1. Archives of Disease in Childhood, 1989, 64, 1403-1409
Regular review
Bone disease in preterm infants
N BISHOP
Dunn Nutritional Laboratory, Cambridge
New work in bone physiology and cell biology In well preterm infants, hypocalcaemia will usually
during the last decade has made it possible to begin to improve by 24-30 hours of age, with values
construct a model for the bone disease of preterm in the adult normal range attained by 48-60 hours.
infants variously labelled 'rickets', 'osteopenia', and Factors unrelated to bone metabolism, particularly
'metabolic bone disease of prematurity'. The model tissue hypoxia with subsequent calcium influx, may
proposed here explains its pathogenesis and its contribute to the low calcium concentrations seen in
outcomes, and suggests a sequence of appropriate the sickest infants, in whom hypocalcaemia is more
investigations as well as a scheme of management. likely to persist and be more pronounced.
The figure illustrates the basic processes of bone Previous workers have suggested, however, that
mineral metabolism in the perinatal period, and the plasma parathormone concentration does not
provides a framework against which the derange- rise after birth, and that parathormone 'resistance' is
ment in mineral homoeostasis leading to bone likely to occur in preterm infants. Much of the early
disease can be more clearly visualised. work on parathormone in the perinatal period was
carried out using radioimmunoassays for either the
Fetal bone mineral homoeostasis carbon or the nitrogen terminal moiety of the
molecule. Parathormone is an 84 amino acid peptide
Mineral accretion rates for both calcium and that is rapidly and continuously synthesised and
phosphorus increase throughout pregnancy, reaching almost immediately subjected to intracellular
a maxiumum during the third trimester of 3-0-3*7 degradation.6 Inactive fragments and intact mole-
mmol/kg/day for calcium and 2-4-2-7 mmol/kg/day cules are stored together and then released,
for phosphorus.' principally in response to hypocalcaemia. An
Fetal plasma calcitonin concentrations are also increase in the amount of active hormone secreted
raised in utero2; though this peptide hormone is could remain undetected, as the total terminal
known principally for its hypocalcaemic action, specific assay activity might not change appreciably.
there is substantial evidence that it has appreciable More recent studies, however, carried out with
anabolic, mineral accreting effects on bone. intact-molecule and active fragment (residues 1-34)
In contrast, the principal hormones mediating assays, have shown a two fold to five fold increase in
bone resorption in later life, parathormone, and 1, active parathormone secretion during the first 48
25 dihydroxycholecalciferol, are found in low con- hours after birth.5 The principal target organs for
centrations in the fetus.2 3 Interestingly, however, the parathormone molecules thus released are bone
prolonged low dose administration of these hor- and kidney. In response to parathormone the kidney
mones in animals results in increased bone mass and reabsorbs calcium and actively excretes phosphorus.
thus both may be actively concerned in the accretion A reasonable indication of the response to para-
rather than resorption of mineral in utero.4 thormone would therefore be to monitor urinary
output of phosphorus over the first days after birth.
The rwst 48 hours The longitudinal changes in whole blood ionised
calcium up to the age of 72 hours, and in urinary
After ligation of the cord, the supply of calcium, phosphorus excretion up to the age of 5 days were
phosphorus, and all other nutrients ceases abruptly. studied in 18 preterm infants. High urinary concen-
The continuing demand by bone for calcium en- trations of phosphorus on days 2 and 3 after birth
trains a rapid fall in blood calcium concentrations; were observed; subsequently, the phosphorus loss
the nadir for ionised calcium is usually at about 18 diminished rapidly and by day 5 phosphorus ex-
hours of age, slightly before that for total calcium.5 cretion had ceased in most of the infants studied
1403

2. 1404 Bishop
In the uterus (i) High blood calcium, phosphate, and calcitonin concentrations with high bone mineral accretion rates
(ii) Low circulating parathormone, and 1,25 dihydroxycholecalciferol concentrations
First 48 hours (i) Transplacental calcium infusion ceases, bone accretion continues, and blood calcium concentration falls
(ii) Plasma calcitonin surge exacerbates fall in blood calcium concentration
(iii) Hypocalcaemia induces parathormone rise in plasma with effects on bone and kidney
Renal effects of parathormone
Increased
production of
1,25 dihydroxycholecalciferol Adaptive reabsorption of
calcium with increased phosphate
excretion: body phosphorus
stores fall
Bone effects of
Bone effects of parathormone 1,25 dihydroxycholecalciferol
Bone resorption
Matrix degradation Release of
products-some act Calcium, Phosphate
as local humoral factors I
Potential for further loss
of phosphorus in urine
Nutrient supply
Production of bone matrix Bone miineral accretion + Influence of favourable
local factors,
matrix vesicles
New bone formation:
remodelling, growth,
and mineralisation
Figure Outline of processes of bone mineral metabolism in the perinatal period.
