Osteopenia de la Prematuridad

Diciembre 2013

 

 

Osteopenia in preterm infants

 

Catherine M Harrison ,   Harrison CM, et al. Arch Dis Child Fetal Neonatal Ed 2013;98:F272–F275. doi:10.1136/archdischild-2011-301025

 

In the newborn preterm infant a combination of inadequate reserves and increased loss of essential minerals is common and frequently compounded by difficulties in obtaining an intake sufficient to replace losses and restore reserves. Deficiencies in calcium and phosphate and disturbed balance between them are frequently encountered, and may lead to significant impairment of bone deposition.

 

Osteopenia of prematurity – also known as neonatal rickets, rickets of prematurity or neonatal metabolic bone disease – is a common and important concern in neonatology, and effective management is hindered by difficulties in accurately assessing calcium and phosphate status and the ‘quality’ of bone deposition.

 

It is well known that preterm infants are at risk of reduced bone mineral content (BMC) and subsequent bone disease and that many factors may contribute to this. The majority of calcium and phosphate accretion and bone mineralisation occur in the third trimester of pregnancy and from 24 weeks of gestation onwards, it has been estimated that the fetus in utero gains about 30 g in weight each day, and this daily requirement includes 310 mg of calcium and 170 mg phosphorus.1

 

It has been shown that BMC and bone mineral density (BMD) correlate positively with gestational age, birth weight, body area and length.2 Mineral deposition may be affected before an infant is born as a number of prenatal factors, particularly placental function, have been shown to play a part in the development of osteopenia. The placenta converts vitamin D to 1,25-dihydrocholecalciferol which enables phosphate to be transported across the placenta. 3 A reduced ability to do so explains the higher incidence of postnatal rickets that may be seen in infants with intrauterine growth restriction suggesting that chronic injury to the placenta may limit the ability to transfer phosphate.4 Poor mineralisation may also occur in pre-eclampsia and chorioamnionitis.5,6

 

Many infants born prematurely develop significant problems that require treatment, and the therapies required such as steroids, methylxanthines and diuretics may have a significant detrimental effect on bone mineralisation.7–9 In addition, postnatal nutrition is often significantly suboptimal, further affecting bone mineralisation and supplementation is often needed, but may be difficult to achieve. Preterm infants fed on human milk without supplementation have evidence of rickets in 40% of cases, compared with 16% of infants fed on formula milk with supplementation.10

 

Extremely preterm infants frequently require a long duration of parenteral nutrition, and adequate mineral provision can be problematic due to difficulties with mineral solubility. Periods of immobilisation – very common for prolonged periods in preterm babies – have been shown to be an additional risk factor for poor bone mineralisation, and there is some evidence that daily passive exercise for infants at risk of bone disease improves BMC, strength and area.11,12

 

Neonatal fractures have been taken as a proxy for the incidence of osteopenia of prematurity and have been reported in 10–32% of very low birthweight infants.13 14 The true incidence of osteopenia is difficult to define however due to the different methods of screening infants at risk and  the difficulty in interpreting results of the screening tests. A recent national survey has shown considerable variation in practice for diagnosis and for treatment for osteopenia.15

 

Alkaline phosphatase (ALP) levels, serum calcium and serum phosphate were commonly used as screening tools and diagnostic markers, alone and in combination, but timing of measurements and the level at which treatment was instigated varied widely. Several units used x-ray appearances to aid diagnosis, some performing routine wrist x-rays at 6 weeks of age, but with no consensus as to how x-ray appearances should be interpreted or responded too.

 

Measurement of ALP is probably one of the commonest techniques used to assess the likelihood of osteopenia, but there is no clear point at which the levels become diagnostic. In one review of 100 extremely low birthweight infants, ALP levels of greater than 600 IU/l were commonly observed. Although birth weight was significantly inversely related to plasma ALP levels and the finding of radiological rickets, no single value of ALP could be found that was predictive of the bone changes.16

