Bone disease in preterm infants

1. Archives of Disease in Childhood, 1989, 64, 1403-1409Regular reviewBone disease in preterm infantsN BISHOPDunn Nutritional Laboratory, CambridgeNew work in bone…
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  • 1. Archives of Disease in Childhood, 1989, 64, 1403-1409Regular reviewBone disease in preterm infantsN BISHOPDunn Nutritional Laboratory, CambridgeNew work in bone physiology and cell biology In well preterm infants, hypocalcaemia will usuallyduring the last decade has made it possible to begin to improve by 24-30 hours of age, with valuesconstruct 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, particularlymetabolic bone disease of prematurity. The model tissue hypoxia with subsequent calcium influx, mayproposed here explains its pathogenesis and its contribute to the low calcium concentrations seen inoutcomes, and suggests a sequence of appropriate the sickest infants, in whom hypocalcaemia is moreinvestigations 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, thatmineral metabolism in the perinatal period, and the plasma parathormone concentration does notprovides a framework against which the derange- rise after birth, and that parathormone resistance isment in mineral homoeostasis leading to bone likely to occur in preterm infants. Much of the earlydisease can be more clearly visualised. work on parathormone in the perinatal period was carried out using radioimmunoassays for either theFetal bone mineral homoeostasis carbon or the nitrogen terminal moiety of the molecule. Parathormone is an 84 amino acid peptideMineral accretion rates for both calcium and that is rapidly and continuously synthesised andphosphorus increase throughout pregnancy, reaching almost immediately subjected to intracellulara 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 secretedraised in utero2; though this peptide hormone is could remain undetected, as the total terminalknown 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 withanabolic, 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 inbone resorption in later life, parathormone, and 1, active parathormone secretion during the first 4825 dihydroxycholecalciferol, are found in low con- hours after birth.5 The principal target organs forcentrations in the fetus.2 3 Interestingly, however, the parathormone molecules thus released are boneprolonged low dose administration of these hor- and kidney. In response to parathormone the kidneymones 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 urinaryAfter ligation of the cord, the supply of calcium, phosphorus excretion up to the age of 5 days werephosphorus, 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 birthtrains a rapid fall in blood calcium concentrations; were observed; subsequently, the phosphorus lossthe 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 BishopIn the uterus (i) High blood calcium, phosphate, and calcitonin concentrations with high bone mineral accretion rates (ii) Low circulating parathormone, and 1,25 dihydroxycholecalciferol concentrationsFirst 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 ofBone effects of parathormone 1,25 dihydroxycholecalciferol Bone resorption Matrix degradation Release of products-some act Calcium, Phosphateas local humoral factors I Potential for further loss of phosphorus in urine Nutrient supplyProduction of bone matrix Bone miineral accretion + Influence of favourable local factors, matrix vesicles New bone formation: remodelling, growth, and mineralisationFigure Outline of processes of bone mineral metabolism in the perinatal period.(unpublished observations). These observations absorption of calcium and phosphorus, but also theparallel 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 maintenancephate metabolism in states of phosphorus repletion of calcium homoeostasis, which is discussed in detailand 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 of1,25 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 inof vitamin D3 affecting not only the gastrointestinal response to gastrin production, and the initial surge
  • 3. Bone disease in preterm infants 1405of gastrin after the first feed may be responsible for tion by osteoblasts. The increase in resorptivethe increase in plasma calcitonin concentrations activity initiated by the surge of parathormone afterseen at this time. Calcitonin inhibits the resorptive birth is therefore matched by a concurrent increaseresponse of osteoclasts and so delays the supply of in new bone formation. Though matrix volume iscalcium 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 exogenousachieved 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 mineralbone, and by their separate effects on absorption substrate to normally functioning osteoblasts, aand retention of mineral substrate. favourable local environment for bone mineralisa- tion is also crucial to the remodelling and growth ofBone resorption bone; many factors have been identified in labora- tory studies as having a role. In particular, there is aThe isolation and culture of pure cell lines of growing body of evidence to support the part playedosteoblasts and osteoclasts, have enabled rapid by matrix vesicles in the initiation and propagationadvances in our understanding of the underlying of crystallisation. 2processes in bone.9`11 It is now clear that osteoblasts Matrix vesicles are discrete sacs that are derivedand osteoclasts act. together to undertake bone from the osteoblast cell membrane. They areresorption, 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, alkalineosteoblast permeability to calcium; release of phosphatase functions principally as a phospho-collagenase from osteoblasts; and release of osteo- transferase, transporting phosphate residues thatclast activating factor(s) from osteoblasts, as a result have been cleaved by other phosphatase enzymesof which osteoclasts increase in number and activity. into the vesicles sap. In addition, 1,25 dihydroxycholecalciferol, Calcium enters the vesicle by diffusion, and isproduced in response to the increased concentra- trapped by phosphatidyl serine. The additionaltions of parathormone, exerts synergistic effects on accumulation of phosphate raises the saturation ofbone.