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CAN BE PREDICTED ?Dr. Emad ShatlaMD / MRCPCH / FRCPCH
Senior Consultant Neonatology
Head of NICU
Head of Pediatrics
Sohar Hospital - OMAN
MBDMETABOLIC BONE DISEASE
lifecare
• Preterm 27 weeks
• 6 weeks old
• Osteopenia of prematurity
• X ray
• Vit D ,PTH , …….
• Bone profile , Ca , P , ALP, -------
There are three special types of cells that are found only in the bone.
OSTEOCLASTS
Dissolve the bone. They come from the bone marrow and are related to white blood cells.
They are formed from two or more cells that fuse together, usually have more than one nucleus.
OSTEOBLASTSIt forms new bone ,come from the bone
marrow and have only one nucleus.
They control calcium and mineral deposition.
The old osteoblasts are also called LINING CELLS.
They regulate passage of calcium into and out of the
bone .
OSTEOCYTESThey come from osteoblasts. Some of the osteoblasts turn into
osteocytes while the new bone is being formed can sense
pressures .
Alkaline PhosphataseAlkaline phosphatases (ALPs) are a group of enzymes
that are present in many different tissues.
e.g. …… bone and liver.( Intestine, placenta, tumour )
• in vitro activity at a pH of 10 .
• reference range of 35 to 125 IU per liter in an adult population .
Total BALP can be further separated into
isoforms that are specific for cortical and
trabecular bone, respectively .
The role of ALP in the skeleton involved
in the mineralization process.
The clearance of ALP from serum may be
transiently impaired after viral infections in
children (transient Hyperphosphatasemia),
leading to excessively high total ALP.
Cholestasis ---- ALP
Backstrom and colleagues suggested that
Serum alkaline phosphatase levels higher than 900 U.I/l
associated with a serum phosphate level lower than 1.8 mmol/l have a
diagnostic sensitivity of 100% and specificity of
70% .
The reliability of alkaline phosphatase to predict
the status of bone mineralization are still
conflicting ?
Serum level of calcium is usually within the
normal range .
Dick H. Kleyn
This figure indicates that the activity of alkaline phosphatase is decreases with the advancement of GA
Osteocalcin
• Osteocalcin is metabolized primarily by the kidneys .
• It has been observed that higher serum-osteocalcin levels are relatively well correlated with increases in bone mineral density (BMD) .
Osteocalcin is secreted
by osteoblasts
It is secreted and
incorporated into
the organic bone matrix
during the matrix
mineralization phase.
Some newly
synthesized
Osteocalcin
reaches the
bloodstream.
Osteocalcin, or( bone
gamma-
carboxyglutamic acid
containing
Protein ) (BGLAP)
It has gla domains, its
synthesis is
vitamin K dependent.
Reference Range:
18 years or older - 9-42 ng/mL
Bone Mineral Density Test
Bone density testing can be done several ways.
The most common and accurate way uses a dual-energy x-ray absorptiometry
(DEXA) scan. DEXA uses low-dose x-rays. (You receive more radiation with a
chest x-ray.)
There are two types of DEXA scans:
Central DEXA. You lie on a soft table. The scanner passes over your
lower spine and hip.
Peripheral DEXA (p-DEXA). These smaller machines measure the
bone density in your wrist, fingers, leg, or heel.
Diagnostic use of this molecule is hampered by its significant
I n s t a b i l i t y
Found in the circulation
In small amount
Difficulties in distinguishing between the various
molecular forms.
Osteocalcin
J Diabetes Investig. 2016 Jul; 7(4): 522–528.
Published online 2015 Dec 16. doi: 10.1111/jdi.12439
Low Osteocalcin levels are associated with insulin resistance, diabetes and metabolic syndrome in observational studies.
New therapeutic approaches to diabetes and heart disease may be anticipated if this bone-derived protein is involved in the regulation of glucose metabolism and cardiovascular risk.
The placenta is impermeable to parathyroid hormone (PTH),
PTHrP, and calcitonin.
but !!!!!!!!!
Vitamin D (1) or (1 ,25) are transported across the placenta, and free vitamin
D concentrations in foetal blood are similar to or higher than maternal values.
PTH serum calcium concentrations directly by increasing bone resorption
and renal calcium reabsorption and indirectly by increasing
renal synthesis of 1,25(OH)2D3 .
