increased dietary calcium levels up to 1600 mg/ d observed in shortterm balance studies. 57 Whether this will be maintained in the long-term with positive consequence on bone mass gain is· not known. Thus, substantial benefits on bone mass accrual as a result of increasing calcium intake from 1200 mg daily to 1600 remains to be proven, prior to recommending changing the RDAs for this age group. Dietary surveys in the United States12,91 have shown that on average children consume sufficient calcium to meet the current RDA. Nevertheless, these surveys report decreased calcium intakes in females in adolescence at a time when their requirements are more than doubled. Consequently, female adolescents often do not meet their RDA. A low calcium intake at this age may partly account for the lower bone mass observed in older women, as suggested from retrospective studies.32, 37, 66, 70, 79, 86, 94 A 0.5 SD difference in bone mass has been estimated between women who reported consuming milk at every meal in youth and those who reported rarely or never consuming milk during this period. 43,79 Because a 1 SD difference in bone mass may increase the risk fracture by 50% to 160%, depending on the site, a high calcium intake in childhood and adolescence may reduce the fracture risk in later adulthood and in the elderly. The main food sources of calcium are dairy products; when these are excluded from the usual American diet, calcium intake is about 300 mg/ d. Efforts could therefore be focused on promoting, especially to adolescent girls, the consumption of dairy products or, alternatively, calcium-fortified foods whenever possible, because little or no risk to the consumer has been reported for calcium intakes in the range reported to be effective. A low calcium intake during growth is likely to decrease PBM;
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however, further research is required to establish the effects of calcium intakes on the magnitude of bone-mass gain before, during, and after puberty, particularly at sites such as the lumbar spine and the femoral neck, where osteoporotic fractures have their most devastating consequences in terms of both morbidity and mortality. It is essential to determine the growth period during which any dietary intervention can be most effective for bone mass gain, and when an intervention may still compensate for a former deficit, before generally recommending calcium supplementation for normal children. The response of bone mass accumulation to a given calcium intake is variable. Whether allelic variations in the vitamin D receptor gene may explain this uneven responsiveness remains to be determined. Hence, developments in the identification of genetic factors involved in bone mass may lead to future strategies aimed at maximizing PBM within each individual's genetic potential.
SUMMARY
Osteoporosis has long been considered a disease of the elderly; however, there is now a general agreement that predisposition begins in childhood and adolescence; thus, rational approaches to prevention of the disease should be started during childhood and adolescence. Indeed, by determining PBM, events occurring in the first two decades of life may determine in large part the subsequent risk of osteoporosis. Attention has thus been focused on the physiology of bone mass accumulation during growth, including the role of environmental factors such as dietary calcium and exercise. Because their patients are at this particular time of life, when PBM is being achieved, pediatricians are in a critical position to affect changes in the long-term risk of osteoporosis in their female and male patients. ACKNOWLEDGMENTS The authors are grateful to Professor John Eisman (Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia) for his critical review of this article.
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55. Matkovic V: Calcium metabolism and requirements during skeletal modeling and consolidation of bone mass. Am J Clin Nutr 54:245-260, 1991 56. Matkovic V, Heaney RP: Calcium balance during human growth: Evidence for threshold behavior. Am J Clin Nutr 55:992-996, 1992 57. Matkovic V, Fontana D, Tominac C, et al: Factors that influence peak bone mass formation: A study of calcium balance and the inheritance of bone mass in adolescent females. Am J Clin Nutr 52:878-888, 1990 58. Matkovic V, Kostial K, Simonovic I, et al: Bone status and fracture rates in two regions of Yugoslavia. Am J Clin Nutr 32:540-549, 1979 59. Mawer EB: Functional control over the