The “fragile” infant: osteopenia in preterm newborn
The continuous advances in intensive care of preterm newborns have led to a progressive decline of mortality in institutions where facilities and expertise for respiratory distress syndrome are available. However, the success in the survival achieved through aggressive intensive care is not always paralleled by the subsequent fully healthy development of the newborn.
Among the common conditions of morbidity due to prematurity a grow interest is focusing on osteopenia (metabolic bone disease, MBD); a condition characterised by a reduction in bone mineral content. This is a common disease of preterm babies between the tenth and sixteenth week of life, because prematurely born infants are deprived of the intrauterine supply of minerals.
The clinical picture varies: the disease may remain dormant until severe demineralisation occurs (reduction of BDM by 20-40%) leading to symptoms and signs of rickets with multiple fractures and others alterations.
The prevalence of neonatal osteopenia varies depending on gestational age, birth weight and the kind of alimentation. It occurs in up to 55% of babies born weighing under 1000g, 23% of infants weighing less than 1500g at birth; and it’s especially frequent in babies under 28 weeks of gestation. The prevalence is 40% in premature infants who are breastfed in contrast to 16% of those fed with a formula designed for preterm infant supplemented with calcium and phosphorus.
Prenatal bone physiology:
The period of greater skeletal development is during the intrauterine life, especially during the last trimester. The mineralisation process is determined by synthesis of the organic bone matrix by osteoblasts where calcium and phosphate salt are deposited. This process increased exponentially between 24 and 37 weeks of gestation, reaching 80% of mineral accretion in the third trimester.
During gestation developing the foetus receives supplies of energy, proteins and minerals for adequate growth (1.2cm/week) and bone development. At term the newborn skeleton has a high physical density. The placenta has a very important role in the skeletal accretion of the foetus. In fact the transfer of calcium from the mother to the foetus occurs via an active transport done by the calcium pump in the basal membrane. There is a 1:4 maternal to foetal calcium gradient. There is evidence that mothers increase calcium supplies during pregnancy by increased intestinal absorption of Ca. and increased skeletal mobilisation. The importance of maternal Ca. consumption is suggested by the improvement of adverse effects of severe maternal dietary restrictions by Ca. supplementation. During pregnancy supplement of Ca. 2g from before 22weeks of gestation is recommended, even if Ca. supplementation may have important adverse effects for the mother. Moreover, the placenta is seriously involved in determining bone mineral content: vitamin D is transferred transplacentally predominantly as 25-hydroxyvitamin D and subsequently converted 1,25-hydroxyvitamine D in foetal kidney. Although the foetal role of 1,25-hydroxyvitamine D in foetal bone mineralisation is unclear, it has been shown that chronic maternal vitamin D deficiency can adversely affect foetal skeletal development. Furthermore the placenta is fundamental for transferring phosphate to the foetus. That’s why corioamniostis and placenta chronic damage may cause infants demineralisation.
Figure 1: Pattern of prenatal bone physiology
Postnatal bone physiology:
As the postnatal growth of an infant’s bone marrow cavity is faster than the increase in the cross sectional area of the bony cortex, over the first 6 months of life, the long bone density can decrease almost 30%. In term infants these postnatal changes are not accompanied by an increase in bone fragility * because bone is exposed to different conditions before and after birth. First, there are important changes of hormonal environments: a significant reduction of maternal estrogens and a postnatal increase of PTH level, due to a reduction of the Ca. supplied by the placenta. The fall of serum calcium levels in the first day stimulates the PTH secretion that continues for 48 hours after birth. At this point we have maximum increase of serum Ca. and stabilisation of the mineral level.
Figure 2: Pattern of posnatal bone physiology
Neonatal mineral requirements:
The requirements of calcium and phosphorus are based on demands for matching intrauterine bone mineral accretion rates. Because of the limited solubility of calcium and phosphate, supplying these two minerals in parenteral nutrition is a challenge. Calcium and phosphorus’s solubility in nutritional mixture depends on temperature, type and concentration of amino acid, glucose concentration, type and concentration of calcium salts, pH, the presence of lipids and so on. In parenteral nutrition calcium is administrated as inorganic salt and phosphorus as inorganic sodium and potassium phosphate or sodium-glucose phosphate or glycerol phosphate, which are quite soluble in water. The solubility of calcium and phosphate can be improved by adding cysteine to lower the pH of the parenteral admixtures. For all these reasons it is not possible to supply these minerals according to the physiologic requirements of the preterm to reach an adequate bone mineralisation. In the transition period of very low birth weight (VLBW) neonates, most receive full or partial parenteral nutrition with the goal to maintain the normal levels of calcium and phosphorus. Hypocalcaemia, in fact, is a common event during the first days of life because of the sharp decrease of the calcium supply by the placenta and the delayed release of PTH due to immature response of the parathyroid glands. Through the parenteral administration of calcium and phosphorus (40-70 mg/kg/day and 25-45 mg/kg/day) it is possible to achieve 60-70% intrauterine mineralisation. In preterm babies receiving parenteral nutrition only limited amounts of vitamin D are required since calcium is given by vein there is no need of calcitriol to facilitate the intestinal uptake. It is now generally accepted that the daily recommended dose of vitamin D is 400 U.I/day. For the transitional period, when infants are weaned from parenteral nutrition to the enteral one, the aim usually is to maintain an adequate serum level of calcium and phosphorus; however you should be aware that a normal serum level of these minerals is not guarantee for an adequate whole body accretion as in intrauterine life. The enteral administration of calcium is fraught with many problems as regards the calcium bioavailability such as vomiting, large gastric aspirates, constipation and abdominal distension. Moreover gut absorption capacity is impaired due to the immaturity of the gastrointestinal mucosa.