Parathyroid Hormone (PTH)
Ginekol Pol. 2005
In humans, maternal hyper-parathyroidism may
lead to stillbirth or neonatal hypo-calcemiasecondary to suppression
of fetal PTH.
Maternal hypo-parathyroidism leads to increased levels of fetalPTH via fetal parathyroid
hyperplasia, and generalized skeletal
demineralization
PARATHYROID HORMONE-RELATED PEPTIDE (PTHRP)
There is increasing evidence that PTHrP is the major determinant of
placental calcium transport in animals, and that levels of PTHrP are
increased in response to a low fetal plasma calcium level .
The role of PTHrP is less well characterized in human pregnancy, but may be
produced in the placenta, and is present in breast milk .
Reducing the risk of multiple sclerosis, according to a 2006 study published in the Journal of the American Medical AssociationDecreasing the chance of developing heart disease, according to 2008 findings published in Circulation journal
Helping to reduce the likelihood of developing the flu, according to 2010 research published in the American Journal of Clinical Nutrition
Also has role in:
Hypertension Diabetes
Depression Autoimmune disorders
Obesity Osteoporosis
Rheumatoid arthritis
Vit. D
Urine R/E
CBC
What I should do ????
The period of greater skeletal development is
during the intrauterine life and specifically during the
last trimester.
The bone volume increases significantly with gestational age and the high net bone formation activity is mainly due to modelling, with a rapidly increasing trabecular thickness (the trabecular thickening rate being approximately 240 times faster in the foetus than in the children).
Magnitude of the problem
The prevalence of MBD varies
depending on gestational age, birthweight and
kind of alimentation.
it occurs in up to 55% of babies born with weight under 1000 g ,and 23% of infants weighing < 1500 g frequent in babies under 28 weeks of
gestation.
MBD remains silent until a severe demineralisation
occurs.
The most evident clinical findings of osteopenia are
deformity of the skull (diastasis of the suture,
enlargement of the sagittal fontanelle and frontal bosses, craniotabe).
Also,thickening of the of the wrists, rib and long bones fractures.
Softening and/or fractures of the ribs can cause pulmonary changes and respiratory distress, typically between 6 and 16 weeks of age .
The mineralization process is determined by synthesis of the
organic bone matrix by osteoblasts (osteoid) onto which
calcium and phosphate salts are deposited.
This process increases exponentially between 24 and 37 weeks
of gestation, reaching the 80% of mineral accretion in the third
trimester .
The main determinant of skeletal mineralization in utero
appears to be the foetal plasma calcium concentration and
this is mainly influenced by fetal PTH activity.
Lack of parathyroid in fetal mice leads to
low foetal calcium and skeletal mineralization .
NEWBORN
The supply of calcium and phosphorus halts abruptly at birth when the
umbilical cord is cut. Whole blood ionized calcium falls rapidly,
reaching a nadir of 1.2 mmol/L by around 16 hours of age.
Paradoxically, plasma calcitonin rises rapidly after birth in infants.
In the adult, calcitonin is secreted in response to hyper-calcemia, and in
response to elevated plasma gastrin concentrations.
The infant surge in plasma calcitonin peaks at approximately 12 hours after
birth and is greater in preterm infants than in term small for gestational age
(SGA) infants .
The surge can be ameliorated in preterm infants by the provision of large
supplements (2 mmol/kg/day) of calcium .
Italian Journal of Pediatrics 2009, 35:20
Many factors affect calcium absorption including the maternal vitamin D
status, solubility of calcium salts, quality and quantity of calcium, amount
and type of lipids and, obviously, gut function.
Calcium absorption from the intestine occurs both passively and through
a vitamin-D dependent active transport mechanism.
occurs within 48-72 hours of birthcommonly seen in preterm and very low birth weight infants, infants
asphyxiated or depressed at birth, infants of diabetic mothers, and the
intrauterine growth restricted infants.
The mechanisms
inadequate nutritional intake
decreased responsiveness of
parathyroid hormone to vitamin D
increased calcitonin level
increased urinary losses
hypoalbuminemia
increased endogenous
phosphate load due to
tissue catabolism metabolic acidosis
Late-onset neonatal hypocalcemia
Occurs 3-7 days after birth .
Vitamin D deficiency .
Exogenous phosphate load .