metabolic activation of calciferol. In Parsons JA (ed): Endocrinology of Calcium Metabolism. New York, Raven Press, 1982, pp 271-295 60. Mazess RB: Bone densitometry for clinical diagnosis and monitoring. In Deluca HF, Mazess RB, (eds): Osteoporosis: Physiological Basis, Assessment and Treatment. New York, Elsevier, 1990, pp 63-85 61. Mazess RB: On aging bone loss. Clin Orthop 165:239-252, 1982 62. Mazess RB, Barden HS, Ettinger M, et al: Spine and femur density using dual photon absorptiometry in US white women. Bone Miner 2:211-219,1987 63. Melton LI, Chaos EYS, Lane J: Biomechanical aspects of fractures. In Riggs BL, Melton LJ (eds): Osteoporosis: Etiology, Diagnosis and Management. New York, Raven Press, 1988, pp 111-131 64. Melton LJ, Chrischilles EA, Cooper C, et al: How many women have osteoporosis? J Bone Miner Res 7:1005-1010, 1992 65. Melton LI, O'Fallon WM, Riggs BL: Secular trends in the incidence of hip fractures. Calcif Tissue Int 41:57-64, 1987 66. Murphy S, Khaw KT, May H, et al: Milk consumption and mineral density in middle aged and elderly women. Br Med J 308:939-941, 1994 67. Newton-John H, Morgan DB: The loss of bone with age, osteoporosis and fracture. Clin Orthop 71:229-252, 1970 68. Ott S: Editorial: Attainment of peak bone mass. J Clin Endocrinol Metab 71:1082A1082C, 1990 69. Parfitt MA: Bone age, mineral density, and fatigue damage. Calcif Tissue Int 53(suppl 1):82-86, 1993 70. Picard D, Ste-Marie LG, Coutu D, et al: Premenopausal mineral content relates to height, weight and calcium intake during early adulthood. Bone Miner 4:299-309,1988 71. Pitt MJ: Rickets and osteomalacia are still around. Radiol Clin North Am 29:97-118, 1991 72. PocQck NA, Eisman JA, Hopper JL, et al: Genetic determinants of bone mass in adults: A twin study. J Clin Invest 80:706-710, 1987 73. Qi Jc, Morrison NA, Kelly PI, et al: Vitamin D receptor alleles and prediction of bone mineral density. J Bone Miner Res 8(suppl 1):131, 1993 74. Recker RR, Davies MK, Hinders SM, et al: Bone gain in young adult women. JAMA 268:2403-2408, 1992 75. Report of WHO study group: Assessment of fracture risk and its application to screening for post-menopausal osteoporosis. In World Health Organization Geneva (eds): WHO Technical Series 843. 1994 76. Riggs BL, Wahner HW, Dunn WL, et al: Differential changes in bone mineral density of the appendicular and axial skeleton with aging. J Clin Invest 67:328-335, 1981 77. Riggs BL, Wahner HW, Melton LJ, et al: Rates of bone loss in the appendicular and axial skeletons of women: Evidence for substantial vertebral bone loss before menopause. J Clin Invest 77:1487-1491, 1986 78. Rodin A, Murby B, Smith MA, et al: Premenopausal bone loss in the lumbar spine and neck of the femur: A study of 225 Caucasian women. Bone 11:1-5, 1990 79. Sandler RB, Slemenda CW, Laporte RE, et al: Postmenopausal bone density and milk consumption in childhood and adolescence. Am J Clin Nutr 42:270-274, 1985 80. Seeman E, Hopper JL, Bach LA, et al: Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 320:554-558, 1989 81. Seeman E, Tsalamandris C, Formica C, et al: Reduced femoral neck bone density in
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the daughters of women with hip fractures: The role of low peak bone mass density in the pathogenesis of osteoporosis. J Bone Miner Res 5:739-743, 1994 Slemenda CW, Christian Je, Williams CJ, et al: Genetic determinants of bone mass in adult women: A reevaluation of the twin model and the potential importance of gene interaction on heritability estimates. J Bone Miner Res 6:561-567, 1991 Slemenda CW, Reister TK, Peacock M, et al: Bone growth in children following the cessation of calcium supplementation. J Bone Miner Res 8 (suppl 1):154, 1993 Slosman DO, Rizzoli R, Pichard C, et al: Longitudinal measurement of regional and whole body bone mass in young healthy adults. Osteoporos Int 4:185-190,1994 Smith DM, Nance WE, Kang KW, et al: Genetic determinants of bone mass. J Clin Invest 52:2800-2808, 1973 Stracke H, Renner E, Knie G, et al: Osteoporosis and bone metabolic parameters in dependence upon calcium intake through milk and milk products. Eur J Clin Nutr 47:617--622, 1993 Tanner JM, Whitehouse RH, Hughes PCR, et al: Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone deficient children. J Pediatr 89:1000-1008, 1976 Theintz G, Buchs B, Rizzoli R, et al: Longitudinal monitoring of bone mass accumulation in healthy adolescents: Evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects. J Clin Endocrinol Metab 75:1060-1065, 1992 