Metabolic bone disease of prematurity is characterised by disordered bone mineralisation and is therefore an increased fracture risk. Preterm infants are especially at risk due to incomplete in utero bone accretion during the last trimester. Currently, diag- nosing metabolic bone disease mainly relies on biochemistry and radiographs. Dual-energy x-ray absorptiometry and quantitative ultrasound (US) are used less frequently. However, biochemical measurements correlate poorly with bone mineralisation and although scoring systems exist for metabolic bone disease, radiographs are subjective and do not detect early features of osteopenia. Dual energy x-ray absorptiometry is the reference standard for determining bone density in older children and adults. However, challenges with this method include movement artefact, difficulty scanning small and sick infants and a lack of normative data for young children. Quantitative US has a relatively low cost, is radiation-free and portable, and may hence be suitable for assessing bone status in preterm infants. This review aims to provide an overview of the use of quantitative US in detecting metabolic bone disease in preterm infants. . . . . . . Keywords Bone mineral density Children Metabolic bone disease Preterm infants Quantitative ultrasonography Review Speed of sound Ultrasound Introduction mineral accumulation, have low skeletal mineral stores and are predisposed to developing metabolic bone disease . Metabolic bone disease and osteogenesis imperfecta are the Other factors that increase their risk of metabolic bone dis- two most common causes of fragile bones in infancy . ease include comorbidity, immobility and the use of drugs Metabolic bone disease is characterised by skeletal such as steroids and loop diuretics . Concurrent use of total demineralisation and fractures that can occur during normal parenteral nutrition with an inadequate mineral content to handling . The in utero process of bone accretion increases match the infant’s higher metabolic demand leads to abnormal exponentially during the last trimester of pregnancy . bone remodeling and metabolic bone disease [2, 4]. Preterm infants are, therefore, deprived of this period of In a recent study, 30.9% of extremely low birth weight infants had radiologic evidence of metabolic bone disease . In the short term, metabolic bone disease may impair the infant’srespi- Electronic supplementary material The online version of this article ratory status and may be a factor in the development of myopia (https://doi.org/10.1007/s00247-018-4161-5) contains supplementary material, which is available to authorized users. of prematurity associated with impaired growth of the skull . These infants are also more at risk of fractures beyond the neo- * Amaka C. Offiah natal period, especially during the first 2 years of life . In the firstname.lastname@example.org same study, about a third of infants with metabolic bone disease developed spontaneous bone fractures . Mid Yorkshire Hospitals NHS Trust, Wakefield, UK In adolescence, former preterm infants tend to be shorter and Department of Oncology and Metabolism, lighter for their age and have been reported to have lower bone University of Sheffield, mass, bone mineral content, bone density and cortical cross- Sheffield, UK sectional area [4, 7, 8]. Despite the use of mineral-enriched Academic Unit of Child Health, Damer Street Building, Sheffield preterm formulas, advances in intensive neonatal care and a Children’s NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK reduction in the use of steroids and diuretics, metabolic bone 1538 Pediatr Radiol (2018) 48:1537–1549 disease remains a significant comorbidity. It has been reported methods of measuring bone health . Quantitative US follows that the incidence of metabolic bone disease in very low birth the principle that velocity of transmission and amplitude are in- weight infants and extremely low birth weight infants is 32% fluenced when a US wave is propagated through bone . and 54%, respectively, and that 10% of very low birth weight Many quantitative US devices are specific to only one skeletal infants may be at risk for fractures [9, 10]. site, such as the calcaneum or tibia. A US transducer and receiver Considering these short- and long-term complications of are placed at opposite ends of the bone. The US wave passes poor neonatal bone health and the increasing survival rates through the area of interest and parameters such as speed of for very low and extremely low birth weight preterm infants, sound (speed of propagation of US wave through bone) and bone an improved method of assessing bone health is necessary. transmission time (time taken for ultrasonic wave to pass through bone) are recorded . Speed of sound increases and bone trans- mission time decreases with an increase in bone density and Current assessment of bone health strength. The parameters reflect bone density, architecture and elasticity, including qualitative bone properties such as bone Currently, metabolic bone disease diagnosis relies on bio- mineralisation and quantitative properties such as cortical thick- chemical evaluation and radiologic investigation . ness, elasticity and microarchitecture, providing a more complete Biochemical measurements include serum or urinary phos- picture of bone health as compared to current