(unpublished observations). These observations absorption of calcium and phosphorus, but also the
parallel results from animal studies of the effects of mobilisation of calcium from bone. 1,25 dihydroxy-
exogenously administered parathormone on phos- cholecalciferol has a central role in the maintenance
phate metabolism in states of phosphorus repletion of calcium homoeostasis, which is discussed in detail
and depletion.4 below.
Another important consequence of the action of The release of parathormone is probably poten-
parathormone on the kidney is the enhancement of tiated by the apparently paradoxical release of
1,25 dihydrocholecalciferol synthesis. 1,25 di- calcitonin almost immediately after birth.7 In post-
hydroxycholecalciferol is the most active metabolite natal life calcitonin is secreted postprandially in
of vitamin D3 affecting not only the gastrointestinal response to gastrin production, and the initial surge

3. Bone disease in preterm infants 1405
of gastrin after the first feed may be responsible for tion by osteoblasts. The increase in resorptive
the increase in plasma calcitonin concentrations activity initiated by the surge of parathormone after
seen at this time.' Calcitonin inhibits the resorptive birth is therefore matched by a concurrent increase
response of osteoclasts and so delays the supply of in new bone formation. Though matrix volume is
calcium from bone to the circulation. The postnatal not reduced during this period of intense activity,
regulation of calcium homoeostasis is principally net loss of bone mineral will occur if the exogenous
achieved by the interlocking actions of para- supply of mineral substrate is inadequate.
thormone and 1,25 dihydroxycholecalciferol on In addition to the supply of adequate mineral
bone, and by their separate effects on absorption substrate to normally functioning osteoblasts, a
and retention of mineral substrate. favourable local environment for bone mineralisa-
tion is also crucial to the remodelling and growth of
Bone resorption bone; many factors have been identified in labora-
tory studies as having a role. In particular, there is a
The isolation and culture of pure cell lines of growing body of evidence to support the part played
osteoblasts and osteoclasts, have enabled rapid by matrix vesicles in the initiation and propagation
advances in our understanding of the underlying of crystallisation. 2
processes in bone.9`11 It is now clear that osteoblasts Matrix vesicles are discrete sacs that are derived
and osteoclasts act. together to undertake bone from the osteoblast cell membrane. They are
resorption, and that osteoclasts, having no para- composed of a phospholipid bilayer rich in phos-
thormone receptors, exert resorptive activity in phatase enzymes including alkaline phosphatase,
response to signals from osteoblasts. The specific and they accumulate at the growing front of bone.
effects of parathormone on bone are4: increased At the pH of the mineralisation front, alkaline
osteoblast permeability to calcium; release of phosphatase functions principally as a phospho-
collagenase from osteoblasts; and release of osteo- transferase, transporting phosphate residues that
clast activating factor(s) from osteoblasts, as a result have been cleaved by other phosphatase enzymes
of which osteoclasts increase in number and activity. into the vesicle's sap.
In addition, 1,25 dihydroxycholecalciferol, Calcium enters the vesicle by diffusion, and is
produced in response to the increased concentra- trapped by phosphatidyl serine. The additional
tions of parathormone, exerts synergistic effects on accumulation of phosphate raises the saturation of
bone.9 1 These are: activation of an osteoblastic the vesicle sap to the point where the calcium/
calcium pump; increased activation and fusion of the phosphate solubility product is exceeded and
monocyte/macrophage precursors of osteoclasts; crystallisation begins. Electron microscopic pictures
production by osteoblasts of osteocalcin (Gla have shown the growth of crystals on the inner
protein), which is chemotactic for osteoclasts; leaflet of the vesicle that leads to its subsequent
effects on immune cell function, particularly disruption as the ends of the crystal pierce the
lymphocytes, with reduced interleukin 2, and in- bilayered membrane.
creased interleukin 1 production, which enhances These crystals then seed into the fluid at the
osteoclast formation and activity; and possibly a mineralisation front and, given adequate mineral
reduced response of osteoblasts to parathormone substrate there, act as foci for further crystallisation.