Theintz GE, Howald H, Weiss U, et al: Evidence for a reduction of growth potential in adolescent female gymnasts. J Pediatr 122:306-313, 1993 Tokita A, Morrison NA, Qi JC, et al: Vitamin D receptor gene polymorphisms and peak bone mass. J Bone Miner Res 8(suppl 1):124, 1993 United States Department of Agriculture. Food and nutrient intakes of individuals in 1 day in the United States, spring 1977: Nation wide food consumption survey 1977-1978. Hyattsville, Maryland, USDA, Consumer Nutrition Center, 1980 Valimaki M, Karkkainen M, Lamberg-AHart C, et al: Exercise, smoking and calcium intake during adolescence and early adulthood as determinants of peak bone mass. Br Med J 309:230-235, 1994 Warnich RD, et al: Prediction of postmenopausal fracture risk with use of bone mineral measurements. Am J Gynecol 153:745-751, 1985 Wickham CAC, Walsh K, Cooper e, et al: Dietary calcium, physical activity, and risk of hip fracture: A prospective study. Br Med J 299:889-892, 1989 Address reprint requests to Anne-Lise Carrie Fassler, PhD Department of Nutrition Nestec Ltd. Nestle Research Center Vers-chez-les-Blanc Route du Jorat CH-lOOO Lausanne 26 Switzerland
PEDIATRIC NUTRITION
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OSTEOPOROSIS AS A PEDIATRIC PROBLEM Anne-Lise Carrie Fassler, PhD, and Jean-Philippe Bonjour, MD
Because osteoporosis is a major cause of morbidity, mortality, and medical expense worldwide, it has become a concern of public health authorities. Variation in bone mass accumulation during childhood and adolescence is now recognized as an important determinant of the risk of sustaining osteoporotic fractures during adult life; therefore, recent investigations have focused on the prevention of the disease. Some findings suggest that maximizing bone mass during growth constitutes one of the best preventive strategies. A consensus development conference in 199p4 dearly defined osteoporosis as "a disease characterized by low bone mass and micro architectural deterioration of bony tissue, leading to enhanced bone fragility and a consequent increase in fracture risk." This definition has been accepted by the World Health Organization, which now considers osteoporosis a major health problem?5 Although osteoporosis occurs in both sexes, women are more often affected, with a fracture prevalence about six times greater than in men in most populationsY, 64 At present, the lifetime risk for a 50-year-old white woman to sustain an osteoporotic fracture is estimated between 30% to 40%,64 The observation in many countries of increasing agespecific fracture incidence52, 65 and the continuing rise in life expectancy suggest that the incidence of osteoporosis is likely to worsen in the future for both men and women. Research by the authors of this article is supported by the Swiss National Foundation (grant no. 32-32415.91) and Nestec Ltd. From the Department of Nutrition, Nestec Ltd. Research Center, Lausanne (ALC); and the Division of Clinical Pathophysiology, World Health Organization Collaborating Center for Osteoporosis and Bone Disease, Department of Medicine, University Hospital, Geneva (JPB), Switzerland
PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 42 • NUMBER 4 • AUGUST 1995
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Cross-sectional and longitudinal studies show that bone mass develops with age, increasing to a peak value attained in early adulthood, remaining stable for some years, and decreasing thereafter. 61 , 62, 76 Peak bone mass (PBM) and rate of bone loss are therefore important determinants of the risk of osteoporotic fracture in the elderly. Because none of the present treatments can significantly restore the amount of bone lost in severe osteoporosis, emphasis is on prevention through maximizing PBM reached at maturity and through reducing subsequent bone loss. Therefore, even though osteoporosis is considered a disease of the elderly, prevention should be focused not only on preventing the bone loss occurring from the sixth decade but also on achievement of optimal PBM during childhood and adolescence. Thus the adolescent period may be critical for the development of the disease later in life. Although building the greatest skeletal mass within genetic limits is considered the best approach in preventing osteoporotic fractures,44, 67 little is known about the mechanisms involved in the attainment of a maximal PBM. Although some factors influencing bone mass have already been identified (e.g., dietary calcium and exercise), a better understanding of the physiology of bone mass growth is essential to further define adequate strategies for achieving optimal PBM and preventing osteoporosis. LOW BONE MASS: A MAJOR DETERMINANT OF FRACTURE RISK