assessment tech- phate, serum calcium and alkaline phosphatase . A raised niques [4, 11]. This is useful in preterm infants because qualita- alkaline phosphatase and low serum phosphate may indicate tive bone properties may be affected in addition to bone mineral metabolic bone disease. However, biochemical features corre- density, further predisposing them to metabolic bone disease . late poorly with bone mineralisation and may not be consistent Quantitative US techniques can be applied to peripheral indicators of bone strength or mineralisation . Conventional sites, are safe, easy to use and cost effective; the devices are radiographs may be used to look for osteopenia or fractures portable and only a few minutes are needed to perform the and to grade metabolic bone disease . However, radio- measurements at the bedside. These characteristics make it graphs are poor at diagnosing mild bone disease and radiolog- favourable for use in assessing bone status in children . ic features of osteopenia only become reproducibly apparent In vitro studies have shown that forearm quantitative US after 30–40% of mineral loss [2, 4]. variables correlate significantly with bone strength, and these Dual energy x-ray absorptiometry (DXA) is used to determine parameters have been found to correspond to bone mineral bone mineral density, which correlates with bone mineralisation assessment by DXA in children . Results have demonstrated and bone mineral content. DXA is the gold standard in adults and that quantitative US devices adapted for children can be used as children. However, the lack of portable machines and the small frequently as DXA to estimate bone mineral status and bone size of (preterm) neonates and infants (who may be very ill) pose fragility, but current data are not sufficient to establish which of challenges for its use . Furthermore, data from DXA scans are them is the best choice . This review will evaluate the po- difficult to interpret in newborns due to movement artefact and tential of quantitative US as an important tool in the diagnosis, variations in technique . Overall, it is also relatively expensive management and follow-up of metabolic bone disease in pre- . Another important limitation of DXA is that it measures bone term infants. In this review, we evaluate studies that have used a in just two dimensions, thus only providing an estimate of bone total of four commercially available quantitative US devices: mineral density, which in children is highly variable because of Omnisense 7000P (Sunlight Medical Inc., Tel Aviv, Israel), changes in bone geometry with growth. Scientists have not DBM Sonic (IGEA, Capri, Italy), DBM Bone Profiler (IGEA, agreed on a mathematical formula to fully account for differences Capri, Italy) and Osteoson KIV (Minhorst, Medut, Germany). in bone size . The main advantages of DXA are its wide availability, short scanning times and low radiation dose . Search strategy Assessing bone health and/or diagnosing metabolic bone dis- ease in the preterm infant remains difficult as there is no screen- For literature analysis we used the Critical Appraisal Skills ing test that is both specific and sensitive. Biochemical indices Programme tool . A systematic search (Fig. 1) was per- are not diagnostic, radiographs have low sensitivity, and DXA is formed of Medline and Embase (Table 1). Reference lists from impractical for routine use and of questionable reliability . identified studies were hand-searched to identify further rele- vant studies. No time limits were applied. Unpublished data such as conference proceedings were not included. Articles Quantitative ultrasonography not written in English were excluded. Twenty-nine papers were included and are summarised in Table 1. The Critical Quantitative ultrasonography (US) was developed in 1984 as a Appraisal Skills Programme tool  was also used to assess non-ionising, portable and low-cost alternative to conventional the quality of these papers and is shown in Table 2. Pediatr Radiol (2018) 48:1537–1549 1539 Records identified through Records identified through Identification Embase (n =385) Medline (n =200) Records screened after removing Screening duplicates ( n=571) Records screened Records excluded (n =571) (n =526) Full-text articles 16 full-text articles assessed for eligibility excluded: non-English Eligibility (n=45) language (n=11), age range (n=3), no extractable data ( n=1), case report (n=1) Studies eligible for Inclusion inclusion ( n =29) Fig. 1 Identification and inclusion of articles for analysis Analysis measurements from various sites has significant potential ad- vantages and the absence of large differential measurement Feasibility errors between sites is important. Twenty-eight studies reported successful scanning of all study Quantitative US values subjects including premature and very low birth weight in- fants, while one study reported a proportion of failed scans. Table 1 summarises the equipment used and speed of sound Quantitative US appeared well-tolerated, had no adverse side values in the 29 reviewed studies. Most studies (23) used effects, and was appropriate for use for both single and serial Omnisense 7000P at the tibial site, and their values were com- scans. Fewtrell et al.  reported failed scans, due to techni- parable for the term and preterm populations. cal problems. In