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 andmonocyte/macrophage precursors of osteoclasts; crystallisation begins. Electron microscopic picturesproduction by osteoblasts of osteocalcin (Gla have shown the growth of crystals on the innerprotein), which is chemotactic for osteoclasts; leaflet of the vesicle that leads to its subsequenteffects on immune cell function, particularly disruption as the ends of the crystal pierce thelymphocytes, with reduced interleukin 2, and in- bilayered membrane.creased interleukin 1 production, which enhances These crystals then seed into the fluid at theosteoclast formation and activity; and possibly a mineralisation front and, given adequate mineralreduced 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 osteoblast permeability to calcium flux with the Laboratory studies have shown that there areactivation of a specific calcium pump provides an greatly increased numbers of matrix vesicles inacute response to falling ionised calcium concen- rachitic growth plates3; this lends support to thetrations. The recruitment, activation, and fusion of concept that increased alkaline phosphatase activityosteoclast precursors, and their subsequent activity in plasma may represent increased vesicle turnoverin 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, andNew bone formation growth are those that have been discussed in detail above. There are, however, many other factorsThe result of the resorptive process is to produce affecting the fine control of bone homoeostasis,9 11calcium, phosphorus, and breakdown products of of which two are of particular relevance to thebone 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 Bishopsation, and is present as a contaminant in parenteral in order to supply the needs of other tissues. Thenutrition 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 indeposition was found in bone after three weeks of urine and plasma precede the increasing urinary lossparenteral 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 isintravenously. seen principally after 6 weeks of age. Immobility also causes loss of bone mass. Stress Radiological and anthropometric changes occurgenerated electrical potentials have been implicated slowly,15 being seldom evident before 6 weeks ofin the osteogenic process, and prolonged periods of age. l In the long term the principle outcomes forsedation or paralysis during mechanical ventilation bone are linear growth, mineral content, andincrease the possibility of the loss of bone mass. structural integrity. In a large study of preterm infants receiving different diets during the neonatalMineral substrate insufficiency period, we found a significant association between the increase in plasma alkaline phosphatase activityGiven an adequate nutrient supply, remodelling, and a reduction in height achieved at both 9 and 18mineralisation, and growth of bone should proceed months implying that bone disease, reflected bynormally in most infants. For bone disease to increased remodelling activity during the first weeksdevelop, depletion of mineral substrate must occur. of life, had a lasting effect on the infants growthPhosphorus depletion is likely to develop more potential up to the age of 18 months.16rapidly as it may initially be lost in the urine, and If these differences persist, then it is likely that theprotoplasmic metabolic requirements for phos- nutritional deprivation sustained by bone during thisphorus 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 upposition studies, 0-6-0-7 mmol/kg/day compared growth would otherwise be observed when dietarywith 0-2-03 mmol/kg/day). sufficiency was achieved.6 Inadequate dietary provision of phosphorus-for The regulatory mechanisms for this adaptiveinstance, the exclusive use of unsupplemented change remain to be elucidated, but could involvehuman milk-compounded by the initial urinary changes in cell number, type, or function, eitherphosphorus losses will result in low tissue phos- locally or systemically.phorus stores, and low circulating concentrations ofphosphorus. Investigation of early bone disease The reduced delivery of phosphorus to the kidneyprevents further appreciable urinary losses and Plasma phosphate concentrations fall gradually fromenhances renal production of 1,25 dihydroxy- 2 mmol/l to 10-O1-5 mmol/l over the first week, andcholecalciferol. The increase in circulating 1,25 often reach a nadir during the second week afterdihydroxycholecalciferol in turn increases gastro- birth (unpublished observations). In infantsintestinal absorption of both calcium and phos- depleted of phosphorus as a result of urinary lossesphorus. In addition, the release of parathormone is and poor intake a further reduction to <1 mmol/linhibited, further reducing the risk of phosphorus may occur, and this has been reported to beloss 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. Byabsorption; nevertheless, the potent bone resorbing contrast, urinary calcium losses increase and persistactivity of 1,25 dihydroxycholecalciferol will during the period that tissue phosphorus storescontinue to remove some calcium and phosphorus remain depleted. A prolonged absence of phosphatefrom bone. from the urine with persisting calciuria would imply In addition to the phosphorus absorbing and continued tissue phosphorus depletion, and mightretaining processes detailed above, it is possible that be a useful marker to follow sequentially in anhypophosphataemia 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 andactivity. 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 withinadequate, further substrate will be lost from bone persistently low plasma phosphorus concentrations
  • 5. Bone disease in preterm infants 1407receiving low phosphate diets-for instance, un- rate of mineral crystallisation; photonabsorptio-supplemented human milk. Increased plasma metry gives an estimation of the amount of mineralalkaline phosphatase activity is widely quoted as actually in bone; and radiographs best show thebeing indicative of bone disease; difficulties arise in abnormal remodelling resulting from an inadequatethe interpretation of results and comparison with provision of mineral substrate for bones that areother centres because of the use of different assay continuing to increase their matrix 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 biochemicalgreater 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 furtherhave been associated with reduced linear growth evidence to support the diagnosis of bone disease. 16velocity in the short term.14 In the work previously For practical purposes, sequential analysis ofreferred to we found an area of demarcation at five urinary calcium and phosphorus losses is likely totimes the maximum normal adult value for plasma provide the earliest evidence of incipient metabolicalkaline phosphatase activity, with appreciable bone disease. If by the age of 3 weeks calciumreductions 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, - Managementand-in extreme cases-there may be fractures ofboth ribs and long bones. The interpretation of The management of this condition should essentiallyradiographs 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 bonesation. disease and the amount of supplementation that will Photonabsorptiometry is a quick and accurate prevent it are unknown. It is nevertheless possible tomethod of assessing sequentially the changes in look at the provision of substrate by current feedingbone mineral content at a specific site, usually the practices, formulate estimates of comparative bonedistal radius. 17 Photonabsorptiometry has shown mineral accretion rates, and so assess the minimumthat 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 200increase 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 m
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