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Determination of radial bone mineral content in low birth weight infants by photon absorptiometry
Determination of radial bone mineral content in low birth weight infants by photon absorptiometry Frank R. G r e e r , MD From the Department of Pediatrics, University of Wisconsin, Madison
Studies at the University of Wisconsin have demonstrated that photon absorptiometry is a precise, accurate, a n d reproducible technique for measuring bone mlneral content in premature infants and can be used to establish an "intrauterine" curve of bone mineralization in the fetus. Photon absorptlometry can also be used to measure bone width, thereby documenting appositional bone growth. The bone mineral c o n t e n t / b o n e width ratio may be helpful in identifying disorders of bone mineral metabolism in premature infants. The technique has been used to demonstrate that relatively poor bone mineralization ( c o m p a r e d with the intrauterine curve) occurs in very low birth weight infants after birth, regardless of the type of feeding or the presence or absence of bronchopulmonary dysplasia. (J PEDIATR1988;113:213-9)
The use of photon absorptiometry to determine bone mineral content in the pediatric population first appeared in the U.S. literature in 1972.1 This technique, as introduced by Mazess and Cameron, ~ who were working in the bone mineral laboratory of the University of Wisconsin, showed great promise over existing techniques for measuring bone mineralization. Conventional radiologic methods did not detect decreases in bone mineral of less than 30% to 40%, 2'3 and quantitative morphometric and photodensitometric methods could determine bone loss only within broad limits (10% to 20% error).4 Bone biopsy, tetracycline labeling, technetium scanning, and total skeletal biochemical analysis were not practical for serial determinations of bone mineral in infants and children. Photon absorptiometry for determining BMC in infants with very low birth weight was first used by Minton et al. 5 at the University of Cincinnati in 1979. In their report, BMC was measured longitudinally in six infants between 31 and 32 weeks gestational age at birth. Subsequently, in a small group of infants between 28 and 32 weeks gestation at birth, they demonstrated that BMC was dramatically Reprint requests: Frank R. Greer, MD, University of Wisconsin, Wisconsin Perinatal Center, 202 S. Park St., Madison, WI 53715.
improved in those infants fed an experimental formula containing high levels of calcium and phosphorus (126 mg/dl Ca and 63 mg/dl P) for the first 12 weeks of life.6 These two studies used a modified Norland-Cameron bone mineral analyzer (Norland Corp., Fort Atkinson, Wis.) to determine BMC. Although the accuracy and reproducibility in vivo of this technique had previously been demonstrated for adults, 7 these earlier reports did not include measurements of the BMC BPD BW Ca P VLBW
Bone mineral content Bronchopulmonary dysplasia Bone width Calcium Phosphorus Very low birth weight
small bones of the newborn infant. This distinction is important because the width of the distal radius in the infant at 28 weeks gestation averages 3.3 mm, in comparison with 147 +__ 14 mm in the young male adult) ,9 At this time, the technique as introduced for newborn infants was criticized both for its inaccuracy and its nonreproducibility, because the point of measurement on the radius was located by external measurement and the subject was not to move the arm during measurement.
213
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The Journal of Pediatrics July 1988
:.:.ii::.::.::.::.i:.i:,;iii: IU (3- - " 0
e-~-e
8O
-+ S.O. Controls
BPD ~ SD
E 0 "~ 60 E t,3 4 0 tn
11,15
20
n-13
//
I
, I
28-29
30-31
I
n-f3
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32-33 34-35
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Weeks Post Conception gig. 1. Bone mineral content as measured in milligrams per centimeter by photon absorptiometry versus weeks postconceptional age in growing VLBW premature infants with BPD and without BPD (control subjects). Unbroken, shaded line represents intrauterine change in BMC _+ SD. (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.)
CLINICAL
STUDIES
Accuracy and reproducibility of photon absorptiometry for infants. In 1980 and 1981, at the University of Wisconsin Bone Mineral Laboratory, a microcomputerbased, digital readout system of photon absorptiometry was designed specifically for determining BMC and bone width (a measure of appositional bone growth and hence of bone diameter) in the full-term and the preterm infant. 9 This system used a collimated, 2 mm diameter photon beam from a low-activity [12q], "spent" source (20 to 50 mCi) (Lunar Radiation Corp, Madison, Wis.). The accuracy of this technique was demonstrated on a series of very small bone sections (29 to 212 mg/cm, compared with the adult range of 600 to 1300 mg/cm), which were ashed after measurement of BMC by photon absorptiometry. The correlation coefficient for the ashed weight versus the measured BMC of the small bone section was r = 0.99 (standard error of estimate = 2.1 mg/cm). Immediate reproducibility (without repositioning of the arm) of the four to six scans for each BMC determination was good (coefficient of variation 3.9%). The repositioning error was small in 84 infants who were remeasured after the arm had been repositioned; the correlation coefficient before and after repositioning was 0.97 (standard error of estimate = 6.0 mg/em) for BMC. Initial clinical studies measuring bone mineral content and bone width in newborn infants. Our laboratory measured BMC and BW in 175 appropriate-for-gestationalage infants from 22 to 42 weeks gestation9,1~ 75 infants
were --<32 weeks gestational age. We then used these data to construct a curve of intrauterine BMC for further clinical studies?, 10By means of thermoluminescent dosimetry with lithium fluoride chips, we also determined that a series of four scans with this system delivered a radiation dose that did not exceed 13 mrad. This dosage is comparable to the radiation dose needed to obtain a pediatric chest radiograph, although the path of the scan with photon absorptiometry is only 0.3 mm wide. 9 In the initial clinical studies at the University of Wisconsin, we also observed that there were strong correlations between BMC and gestational age (r -- 0.92) and between BMC and birth weight (r = 0.89). 9 Likewise, BW correlated with gestational age and birth weight, with correlation coefficients of 0.84 and 0.85, respectively. Finally, we found a high correlation between BMC and BW (r -- 0.92) in newborn infants. Because of this direct relationship, we postulated that the ratio of BMC to BW would be useful in identifying disorders of bone mineral metabolism in low birth weight infants? Bone mineral content and bone width measurements in infants with and without bronchopulmonary dysplasia. In a subsequent study, we reported serial measurements of BMC and BW through the first 10 weeks of life in 38 VLBW premature infants (birth weight <1300 gm, gestational age <32 weeks). We hypothesized that during this period of active growth (as measured by increases of weight and length), BW would increase as a result of increased matrix formationJ ~ However, it was predicted that BMC would decrease or remain unchanged because of a mineral intake that was not sufficient to achieve the intrauterine rate of bone mineralization. In this study, 15 of 38 infants developed bronchopulmonary dysplasia. We hypothesized that this group could be distinguished from the 23 non-BPD infants by the close association between BPD and metabolic bone diseases, and we anticipated that the ratio of BMC to BW would be lower in the BPD group than in the control group. 1~ The results of this study showed that during the first 10 weeks of life, both BPI) and non-BPD groups had a low BMC in comparison with the intrauterine values (Fig. 1). Although appositional bone growth occurred (as measured by increase in radial BW), it was considerably slower than the intrauterine rate, both for control subjects and for infants with BPD (Fig. 2). Therefore it is not surprising that the B M C / B W ratio tended to decrease in both groups as age increased (Fig. 3). Finally, overall skeletal growth was documented by increases in length during the study period. The fact that BMC and BW are relatively decreased in these infants during a time when skeletal growth was occurring suggests a disorder of formation or remodeling of cortical bone, or both. This observation is
Volume 113 Number 1, part 2
Radial BMC in L B W infants by photon absOrptiometry
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Weeks Post Conception 2. Bone width measured in millimeters by Photon absorptiometry verSus weeks postconceptional age in growing VLBW premature infants with BPD and without BPD (cohtroi subjects). Unbroken, shaded line represents intrauterine change iia BW + SD. (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.) Fig.