Fracture risk is determined by a number of factors, including low bone mass, skeletal microdamage, geometric properties, and traumaP' 21,40,69 Among these factors, bone mass is the main determinant because it can account for up to 80% of the variance in skeletal strength as determined in vitro. 5 , 38, 61 Bone mass resistance to mechanical stress depends on both bone density and bone volume or size. 34 This has been confirmed by several prospective or longitudinal studies showing that patients with fractures have lower bone mass at the fracture site than controls. 23, 40, 63 Furthermore, one standard deviation (1 SD) decrease in bone mass has been estimated to account for a 50% to 100% increase in the risk of nonspinal fractures/ 5, 41, 93 and a 1 SD decrease in bone mass at the femoral neck is associated with a 160% increase in risk of hip fracture. 16 Therefore, low bone mass constitutes the major factor for sustaining a fracture, and consequently optimal bone mass is essential for osteoporosis prevention. TECHNIQUES FOR BONE MASS MEASUREMENT
Bone mass is generally estimated from measurements of bone mineral content (BMC) or bone mineral density (BMD) in the entire skeleton or at given sites. A number of noninvasive methods, with varying accuracy and precision depending on the skeletal region assessed,13, 14
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are currently available for bone mass measurements. Particularly in pediatrics, the most commonly used approach is dual X-ray absorptiometry. Mean volumetric mineral density (g hydroxyapatite/cm3 ) of bone can be determined by quantitative computed tomography (QCT). This technique can be used to measure the quantity of trabecular bone within fue vertebral bodyll; however, other densitometric techniques, including single- and dual-energy photon (spa, dpa) or x-ray (sXA, DXA) absorptiometry, which express BMC with respect to bone width (g/ cm) or bone area (g/cm2), are more useful in pediatrics. To estimate bone mass at the lumbar spine, femoral neck, or the total skeleton, the most commonly used technique at present is DXA, which provides areal BMD measurements (g/ cm2) that have been shown to be inversely related to bone strength and fue prevalence of osteoporotic fractures. 61 ,64 Because this measurement encompasses both volumetric mineral density and overall fuickness of scanned bone, it is particularly useful during puberty to assess bone mass changes, which are mostly due to increases in bone size. 7,88
OPTIMIZED PEAK BONE MASS FOR PREVENTION OF OSTEOPOROSIS
Adult bone mass at any time depends on both the amount achieved at skeletal maturity (Le., PBM) and the subsequent rate of bone 10ss.16, 41,76 Consequently, fue lower bone mass found in patients with fractures may be due to a lower PBM or to a greater bone 10ss.67, 80, 81 These two determinants may partly account for the sex differences in fue ageadjusted occurrence of osteoporotic fracture, because PBM is lower and subsequent rate of bone loss is greater in women fuan in men. Similarly, fue greater bone mass in black subjects fuan in white subjects may be attributed to the attainment of a greater PBM.27 The relative contribution of PBM and bone loss to fue development of fracture is difficult to evaluate, however, because of the time interval between fue attainment of PBM and fue occurrence of fractures. This issue has been addressed indirectly by studying fue premenopausal daughters of postmenopausal women wifu osteoporotic fractures; both mofuers and daughters were found to have lower spinal bone densities fuan could be predicted from age, menopausal status, height, and weight. 8o The influence of a low PBM in the development of osteoporosis was further supported by the finding that fuese daughters had reduced bone mass at fue lumbar spine and possibly at fue femoral neck compared wifu daughters of normal postmenopausal women. 81 The broad variability in bone mass observed in adults, particularly at sites such as the lumbar spine and fue femur,8 appears during adolescence, suggesting that fuese differences must occur during the rapid phase of bone mass accumulation at puberty.7, 8, 88 Uneven rates of bone loss after the
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menopause or with aging should also contribute to the bone mass variability observed in the elderly.