that study, 17 of 99 patients had at least one failed scan and 4 patients had no successful scans at all. There Speed of sound and gestational age were no clinical features or patterns related to the failed scans, but it was suggested that oedema from illness or fat deposition Regardless of quantitative US equipment used, a positive cor- from rapidly growing infants could be affecting scan success. relation was found between speed of sound values and gesta- tional age, with term infants having higher speed of sound Reproducibility values than preterm infants reflecting the increased maturity of their bones. It is to be noted that significant correlation does Reproducibility of the technique (as mentioned in 11 studies) not mean diagnostic accuracy in any of the presented results. is summarised in Table 3. Intraobserver coefficient variant, Ashmeade et al.  found a positive correlation between interobserver coefficient variant and instrumental precision speed of sound and gestational age in preterm but not in term coefficient variant were all less than 2%. Instrumental preci- infants. Similarly, Zuccotti et al.  found no correlation sion reported for Omnisense 7000P is 0.25–0.5%. between gestational age and speed of sound values in term No significant differences were found in readings taken infants. Conversely, Tansug et al.  suggested that speed from different anatomical sites . The ability to take of sound and gestational age are positively correlated when 1540 Pediatr Radiol (2018) 48:1537–1549 Table 1 Summary of papers included in review Reference Year Quantitative Site/parameter Term/ Study design n Speed of sound (term) Age at scan (term) Preterm speed of sound values Age at scan (preterm) ultrasound preterm device Mercy et al.  2007 Omnisense Tibia/ SOS No/Yes Longitudinal 84 5(2–9) (days) b b Ashmeade et al.  2007 Omnisense Tibia/ SOS Yes/Yes Cross-sectional/ 108 3,036 (2,843–3,333) ≤72 h of life 2,924 (2,672–3,220) ≤1 week of life longitudinal b b McDevitt et al.  2007 Omnisense Tibia/ SOS No/Yes Cross-sectional/ 39 2,942 (2,609–3,064) (corrected 32 (2–104) (days) longitudinal gestational age 0–6 months) 3,269 (3,009–3,413) (corrected gestational age 6–12 months) 3,327 (3,110–3,495) (corrected gestational age ≥ 12 months) Zuccotti et al.  2011 Omnisense Tibia/SOS Yes/No Cross-sectional/ 116 2,964 (2,811–3,282) <9 days Longitudinal (girls) 3,042 (2,656–3,349) (boys) a a Tansug et al.  2011 Omnisense Tibia/ SOS Yes/Yes Longitudinal 126 3,114 (139) 10th day 2,995 (143) 10th day Gonnelli et al.  2004 DBM Bone Humerus/ Yes/No Cross-sectional 140 1,724.8 (25.3) <3 days profiler BTT, SOS Betto et al.  2014 DBM Sonic Metacarpal/ No/Yes Cross-sectional/ 154 1,642.17 (28.35) <24 h of birth BTT, SOS Longitudinal a a Ritschl et al.  2005 DBM Sonic Second metacarpus/ Yes/Yes Cross-sectional/ 338 1,684 (27) <24 h 1,636 (17) <24 h BTT, SOS Longitudinal Litmanovitz et al.  2007 Omnisense Tibia/ SOS No/Yes Interventional 16 ≤7days a a Liao et al.  2005 Omnisense Tibia/SOS Yes/Yes Cross-sectional 542 2,984 (116) <3 months 2,935 (96) <3 months b b b b McDevitt et al.  2005 Omnisense Tibia, distal third Yes/Yes Cross-sectional 110 3,079 (3,010–3,142) 3(2–5) (days) 2,994 (2,917–3,043) 3(2–5) (days) of radius/ SOS (gestational age 32–36 weeks) 2,911 (2,816–2,982) (gestational age <32 weeks) Altuncu et al.  2007 Omnisense Tibia/SOS Yes/Yes Cross-sectional/ 55 z-score: 0.0 <1 week z-score: 0.4 ([−0.2]-1.4) <1 week and Longitudinal ([−0.8]-0.5) term-corrected age a a Chen et al.  2012 Omnisense Tibia/ SOS Yes/Yes Cross-sectional 667 2,971.7 (1,06.3) ≤7 days 2,932.9 (112.4) ≤7days a a Rack et al.  2012 Osteoson KIV 4 different Yes/Yes Longitudinal 172 1,785 (27) ≤7 days 1,720 (24) ≤7days sites/ SOS Littner et al.  2004 Omnisense Tibia/SOS Yes/No Cross-sectional 25 3,082.4 (93.7) <96 h of life b a Fewtrell et al.  2008 Omnisense Tibia/ SOS No/Yes Cross-sectional/ 99 2,950 (2,821–3,220) 2.6 (2.6) (weeks) longitudinal Chen et al.  2010 Omnisense Tibia/ SOS No/Yes Interventional 16 2,851.5 (89)a At birth Litmanovitz et al.  2003 Omnisense Tibia/SOS No/Yes Interventional 24 2,892.3 (29.5) (Control] <1 week 2,825.0 (32.2) [Intervention] Pereda et al.  2003 Omnisense Tibia/SOS No/Yes Cross-sectional 95 No numerical data 2.7 (1.9) [days] Littner et al.  2003 Omnisense Tibia/SOS Yes/Yes Cross-sectional 73 No numerical data <96 h of life No numerical data <96 h of life a a Rubinacci et al.  2003 DBM Sonic Humerus/BTT, Yes/Yes Cross-sectional 94 1,734 (28) <1 week 1,664 (42) At least 34 weeks SOS post conceptual age a a Littner et al.  2004 Omnisense Tibia/SOS Yes/Yes Cross-sectional 50 3,010 (118) <96 h of life 3,010 (118) <96 h of life (no specific data (no specific data based on based on gestation) gestation) Pediatr Radiol (2018) 48:1537–1549 1541 Table 1 (continued) Reference Year Quantitative Site/parameter Term/ Study design n Speed of sound (term) Age at scan (term) Preterm speed of sound values Age at scan (preterm) ultrasound preterm device a a Littner et al.  2005 Omnisense Tibia/SOS Yes/Yes Cross-sectional 22 3,063 (126) <96 h of life 3,063 (126) <96 h of life (mean gestation: (mean gestation: 34 weeks) 34 weeks) a a Teitelbaum et al.  2006 Omnisense Tibia/SOS Yes/Yes Cross-sectional 235 3,012 (98) <96 h of life 2,963 (132) <96 hs of life Chen et al.  2007 Omnisense Tibia/SOS No/Yes Cross-sectional 144 