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Weeks Post Conception Fig. 3. Ratio of BMC to BW versus postconceptional age, calculated from values used in Figs. 1 and 2, for BPD and control infants. Unbroken, shaded line represents intrauterine change in BMC/BW ratio + SD (see text). (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.)
supported by many reports Of diffusely demineralized bones Seen in routine x-ray studies of growing premature infants with metabolic bone disease. 1]'14 Such a disorder may be a result of a defect in the overall mineral{-zation process of cortical bone, of extensive cortical thinning and remodeling of normally mineralized bone, or of a combination thereof. In this study, although all infants received 400 IU/day of vitamin D, intakes of Ca (56 to 114 mg/kg/day) and P (49 to 67 mg/kg/day), even in the infants without BPD, Were generally lower than is needed to support the intrauterine rate of bone mineralization.~5-~7Insufficient intakes
of Ca and P would explain the lack of catch-up bone mineralization in infants both with and without BPD. Although a confirming study has recently been Published,18 we were surprised tha t bone mineralization was delayed to an equal degree in both conti'ol and BPD groups. Available evidence suggests that VLBW infants with BPD are at a greater risk for metabolic bone disease. 19Such infants are generally "sicker" than control infants, as documented by the duration of assisted~ ventilation, hospitalization, and supplemental oxygen therapy) ~ These infants also usually receive furosemide therapy, which increases Urinary Ca losses in premature infants) ~ Thus the data suggest that
2 16
Greer
The Journal of Pediatrics July 1988
T a b l e I. M e a s u r e m e n t s * of B M C , weight, length, and h e a d circumference ( O F C ) in B P D vs control infants during first year of life Birth Controls (n
BMC (mg/cm) Weight (gm) Length (cm) OFC (cm)
=
36.4 1037 36.5 25.3
16)
_+ 7.5 _+ 147 _+ 1.7 _+ 1.2
BPD (n
=
16)
32.9 -+ 6.3 986 _+ 158 35~6 _+ 2.7 25.9 _+ 1.8
3 Months
6 Weeks Controls
35.1 1464 39.9 28.4
+_ 10.7 _+ 334 + 2.0 _+ 1.0
BPD
28.1 1275 39.1 27.8
+- 7.2 + 227 _+ 2.0 _+ 1.8
Controls
56.9 3165 48.5 35.1
+ 18.2 _+ 704 _+ 3.4 _+ 2.1
BPD
43.0 2834 46.9 34.4
_+ 12.9 _+ 610 +__3.2 _+ 1.8
From Greer F, McCormick A. Am J Dis Child 1987;141:179-83. Copyright 1987, American Medical Association. *All values _+1 SD.
T a b l e II. B M C and B W _+ SD as measured by phOton a b s o r p t i o m e t r y
BMC (mg/crn, wk 0)t BMC (mg/cm, wk 6)~ ABMC (mg/cm) Bone width (mm, wk 0) Bone width (mm, wk 6) AB0ne width (mm)
Human milk (n = 40)
Foitified h u m a n milk (n = 40)
Similac SC (n = 8)
Similac (n = 40)
39.0 _+ 5.7
37.0 _ 7.4
35.0 _+ 7.4
36.8 +_ 4.4
NS
37.2 _+ 6.3
36.7 + 6.7
39.3 _+ 9.3
37.3 + 10.5
30.4 _+ 6.4
NS
72.6 _+ 14.1
-2.3 _+ 2.9 3.42 +_ 0.34
2.3 _+ 5.4 3.45 + 0.29
2.3 _+ 4.1 3.26 _+ 0.40
-6.4 _+ 5.3 3.27 _+ 0.42
p <0.01w NS
35.4 3.3 _+ 0.4
3.91 _+ 0.33
3.76 _+ 0.38
3.96 + 0.64
3.42 _+ 0.44
NS
4.5 _+ 0.5
0.49 _+ 0.23
0.31 _+ 0.32
0.70 _+ 0.54
0.15 -+ 0.32
p <0.0511
ANOVA
"Intrauterine"*
1.2
Sc, Special Care; .4NOVA, analysis of variance; NS, not significant. *"Intrauterine" values from reference t0. ~'Week 0 corresponds to age at which full feeds were obtained at approximately 30 to 31 weeks postconceptionalage. :~Week6 corresponds to 36 to 37 weeks p~176176 age: BMC~vs BMCo (Student t test): human milk, p <0.05; fortified human milk, NS; Similae SC, NS; Similac, p <0.05. w t test results: human milk vs fortified human milk, p <0.1; human milk vs Similac SC, fortified human milk vs Similac, and Simitac SC vs Similac, p
factors other t h a n the presence or absence of B P D are responsible for the 10w B M C in p r e m a t u r e infants. E x t r e m e p r e m a t u r i t y a n d inadequate C a and P intake m a y be more i m p o r t a n t t h a n the presence or absence of BPD. In a second clinical Study with p r e m a t u r e i n f a n t s with and without BPD, we c o m p a r e d bone mineralization and growth during the entire first year of life. s~ Again, we hypothesized t h a t B P D would be a major factor in the delay of bone m i n e r a l i z a t i o n and growth. This study differed from the previous study not only by its length of foll0w-up but als0 by the fact t h a t BPD infants were m a t c h e d with a control group for both b i r t h weight (986 _+ 158 vs 1037 _+ 147 gm) and gestational age (28:2 _+ 0.8 vs 28.4 + 1.2 weeks). W e were again surprised to find no differences in B M C between these two m a t c h e d groups of 16 V L B W prema-
ture infants during the first year of life ( T a b l e I). T h e absolute difference in B M C at i 2 m o n t h s was 5.3 m g / c m . As before, these data suggest t h a t factors o t h e r t h a n the presence or absence of B P D are responsible for the low B M C in these infants. E x t r e m e p r e m a t u r i t y a n d its prolonged, complicated course m a y explain this finding. Since most skeletal accretion of minerals in the fetus occurs d u r i n g the last :trimester Of pregnancy, all infants in this study were born with m u c h lower skeletal stores of Ca and P than term infants have. Significantly, infants in this study failed to achieve t h e B M C of full-term infants (90 m g / c m ) until after 6 m o n t h s chronologic age. Such hypomineralization results largely from initially low stores of C a and P and subsequently insufficient intakes. It is unlikely t h a t this slow rate of mineralization is due even in part to vitamin D deficiency. All infants in this study