GREAT HETEROGENEITY IN SKELETAL DEVELOPMENT
Skeletal development is not linear throughout childhood and adolescence but varies according to sex, sexual maturation, and skeletal sites. Indeed, differences in skeletal development can be observed at several organization levels, for instance between axial and appendicular, or between proximal and distal limb segments, or between cortical and trabecular bone.
Longitudinal Growth and Rates of Bone Mass Accumulation
During the first years of life, the appendicular skeleton grows faster than the axial skeleton. During puberty, the axial skeleton growth is accelerated while appendicular skeleton growth remains linear.87 This heterogeneity in longitudinal bone growth could be the consequence of site-specific differential responses to various growth factors, including the growth hormone-insulin-like growth factor 1 (IGFl) system. 42, 87, 89 Similarly, distal limb segments' growth precedes growth of the proximal limb segments of the appendicular skeleton.lO In addition, heterogeneity in rates of bone mass accrual has been shown according to sites. 22 In this study, regional BMC from 8 years of age onward are reported as a percentage of regional peak BMC obtained at 15 years of age. At 8 years of age the skull bone density was 70% of its peak, whereas other sites were only about 30% of their peak. Bone mass is largely independent of height in adults, but in children there is a close relationship between bone mass and height, which disappears during puberty. This has been observed in a number of cross-sectional and longitudinal studies that showed a dissociation in rates of bone growth velocity and bone mass gain. 7,48, 88 Therefore, some determinants of bone mass accumulation during puberty at some sites of the skeleton must be independent from those responsible for gain in height. Bone mass accrual follows longitudinal growth, and the greatest disparity between height gain and bone mass accumulation rate is observed when growth velocity is at its maximum, that is from 11 to 12 years of age in girls and 13 to 14 years of age in boys?' 88 This asynchrony may result in transient bone fragility during adolescence that could explain the peak of fracture incidence reported at these ages, which has usually been attributed to risk-taking behavior. 1, 31
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Sex Differences Expressed During Pubertal Changes
During puberty, increases in bone mass gain do not occur at all skeletal sites at the same rate. In a longitudinal study using DXA, bone mass in both the lumbar spine (L5) and the femoral neck (FN) increased four- to sixfold in girls between 11 to 14 years of age and in boys 13 to 17 years of age. 88 In contrast, only a twofold increase in bone mass was observed at the midfemoral shaft, during the same period in both sexes. 88 It is well-known that bone mass at adulthood is greater in men than in women, with a significant sex difference in size and cortical thickness of most axial and appendicular bones. This gender difference develops during puberty; no consistent differences are observed in bone mass between male and female prepubertal children.?' 39, 48 In contrast, volumetric bone density is similar in both males and females from childhood to young adulthood. 2o,26 Thus, the greater bone mass, expressed in BMD jBMC as measured by DXA, accumulated during puberty in male adolescents as compared with female adolescents seems to result from a greater increase in bone size and cortical thickness.? Moreover, the increase in BMC at the lumbar spine during puberty is about tenfold greater than the corresponding mean increase in the volumetric trabecular density of the vertebrae, in both male and female adolescents. This suggests that a large part of bone mass increment observed during puberty results from an increase in size that is associated, at least at several axial and appendicular sites, with an increased thickness of the cortical shell. Both components are usually greater in male than in female adolescents. 8 As mentioned above, bone mass accrual accelerates at 11 years of age and 13 years of age in girls and boys, respectively, and BMD increases at a high rate for 3 consecutive years in girls as compared with 4 years in boys7, 88; however, BMD increments at the L5, the midfemoral shaft, and the FN slow sharply after 16 years of age in girls and virtually cease from 17 to 20 years of age (or 2 years after menarche). The gain in BMD is maintained in boys at the L5 and the midfemoral shaft but not at the FN up to 20 years of age. 88 Hence, these studies suggest that the greater bone mass in young adult males may be due to a longer pubertal maturation rather than to a greater rate of bone mass gain, and possibly to a greater "consolidation period" in duration or magnitude in boys than in girls. 8 The 2 years of additional prepubertal growth in boys may also be an important determinant of the sex difference in bone mass. 29 As previously mentioned, puberty is also the period during which the broad variability in bone mass observed in adults develops. The greatest increases in the variability of bone mass are found at the L5 and FN, two sites particularly susceptible to osteoporotic fractures, whereas the variability remains constant at the midfemoral shaft,?, 88 These differential changes in bone mass variability according to sites are not understood. They seem to result from a broader range of the variability in bone size rather than in volumetric bone mineral density.