3,098 (135) <1 week of life 7000P (small for gestational age infants) 3,003 (122) (appropriate for gestational age infants) Ahmad et al.  2010 Omnisense Tibia/SOS Yes/Yes Cross-sectional 102 3,168.4 <3 months 2,797.4 (2,720.4–2,874.4) <3 months 7000P (3,129.0–3,207.9) (23–28 weeks) 3,003.9 (2,949.8–3,058) (29–32 weeks) 2,470 (2,267.2–2,673.4) (33–36 weeks) a a Liao et al.  2010 Omnisense Tibia/ SOS Yes/Yes Longitudinal 267 2,979 (113) ≤6 days of delivery 2,945 (89) ≤6 days of delivery 7000P a a Savino et al.  2013 DBM sonic Metacarpal/ Yes/No Cross-sectional 103 1,640 (26) 127 (81) (days) BTT, SOS Erdem et al.  2015 Omnisense Tibia/SOS No/Yes Interventional 28 2,901.28 (120.08) (control) Unknown 7000P 2,812.0 (149.69) (Intervention) BTT bone transmission time, SOS speed of sound a b mean (standard deviation), median (range) 1542 Pediatr Radiol (2018) 48:1537–1549 Table 2 Application of the Critical Appraisal Skills Programme tool  Quantitative ultrasound device Study Year Type of study Are the results of What are Will the results the study valid? the results? help locally? Omnisense 7000P Mercy et al.  2007 Cohort + + ± Ashmeade et al.  2007 Case control ± ± ± McDevitt et al.  2007 Cohort + + ± Zuccotti et al.  2011 Cohort ± + ± Tansug et al.  2011 Case control ± + ± Litmanovitz et al.  2007 Randomised controlled trial ± + ± Liao et al.  2005 Case control ± + – McDevitt et al.  2005 Cohort ± + ± Altuncu et al.  2007 Diagnostic accuracy ± ± ± Chen et al.  2012 Case control ± + ± Littner et al.  2004 Case control ± ± ± Fewtrell et al.  2008 Cohort ± ± ± Chen et al.  2010 Randomised controlled trial ± + ± Litmanovitz et al.  2003 Randomised controlled trial + + ± Pereda et al.  2003 Cohort ± + ± Littner et al.  2003 Cohort ± ± ± Littner et al.  2004 Case control ± ± ± Littner et al.  2005 Case control ± ± ± Teitelbaum et al.  2006 Case control ± ± ± Chen et al.  2007 Case control ± + ± Ahmad et al.  2010 Case control ± ± ± Liao et al.  2010 Case control – ±± Erdem et al.  2015 Randomised controlled trial ± + ± DBM Sonic Gonnelli et al.  2004 Cohort ± + ± Betto et al.  2014 Cohort ± + ± Ritschl et al.  2005 Cohort ± + ± Rubinacci et al.  2003 Case control ± + ± Savino et al.  2013 Cohort ± + ± Osteon KIV Rack et al.  2012 Case control – +± + Yes - No ± Unable to tell reviewing values from preterm and term infants as a whole, [7, 17, 19]. This trend seems counterintuitive as one would but the correlation did not seem to apply to the preterm group expect bone density and strength to increase as infants grow. alone. The small sample size (three infants with gestational This may be because the postnatal trend of speed of sound age <28 weeks) could be the reason for this finding. values in preterm infants differs from that of term infants, and quantitative US is able to reflect a decline in either quantitative or qualitative bone properties despite linear growth. Postnatal trend of speed of sound values Postnatal speed of sound values decrease in preterm infants. A Catch-up growth similar decrease has been seen in term infants [15–17]. This is mentioned in 14 studies and summarised in Table 4.Aspost- Catch-up growth of preterm infants has been documented natal age increases, speed of sound values decrease despite from longitudinal studies. This is shown by the postnatal overall growth, as shown by limb length and biochemical equalising of speed of sound values between preterm and term markers . The rate of decline in speed of sound values is infants. McDevitt et al.  reported that catch-up in speed of related to the prematurity of the infant, with most preterm sound values is independent of postnatal growth and occurs in infants having the steepest decline in speed of sound values most infants by 6 months. The fastest rate of catch-up in speed Pediatr Radiol (2018) 48:1537–1549 1543 Table 3 Reproducibility of quantitative ultrasound technique Study Year Equipment Number Intraobserver Interobserver Instrumental precision Intersite variation name/model of patients coefficient coefficient coefficient variant (%) coefficient variant (%) variant (%) variant (%) Mercy et al.  2007 Omnisense 7000P 84 1.26 McDevitt et al.  2007 Omnisense 7000P 39 1.1 1.2 Zuccotti et al.  2011 Omnisense 7000P 116 0.34 Gonnelli et al.  2004 DBM Bone Profiler 140 1.0 McDevitt et al.  2005 Omnisense 7000P 110 1.2 2.4 Rack et al.  2012 Osteon KIV 172 0.62 Fewtrell et al. 2008 99 1–2 Littner et al.  2003 Omnisense 7000P 73 <1.2 Rubinacci et al.  2003 DBM Sonic 1200 94 1.76 (standardised) Littner et al.  2005 Omnisense 7000P 22 <1.2 Liao et al.  2010 Omnisense 7000P 267 1.23–1.84 of sound values was seen in infants who had the lowest initial made mention of the effects of size for gestational age on speed of sound. This finding agrees with Tansug et al. , speed of sound values (Table 6). who demonstrated no significant difference in speed of sound McDevitt et al.  found no significant difference in values between term and preterm infants by month 12. A speed of sound values between small for gestational age and appropriate for gestational age infants of more than 32 weeks’ similar catch-up phenomenon was seen for metacarpal bone transition time in the preterm cohort in Ritschl et al. . In gestation. Younger than 32 weeks’ gestation, small for gesta- this study, metacarpal bone transmission time values were tional age infants