Volume 113 Number 1, part 2
Radial B M C in L B W infants by photon absorptiometry
2 17
12.0 r"
9149
I1.0 Controls n =16
io9 t2 Months 6 Months Controls
71.7 5531 56.5 40.1
BPD
Controls (n = 15)
BPD (n = 14)
4-_ 20.7 65.4 _+ 11.7 109.7 _+ 19.2 104.4 +__21.4 +_ 1242 4900 + 1051 7420 _ 826 7440 _+ 1090 ___5.0 55.9 ___4.1 67.7 _+ 3.0 66.9 ___3.4 + 2.0 39.4 + 2.1 44.0 + 1.0 45.1 -!-_1.5
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receiVed at least the daily recommended vitamin D dose for premature infants of 400 I U / d a y throughout the first year of life, once full oral feedings were achieved. Because there was no difference in BMC between infants with BPD and the control groupr one would expect that these two groups would not differ in growth. In fact, the two groups did not differ during the first year of life in weight, length, or head circumference (Table I). In Fig. 4, the weights of the two groups are compared with the standard Babson curve for Weight in premature infants for the first year of life. The Babson curve is derived from the intrauterine growth curve for preterm infants and the extrauterine growth curve for full-term infants7 ~ Both groups showed considerable but nearly equal growth delays in weight9 Again, these findings contradict those reports that ascribe growth'retardation to the presence of BPD,Z2:26 along with poor nutritional intake and a greater expenditure of energy associated with severe pulmonary disease9 Formulas and bone mineral content in low birth weight infants. Neither mature human milk, preterm human milk,
nor standard commercial infant formula contains enough Ca and P (theoretically)to support optimal bone growth and mineralization in the low birth Weight infant,E7.28 unlike some of the high-mineral-content special formulas available for this group9 In our most recent study using photon absorptiometry to measure BMC in premature infants (birth Weight <1600 gm, gestational age <32 weeks), 29 we compared preterm human milk fortified with 0.85 gm/dl bovine whey, 90 mg/dl Ca, and 45 mg/dl P to three feeding regimens for 10w birth weight infants: !1) unfortified preterm human milk, (2) a special formula (or low birth weight infants (Similac Special Care, Ross Laboratories, Columbus, Ohio), and (3) a standard 20 cal/0z formula (Similac, Ross Laboratories). We hypothesized ihat adding Ca, P, and protein to the milk of mothers lactating prematurely would improve the rate of bone mineralization of infants fed such milk, in comparison with those being fed unfortified preterm human milk or standard commercial formula9 It was also expected that
o
._.2. 2 4 6 8
(28) (30)(32)
(34)(36)
12 r16
(40) (44)
20
(48}
24
(52)
38
(66)
52
(80)
Weeks Post Portum (Weeks Post Conception)
Changes in weight during first year of life in two groups of VLBW premature infants (with and without BPD) comPared with the intrauterine and extrauterine growth curves for weight, as derived by Babson for premature infants. (From Greer F, McCormick A. Am J Dis Child 1987;141:179-83. Copyright 1987, American Medical Association.) Fig. 4,
infants fed fortified human milk would compare favorably with those fed a special formula for preterm infants. Finally, we hypothesized that improvements in B M C would parallel gains in growth. Thirty-eight VLBW premature infants completed this study9 BMC showed improvement in the fortified human milk and Similac Special Care groups in comparison with those who received unfortified human milk or Similac during the first 6 weeks of full oral feedings (Table II). Infants in the fOrtified human milk or Similac Special Care g~'oups, who were receiving large amounts of supplementary Ca and P, achieved Ca intakes that approached 150 mg/kg/day, which is the intrauterine "requirement '' for Ca during the third trimester of pregnancy? 5-]7Despite these relatively high mineral intakes, the values for BMC in these two groups were still considerabiy lower than the comparable inti'auterine value for radial BMC (72.6 + 14.1 mg/cm at 36 to 37 weeks gestational age) at the time of discharge, 1~ although the bones continued to grow, as indicated by increases in BW (Table II) and overall body length9 The likely explanation for the relatively low values of BMC is that the percentage of Ca absorption and retentio n was considerably less than 100%. In addition, Ca and P salts contained in the fortifier are generally insoluble in water, although earlier studies of these Salts showed 65% to 75% intestinal absorption in preterm infants. 3~ The largest Change in B/VI~ was in the Similac group. In comparison with the fortified human milk and the Simiiac Special Care groups, the Similac group showed a loss of BMC (Table II). The major difference was that the
2 1$
Greer
The Journal of Pediatrics July 1988
T a b l e III. Rate of change in weight measurements (_+ SD) during 6 weeks of full feedings
Weight gain (gm/kg/day)
Human milk (n = 10)
Fortified human milk (n = 10)
Slmllac $C (n = 8)
Slmilac (n -- 10)
13.43 + 0.94
17.29 + 1.98
16.59 + 2.24
13.70 _+ 2.54
ANOVA
p <0.001"
sc. SpecialCare; ANOVA. analysisof variance.
*Student t test results:human milkvs fortifiedhumanmilk,p <0.001; human milkvs SimilacSC, p <0.001; fortifiedhumanmilkvs Similac,p <0.01;SimilacSC vs Similac,p <0.05.