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Time of Peak Bone Mass Attainment
Some cross-sectional and longitudinal studies have suggested that PBM at various skeletal sites in both men and women is attained in the mid-30s,24, 50, 74, 78 whereas others failed to show an increase in bone mass during the third decade, or even indicated a decreased bone mass during the same period. 25, 30, 39, 40, 77 Some investigations favor the conclusion that PBM in both the spine and the proximal femur is almost reached at 16 years of age in female adolescents?, 88 In addition, BMD at these sites was independent of age in a cohort of young adults from 20 to 35 years of age, and changes in bone mass at both the LS and the FN were not significant at a 1 year interval in either sex. 84 These longitudinal and cross-sectional studies are consistent with other published data reporting that bone mass gain ceased in the late teens. 28, 39, 51 This, however, does not mean that bone mass cannot be positively influenced by some appropriate lifestyle changes later in life. Skeletal development is therefore heterogeneous. Longitudinal growth and bone mass accumulation are sex-, pubertal stage-, and sitespecific in both rates and duration. Hence, exposure to protective or detrimental factors during growth may produce generalized and sitespecific effects that could influence the fracture risk later in life. INFLUENCE OF ENVIRONMENTAL FACTORS ON THE A ITAINMENT OF PBM
Many factors, including heredity, sex, diet, body weight, physical activity, hormonal status, and exposure to risk factors, are thought to influence bone mass accumulation during growth. IS, 33, 49, 68 It has been proposed from twin studies that the level of PBM achieved at maturity is largely dependent on genetic factors influencing both the overall growth pattern and the osteotropic endocrine system.72, 82, 85 Among these genetic factors, allelic variation in the vitamin D gene receptor may play a major role?3, 90 Some lifestyle factors, namely exercise and dietary calcium, are obviously of interest because they are susceptible to intervention. It is generally accepted that moderate physical activity positively influences bone mass development, especially at weight-bearing sites, during childhood and adolescencel9, 32,46, 92; however, any additional bone mass gain that possibly could be obtained with moderately increased levels of physical activity remains to be determined in wellcontrolled prospective longitudinal studies during growth. Such information is essential in order to provide credible public health recommendations. Importance of Calcium Metabolism for Bone Health
Calcium is an essential dietary nutrient not only as a major constituent of bone mineral (99% of body calcium is found in the skeleton),
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but also because of its involvement in numerous fundamental cellular mechanisms. To safeguard these essential functions when calcium intake is reduced, plasma calcium is maintained constant by effective regulatory mechanisms involving increased intestinal calcium absorption and renal tubular reabsorption capacities, and increased calcium mobilization from the skeletal pool. This regulation is achieved through increased production of parathyroid hormone (PTH) and 1,25 (OHh vitamin D (calcitriol, the active hormonal form of vitamin D). PTH acts primarily at the kidney level by enhancing the tubular reabsorption of calcium and stimulating the formation of calcitriol, but also at the skeletal level by mobilizing or storing calcium. Calcitriol stimulates intestinal calcium absorption, affects bone turnover, and down-regulates its own formation and the synthesis of PTH. The precursor of calcitriol is vitamin D, which therefore plays a central role in plasma calcium homeostasis. This vitamin is derived mainly from the skin, where it is synthesized from 7-dehydrocholesterol by ultraviolet light irradiation, and from the diet. Vitamin D deficiency may be present in individuals not exposed to sunlight, leading to defective mineralization with osteomalacia and rickets as a consequence 71 ; however, individuals with adequate vitamin D status metabolize vitamin D in the liver to form 25-hydroxyvitamin D, the storage form of the vitamin. Further metabolism to calcitriol is controlled in the kidney by PTH, IGFl, and plasma concentrations of calcium and phosphate. 59 Phosphate is as important as calcium for bone health because it contributes to about 50% of bone mineral weight. Both calcium and phosphate levels should be present in adequate quantities in the diet to ensure proper bone mass development. Low dietary phosphate levels are unusual in the United States because almost all foods contain phosphates as organic or inorganic phosphates; however, concern has arisen over a possible detrimental effect of excessive phosphate intakes on bone mass, because diets high in phosphates and low in calcium have been shown to increase serum PTH level,2,9 Although information is available about the phosphate effect on calcium-regulating hormones, consequences for bone mass development have not yet been shown. Recommended dietary allowances (RDA) for phosphorus levels are arbitrarily set to be identical to calcium RDAs, but the calcium-to-phosphorus ratio is considered less important than adequate calcium intake, as mentioned in a report of the Life Science Research Office. 