A number of studies have evaluated the use of absorptiometic methods for assessing bone density in at-risk infants. Low bone density can be assessed by dual-energy x-ray absorptiometry (DEXA) and is now regarded by many as the gold standard for use in adults. DEXA scans have been shown to be sensitive in detecting small changes in bone mass content and density, and can predict the risk of fractures in adults.17 18 DEXA scans cost between £50 and £200 and are thus financially as well as technically possible in infants, but it is  unlikely that many practitioners would regard this as a justifiable additional expense if performed as a routine screening test on all infants. There is limited availability of this technology however, and this, combined  ith the size of the scanner, the length of time needed to complete a scan and movement artefact (technically possible does not mean that the procedure is free of technical difficulties) have meant that there has been relatively restricted use in preterm and term infants, although there has been enough use in a research environment to permit validation of the technique.19 The data that are available have supported the use of DEXA scans in preterm and term infants as an aid to diagnosing and monitoring metabolic bone disease of prematurity but have also confirmed that artefact induced by a baby’s spontaneous movement can substantially decrease precision.20 If this technique were to be adopted as a routine method of screening for either the risk or the presence of metabolic bone disease, issues of availability would need to be resolved and agreement would need to be reached on practical questions including the timing of the initial scan, the frequency with which scans should be repeated, the point at which intervention would be offered and what intervention, if any, would be appropriate.

 

Quantitative ultrasound has also been evaluated as a noninvasive method of assessment, with varying conclusions being reached. One study has reported that speed of sound or broadband attenuation could be used to assess changes in bone health and demonstrated that speed of sound fell on longitudinal follow-up despite adequate nutrition with sustained weight gain.21 All infants followed up in this study (between 24 and 31 weeks gestation) showed a decrease in speed of sound even when ALP measurements were clearly within the normal range, questioning the use of ALP as a diagnostic marker. However, other studies have shown no significant correlation between speed of sound and lumbosacral DEXA measurements and could find no evidence that speed of sound could predict biochemical indicators of metabolic bone disease in preterm infants.22 23

 

So what is the burden of osteopenia of prematurity?

 

There is limited information on which to base an answer to this question. In the short term the main complication is neonatal fractures, mainly of the long bones and ribs with a reported incidence of between 10% and 32%, as discussed earlier. Current experience in neonatal intensive care would suggest an incidence substantially lower than either of these quoted figures.

 

Fractures respond well to dietary supplementation and splinting of long bones, and there is no information to suggest long-term problems attributable to the fractures.13 The cost of treatment in infancy is difficult to quantify but unlikely to be substantial. The length of stay anecdotally seems to be unaffected by the diagnosis of osteopenia of prematurity and the majority of neonatal units routinely give mineral supplementation with an aim to prevent or treat neonatal rickets.13 Phosphate and other mineral supplements are relatively cheap, and a 6- month period of supplementation with potassium dihydrogen phosphate would cost about £150 at current prices. Altered head growth (dolichocephalic flattening) has been associated with poor BMC, and a correlation between osteopenia, dolicocephaly and myopia has been proposed and refuted.24 25 The literature describes a small cohort of infants with subacute respiratory distress with x-ray changes similar to Wilson Mikity syndrome, severe metabolic bone disease affecting the thoracic cage, and mild cholestasis.26 This observation has not been repeated. It is possible that such changes were at least in part associated with more liberal use of certain medications. Preterm infants are at risk of bronchopulmonary dysplasia, and therapies used to modulate this, steroids and diuretics particularly, may have a detrimental effect on bone content. It has been shown that postnatal steroids are associated with a rapid and often severe reduction in skeletal growth that may be due to an acute reduction in bone formation and increase in bone resorption.27 28

 

A small number of studies have investigated the longer-term implications of osteopenia, with mixed results. Eelloo and coworkers carried out bone densitometry measurements and anthropometry at the age of 5–9 years in children who had developed chronic lung disease in the neonatal period and who were treated with dexamethasone and compared them with preterm infants who did not develop chronic lung disease.29 They found that the total body BMC and BMD of the lumbar spine were lower in children who had received dexamethasone for their lung disease in the neonatal period, compared with the preterm controls who had not. Bowden and colleagues have published data on anthropometry and bone mineralisation in ex-preterm infants at the age of 8 and showed a significant reduction in height and weight.30 BMC and BMD were measured at various sites including lumbar area, spine, forearm and hip, and BMC was lower in the preterm group compared with term controls.

