Metabolic Bone Disease Bone Study Day, 28th September 2012 of Prematurity Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's Hospital Manchester M13 0JH Bone Study Day, 28th September 2012

Metabolic Bone Disease of Prematurity Aetiology Fractures Assessment Prevention

Aetiology of Metabolic Bone Disease of Prematurity

Aetiology of Metabolic Bone Disease of Prematurity Preterm birth - bulk of the mineral transfer from mother to baby occurs in last third of pregnancy Inadequate supply of minerals in diet after birth Increased loss of minerals from infant’s bones after birth: Stoppage of movements Loss of oestrogen MBP is a well known complication of prematurity. Risk inversly related to BW and gestational age and directly with postnatal morbidity (CLD, TPN & delay in enteral feeding). Usually diagnosed at 2 to 4 months postnatal age: Osteopenia on a radiograph Low BMD for corrected gestation. Abnormal biochemistry (low Pi & high ALP) Fractures Cause multifactorial: Missed out on 3rd trimester package of minerals Decreased availability of minerals postnatally Feeds deficient in Ca & P Inability to tolerate/absorb enteral feeds, e.g. due to NEC or short bowel syndrome Low Ca & P in TPN solution Skeletal demineralisation, especially during the rapid postnatal growth phase Drugs – Frusemide & corticosteroids Imobilisation No evidence that vitamin D def. plays an important part unless mother is deficient. Or the child has liver disease.

Aetiology of Metabolic Bone Disease of Prematurity Increased risk of MBP <1000 gm birth weight (ELBW) Prolonged TPN (>2 weeks) Medications Corticosteroids Frusemide Inadequate bone-nutrient intake Increased urinary Phosphate wastage

Metabolic Bone Disease of Prematurity Humerus of 26 week gestation, preterm infant at birth (A) and 6 weeks later (B) Marked thinning of the cortex Osteopaenia Poznanski et al. Radiology 1980

Post-natal Changes in Bone Mineralisation Greer FR J Peds 1988

Aetiology of Metabolic Bone Disease of Prematurity Longitudinal study in 85 preterm infants < 1.5 kg Measured Speed of Sound (SOS m/s) Tibial length (measured by knemometry) SOS measurements was 27 weeks (23 to 37.6) and 877 grams (418 to 1495), respectively. Measurements were performed weekly; median period of 4 weeks (1 to 16). The data for knee heel length and tibial SOS over time in 85 babies (Figs.5&6) and preliminary data for markers of bone turnover in a subset of 24 babies (Figs.9&10), was analysed by a ‘within subjects’ correlation.

A longitudinal study of tibial speed of sound and lower limb length in preterm infants Knee heel length (mm) over time Tibial SOS (m/s) Knee heel length (mm) r=0.96;p<0.001 r=-0.28; p<0.033 r = 0.96; p < 0.001 Postnatal age (weeks)

A longitudinal study of tibial speed of sound and lower limb length in preterm infants r=0.96;p<0.001 r=-0.28; p<0.033

Post-natal Immobilisation Hormones (e.g. oestrogen) LOAD (muscle) Hormones (e.g. oestrogen) Cytokines Calcium Vitamins Growth factors etc Bone Deformation Remodelling 800µ strains Material quality Osteocytes Architecture Mechanostat 2000µ strains Modelling <100 µ strains STRAIN Frost (1987) Anat Rec 219: 1-9

Fractures

Fracture Incidence in Low Birth Weight Infants 78 VLBW infants; 23 to 36 week gestation Human milk or formula fed 69% had evidence of fracture Most common sites: Ribs Radius ± ulna Femur Koo WWK et al J Pediar Orthop 9:326, 1989