(reduced cyclic adenosine monophosphate response). The rate of turnover of matrix vesicles with the
Thus parathormone and 1,25 dihydroxychole- release of their membrane constituents, therefore,
calciferol have complementary actions; the increase reflects the rate of initiation of crystallisation.
in osteoblast permeability to calcium flux with the Laboratory studies have shown that there are
activation of a specific calcium pump provides an greatly increased numbers of matrix vesicles in
acute response to falling ionised calcium concen- rachitic growth plates'3; this lends support to the
trations. The recruitment, activation, and fusion of concept that increased alkaline phosphatase activity
osteoclast precursors, and their subsequent activity in plasma may represent increased vesicle turnover
in response to osteoblast derived humoral factors, in substrate or vitamin D deficient states.
provides a longer term source of calcium. During the early neonatal period the main deter-
minants of bone remodelling, mineralisation, and
New bone formation growth are those that have been discussed in detail
above. There are, however, many other factors
The result of the resorptive process is to produce affecting the fine control of bone homoeostasis,9 11
calcium, phosphorus, and breakdown products of of which two are of particular relevance to the
bone matrix. These breakdown products are preterm infant.
thought to act locally to promote new bone forma- Aluminium is a potent inhibitor of bone minerali-

4. 1406 Bishop
sation, and is present as a contaminant in parenteral in order to supply the needs of other tissues. The
nutrition solutions. 13 Up to 80% of the intravenously biochemical outcomes of these processes are inter-
administered load may be retained, and significant linked; reduced concentrations of phosphate in
deposition was found in bone after three weeks of urine and plasma precede the increasing urinary loss
parenteral feeding. It is possible that aluminium of calcium, and in extreme cases, hypercalcaemia.
may exacerbate bone disease in preterm infants fed Raised plasma alkaline phosphatase activity is
intravenously. seen principally after 6 weeks of age.
Immobility also causes loss of bone mass. Stress Radiological and anthropometric changes occur
generated electrical potentials have been implicated slowly,15 being seldom evident before 6 weeks of
in the osteogenic process, and prolonged periods of age. l In the long term the principle outcomes for
sedation or paralysis during mechanical ventilation bone are linear growth, mineral content, and
increase the possibility of the loss of bone mass. structural integrity. In a large study of preterm
infants receiving different diets during the neonatal
Mineral substrate insufficiency period, we found a significant association between
the increase in plasma alkaline phosphatase activity
Given an adequate nutrient supply, remodelling, and a reduction in height achieved at both 9 and 18
mineralisation, and growth of bone should proceed months implying that bone disease, reflected by
normally in most infants. For bone disease to increased remodelling activity during the first weeks
develop, depletion of mineral substrate must occur. of life, had a lasting effect on the infants' growth
Phosphorus depletion is likely to develop more potential up to the age of 18 months.16
rapidly as it may initially be lost in the urine, and If these differences persist, then it is likely that the
protoplasmic metabolic requirements for phos- nutritional deprivation sustained by bone during this
phorus are greater than for calcium (extrapolating apparently critical phase of development has 'pro-
from data on fetal accretion rates and body com- grammed' the bone to grow less slowly, as catch up
position studies, 0-6-0-7 mmol/kg/day compared growth would otherwise be observed when dietary
with 0-2-03 mmol/kg/day). sufficiency was achieved.'6
Inadequate dietary provision of phosphorus-for The regulatory mechanisms for this adaptive
instance, the exclusive use of unsupplemented change remain to be elucidated, but could involve
human milk-compounded by the initial urinary changes in cell number, type, or function, either
phosphorus losses will result in low tissue phos- locally or systemically.
phorus stores, and low circulating concentrations of
phosphorus. Investigation of early bone disease
The reduced delivery of phosphorus to the kidney
prevents further appreciable urinary losses and Plasma phosphate concentrations fall gradually from
enhances renal production of 1,25 dihydroxy- 2 mmol/l to 10-O1-5 mmol/l over the first week, and
cholecalciferol. The increase in circulating 1,25 often reach a nadir during the second week after
dihydroxycholecalciferol in turn increases gastro- birth (unpublished observations). In infants
intestinal absorption of both calcium and phos- depleted of phosphorus as a result of urinary losses
phorus. In addition, the release of parathormone is and poor intake a further reduction to <1 mmol/l
inhibited, further reducing the risk of phosphorus may occur, and this has been reported to be
loss in the urine. As a corollary, however, renal associated with the later development of bio-
reabsorption of calcium is reduced, with consequent chemical and radiological evidence of bone disease.