 

However, the difference was not significant when adjusted for height and weight. BMD was significantly reduced in the hip area. The lowest BMC was found in infants who had been ventilated for the most prolonged period. In another study 20 children who had been born prematurely with a birth weight of less than 1500 g were assessed at a mean age of 7 years and compared with 15 term-born controls. Compared with the reference population, children who were born prematurely had a lower weight, height and body mass index and a lower lumbar BMC and BMD.31 Three of the preterm infants had a history of fractures, whereas none were reported in the control group.

 

Zamora and colleagues assessed 25 prepubertal ex-preterm children (mean gestational age 30.8 weeks and birth weight 1461 grams) at 7–9 years and compared them with 50 control termborn girls.32 Former preterm girls were of a similar height to controls but were lighter and had a higher mean calcium intake on dietary assessment. Areal bone mineral density (aBMD; grams per square centimetre) was assessed by DEXA and was lower in ex-preterm girls at the level of the radial metaphysis, femoral neck and total hip but was similar at the radial and femoral diaphyses. Femoral neck aBMD remained lower when assessed 1 year later. A similar study compared three groups of  prepubertal boys, those ≤34 weeks gestation (preterm group), those >34 and ≤37 (late preterm group) and term controls.33 Twenty-four children were assessed by total body, spine and hip DEXA and tibia peripheral quantitative CT measures at 5.7–8.3 years. When adjusted for age, weight, height and jump power, the boys born at term had greater bone size and mass than children born preterm and higher bone mass than boys in the late preterm group. Activity level was assessed in the different groups and did not explain bone differences.

 

In adults, the Carter method allows BMC of the lumbar spine to be separated into components of bone volume (BV) and bone mineral apparent density (BMAD). It does not account for the effects of body habitus on bone mass. One study has been performed in which the Carter method was modified for use in children.34 Twenty-five children born preterm were matched with term controls and lumbar spine bone mass was assessed by dual-energy x-ray absorptiometry and BV and BMAD were calculated.

 

Children in the preterm group had reduced absolute height, weight, BMC, BV and BMAD, and reduced height, weight and BMC for their age. The major abnormality found in preterm infants was a decrease in volumetric density at the lumbar spine. The decrease was proportional to the reduced stature, and the authors speculated that there was no reduction in the strength of the lumbar spine.

 

It has been postulated that infants with altered bone geometry may walk later than control infants. Samra and coworkers used peripheral quantitative computerised tomography to measure bone size at the distal tibia and found that preterm boys had larger periosteal and endosteal circumferences and smaller cortical thickness and area than boys born at term.35 They also found that children with a history of preterm birth walked  significantly later than children born at term, but this difference was no longer significant when corrected for gestational age differences. Activity levels were also assessed and, contrary to the study described above, postulated that the differences in bone geometry were explained by activity levels.

 

Fewtrell and colleagues used a cohort of 202 children who had been recruited to a nutritional study 20 years ago to test the hypotheses that early diet could programme bone mass and turnover, that human milk could be beneficial for these outcomes and that those born preterm would have a lower peak bone mass when compared with controls.36 Their original study randomised more than 900 infants to preterm formula versus banked breast milk or preterm versus term formula and as a sole diet or as a supplement to mother’s breast milk. The 20-year follow-up assessed the anthropometry, hip, lumbar spine and whole body BMC and bone area using DEXA and measured markers of bone turnover. The study found that the infants born preterm had a lower height SD score (SDS), higher body mass index SDS and lower lumbar spine BMD SDS when compared with population standards, and that height and bone mass deficits were greatest in those born small for gestational age with a birth weight below 1250 g. The dietary group into which the infant was randomised did not have an effect on peak bone mass or turnover, but the whole body bone area and BMC were significantly higher when the proportion of human milk in the diet was greater. The authors concluded that the observed reduction in final height and lumbar spine bone mass might not be related to suboptimal early nutrition and, furthermore, that the higher whole body bone mass associated with human milk intake (with a relatively low nutrient content) might reflect the presence of non-nutritive factors in breast milk.