Similac group h a d a significantly lower intake of Ca that resulted in a lower C a / P intake ratio (1.3 vs 2.0). Thus this study suggests that the C a / P ratio of 1.3 in Similac, a standard infant formula, may not be the most advantageous for bone mineralization in preterm infants in the early weeks of life. As expected fro m our previous studies, those groups with improved BMC (the fortified own mother's milk and the Simiiac Special Care groups) showed a faster rate of weight gairi than those groups without improvement in BMC (the human milk and the Similac groups) (Table III). As with BMCI however, all feeding groups at the time of discharge (36 to 37 weeks postconceptional age) were under the 50th percentile for weight according to the Babson growth curves for preterm infarits. 21 CONCLUSIONS Our clinical studies demonstrated that photon absorptiometry, in which very low doses Of ratiation are used, is a precise, accurate, and i'eproducible technique for measuring BMC in premature infants. When BMC is measured at birth, an intrauterine Curve of bone mineralization can be established for the fetus from 22 to 40 weeks gestation. This technique has also demonstrated that relatively poor bone mineralization may occur in premature infants after birth, regardless of the type of feeding. It is surprising that BMC is not, as a general rule, affected by the Presence or absence of BPD. One limitation of this technique is that only relatively s m a l l changes in BMC are evident over short periods. With our equipment, up to 5 to 6 weeks of serial measurements are needed before significant differences in BMC can be measured. We also demonstrated that photon absorptiometry can be Used to measure BW, thus documenting appositional bone growth in spite of relatively poor bone mineralization. In addition, the ratio of BMC to BW may be used to identify disorders of bone mineral metabolism in premature infants. REFERENCES
1. Mazess RB, Cameron JR. Growth of bone in school children: comparison of radiographic morphometry and photon absorptiometry. Growth 1972;36:77-92. 2. Griffiths H J, Zimmerman RE, Barty G, Snider R. The use of
photon absorpti0metry in the diagnosis of renal osteodystrophy. Radiology 1973;109:277-81. 3. Lachman E. Osteoporosis: the potentialities and limitations of its roentgenologic diagnosis. Am J Roentgenol 1955;74: 712-5. 4. Mazess RB, Cameron JR, Sorenson JA. A comparison of radiological methods for determining bone mineral content. I n : Whedon GD, Cameron JR, eds. Progress in methods of bone mineral measurement. Washington, D.C.: U.S. Department of Health, Education, and Welfare, 1970;455-79. 5. Minton SD, Steichen J J, Tsang RC. Bone mineral content in term .and preterm appropriate-for-gestational-ageinfants. J PEDXATR1979;95:1037-42. 6. Steichen J J, Gratton TL, Tsang RC. Osteopenia of prematurity:~ the cause and possible treatment. J PEDIATR 1980;96:528-34. 7. Cameron JR, Mazess RB, Sorenson JA~ Precision and accuracy of bone mineral determination by direct photon absorpti0metry. Invest Radiol 1968;3:141-50. 8. Mazess RB, Cameron JR. Bone mineral content in normal U.S. whites. Washington, D.C.: U.S. Department of Health, Education, and Welfai'e, 1973:228-38; DHEW publication no. (NIH) 75-683. 9. Greer FR, Lane J, Weiner S, Mazess RB. An accurate and reproducible absorptiometric technique for determining bone mineral content in newborn in fants. Pediatr Res 1983;17:25962. 10. Greer FR, McCormick A. Bone growth with low bone mineral content in very-low-birth-weight premature infants. Pediatr Res 1986;20:925-8. 11. Koo WW, Gupta JM, Nayanar VV, Wilkinson M, Posen S. Skeletal changes in preterm infants. Arch Dis Child t 982;57:447-52. 12. Hillman LS, Salmons S J, Slatopolsky E, McAllister WH. Serial serum 25-hydroxyvitamin D and mineral homeostasis in very premature infants~fed preterm human miik. J Pediatr Gastroenterol Nutr 1985;4:762-70. 13. Hillman LS, Holt N, Salmons S, Martin L; McAllister W, Haddad J. Mineral homeostasis in Very premature infants: Serial evaluation of serum 25-hydroxyvitamin D, serum minerals and bose mineralization. J PEDIATR 1985;106:970-80. 14. Laing IA, Glass EJ, Hendry GMA, et al. Rickets of prematurity: calcium and phosphorus supplementation. J PEDIATR 1985;106:265o8. 15. Shaw JCL. Parenteral nutrition in the management of sick low birth weight infants. Pediatr Clin North Am 1973;20:333-58. 16. Ziegler EE, O'Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. 17. Forbes GB. Calcium accumulation by the human fetus. Pediatrics 1976;57:976-7.
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Radial B M C in L B W infants by photon absorptiometry
18. Ryan S, Congelon P J, Horsman A, James JR, Truscott J, Arthur R. Bone mineral content in bronchopulmonary dysplasia. Arch Dis Child 1987;62:889-94. 19. Greer FR, Tsang RC. Calcium and vitamin D metabolism in term and low birth weight infants: review of recent investigations. Perinatology-Neonatology 1986;9:14-21. 20. Greer FR, McCormick A. Bone mineral content and growth in very low-birth-weight premature infants. Am J Dis Child 1987;141:179-83. 21. Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J PEDIATR 1976;89:814-20. 22. Markestad T, Fitzhardinge PM. Growth and development in children recovering from bronchopulmonary dysplasia. J PEDIATR 1981;98:597-602. 23. Shankaran S, Szego E, Eizert D, Seigel P. Severe bronchopulmonary dysplasia: predictors of survival and outcome. Chest 1984;86:607-10. 24. Mayes L, Perkett E, Stahlman MT. Severe bronchopulmonary dysplasia: a retrospective review. Acta Paediatr Scand 1983;72:225-9. 25. Yu VYH, Orgill AA, Lim SB, Bajuk R, Astbury J. Growth and development of very low birth weight infants recovering
26.
27.
28.
29.
30.
31.
2 19
from bronchopulmonary dysplasia. Arch Dis Child 1983; 58:791-4. Koops BL, Abman SH, Accurso FJ. Outpatient management and follow-up of bronchopulmonary dysplasia. Clin Perinatol 1984;11:101-23. Forbes GB. Nutritional adequacy of human breast milk for premature infants. In: Lebenthal E, ed. TextbOok of gastroenterology and nutrition in infancy; vol I. New York: Raven Press, 1981;321-9. Greer FR, Steichen J J, Tsang RC. Calcium and phosphate supplements in breast milk-related rickets. Am J Dis Child 1982;136:581-3. Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. J PEDIATR 1988;112:961-9. Shenai JP, Reynolds JW, Babson SG. Nutritional balance studies in very-low-birth-weight infants: enhanced nutrient retention rates by an experimental formula. Pediatrics 1980;66:233-8. Huston R, Reynolds J, Jensen C, Buist W. Nutrient and mineral retention and vitamin D absorption in low-birthweight infants: effect of medium-chain triglycerides. Pediatrics 1983;72:44-8.