Figure 3: Pattern of postnatal bone physiology in preterm newborns
The human milk content is inadequate for preterm requirements and the premature formulas is suggested with a dose approximately 4-6 times higher. Even when VLBW are fed at high feeding volumes, this would provide only one-third of the in uterus levels of absorbed calcium and phosphorus. Formula milk is richer in calcium and phosphorus than human milk but calcium absorption in premature formulas is usually less than in human milk, ranging from 35 to 60% of the intake. Hence the human milk intake has to be promoted, but a fortification with minerals and protein fortifier is necessary to achieve adequate nutrient intake. With the current fortifiers, containing highly soluble calcium glycerol phosphate, calcium retention reaches 88% of the overall intake(90 mg/kg/day); however this results aren’t comparable with the values achieved during the last trimester of gestation (100-120 mg/kg/day). Finally it must be noted that high calcium supplementation of milk is not well tolerated, it is associated with high faecal calcium, prolonged gastrointestinal transit time and impaired fat absorption. All these effects are potential risk factors for developing necrotizing enter colitis.
Prematurity :as mentioned above prematurity is a very important risk factor because transplacental Ca and P delivery is greatest after 24th gestation week. As a result, premature infants have depleted their bone minerals store at birth and there may not be adequate for the rapid bony growth that occurs during the postnatal period. From that week onwards the foetus gains circa 30g per day which requires approximately 310mg Ca and 170mg P per day. It seems that the amounts of mineral required for bone regeneration are widely different depending on the age of the neonates.
Lack of mechanical stimulation : Mechanical force pattern, for example foetal movements such as kicking against the uterine wall, may stimulate cortical bone growth. This kind of training is missed during the extra uterine life since preterm babies are usually kept in incubators. Inactivity due to immobilisation stimulates bone reabsorption by oteoclasts and urinary calcium excretion. Furthermore, the reduced muscle activity prevents the addition of new bone tissue. Lack of mechanical stimulation in preterm infants places them at increased risk of osteopenia. Thought the current biography there is also a strong link between skeletal development and the nervous system. Mechanical factors are also thought to contribute to an inadequate bony growth in infants born with hypotonic muscular disorders.
Drugs administrations :use of various medications for neonatal disease increases the risk of osteopenia in newborn infants. For example in preterm infants the use of long methylxanthines and diuretics such as furosemide, increase renal calcium excretion required for bony growth. Also use of high dose systemic corticosteroids has been demonstrated to impair bony growth.
Other pathological conditions :it has been shown that osteopenia is associated with infection, despite a lack of alteration in bony biomarkers during infection. It’s thought that this is related to the infant’s catabolic state during infection periods. Sepsis, cerebral pathology, neuromuscular disorders may results in prolonged periods of immobility associated with poor bone mineralisation. As stated previously placenta damage can also cause demineralisation.
Serum biochemical markers:
Alkaline phosphates : bone is constantly being remodelled by a process involving resorption by osteoclasts and formation by osteoblasts. ALP is a glycoprotein enzyme produced by a variety of tissue including bone, liver, kidney and intestine. Tissue non specific ALP is generally measured; however 90% of ALP in infants is of bone origin and it’s thought to reflect bone turnover. ALP rises in all newborns in the first 2-3 weeks of life and increases further if there is insufficient mineral supply. Appropriate mineral supplementation of preterm infants may lead to smaller rises in ALP: Even if the literature regarding total ALP is conflicting with poor associations reported in studies, serum total ALP concentration has been used as a marker of bony turnover. Concentration is elevated by increased bone cellular activity. Literature has been shown that concentrations > 750IU/L are associated with neonatal osteopenia and may precede clinical features of osteopenia of prematurity. Bone-specific ALP, a more specific biomarker that is located on the osteoblast surface may present a more accurate picture of bone turnover, and may be considered in cases with a high level of total ALP to increase diagnostic values. Other minerals can affect serum ALP levels. Copper deficiency causes raised levels associated with neutropenia and hypoalbuminaemia. Zinc deficiency is associated with decreased ALP levels. Despite the controversies, ALP is a readily available measurement and provides a trend that can be easily followed. It therefore remains a frequently used screening tool for metabolic bone disease.
Figure 4 : Flow diagram to guide radiographic and alkaline phosphatase activity evaluation for rickets.