 

In summary, it has been suggested that the changes seen in childhood or as young adults could precede the development of early osteoporosis in later adult life, although this is speculative rather than evidence based. Were they to do so there could be serious long-term morbidity and it is extremely important that cohorts of preterm infants continue to be closely followed until the uncertainties of long-term outcome are fully apparent. Can the available evidence be used to give firm guidelines as to how best to screen for metabolic bone disease and to select a population who would benefit most from routine supplementation? The most honest answer is ‘not really’, but we would tentatively make the following suggestions to fuel further discussion.

 

SCREENING TESTS

 

Alkaline phosphatase

 

ALP rises in all newborns in the first 2–3 weeks of life and increases further if there is insufficient mineral supply, and appropriate mineral supplementation may lead to smaller increases. Potentially, a biochemical marker that reflects an abnormal rise in bone activity due to either rapid growth or lack of minerals may help detect osteopenia in infants, but there is conflicting evidence as to whether ALP is such a marker. DEXA studies have concluded that there is no association etween ALP levels and BMC. Despite this controversy, 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, but we would recommend caution in interpreting results in isolation.

 

Serum 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.

 

Serum phosphate

 

Preterm infants with low serum inorganic phosphate (<2 mmol/l) are at risk of osteopenia, and levels less than 1.8 mmol/l have been strongly associated with the presence of radiographically evident rickets. Data have confirmed that although phosphate concentration is related to BMD, 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 infants at risk of metabolic bone disease.

 

Urinary excretion of calcium and phosphorus

 

Studies using this measure as a marker of postnatal mineralisation found that infants who simultaneously excreted calcium >1.2 mmol/l and inorganic phosphorus at >0.4 mmol/l showed the highest bone mineral accretion. Infants between 26 and 31 weeks were found to have a renal phosphate threshold in the range of normal serum phosphate values (2 mmol/l). Data have shown that extremely preterm infants had a much lower renal phosphate threshold, leading to urinary phosphate excretion even in the presence of low phosphate levels. Phosphate is not bound in the plasma like calcium, and thus the tubular reabsorption of phosphate is the best guide to adequacy of phosphate supplementation. A tubular reabsorption of >95% shows inadequate supplementation. On a practical note, urinary electrolyte levels are the same cost as blood tests such as calcium, phosphate and ALP.

 

Urinary calcium and phosphate creatinine ratios

 

Variations in urinary calcium and phosphate concentrations are well recognised, and simultaneous measurement of creatinine may allow correction for changes in urine volume. Use of urinary mineral to creatinine ratios may therefore be appropriate. Reference ranges for these ratios in preterm infants have been reported with the 95th centile for urinary calcium:creatinine ratio of 3.8 mmol/mmol and decreasing with increasing postnatal age, while the 95th centile for urinary phosphate creatinine ratio is 26.7 mmol/mmol, remaining stable with increasing postnatal age. Difficulties in interpretation may arise because of very specific patterns of urinary calcium and phosphate levels depending on whether babies are formula-fed or breast-fed. Formula-fed infants show very low urinary calcium concentrations but a high urinary phosphate, attributed to a low absorption rate of calcium from preterm formulas. Breast milk contains insufficient phosphate for the needs of preterm infants, and therefore infants maximise renal phosphate reabsorption. As urinary ratios depend heavily on type of feed, standard reference ranges are less useful. It has still not been proven that urinary ratios are a reliable substitute for direct measurement of BMC, and more research is needed in this area.

 

X-ray

 

‘Thin bones’, increased translucency of bone and healing fractures may be detected on x-ray. However, studies have suggested that BMD must be reduced by at least 20–40% before x-ray changes are visible.

 

Dual-energy x-ray absorptiometry

 

This has been discussed above. Normal ranges exist for preterm infants, and the technique has been validated. Availability is limited however, and there are significant technical difficulties. Routine usage seems unlikely.

 

Quantitative ultrasound

 

Ultrasound gives measurements that are related to BMD and structure. It is simple, non-invasive, and a relatively cheap bedside test and machines have been developed to measure broadband ultrasound attenuation or the speed of sound, commonly on the tibia. Reference values are available for term and preterm infants, and there is limited data suggesting that the technique may be useful. Availability is very limited and a routine role in screening has not been established.

 

 

SUGGESTED GUIDELINE FOR SCREENING AND TREATMENT OF BABIES AT RISK FOR OSTEOPENIA OF PREMATURITY

 

All babies should be monitored for bone disease if

 

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