Studies at the University of Wisconsin have demonstrated that photon absorptiometry is a precise, accurate, a n d reproducible technique for measuring bone mlneral content in premature infants and can be used to establish an "intrauterine" curve of bone mineralization in the fetus. Photon absorptlometry can also be used to measure bone width, thereby documenting appositional bone growth. The bone mineral c o n t e n t / b o n e width ratio may be helpful in identifying disorders of bone mineral metabolism in premature infants. The technique has been used to demonstrate that relatively poor bone mineralization ( c o m p a r e d with the intrauterine curve) occurs in very low birth weight infants after birth, regardless of the type of feeding or the presence or absence of bronchopulmonary dysplasia. (J PEDIATR1988;113:213-9)
The use of photon absorptiometry to determine bone mineral content in the pediatric population first appeared in the U.S. literature in 1972.1 This technique, as introduced by Mazess and Cameron, ~ who were working in the bone mineral laboratory of the University of Wisconsin, showed great promise over existing techniques for measuring bone mineralization. Conventional radiologic methods did not detect decreases in bone mineral of less than 30% to 40%, 2'3 and quantitative morphometric and photodensitometric methods could determine bone loss only within broad limits (10% to 20% error).4 Bone biopsy, tetracycline labeling, technetium scanning, and total skeletal biochemical analysis were not practical for serial determinations of bone mineral in infants and children. Photon absorptiometry for determining BMC in infants with very low birth weight was first used by Minton et al. 5 at the University of Cincinnati in 1979. In their report, BMC was measured longitudinally in six infants between 31 and 32 weeks gestational age at birth. Subsequently, in a small group of infants between 28 and 32 weeks gestation at birth, they demonstrated that BMC was dramatically Reprint requests: Frank R. Greer, MD, University of Wisconsin, Wisconsin Perinatal Center, 202 S. Park St., Madison, WI 53715.
improved in those infants fed an experimental formula containing high levels of calcium and phosphorus (126 mg/dl Ca and 63 mg/dl P) for the first 12 weeks of life.6 These two studies used a modified Norland-Cameron bone mineral analyzer (Norland Corp., Fort Atkinson, Wis.) to determine BMC. Although the accuracy and reproducibility in vivo of this technique had previously been demonstrated for adults, 7 these earlier reports did not include measurements of the BMC BPD BW Ca P VLBW
Bone mineral content Bronchopulmonary dysplasia Bone width Calcium Phosphorus Very low birth weight
small bones of the newborn infant. This distinction is important because the width of the distal radius in the infant at 28 weeks gestation averages 3.3 mm, in comparison with 147 +__ 14 mm in the young male adult) ,9 At this time, the technique as introduced for newborn infants was criticized both for its inaccuracy and its nonreproducibility, because the point of measurement on the radius was located by external measurement and the subject was not to move the arm during measurement.
213
21 4
Greer
I00
The Journal of Pediatrics July 1988
:.:.ii::.::.::.::.i:.i:,;iii: IU (3- - " 0
e-~-e
8O
-+ S.O. Controls
BPD ~ SD
E 0 "~ 60 E t,3 4 0 tn
11,15
20
n-13
//
I
, I
28-29
30-31
I
n-f3
I
32-33 34-35
nM4
I
I
36-37
38-59
Weeks Post Conception gig. 1. Bone mineral content as measured in milligrams per centimeter by photon absorptiometry versus weeks postconceptional age in growing VLBW premature infants with BPD and without BPD (control subjects). Unbroken, shaded line represents intrauterine change in BMC _+ SD. (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.)
CLINICAL
STUDIES
Accuracy and reproducibility of photon absorptiometry for infants. In 1980 and 1981, at the University of Wisconsin Bone Mineral Laboratory, a microcomputerbased, digital readout system of photon absorptiometry was designed specifically for determining BMC and bone width (a measure of appositional bone growth and hence of bone diameter) in the full-term and the preterm infant. 9 This system used a collimated, 2 mm diameter photon beam from a low-activity [12q], "spent" source (20 to 50 mCi) (Lunar Radiation Corp, Madison, Wis.). The accuracy of this technique was demonstrated on a series of very small bone sections (29 to 212 mg/cm, compared with the adult range of 600 to 1300 mg/cm), which were ashed after measurement of BMC by photon absorptiometry. The correlation coefficient for the ashed weight versus the measured BMC of the small bone section was r = 0.99 (standard error of estimate = 2.1 mg/cm). Immediate reproducibility (without repositioning of the arm) of the four to six scans for each BMC determination was good (coefficient of variation 3.9%). The repositioning error was small in 84 infants who were remeasured after the arm had been repositioned; the correlation coefficient before and after repositioning was 0.97 (standard error of estimate = 6.0 mg/em) for BMC. Initial clinical studies measuring bone mineral content and bone width in newborn infants. Our laboratory measured BMC and BW in 175 appropriate-for-gestationalage infants from 22 to 42 weeks gestation9,1~ 75 infants
were --<32 weeks gestational age. We then used these data to construct a curve of intrauterine BMC for further clinical studies?, 10By means of thermoluminescent dosimetry with lithium fluoride chips, we also determined that a series of four scans with this system delivered a radiation dose that did not exceed 13 mrad. This dosage is comparable to the radiation dose needed to obtain a pediatric chest radiograph, although the path of the scan with photon absorptiometry is only 0.3 mm wide. 9 In the initial clinical studies at the University of Wisconsin, we also observed that there were strong correlations between BMC and gestational age (r -- 0.92) and between BMC and birth weight (r = 0.89). 9 Likewise, BW correlated with gestational age and birth weight, with correlation coefficients of 0.84 and 0.85, respectively. Finally, we found a high correlation between BMC and BW (r -- 0.92) in newborn infants. Because of this direct relationship, we postulated that the ratio of BMC to BW would be useful in identifying disorders of bone mineral metabolism in low birth weight infants? Bone mineral content and bone width measurements in infants with and without bronchopulmonary dysplasia. In a subsequent study, we reported serial measurements of BMC and BW through the first 10 weeks of life in 38 VLBW premature infants (birth weight <1300 gm, gestational age <32 weeks). We hypothesized that during this period of active growth (as measured by increases of weight and length), BW would increase as a result of increased matrix formationJ ~ However, it was predicted that BMC would decrease or remain unchanged because of a mineral intake that was not sufficient to achieve the intrauterine rate of bone mineralization. In this study, 15 of 38 infants developed bronchopulmonary dysplasia. We hypothesized that this group could be distinguished from the 23 non-BPD infants by the close association between BPD and metabolic bone diseases, and we anticipated that the ratio of BMC to BW would be lower in the BPD group than in the control group. 1~ The results of this study showed that during the first 10 weeks of life, both BPI) and non-BPD groups had a low BMC in comparison with the intrauterine values (Fig. 1). Although appositional bone growth occurred (as measured by increase in radial BW), it was considerably slower than the intrauterine rate, both for control subjects and for infants with BPD (Fig. 2). Therefore it is not surprising that the B M C / B W ratio tended to decrease in both groups as age increased (Fig. 3). Finally, overall skeletal growth was documented by increases in length during the study period. The fact that BMC and BW are relatively decreased in these infants during a time when skeletal growth was occurring suggests a disorder of formation or remodeling of cortical bone, or both. This observation is
Volume 113 Number 1, part 2
Radial BMC in L B W infants by photon absOrptiometry
A
E E e" "10 ~
i'ii!!::::i:i TU:I:SD ..:.:.:........... 0---0 Controls e- - -0 BP D
5.0
i
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4.0
~ii~l!,..~:.~)t;: .....