hypercalcuria. The inhibition of parathormone Urinary phosphate excretion initially may be in-
release may also slow the process of bone re- creased but by day 5 is usually negligible. By
absorption; nevertheless, the potent bone resorbing contrast, urinary calcium losses increase and persist
activity of 1,25 dihydroxycholecalciferol will during the period that tissue phosphorus stores
continue to remove some calcium and phosphorus remain depleted. A prolonged absence of phosphate
from bone. from the urine with persisting calciuria would imply
In addition to the phosphorus absorbing and continued tissue phosphorus depletion, and might
retaining processes detailed above, it is possible that be a useful marker to follow sequentially in an
hypophosphataemia is a key factor in accelerating individual infant.
directly or indirectly the turnover of matrix vesicles The natural history of plasma alkaline phos-
and hence increasing plasma alkaline phosphatase phatase activity is to rise over the first 3 weeks and
activity. plateau until the age of 5-6 weeks. Rises that occur
If mineral substrate provision continues to be after this are seen principally in infants with
inadequate, further substrate will be lost from bone persistently low plasma phosphorus concentrations

5. Bone disease in preterm infants 1407
receiving low phosphate diets-for instance, un- rate of mineral crystallisation; photonabsorptio-
supplemented human milk. Increased plasma metry gives an estimation of the amount of mineral
alkaline phosphatase activity is widely quoted as actually in bone; and radiographs best show the
being indicative of bone disease; difficulties arise in abnormal remodelling re'sulting from an inadequate
the interpretation of results and comparison with provision of mineral substrate for bones that are
other centres because of the use of different assay continuing to increase their matrix volume.
systems with widely varying ranges and different Short term anthropometry is useful as a non-
units of measurement. Peak concentrations of specific adjunct to the radiological and biochemical
greater than 7-5 times the maximum adult normal investigations in that a reduced linear growth velo-
value for that particular alkaline phosphate assay city at the age of 6 weeks would provide further
have been associated with reduced linear growth evidence to support the diagnosis of bone disease. 16
velocity in the short term.14 In the work previously For practical purposes, sequential analysis of
referred to we found an area of demarcation at five urinary calcium and phosphorus losses is likely to
times the maximum normal adult value for plasma provide the earliest evidence of incipient metabolic
alkaline phosphatase activity, with appreciable bone disease. If by the age of 3 weeks calcium
reductions in growth potential for infants with peak excretion is continuing, with no phosphorus appear-
concentrations exceeding this limit.16 ing in the urine despite adopting the prophylactic
Radiological changes are usually not seen until measures outlined below, further mineral supple-
the age of 6 weeks; reduced bone density, and mentation should be instituted.
abnormal bone remodelling in the form of cuppin ,
splaying, and fraying of epiphyses may occur, -
Management
and-in extreme cases-there may be fractures of
both ribs and long bones. The interpretation of The management of this condition should essentially
radiographs is, however, subjective and the use of follow the dictum 'prevention is better than cure'.
scoring systems has not improved their predictive The degree and duration of mineral, and in parti-
value for minor to moderate degrees of deminerali- cular phosphorus, depletion that will result in bone
sation. disease and the amount of supplementation that will
Photonabsorptiometry is a quick and accurate prevent it are unknown. It is nevertheless possible to
method of assessing sequentially the changes in look at the provision of substrate by current feeding
bone mineral content at a specific site, usually the practices, formulate estimates of comparative bone
distal radius. 17 Photonabsorptiometry has shown mineral accretion rates, and so assess the minimum
that in infants receiving diets containing little 'preventative' amounts of substrate intake required.
mineral substrate, bone mineral content may remain Unsupplemented human milk contains 0-5 mmol/
unchanged, or even decrease initially, and then 100 ml of phosphorus. For infants receiving 200
increase at a rate much less that attained in the ml/kg/day, and assuming 90-95% retention, 0-9-
uterus. By contrast, infants supplied with mineral in 0-95 mmol/kg/day of phosphorus will be delivered.