53 Two other nutrients, sodium and protein, are reported to increase urinary calcium excretion; however, so far no study indicates that large intakes of either sodium or proteins would exert a deleterious effect on bone mass acquisition during growth. Whether variations within the "normal" range in the protein intake in well-nourished children and adolescents, independently of changes in energy supply, can influence skeletal growth and thereby modulate the genetic potential in PBM attainment is not known. This question is interesting because the protein intake can affect the growth hormone-IGFI system and thereby could modulate the rate of skeletal growth. 6
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Dietary Calcium and Peak Bone Mass
The earliest data suggesting an influence of dietary calcium on the achievement of PBM found a difference in bone mass and fracture rate in two Croatian populations with substantially different calcium intakes. 58 Although this study does not demonstrate a causal relationship between calcium intake and bone mass, the difference in bone mass was already present at 30 years of age, suggesting that the greatest effect of dietary calcium probably occurred during growth rather than at adulthood. Additional evidence for a positive effect of increased calcium intake on bone mass development was obtained in recent intervention and longitudinal studies. 45, 54, 74 Bone mass has been reported to be positively correlated with calcium and protein intake, and increased self-selected calcium intake was positively correlated with increased spinal bone mass in a cohort of young adult women. 74 A 3-year intervention study was conducted in 45 pairs of monozygotic twins, 6 to 14 years old at entry, whose usual calcium intake was about 900 mg/d. 45 One of each twin pair received supplemental calcium raising overall daily calcium intake to 1600 mg. No significant differences in BMD were found in subjects having already entered puberty; however, in the prepubertal twins taking 1600 mg calcium daily, midradius bone density gains were significantly greater from 6 months up to 3 years of supplementation. The authors suggested that calcium supplementation may have been beneficial in the older children, but its effect on bone mass accumulation was possibly masked by more potent factors expressed during puberty (e.g., growth hormone and sex steroids); however, in the prepubertal children, the observed benefit was not sustained 1 year after the supplementation at the level of the forearm. 83 Calcium supplementation during growth is proposed to exert its effect by a reduction in bone turnover and remodeling; the transient effect of calcium after cessation of the supplementation could result from a rapid return to normal bone turnover. Therefore, a continued high calcium intake throughout childhood and adolescence may be required for the achievement of a maximal PBM, as has been suggested from a number of retrospective studies. 66,70, 79, 86 Interestingly, calcium deficiency during growth may be a greater risk factor for hip fractures than spine fractures. 37, 66, 94 Recker and colleagues 74 have estimated that the risk of fracture at 70 years of age could be doubled by low calcium intakes in the first 30 years of age . . It remains intriguing that some studies have failed to show a relationship between calcium intake and bone mass. 3,92 These negative observations are usually explained by the possible interaction of confounding factors, such as other nutritional factors or physical activity differences, or due to too-small differences in calcium intakes between the groups studied. 4, 19, 36, 89 Indeed, there may be a threshold in calcium intake below which calcium balance increases with additional calcium but above which no further beneficial effects can be observed (e.g., up to 2.5 g of calcium intake daily).56 For PBM to be achieved within the
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genetic potential, the fraction of dietary calcium absorbed by the intestine must be sufficient to cover both skeletal demand during growth and obligatory losses (i.e., fecal, urinary, and dermal). The magnitude of positive balance required for optimal PBM is unknown. Calcium requirements have been reported to be greatest during infancy and adolescence. 