had higher speed of sound values than ap- stable for the term cohort, and the preterm cohort displayed propriate for gestational age infants. Liao et al. and increasing metacarpal bone transmission time values after Altuncu et al.  also found no difference in speed of sound birth, reaching the values of term infants at around 6 months values between small for gestational age and appropriate for of life . gestational age infants. Chen et al.  suggested that the higher speed of sound may be attributable to the older gesta- tional age in small for gestational age infants compared to Anthropometry appropriate for gestational age infants with similar birth weight. This may show that maturity of the fetus has a larger There are contradicting reports on whether speed of sound bearing on bone speed of sound than birth weight. However, values are positively correlated, negatively correlated or not Rack et al.  reported lower speed of sound values in small significantly correlated to birth weight. This is evaluated in 19 for gestational age infants than appropriate for gestational age studies and summarised in Table 5. In Tansug et al. , Day infants. This could be explained by a deficiency in calcium 10 speed of sound values correlated with birth weight when and phosphate leading to reduced placental transfer and di- considering both preterm and term infants as a whole, but minished bone mineralisation in small for gestational age in- when looking at preterm infants alone, there was no signifi- fants or perhaps a soft-tissue effect causing higher speed of cant correlation. However, as previously alluded to, a limita- sound values in small for gestational age infants than appro- tion is the small number of preterm births included in this priate for gestational age infants. Mercy et al. found arapid study. Zuccotti et al.  only looked at term infants and decline in speed of sound values postnatally in small for ges- found no relation between weight and speed of sound values. tational age infants as compared to appropriate for gestational age infants, while there was an upward trend for large for In Ashmeade et al. , there was a significant positive corre- lation between speed of sound measurements and birth weight gestational age infants. There were no explanations provided, among preterm infants. In contrast, the correlation was nega- but it was stated that this is the first time such a trend has been tive in term infants. This suggests that lower rates of intrauter- reported. ine growth are associated with high speed of sound values at In Littner et al. , large for gestational age infants were birth. found to have lower speed of sound values than appropriate Perhaps more interesting is the new insight into appropri- for gestational age infants. This finding is not reproduced in ate, small and large for gestational age infants and how their Liao et al. , where it was concluded that no differences in speed of sound values differ. Ten studies in this review have speed of sound values were found between appropriate for 1544 Pediatr Radiol (2018) 48:1537–1549 Table 4 Postnatal trend in quantitative ultrasonography values Reference Year Quantitative Site/parameter Trend of speed of Trend of speed of Comments ultrasound device sound/bone sound/ bone transmission time transmission time values postnatally values postnatally (preterm) (term) Mercy et al.  2007 Omnisense 7000P Tibia/SOS Decreasing The overall trend in tibial SOS showed a decrease with postnatal age. Ashmeade et al.  2007 Omnisense 7000P Tibia/SOS Decreasing There was a significant decrease over time for entire cohort of preterm infants. Tansug et al.  2011 Omnisense 7000P Tibia/ SOS Decreasing SOS values of preterm infants decreases until 2nd month of life. Gonnelli et al.  2004 DBM Sonic Humerus/BTT, SOS Decreasing in SOS Decrease in SOS values for term infants at 12-months follow-up. Steady Increasing in BTT increases in BTT for term infants after birth at 12-months follow up. Betto et al.  2014 DBM Sonic Metacarpal/BTT, SOS Decreasing Decreasing Deflection of metacarpal BTT from birth to 3rd week of life, followed by increase in this parameter during first few months of life. Ritschl et al.  2005 DBM Sonic Second metacarpal/ Decreasing in SOS Decreasing in SOS Decline in SOS values for up to 6 months in term and preterm infants, then BTT, SOS Increasing in increasing trend up to 18 months of life. metacarpal BTT Steady increase in metacarpal BTT after birth in preterm infants. Litmanovitz et al.  2007 Omnisense 7000P Tibia/ SOS Decreasing Bone SOS decreases during the first 4 postnatal weeks in very low birth weight premature infants. Liao et al.  2005 Omnisense 7000P Tibia/SOS Decreasing The SOS of infants showed an inverse correlation with postnatal age, and the decrease of bone SOS with age in premature infants was more marked than in full-term infants. Altuncu et al.  2007 Omnisense 7000P Tibia/SOS Decreasing Serial assessment of tibia SOS z-scores of preterm infants showed that tibia SOS z-scores of preterm infants at term-CA (corrected age) were significantly lower than the scores at first postnatal week of life. Rack et al.  2012 Osteoson KIV 4 different sites/SOS Decreasing Rapid decline in SOS values in first few weeks of life, plateauing after 40 weeks post-conceptual age. Fewtrell et al.  2008 Omnisense 7000P Tibia/SOS Decreasing