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qr
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n=13
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.,
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j. n=15
0
nn 2 . 5 //
2 15
I
t
32-33
34'35
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I
36-37
38-39
Weeks Post Conception 2. Bone width measured in millimeters by Photon absorptiometry verSus weeks postconceptional age in growing VLBW premature infants with BPD and without BPD (cohtroi subjects). Unbroken, shaded line represents intrauterine change iia BW + SD. (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.) Fig.
:.:.:..............,
2O
:.:.::............. IU • SD 0--'0 Controls
16
nn
iii!iii~i!~!ii~~:i:i:"~:i:!:""~z' i~'i:i~:i:"!!~:~":i:,~:~ :"":_n:2l ':~2222__(~~: _t~:22'1}1:2_~n=16 22
12
0
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:58-59
Weeks Post Conception Fig. 3. Ratio of BMC to BW versus postconceptional age, calculated from values used in Figs. 1 and 2, for BPD and control infants. Unbroken, shaded line represents intrauterine change in BMC/BW ratio + SD (see text). (From Greer FR, McCormick A. Pediatr Res 1986;20:925-8.)
supported by many reports Of diffusely demineralized bones Seen in routine x-ray studies of growing premature infants with metabolic bone disease. 1]'14 Such a disorder may be a result of a defect in the overall mineral{-zation process of cortical bone, of extensive cortical thinning and remodeling of normally mineralized bone, or of a combination thereof. In this study, although all infants received 400 IU/day of vitamin D, intakes of Ca (56 to 114 mg/kg/day) and P (49 to 67 mg/kg/day), even in the infants without BPD, Were generally lower than is needed to support the intrauterine rate of bone mineralization.~5-~7Insufficient intakes
of Ca and P would explain the lack of catch-up bone mineralization in infants both with and without BPD. Although a confirming study has recently been Published,18 we were surprised tha t bone mineralization was delayed to an equal degree in both conti'ol and BPD groups. Available evidence suggests that VLBW infants with BPD are at a greater risk for metabolic bone disease. 19Such infants are generally "sicker" than control infants, as documented by the duration of assisted~ ventilation, hospitalization, and supplemental oxygen therapy) ~ These infants also usually receive furosemide therapy, which increases Urinary Ca losses in premature infants) ~ Thus the data suggest that
2 16
Greer
The Journal of Pediatrics July 1988
T a b l e I. M e a s u r e m e n t s * of B M C , weight, length, and h e a d circumference ( O F C ) in B P D vs control infants during first year of life Birth Controls (n
BMC (mg/cm) Weight (gm) Length (cm) OFC (cm)
=
36.4 1037 36.5 25.3
16)
_+ 7.5 _+ 147 _+ 1.7 _+ 1.2
BPD (n
=
16)
32.9 -+ 6.3 986 _+ 158 35~6 _+ 2.7 25.9 _+ 1.8
3 Months
6 Weeks Controls
35.1 1464 39.9 28.4
+_ 10.7 _+ 334 + 2.0 _+ 1.0
BPD
28.1 1275 39.1 27.8
+- 7.2 + 227 _+ 2.0 _+ 1.8
Controls
56.9 3165 48.5 35.1
+ 18.2 _+ 704 _+ 3.4 _+ 2.1
BPD
43.0 2834 46.9 34.4
_+ 12.9 _+ 610 +__3.2 _+ 1.8
From Greer F, McCormick A. Am J Dis Child 1987;141:179-83. Copyright 1987, American Medical Association. *All values _+1 SD.
T a b l e II. B M C and B W _+ SD as measured by phOton a b s o r p t i o m e t r y
BMC (mg/crn, wk 0)t BMC (mg/cm, wk 6)~ ABMC (mg/cm) Bone width (mm, wk 0) Bone width (mm, wk 6) AB0ne width (mm)
Human milk (n = 40)
Foitified h u m a n milk (n = 40)
Similac SC (n = 8)
Similac (n = 40)
39.0 _+ 5.7
37.0 _ 7.4
35.0 _+ 7.4
36.8 +_ 4.4
NS
37.2 _+ 6.3
36.7 + 6.7
39.3 _+ 9.3
37.3 + 10.5
30.4 _+ 6.4
NS
72.6 _+ 14.1
-2.3 _+ 2.9 3.42 +_ 0.34
2.3 _+ 5.4 3.45 + 0.29
2.3 _+ 4.1 3.26 _+ 0.40
-6.4 _+ 5.3 3.27 _+ 0.42
p <0.01w NS
35.4 3.3 _+ 0.4
3.91 _+ 0.33
3.76 _+ 0.38
3.96 + 0.64
3.42 _+ 0.44
NS
4.5 _+ 0.5
0.49 _+ 0.23
0.31 _+ 0.32
0.70 _+ 0.54
0.15 -+ 0.32
p <0.0511
ANOVA
"Intrauterine"*
1.2
Sc, Special Care; .4NOVA, analysis of variance; NS, not significant. *"Intrauterine" values from reference t0. ~'Week 0 corresponds to age at which full feeds were obtained at approximately 30 to 31 weeks postconceptionalage. :~Week6 corresponds to 36 to 37 weeks p~176176 age: BMC~vs BMCo (Student t test): human milk, p <0.05; fortified human milk, NS; Similae SC, NS; Similac, p <0.05. w t test results: human milk vs fortified human milk, p <0.1; human milk vs Similac SC, fortified human milk vs Similac, and Simitac SC vs Similac, p
factors other t h a n the presence or absence of B P D are responsible for the 10w B M C in p r e m a t u r e infants. E x t r e m e p r e m a t u r i t y a n d inadequate C a and P intake m a y be more i m p o r t a n t t h a n the presence or absence of BPD. In a second clinical Study with p r e m a t u r e i n f a n t s with and without BPD, we c o m p a r e d bone mineralization and growth during the entire first year of life. s~ Again, we hypothesized t h a t B P D would be a major factor in the delay of bone m i n e r a l i z a t i o n and growth. This study differed from the previous study not only by its length of foll0w-up but als0 by the fact t h a t BPD infants were m a t c h e d with a control group for both b i r t h weight (986 _+ 158 vs 1037 _+ 147 gm) and gestational age (28:2 _+ 0.8 vs 28.4 + 1.2 weeks). W e were again surprised to find no differences in B M C between these two m a t c h e d groups of 16 V L B W prema-
ture infants during the first year of life ( T a b l e I). T h e absolute difference in B M C at i 2 m o n t h s was 5.3 m g / c m . As before, these data suggest t h a t factors o t h e r t h a n the presence or absence of B P D are responsible for the low B M C in these infants. E x t r e m e p r e m a t u r i t y a n d its prolonged, complicated course m a y explain this finding. Since most skeletal accretion of minerals in the fetus occurs d u r i n g the last :trimester Of pregnancy, all infants in this study were born with m u c h lower skeletal stores of Ca and P than term infants have. Significantly, infants in this study failed to achieve t h e B M C of full-term infants (90 m g / c m ) until after 6 m o n t h s chronologic age. Such hypomineralization results largely from initially low stores of C a and P and subsequently insufficient intakes. It is unlikely t h a t this slow rate of mineralization is due even in part to vitamin D deficiency. All infants in this study
Volume 113 Number 1, part 2
Radial B M C in L B W infants by photon absorptiometry
2 17
12.0 r"
9149
I1.0 Controls n =16
io9 t2 Months 6 Months Controls
71.7 5531 56.5 40.1
BPD
Controls (n = 15)
BPD (n = 14)
4-_ 20.7 65.4 _+ 11.7 109.7 _+ 19.2 104.4 +__21.4 +_ 1242 4900 + 1051 7420 _ 826 7440 _+ 1090 ___5.0 55.9 ___4.1 67.7 _+ 3.0 66.9 ___3.4 + 2.0 39.4 + 2.1 44.0 + 1.0 45.1 -!-_1.5
------
9.0
BPD
..-9
n=16
.- .." 9
Mean
~ 8.0
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. : 7.O .~ 6.0
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/ r..