Subjects 106 infants identified 72 included in the study Birth weight range 450 - 990g Gestation range 22 - 33 weeks All radiographs reviewed by Dr Neville Wright (n=1762) 20% radiographs reviewed by Dr Sarah Russell (n=558) FIGURE 10 AP radiograph of a newborn with campomelic dysplasia. Of note is the absence of vertebral pedicles (small arrowheads) in the thoracic spine (present in the lumbar spine) and 11 pairs of ribs. A nearly diagnostic and uniform feature is the hypoplastic scapulae (large arrowhead). Not seen here but often present are cervical kyphosis and cervical or thoracic scoliosis. FIGURE 17 (A) Ultrasound performed at 23.5 weeks due to suspicion of skeletal dysplasia. Mildly shortened femurs were noted at 12 weeks and repeat ultrasound at 19 weeks showed micromelia, small thorax, and marked midface hypoplasia. Based on the findings, the parents were counseled that the fetus had a lethal condition and that thanatophoric dysplasia (TD) was the likely diagnosis. This view of the fetus shows the narrow chest diameter compared to the abdomen. After termination of pregnancy, the diagnosis of type 1 was confirmed by radiographs and molecular analysis. (B) Radiograph of the fetus with TDI. This diagnosis was subsequently confirmed by molecular analysis, which showed the C742T mutation in the FGFR3 gene (typical of TDI). The radiographic findings are severely shortened limbs with trident positioning of the fingers and bowed femurs. In the thorax, there are H-shaped platyspondyly and short ribs. TD is broadly classified into two types. TD1 causes bent/angulated femurs. TD2 is associated with cloverleaf skull caused by multiple craniosynostoses and relatively straight femurs. Denise Smurthwaite, Neville Wright, Sarah Russell, Anthony Emmerson & Zulf Mughal. Arch. Dis. Child. Fetal Neonatal Ed., Aug 2008; doi:10.1136/adc.2007.136853

Number and Sites of rib fractures Results 1 5 infants (7%) had Rib #s NONE had posterior shaft #s All infants with rib #s died 3 infants had non Rib #s Number and Sites of rib fractures Denise Smurthwaite, Neville Wright, Sarah Russell, Anthony Emmerson & Zulf Mughal. Arch. Dis. Child. Fetal Neonatal Ed., Aug 2008; doi:10.1136/adc.2007.136853

Results 2 Mann Whitney U Test: Infants with Rib #s vs those with No #s Highest Alkaline Phosphatase (ALP) p = 0.08 Birth weight p = 0.52 Gestation p = 0.22 Corticosteroids p = 0.07 Frusemide p = 0.03 * Chronic Lung Disease p = 0.36 Chest Drains p = 0.57 Total Parentral Nutrition (TPN) p = 0.08 FIGURE 18 A fetus assessed for short limbs at 22 weeks of gestation. Of note, the head was relatively large and on profile had features of achondroplasia. Most noticeable was the prominent forehead and the depressed nasal bridge. (B) On inspection of the extremities, the diagnosis of achondroplasia was supported by the finding of trident hand. The diagnosis was confirmed postnatally. Denise Smurthwaite, Neville Wright, Sarah Russell, Anthony Emmerson & Zulf Mughal. Arch. Dis. Child. Fetal Neonatal Ed., Aug 2008; doi:10.1136/adc.2007.136853

Summary All infants with Rib #s died None had posterior Rib # Only 7% of ELBW infants had radiologically apparent Rib #s All infants with Rib #s died None had posterior Rib # No temporal relationship between CPR & Rib #s Infants with Rib #s more likely to be treated with Frusemide. Denise Smurthwaite, Neville Wright, Sarah Russell, Anthony Emmerson & Zulf Mughal. Arch. Dis. Child. Fetal Neonatal Ed., Aug 2008; doi:10.1136/adc.2007.136853

Assessment & Prevention

Assessment of MBDP Clinical: Research: Serum Calcium and Phosphate concentrations Serum Alkaline Phosphatase activity Serum PTH Radiographs – when necessary Research: Biochemical markers of bone turnover Bone densitometry Quantitative ultrasound

Recommended Intake for Premature Infants (per Kg/day) Energy 110 -130 Kcal Calcium 140 -180 mg Phosphorus 80 - 90 mg Vitamin D 400 IU Needs met by fortification of mother’s milk or premature infant formula

Severe Secondary Hyperparthyroidism

Could a program of daily physical activity with adequate dietary intake improve bone mineralisation in premature infants?

Distal 1/3 Radius Bone Mineral Change by pDXA Prevention of MBDP Ideal postnatal rate of mineralisation not known. Ca 120 to 150 mg/kg & P ~75 mg/kg. VARIABLES: absorption, losses and retention. Breast-milk with a fortifier or high mineral preterm formula milk. Duration ?. Most people would use high formula until postmenstural term age or at lease when body weight is >2kg weight. WEEKLY MEASUREMENT OF Ca, P & ALP. Mineral supplements until radiographic healing of bones Vitamin D ? 400 or 880 i.u? No evidence that Rx with Calcitriol or alphacalcidiol is any better. Biochemical aims: Ca with the normal limits P >4 mg/dl If ALP is > 5 times the upper limits then radiograph of the hand and rist is indicated. CONVERSATION: Calcium 1 mmol = 40 mg Phosphate 1 mmol = 31 mg Moyer-Mileur et al, J Peds 1995

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