Both absolute and z-scores relative to cross-sectional reference data fell during the postnatal period. Litmanovitz et al.  2003 Omnisense 7000P Tibia/SOS Decreasing Rubinacci et al.  2003 DBM Sonic Humerus/BTT, SOS Decreasing Savino et al.  2013 DBM sonic Metacarpal/BTT, SOS Decreasing Decreasing trend of SOS values lasted up to 240 days, followed by slow increases in next months. BTT bone transmission time, SOS speed of sound Pediatr Radiol (2018) 48:1537–1549 1545 Table 5 Correlation between birth weight and quantitative ultrasonography (US) values Reference Year Quantitative US device Site/parameter Correlation between birth weight and quantitative US Comments values Preterm infants Term infants Mercy et al.  2007 Omnisense 7000P Tibia/SOS Positive correlation Significant positive correlation between birth weight and SOS values when using first measure cross-sectional data. Ashmeade et al.  2007 Omnisense 7000P Tibia/SOS Positive correlation Negative correlation Significant positive correlation in birth weight and SOS measurements in preterm infants, but negative correlation in term infants. This might suggest that lower rates of interuterine growth are associated with high SOS values. McDevitt et al.  2007 Omnisense 7000P Tibia/SOS No significant correlation No significant effect of weight or length gain on SOS values. Zuccotti et al.  2011 Omnisense 7000P Tibia/SOS No significant correlation No relation between birth weight and SOS values. Tansug et al.  2011 Omnisense 7000P Tibia/SOS No significant correlation There is positive correlation between birth weight when considering preterm and term infants as a whole, but no significant correlation when looking at preterm infants alone. There are only a small number of preterm births included in this study. Gonnelli et al.  2004 DBM Bone profiler Humerus/BTT, SOS Positive correlation BTT and humerus BTT of neonates showed significant relationship with birth weight. Betto et al.  2014 DBM Sonic Metacarpal/BTT, SOS Positive correlation Weight and length at 3rd week and 36th week of life correlated positively with metacarpal BTT. Ritschl et al.  2005 DBM Sonic Second metacarpus/ Positive correlation Positive correlation Quantitative US parameters were closely correlated with BTT, SOS length and weight of infant. Liao et al.  2005 Omnisense 7000P Tibia/SOS No significant correlation No significant correlation SOS in infants with birth weights <1,500 g was lower than in infants with birth weights >2,500 g. However, there are no significant differences after accounting for gestational age and birth season. McDevitt et al.  2005 Omnisense 7000P Tibia, distal third 32–36 weeks’ gestational No significant correlation There was no significant difference in SOS for SGA and AGA of radius/SOS age: no significant infants in >37 weeks’ gestational age and 32–36 weeks’ correlation gestational age groups. In the <32 weeks’ gestational age <32 weeks’ gestational group, SGA infants had higher SOS values than AGA infants. age: negative correlation However, there was no significant difference between LGA and AGA infants in all groups. Chen et al.  2012 Omnisense 7000P Tibia/SOS Negative correlation Negative correlation Birth weight had a negative effect on increasing SOS values. SOS values were higher in SGA infants than in AGA infants. Rack et al.  2012 Osteoson KIV 4 different sites/SOS Positive correlation No significant correlation Birth weight was the strongest predictor of quantitative US values in the most immature infants, but predictive value becomes insignificant in term infants. Fewtrell et al.  2008 Omnisense 7000P Tibia/SOS No significant correlation There is no significant correlation between SOS and birth weight at time of scan. Littner et al.  2003 Omnisense 7000P Tibia/SOS Positive correlation Positive correlation SOS values were more closely correlated to gestational age than with birth weight. 1546 Pediatr Radiol (2018) 48:1537–1549 gestational age, small for gestational age and large for gesta- tional age infants. Littner et al.  speculate that the relative lack of motion of macrosomic infants as compared to appro- priate for gestational age infants may lead to lower speed of sound, as physical activity is known to enhance mineral accretion. Biochemical bone markers Fewtrell et al. , Chen et al.  and Tansug et al. did not find any relationship between speed of sound values and the bone turnover markers serum alkaline phosphatase and serum phosphate. In Chen et al. , there was only a slight upward trend in alkaline phosphatase, which did not correlate with any speed of sound trends. Serum alkaline phosphatase is the sum of three isoforms from the liver, intestines and bone, as such an increase in serum alkaline phosphatase might be due to a liver dysfunction. Tansug et al.  explained that their findings might be because there were no infants with very low serum phosphate or high serum alkaline phosphatase in their study. As a high serum alkaline phosphatase is known to develop relatively late in the pathological process of meta- bolic bone disease, Fewtrell et al.  aimed to assess the ability of early speed of sound measurements to predict a high serum alkaline phosphatase level later on. They found that speed of sound measurements did not predict a high alkaline phosphatase. Conversely, a high serum alkaline phosphatase was also not