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/
...~;;, j
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4.0 5.0
..
, :,,,/"
.
f
/
f
2.0 1.0
receiVed at least the daily recommended vitamin D dose for premature infants of 400 I U / d a y throughout the first year of life, once full oral feedings were achieved. Because there was no difference in BMC between infants with BPD and the control groupr one would expect that these two groups would not differ in growth. In fact, the two groups did not differ during the first year of life in weight, length, or head circumference (Table I). In Fig. 4, the weights of the two groups are compared with the standard Babson curve for Weight in premature infants for the first year of life. The Babson curve is derived from the intrauterine growth curve for preterm infants and the extrauterine growth curve for full-term infants7 ~ Both groups showed considerable but nearly equal growth delays in weight9 Again, these findings contradict those reports that ascribe growth'retardation to the presence of BPD,Z2:26 along with poor nutritional intake and a greater expenditure of energy associated with severe pulmonary disease9 Formulas and bone mineral content in low birth weight infants. Neither mature human milk, preterm human milk,
nor standard commercial infant formula contains enough Ca and P (theoretically)to support optimal bone growth and mineralization in the low birth Weight infant,E7.28 unlike some of the high-mineral-content special formulas available for this group9 In our most recent study using photon absorptiometry to measure BMC in premature infants (birth Weight <1600 gm, gestational age <32 weeks), 29 we compared preterm human milk fortified with 0.85 gm/dl bovine whey, 90 mg/dl Ca, and 45 mg/dl P to three feeding regimens for 10w birth weight infants: !1) unfortified preterm human milk, (2) a special formula (or low birth weight infants (Similac Special Care, Ross Laboratories, Columbus, Ohio), and (3) a standard 20 cal/0z formula (Similac, Ross Laboratories). We hypothesized ihat adding Ca, P, and protein to the milk of mothers lactating prematurely would improve the rate of bone mineralization of infants fed such milk, in comparison with those being fed unfortified preterm human milk or standard commercial formula9 It was also expected that
o
._.2. 2 4 6 8
(28) (30)(32)
(34)(36)
12 r16
(40) (44)
20
(48}
24
(52)
38
(66)
52
(80)
Weeks Post Portum (Weeks Post Conception)
Changes in weight during first year of life in two groups of VLBW premature infants (with and without BPD) comPared with the intrauterine and extrauterine growth curves for weight, as derived by Babson for premature infants. (From Greer F, McCormick A. Am J Dis Child 1987;141:179-83. Copyright 1987, American Medical Association.) Fig. 4,
infants fed fortified human milk would compare favorably with those fed a special formula for preterm infants. Finally, we hypothesized that improvements in B M C would parallel gains in growth. Thirty-eight VLBW premature infants completed this study9 BMC showed improvement in the fortified human milk and Similac Special Care groups in comparison with those who received unfortified human milk or Similac during the first 6 weeks of full oral feedings (Table II). Infants in the fOrtified human milk or Similac Special Care g~'oups, who were receiving large amounts of supplementary Ca and P, achieved Ca intakes that approached 150 mg/kg/day, which is the intrauterine "requirement '' for Ca during the third trimester of pregnancy? 5-]7Despite these relatively high mineral intakes, the values for BMC in these two groups were still considerabiy lower than the comparable inti'auterine value for radial BMC (72.6 + 14.1 mg/cm at 36 to 37 weeks gestational age) at the time of discharge, 1~ although the bones continued to grow, as indicated by increases in BW (Table II) and overall body length9 The likely explanation for the relatively low values of BMC is that the percentage of Ca absorption and retentio n was considerably less than 100%. In addition, Ca and P salts contained in the fortifier are generally insoluble in water, although earlier studies of these Salts showed 65% to 75% intestinal absorption in preterm infants. 3~ The largest Change in B/VI~ was in the Similac group. In comparison with the fortified human milk and the Simiiac Special Care groups, the Similac group showed a loss of BMC (Table II). The major difference was that the
2 1$
Greer
The Journal of Pediatrics July 1988
T a b l e III. Rate of change in weight measurements (_+ SD) during 6 weeks of full feedings
Weight gain (gm/kg/day)
Human milk (n = 10)
Fortified human milk (n = 10)
Slmllac $C (n = 8)
Slmilac (n -- 10)
13.43 + 0.94
17.29 + 1.98
16.59 + 2.24
13.70 _+ 2.54
ANOVA
p <0.001"
sc. SpecialCare; ANOVA. analysisof variance.
*Student t test results:human milkvs fortifiedhumanmilk,p <0.001; human milkvs SimilacSC, p <0.001; fortifiedhumanmilkvs Similac,p <0.01;SimilacSC vs Similac,p <0.05.