amounts approaching the intrauterine rate can After allowing for basal protoplasmic requirements,
maintain the fetal rate of mineral accretion.18 The approximately 0-3 mmol of phosphorus will be
use of photonabsorptiometry is restricted to a few available for deposition in bone mineral. Calcium
selected centres, however, and its principle use at and phosphorus accrete at a ratio of 5:3 in bone; up
present is for research rather than as an aid to to 0-5 mmol/kg of calcium might therefore be
diagnosis. deposited-about 15% of the intrauterine accretion
Radiographic densitometry is a low dose whole rate.
body technique that provides accurate information By contrast, a preterm formula containing 1
about the overall mineral state of the skeleton. As mmol/100 ml of phosphorus supplied at 180 ml/kg/
yet it has not been applied to preterm infants, but it day should result in a phosphorus retention of
could provide valuable data for body composition 1- 61-7 mmollkg/day. After allowing for proto-
and mineral metabolism studies. plasmic requirements, about 1 mmol/kg/day of
It has been often noted that peak alkaline phosphorus is available for bone mineralisation,
phosphatase activity rarely occurs at the same complexing with 1-6 mmol/kg/day of calcium-
time as radiological evidence of abnormal bone approximately 50% of the intrauterine accretion
remodelling, or the degree of bone demineralisation rate. Formulas with higher calcium and phosphorus
as measured by photonabsorptiometry. This is contents are available in some countries, and have
essentially a reflection of the intrinsic properties of been used widely without adverse effects. Reported
each investigation-plasma alkaline phosphatase mineral accretion rates for infants fed these milks
activity is a measure of bone activity, possibly of the approach those achieved in the uterus,'8 but the

6. 1408 Bishop
reports are usually of well infants, fed fully by the adverse outcome for bone. For infants born to
enteral route by the age of 1 week. In addition, mothers not receiving vitamin D supplementation,
concern has been expressed generally that not all of as much as 1200 IU/day may be required. Increasing
the calcium and phosphate in these milks is available the supply of vitamin D3 further may increase the
for absorption, possibly as a result of precipitation short term retention of calcium, particularly in those
before feeding. infants in whom the supply of substrate is poor, but
Given that protoplasmic requirements may be may also have longer term consequences for bone
increased because of pre-existing tissue phosphorus resorption and remodelling activities. In addition
depletion, particularly in infants who have pre- there may be as yet undefined consequences on
viously been intravenously fed, the provision of 1 cellular differentiation in other tissues; vitamin D3 is
mmol/100 ml of phosphorus in milk given to preterm a steroid type molecule, and a potent mitogenic
infants should be regarded as an absolute minimum. agent.
The addition of phosphorus to expressed human Most preterm infants will not benefit from being
milk is already common. Buffered neutral phos- given the active metabolites of vitamin D3; these
phate can safely be admixed with human milk over a should be confined to those patients in whom a
24 hour period to raise the phosphorus content from vitamin D3 resistant state, for example, X linked
0-5 mmolV100 ml to 1-0 mmol/100 ml. hypophosphataemic rickets, has been confirmed.
Larger quantities of both calcium and phosphorus Intravenously fed preterm infants are most at risk
can be added to human milk. It is important to add from poor supplies of mineral substrate. The solu-
the phosphorus salt (usually disodium phosphate) bility of calcium and phosphorus in parenteral
first so that it can enter the fat micelles. There is an nutrition solutions depends on a number of factors:
appreciable risk of precipitation if calcium (usually the pH and the amino acid composition of the
given as calcium gluconate/glubionate) is added solution, the calcium salt used, and the temperature
before the phosphorus. to which the solution is exposed.
As much as 1-6 mmol of phosphorus and 1-35 The more acidic the solution, the greater the
mmol of calcium can be added in this way. 19 quantity of mineral substrate it can hold, and for
Although some precipitation does occur, balance most solutions calcium gluconate is more soluble
studies indicate that the absorption and retention of than calcium chloride. Recently, amino acid solu-
both calcium and phosphorus from such solutions is tions 'tailored' to the requirements of infants have
good. been produced, with claims of improved capacity for
The multinutrient fortifiers added to breast milk calcium and phosphate. The testing of these
in some countries rely upon 'stabilising agents' to solutions has not, however, taken account of the
hold large quantities of mineral substrate in solu- prolonged exposure to high temperatures (37°C for
tion. Problems with precipitation and reduced more than two hours) that may obtain in clinical
absorption and retention have been reported, practice.