55 For infants with adequate vitamin D status, RDAs are set at 400 mg/ d for up to 6 months and 600 mg/ d from 6 to 12 months. These calcium needs are assumed to be fully covered with breast- or bottle-feeding. Prematurity seems to impair further skeletal development and mineralization, but any long-term effect on PBM has not been yet established. During childhood, dietary intakes of approximately 800 mg/ d, the current RDA, may allow sufficient calcium retention to cover the skeletal requirement of about 100 mg calcium/ d. 55 Increasing calcium levels up to approximately 1400 mg/ d in short-term balance studies permitted greater retention, suggesting that optimal bone mass may not be achieved at current RDA.55 During the accelerated skeletal growth of adolescence, calcium retention has been estimated to range from 360 to 400 mg/ d,35 which would be achieved with intakes of 1200 mg, corresponding to the RDA for this age group55; however, Heaney5 has suggested that a greater RDA for this age group should be considered in view of the unchanged urinary calcium excretion with increased dietary calcium levels up to 1600 mg/ d observed in shortterm balance studies. 57 Whether this will be maintained in the long-term with positive consequence on bone mass gain is· not known. Thus, substantial benefits on bone mass accrual as a result of increasing calcium intake from 1200 mg daily to 1600 remains to be proven, prior to recommending changing the RDAs for this age group. Dietary surveys in the United States12,91 have shown that on average children consume sufficient calcium to meet the current RDA. Nevertheless, these surveys report decreased calcium intakes in females in adolescence at a time when their requirements are more than doubled. Consequently, female adolescents often do not meet their RDA. A low calcium intake at this age may partly account for the lower bone mass observed in older women, as suggested from retrospective studies.32, 37, 66, 70, 79, 86, 94 A 0.5 SD difference in bone mass has been estimated between women who reported consuming milk at every meal in youth and those who reported rarely or never consuming milk during this period. 43,79 Because a 1 SD difference in bone mass may increase the risk fracture by 50% to 160%, depending on the site, a high calcium intake in childhood and adolescence may reduce the fracture risk in later adulthood and in the elderly. The main food sources of calcium are dairy products; when these are excluded from the usual American diet, calcium intake is about 300 mg/ d. Efforts could therefore be focused on promoting, especially to adolescent girls, the consumption of dairy products or, alternatively, calcium-fortified foods whenever possible, because little or no risk to the consumer has been reported for calcium intakes in the range reported to be effective. A low calcium intake during growth is likely to decrease PBM;
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however, further research is required to establish the effects of calcium intakes on the magnitude of bone-mass gain before, during, and after puberty, particularly at sites such as the lumbar spine and the femoral neck, where osteoporotic fractures have their most devastating consequences in terms of both morbidity and mortality. It is essential to determine the growth period during which any dietary intervention can be most effective for bone mass gain, and when an intervention may still compensate for a former deficit, before generally recommending calcium supplementation for normal children. The response of bone mass accumulation to a given calcium intake is variable. Whether allelic variations in the vitamin D receptor gene may explain this uneven responsiveness remains to be determined. Hence, developments in the identification of genetic factors involved in bone mass may lead to future strategies aimed at maximizing PBM within each individual's genetic potential.
SUMMARY
Osteoporosis has long been considered a disease of the elderly; however, there is now a general agreement that predisposition begins in childhood and adolescence; thus, rational approaches to prevention of the disease should be started during childhood and adolescence. Indeed, by determining PBM, events occurring in the first two decades of life may determine in large part the subsequent risk of osteoporosis. Attention has thus been focused on the physiology of bone mass accumulation during growth, including the role of environmental factors such as dietary calcium and exercise. Because their patients are at this particular time of life, when PBM is being achieved, pediatricians are in a critical position to affect changes in the long-term risk of osteoporosis in their female and male patients. ACKNOWLEDGMENTS The authors are grateful to Professor John Eisman (Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, Australia) for his critical review of this article.
References 1. Alffram PA, Bauer GCH: Epidemiology of fractures of the forearm. J Bone Joint Surg Am 44:105-114,1962 2. Anderson JJB: Nutritional biochemistry of calcium and phosphorus. Journal of Nutritional Biochemistry 2:300-307, 1991 . 3. Angus RM, Sambrook PN, Pocock NA, et al: Dietary intake and bone mineral density. Bone Miner 4:465-477,1988 4. Armamento-Villareal R, Villareal DT, et al: Estrogen status and heredity are major determinants of premenopausal bone mass. J Clin Invest 90:2464-2471, 1992
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