Similac group h a d a significantly lower intake of Ca that resulted in a lower C a / P intake ratio (1.3 vs 2.0). Thus this study suggests that the C a / P ratio of 1.3 in Similac, a standard infant formula, may not be the most advantageous for bone mineralization in preterm infants in the early weeks of life. As expected fro m our previous studies, those groups with improved BMC (the fortified own mother's milk and the Simiiac Special Care groups) showed a faster rate of weight gairi than those groups without improvement in BMC (the human milk and the Similac groups) (Table III). As with BMCI however, all feeding groups at the time of discharge (36 to 37 weeks postconceptional age) were under the 50th percentile for weight according to the Babson growth curves for preterm infarits. 21 CONCLUSIONS Our clinical studies demonstrated that photon absorptiometry, in which very low doses Of ratiation are used, is a precise, accurate, and i'eproducible technique for measuring BMC in premature infants. When BMC is measured at birth, an intrauterine Curve of bone mineralization can be established for the fetus from 22 to 40 weeks gestation. This technique has also demonstrated that relatively poor bone mineralization may occur in premature infants after birth, regardless of the type of feeding. It is surprising that BMC is not, as a general rule, affected by the Presence or absence of BPD. One limitation of this technique is that only relatively s m a l l changes in BMC are evident over short periods. With our equipment, up to 5 to 6 weeks of serial measurements are needed before significant differences in BMC can be measured. We also demonstrated that photon absorptiometry can be Used to measure BW, thus documenting appositional bone growth in spite of relatively poor bone mineralization. In addition, the ratio of BMC to BW may be used to identify disorders of bone mineral metabolism in premature infants. REFERENCES
1. Mazess RB, Cameron JR. Growth of bone in school children: comparison of radiographic morphometry and photon absorptiometry. Growth 1972;36:77-92. 2. Griffiths H J, Zimmerman RE, Barty G, Snider R. The use of
photon absorpti0metry in the diagnosis of renal osteodystrophy. Radiology 1973;109:277-81. 3. Lachman E. Osteoporosis: the potentialities and limitations of its roentgenologic diagnosis. Am J Roentgenol 1955;74: 712-5. 4. Mazess RB, Cameron JR, Sorenson JA. A comparison of radiological methods for determining bone mineral content. I n : Whedon GD, Cameron JR, eds. Progress in methods of bone mineral measurement. Washington, D.C.: U.S. Department of Health, Education, and Welfare, 1970;455-79. 5. Minton SD, Steichen J J, Tsang RC. Bone mineral content in term .and preterm appropriate-for-gestational-ageinfants. J PEDXATR1979;95:1037-42. 6. Steichen J J, Gratton TL, Tsang RC. Osteopenia of prematurity:~ the cause and possible treatment. J PEDIATR 1980;96:528-34. 7. Cameron JR, Mazess RB, Sorenson JA~ Precision and accuracy of bone mineral determination by direct photon absorpti0metry. Invest Radiol 1968;3:141-50. 8. Mazess RB, Cameron JR. Bone mineral content in normal U.S. whites. Washington, D.C.: U.S. Department of Health, Education, and Welfai'e, 1973:228-38; DHEW publication no. (NIH) 75-683. 9. Greer FR, Lane J, Weiner S, Mazess RB. An accurate and reproducible absorptiometric technique for determining bone mineral content in newborn in fants. Pediatr Res 1983;17:25962. 10. Greer FR, McCormick A. Bone growth with low bone mineral content in very-low-birth-weight premature infants. Pediatr Res 1986;20:925-8. 11. Koo WW, Gupta JM, Nayanar VV, Wilkinson M, Posen S. Skeletal changes in preterm infants. Arch Dis Child t 982;57:447-52. 12. Hillman LS, Salmons S J, Slatopolsky E, McAllister WH. Serial serum 25-hydroxyvitamin D and mineral homeostasis in very premature infants~fed preterm human miik. J Pediatr Gastroenterol Nutr 1985;4:762-70. 13. Hillman LS, Holt N, Salmons S, Martin L; McAllister W, Haddad J. Mineral homeostasis in Very premature infants: Serial evaluation of serum 25-hydroxyvitamin D, serum minerals and bose mineralization. J PEDIATR 1985;106:970-80. 14. Laing IA, Glass EJ, Hendry GMA, et al. Rickets of prematurity: calcium and phosphorus supplementation. J PEDIATR 1985;106:265o8. 15. Shaw JCL. Parenteral nutrition in the management of sick low birth weight infants. Pediatr Clin North Am 1973;20:333-58. 16. Ziegler EE, O'Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. 17. Forbes GB. Calcium accumulation by the human fetus. Pediatrics 1976;57:976-7.
Volume 113 Number 1, part 2
Radial B M C in L B W infants by photon absorptiometry
18. Ryan S, Congelon P J, Horsman A, James JR, Truscott J, Arthur R. Bone mineral content in bronchopulmonary dysplasia. Arch Dis Child 1987;62:889-94. 19. Greer FR, Tsang RC. Calcium and vitamin D metabolism in term and low birth weight infants: review of recent investigations. Perinatology-Neonatology 1986;9:14-21. 20. Greer FR, McCormick A. Bone mineral content and growth in very low-birth-weight premature infants. Am J Dis Child 1987;141:179-83. 21. Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J PEDIATR 1976;89:814-20. 22. Markestad T, Fitzhardinge PM. Growth and development in children recovering from bronchopulmonary dysplasia. J PEDIATR 1981;98:597-602. 23. Shankaran S, Szego E, Eizert D, Seigel P. Severe bronchopulmonary dysplasia: predictors of survival and outcome. Chest 1984;86:607-10. 24. Mayes L, Perkett E, Stahlman MT. Severe bronchopulmonary dysplasia: a retrospective review. Acta Paediatr Scand 1983;72:225-9. 25. Yu VYH, Orgill AA, Lim SB, Bajuk R, Astbury J. Growth and development of very low birth weight infants recovering
26.
27.
28.
29.
30.
31.
2 19
from bronchopulmonary dysplasia. Arch Dis Child 1983; 58:791-4. Koops BL, Abman SH, Accurso FJ. Outpatient management and follow-up of bronchopulmonary dysplasia. Clin Perinatol 1984;11:101-23. Forbes GB. Nutritional adequacy of human breast milk for premature infants. In: Lebenthal E, ed. TextbOok of gastroenterology and nutrition in infancy; vol I. New York: Raven Press, 1981;321-9. Greer FR, Steichen J J, Tsang RC. Calcium and phosphate supplements in breast milk-related rickets. Am J Dis Child 1982;136:581-3. Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. J PEDIATR 1988;112:961-9. Shenai JP, Reynolds JW, Babson SG. Nutritional balance studies in very-low-birth-weight infants: enhanced nutrient retention rates by an experimental formula. Pediatrics 1980;66:233-8. Huston R, Reynolds J, Jensen C, Buist W. Nutrient and mineral retention and vitamin D absorption in low-birthweight infants: effect of medium-chain triglycerides. Pediatrics 1983;72:44-8.