however, and in one study20 it was found that The risk of precipitation with line blockage, or
retention of substrate from a preterm formula even microembolisation of crystalline particles,
exceeded that from a fortified human milk solution. should not be ignored when using solutions with
The use of such fortifiers is still the subject of calcium and phosphate contents near the limit of
intense research, and they cannot be unreservedly solubility. The use of microporous filters within the
recommended for general use. line would reduce these risks appreciably. Using
The addition of phosphorus to preterm formula is currently available amino acid solutions infused at
unlikely to be beneficial as the total amount of 150 mllkg/day, 1-1 mmol/kg/day of phosphorus and
calcium retained and available for bone mineralisa- 1-5 mmol/kg/day of calcium can be administered at
tion is already completely utilised. Further addition most. Claims of improved solubility and mineral
of phosphate may in fact precipitate calcium from delivery using glucose-i-phosphate have been made,
the milk solution, further reducing availability of the but the use of an intermediary metabolite for this
substrate. purpose is still under investigation.
Vitamin D3 should be given routinely to all In addition to problems with calcium and phos-
preterm infants.2' For infants born in the United phorus delivery, the presence of high concentrations
Kingdom whose mothers have received vitamin D of aluminium in some solutions has given rise to
supplementation during pregnancy the current concern about possible inhibition of osteoblastic
recommendations are for 400-1000 IU/day, function in infants receiving prolonged intravenous
although it should be noted that with adequate feeding.
dietary provision of calcium and phosphorus as little In clinical practice, the infants likely to require
as 100 IU/day has been given without obvious mineral supplementation are those of less than 33

7. Bone disease in preterm infants 1409
weeks' gestation. A reasonable 'prophylactic' Sorcini-Carta M. Plasma thyrocalcitonin and parathyroid
measure would be the addition of 0-5 mmol of hormone concentrations in early neonatal hypocalcaemia. Arch
Dis Child 1987;62:580-4.
neutral phosphate solution to each 100 ml of 8Talmage RV, Cooper CW, Toverud SU. The physiological
expressed breast milk, or the use of a preterm significance of calcitonin. In: Peck WA, ed. Bone and mineral
formula containing at least 1 mmol/100 ml of research. Vol 1. Amsterdam: Excerpta Medica, 1983:74-143.
phosphorus, and 1-75 mmol/100 ml of calcium. 9Sakamoto S, Sakamoto M. Bone collagenase, osteoblasts, and
cell mediated bone resorption. In: Peck WA, ed. Bone and
Supplementation should start as soon as enteral mineral research. Vol 4. Amsterdam: Elsevier, 1986:49-102.
feeds are started, and continue until the infant 0 Mundy GR, Roodman GD. Osteoclast ontogeny and function.
achieves a weight of 2 kg or leaves the nursery. A In: Peck WA, ed. Bone and mineral research. Vol 5. Amster-
urinary calcium: phosphorus ratio of >1 at the age dam: Elsevier, 1987:209-80.
Baron R, Vignery A, Horowitz M. Lymphocytes, macrophages
of 3 weeks is an indication for further supple- and the regulation of bone remodelling. In: Peck WA, ed. Bone
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milks with higher mineral densities are available 175-243.
overseas, and may be introduced in the United 12 Anderson HC. Matrix vesicle calcification: review and update.
In: Peck WA, ed. Bone and mineral research. Vol 3. Amster-
Kingdom in the near future. Breast milk can be dam: Elsevier, 1985:109-50.
supplemented with both calcium and phorphorus 13 Sedman AB, Klein GL, Merritt RJ, et al. Evidence of
using the previously described method. aluminium loading in infants receiving intravenous therapy.
It is hoped that early mineral supplementation N Engl J Med 1985;312:1337-43.
14 Cooper PA, Rothberg AD, Pettifor JM. Early follow-up of very
will result in a reduction in the incidence of low birthweight infants after hospital discharge with respect to
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and maximise the potential for subsequent bone 1988;7:577-82.
growth. s5 Kulkarni PB, Hall RT, Rhodes PG. Rickets in very low
birthweight infants. J Pediatr 1980;2:249-52.
16 Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High
alkaline phosphatase activity and growth in preterm neonates.
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