associated with a lower final speed of sound measurement. However, this study did not consider some con- founding factors, such as factors related to the severity of illness or infant characteristics such as gestational age or birth weight. Conversely, Altuncu et al.  found that there was an inverse correlation between alkaline phosphatase levels and tibia z score at term corrected age in preterm infants. In their study, patients with alkaline phosphatase>900 international units per litre were found to have significantly lower tibia z score for speed of sound, indicating ongoing osteoblastic ac- tivity . Other studies have found significant correlations between biochemical markers and speed of sound values. McDevitt et al.  found that serum phosphate and speed of sound were significantly positively correlated. This correlation is replicat- ed in Betto et al. , with another quantitative US parameter. The study found that metacarpal bone transmission time was correlated to serum phosphate, phosphaturia and calciuria in the third week of life and suggested that these three biochem- ical tests could be used in the workup of metabolic bone dis- ease. This observation was also made in Ashmeade et al.  and Rack et al. . Additionally, in Ashmeade et al. , a significant negative correlation was found at various time points between serum alkaline phosphatase and speed of sound values. This shows that serum markers in combination with longitudinal speed of sound measurements may be useful Table 5 (continued) Reference Year Quantitative US device Site/parameter Correlation between birth weight and quantitative US Comments values Preterm infants Term infants Rubinacci et al.  2003 DBM Sonic Humerus/BTT, SOS Positive correlation SOS values were found to be significantly correlated to birth weight and weight at measurement (postconceptual age of at least 34 weeks for preterm infants). Littner et al.  2004 Omnisense 7000P Tibia/SOS Negative correlation LGA infants had lower SOS values than normal AGA values predicted from standard curves. Teitelbaum et al.  2006 Omnisense 7000P Tibia/SOS Positive correlation Positive correlation There was a significant positive correlation between SOS and birth weight, independent of gestational age. Liao et al.  2010 Omnisense 7000P Tibia/ SOS Positive correlation Positive correlation SOS values of infants with birth weight of <1,500 g was significantly lower than infants with birth weight of >2,500 g. Savino et al.  2013 DBM Sonic Metacarpal/ BTT, SOS No significant correlation No significant correlation Negative correlation was observed between SOS, length and weight. However with multiple regression modelling, no significant relationship was found. AGA appropriate for gestational age, BTT bone transmission time, LGA large for gestational age, SGA small for gestational age, SOS speed of sound Pediatr Radiol (2018) 48:1537–1549 1547 Table 6 Relationship between speed of sound values of appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) infants Study Year Quantitative Site/parameter Relationship between speed of sound Relationship between ultrasonography values of AGA and SGA infants speed of sound values device of AGAand LGAinfants Mercy et al.  2007 Omnisense 7000P Tibia/ SOS Rapid decline in SOS values in SGA infants postnatally as compared to AGA infants. Ashmeade et al.  2007 Omnisense 7000P Tibia/ SOS SOS values were higher in SGA infants as compared to AGA infants. Liao et al.  2005 Omnisense 7000P Tibia/SOS No difference in SOS values between SGA No difference in SOS and AGA infants. values between AGA and LGA infants. McDevitt et al.  2005 Omnisense 7000P Tibia, distal third >32 weeks’ gestation: No significant difference of radius/ SOS in SOS values between AGA and SGA infants <32 weeks’ gestation: SGA infants had higher SOS values than AGA infants Altuncu et al.  2007 Omnisense 7000P Tibia/SOS No difference in SOS values between SGA and AGA infants. Chen et al.  2012 Omnisense 7000P Tibia/ SOS SOS values were higher in SGA infants with higher gestational age as compared to AGA infants with similar birthweight. Rack et al.  2012 Osteoson KIV 4 different Lower SOS values in SGA infants than AGA sites/ SOS infants. Littner et al.  2004 Omnisense 7000P Tibia/SOS LGA infants were found to have lower SOS values than AGA infants. Littner et al.  2005 Omnisense 7000P Tibia/SOS SGA infants have higher SOS values than AGA controls. Chen et al.  2007 Omnisense 7000P Tibia/SOS Preterm SGA infants had higher tibial SOS values than their AGA counterparts; findings were similar regardless of the reference chart used to categorize infants as SGA or AGA. SOS speed of sound, US ultrasonography for identifying infants at risk of developing metabolic bone measurements are well tolerated by all infants, even those in disease. Rack et al.  also found a negative correlation intensive care. This review did not compare the reliability of between serum alkaline phosphatase and quantitative US pa- different US devices; however, the trend of speed of sound rameters. The study also measured urine calcium and phos- values was similar for each device. Intraobserver, interobserv- phate concentrations and serum calcium concentration and er and intersite precision were high in all devices. The studies found that none of these variables correlated with quantitative reviewed showed a