Calcium : serum calcium is not a useful screening test as infants can maintain a normal calcium level at the expense of a loss of bone calcium. Moreover the calcium level can increase with phosphorus depletion and hypophospataemia.
Phosphate : serum P concentrations reflect the bony P well. Preterm infants with low serum P (<2 mmol/L) are at risk of osteopenia, and levels less than 1.8 mmol/L have been strongly associated with the presence of radio graphically evident rickets. Data has confirmed that although phosphate concentration is related to bone mineral density, it is not sensitive enough to identify infants with bone mineral deficits. It is however highly specific. The use of serum phosphate levels in combination with ALP levels can significantly increase the sensitivity of the screening and identification of infant at risk of metabolic bone disease.
OC (osteocalcina): OC, a non collagenous protein of the bony matrix, is another biomarker of osteoblastic activity. It is synthesised by osteoblasts regulated partly by 1, 25 dihydroxyvitamin D. Circulating concentration of OC are elevated during periods of increased bone turnover. Despite its specificity, no correlation between serum OC and bone mineral density has been shown during the first 4 months of age.
X-ray : osteopenia can be discovered as an incidental finding on a plain radiograph, showing thin bones or healing fractures. X-ray examination may also show alterations as reduction of thickness of the cortical, enlargement of the epiphysis, irregular border between growth cartilage and bony metaphysis. Radiologically, bone mineral density is significantly decreased. This may manifest as "disappearing" bones (such as in the image above, where the vertebral bodies and scapulae are barely visible) and in severe cases rib or limb fractures may be seen (in this image the posterior part of the right 7th rib shows a callous indicating a previous fracture).
DEXA : DEXA is now the gold standard for bone mass measurements in adults and results correlate well with risk of fracture, since it is sensitive in detecting small changes in bone mineral content (BMC) and bone mineral density (BMD). It is becoming more widely used in neonates both term and preterm, but availability is limited. DEXA most accurately reflects the state of bone mineralisation in preterm infants but the examinations involve radiation for the baby and the device is not portable.
Quantitative ultrasound : Quantitative ultrasound gives information about the bone structure and density. This technique is simpler than DEXA, non invasive and can be used at the bedside without moving the baby. Reference values are available for both term and preterm infants.
There is a large debate concerning urine analysis of Ca and P excretion as biomarkers of postnatal bone mineralisation. It is known that infants with excretion of Ca and P greater than 1.2mmol/L and 0,4mmol/L respectively have the highest bone mineral accretion. Data confirms that extremely preterm infants (23rd-25th gestation week) have a much lower renal phosphate threshold than any other preterm infants, leading to urinary phosphate excretion even in the presence of low phosphate levels. Phosphate is not bound in the plasma like calcium and so the percent tubular reabsorption of phosphate (TRP) is the best guide to adequacy of phosphate supplementation. A percent tubular reabsorption of >95% shows inadequate supplementation. However it must be considered in relation to plasma calcium; inadequate calcium intake will lead to hyperparathyroidism and hence tubular leak of phosphate. Similarly, if phosphate intake is low, there is breakdown of bone and hence release of calcium. This leads to hypercalcaemia and calcium leaking into the urine.
TRP (%TRP) = 1- urine phosphatase/urine cratinine x Plasma Creatinine/Plasma Phosphatase x 100.
That urinary calcium and phosphate concentrations may vary is well recognised and simultaneous measurements of creatinine and may allow correction for changes in urine volume. Use of urinary mineral to creatinine ratio may therefore be appropriate. Reference ranges for these ratios in preterm infants have been reported. However, results need careful interpretation because drug administration such as furosemide and theophylline lead to significance increase in urinary Ca creatinine ratio.
Figure 5: Flow diagram to guide urine analysis for MBD evaluation.
Treatment and complications:
Prevention of bone disease of prematurity should be the aim rather than treatment of the disease. Known risk factors as described early should be minimized where possible. Osteopenia has a good prognosis since the disease is self resolving, provided that calcium, phosphate and vitamin D are appropriately administered to the babies with breast milk fortifier or formula with a content of minerals suitable for preterm infant’s requirements. A regular physical stimulation, when the preterm infant is clinically stable and is receiving an adequate nutritional implementation of calcium, phosphate and vitamin D, should also be included in the standard preventive approach.
There are still disputes about what the method duration, and the optimum amount of calcium and phosphorus supplementation in children should be, even after they have been discharged and they are in stable growth. It has been shown with studies assessing bone mineralisation with quantitative ultrasound and DEXA that preterm infants show a catch up mineralisation for the first year of life. There is no difference in late childhood of bone mineralisation between term and ex-preterm infants even thought the biochemical evidence of metabolic bone disease during the neonatal period may have a long term stunting affect with continues up to 12 years later. Data states that children who were born prematurely with birth weight less than 1.5kg tend to be significantly smaller for age and have lower lumbar spinal bone mineral content and density compared with children born at term gestation. The long duration of this complication provides further rationale for implementing any practice that can prevent this condition.
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