difference between preterm and term in- US, contrary to Betto et al. . fants at birth, and a decreasing trend in speed of sound values Litmanovitz et al.  usedbone specificalkalinephos- in preterm infants when longitudinal measurements were tak- phatase and carboxy terminal cross-links telopeptide of Type-I en. This may reflect either that the postnatal trend of speed of collagen as markers of bone formation and bone resorption, sound values in preterm infants differs from term infants, or respectively. They found that although there was a significant that quantitative US is able to assess both quantitative and increase in bone specific alkaline phosphatase and significant qualitative bone properties, and gives a more holistic picture decrease in carboxy terminal cross-links telopeptide of Type-1 of bone health. Catch-up growth of preterm infants has been collagen, both parameters remained within the normal range demonstrated in longitudinal studies. and there were no significant correlations between bone turn- Although quantitative US is now widely used in adults in over markers and speed of sound. the context of osteoporosis, its use in infants and children is limited to studies of small sample size . Lack of reference data, use of different quantitative US devices and assessment Summary of findings of different sites makes it challenging to compare the outcome between studies . The correlation of quantitative US pa- In neonates, quantitative US can be measured with Omnisense rameters with various factors mentioned in this review, for 7000P, DBM sonic and Osteon KIV devices. The example biochemical markers and anthropometry, has not 1548 Pediatr Radiol (2018) 48:1537–1549 7. Ashmeade T, Pereda L, Chen M et al (2007) Longitudinal measure- provided consistent results. The correlation between quantita- ments of bone status in preterm infants. J Pediatr Endocrinol Metab tive US parameters and the current gold standard assessment 20:415–424 DXA is also lacking consistent data . US reference values 8. McDevitt H, Tomlinson C, White MP et al (2007) Changes in are available for term and preterm infants, but they are specific quantitative ultrasound in infants born at less than 32 weeks gesta- tion over the first 2 years of life: influence of clinical and biochem- to the manufacturer of the device used and standardised values ical changes. Calcif Tissue Int 81:263–269 have not been achieved . Most importantly, values for 9. Vachharajani AJ, Mathur AM, Rao R (2009) Metabolic bone dis- predicting or monitoring metabolic bone disease have not ease of prematurity. NeoReviews 10:402–411 been established . 10. Koo WKK, Gupta JM, Nayanar VVet al (1982) Skeletal changes in preterm infants. Arch Dis Child 57:447–452 11. Baroncelli GI (2008) Quantitative ultrasound methods to assess bone mineral status in children: technical characteristics, perfor- Conclusion mance and clinical application. Pediatr Res 63:220–228 12. CASP UK (1993) CASP Checklists. CASP International. https:// casp-uk.net/casp-tools-checklists/. Accessed 27 March 2018 The noninvasive, financially viable and convenient monitor- 13. Zuccotti G, Vigano A, Cafarelli L et al (2011) Longitudinal changes ing of bone health with US might hold potential as an initial of bone ultrasound measurements in healthy infants during the first screening tool to predict metabolic bone disease but also for year of life: influence of gender and type of feeding. Calcif Tissue Int 89:312–317 follow-up to review treatment efficacy and assess subsequent 14. Tansug N, Yildirim SA, Canda E et al (2011) Changes in quantita- trends in bone health. However, the results presented in the tive ultrasound in preterm and term infants during the first year of papers we evaluated were not always concordant. More stud- life. Eur J Radiol 79:428–431 ies focusing on the association of biochemical bone markers, 15. Gonnelli S, Montagnani A, Gennari L et al (2004) Feasibility of DXA, radiographs and quantitative US parameters will be quantitative ultrasound measurements on the humerus of newborn infants for the assessment of the skeletal status. Osteoporos Int 15: essential in assessing the accuracy and reproducibility of 541–546 quantitative US variables before widespread clinical use on 16. Betto M, Gaio P, Ferrini I et al (2014) Assessment of bone health in neonatal units. preterm infants through quantitative ultrasound and biochemical markers. J Matern Fetal Neonatal Med 27:1343–1347 Acknowledgements We thank Mrs. Sarah Massey for her help with the 17. Ritschl E, Wehmeijer K, Terlizzi FD et al (2005) Assessment of literature search. skeletal development in preterm and term infants by quantitative ultrasound. Pediatr Res 58:341–346 18. Litmanovitz I, Dolfin T, Arnon S et al (2007) Assisted exercise and Compliance with ethical standards bone strength in preterm infants. Calcif Tissue Int 80:39–43 19. Liao XP, Zhang WL, He J et al (2005) Bone measurements of Conflicts of interest None infants in the first 3 months of life by quantitative ultrasound: the influence of gestational age, season, and postnatal age. Pediatr Radiol 35:847–853 Open Access This article is distributed under the terms of the Creative 20. 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Pediatric Radiology – Springer Journals
Published: Jun 16, 2018
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