Primary immunodeficiency disorder: DiGeorge Syndrome .
Gentamicin therapy .
Absorption of phosphorus takes place in the jejunum and
depends on the dietary intake.
The phosphorus supply regulates calcium absorption and retention:
the higher is the phosphorus content of the diet, the higher is the
calcium retention.
Chronic damage to
placenta— phosphorus
transport osteopenia
(IUGR).
Phosphorus
Moreover, while in utero fetus experiments mechanical
stimulation by kicking against the uterine wall,
extra-uterine LIFE incubator.
Immobilisation stimulates bone reabsorption
by osteoclasts and urinary calcium excretion.
TOP 8 CALCIUM RICH FOODS
• 1) Raw Milk. 1 cup: 300 mg (30% DV)
• 2) Kale (cooked) 1 cup: 245 mg (24% DV)
• 3) Sardines (with bones) 2 ounces: 217 mg (21% DV)
• 4) Yogurt or Kefir. 6 oz: 300 mg (30% DV)
• 5) Broccoli. 1 ½ cup cooked: 93 mg (9% DV)
• 6) Watercress. 1 cup: 41 mg (4% DV)
• 7) Cheese. 1 oz: 224 mg (22% DV)
• 8) Bok Choy.
Recent work in human subjects has shown
.
placenta
The plasma membrane Ca2+ ATPase (PMCA)
The level of mRNA
expression of an active
placental calcium
transporter (PMCA 3),
on the basal
membrane
of the placenta, is
positively correlated
with whole body bone
mineral content (BMC)
in the offspring at birth.
These observations may
suggest a possible
mechanism for the
influence of maternal
vitamin D status on
placental calcium
transport
and intrauterine bone
mineral accrual .
NEONATAL MINERAL REQUIREMENTS
Supplying calcium and phosphorus in parenteral nutrition
is a challenge because of limited solubility of these
two minerals.
Calcium and phosphorus's solubility depends on:
Temperature
Type and
concentration
of amino acid
Glucose
concentrationPH
Type and
concentration
of calcium salts
Presence of lipid
In parenteral nutrition calcium is administered as inorganic salt and phosphorus
may be administered as inorganic sodium and potassium phosphate or
glycerol-phosphate, which are quite soluble in water.
The addition of cysteine to lower pH of the parenteral admixtures improves the
solubility of calcium and phosphorus.
Adding cysteine increased the amount of NaPhos
that could be added to solutions .
The human milk content is inadequate for preterm requirements since the
content of calcium and phosphorus in preterm human milk is 31 mg/100 kcal
and 20 mg/ 100 kcal .
Assuming calcium and phosphorus absorption of 70% and 80% respectively,
this would provide only one-third of the in utero level of absorbed calcium
and phosphorus .
Low concentrations of calcium
and phosphorus in the urine
suggest an inadequate intake.
Markers of nutritional status should be assessed baseline, and then weekly
during the initial phase; once the newborn is stable, assessment must
be done at the starting of total enteral nutrition and every 2–3 weeks.
Parenteral administration of 50–75 mg of calcium/kg/day can prevent early
neonatal hypo-calcaemia in preterm infants
The best calcium to phosphorus ratio
for bone mineralization is 1.7:1 .p
CaCa +P
P+Ca
Clinical Features and Diagnosis
MBD
Diagnosis of osteopenia is mainly done by serum analysis.
Biochemically osteopenia is characterised by low serum levels of phosphorus
and by an increase in serum levels of alkaline phosphatase that can reach
values 5 times higher than the upper reference range used for adults .
If MBD is diagnosed and nutritional supplementation is started, a
periodic assessment of laboratory data is necessary to evaluate the
response to treatment also when babies are discharged from
hospital .
Requirements ESPGAN LSRO Atkinson Rigo
1987 2002 2005 2007
Calcium
(mg/kg/day)
70–140 150–220 120–200 100–160
Phosphorus
(mg/kg/day)
50–90 100–130 60–140 60–90
Vitamin D
(I.U./day)
800–1600 200–1000 800–1000
(I.U./kg/day) 90–225 150–400
Minerals and vitamin D recommended intakes in growing preterm infants.
Osteopenia has a good prognosis, provided that calcium,
phosphates and vitamin D are appropriately administered to the
babies.
It is still controversial the need for high calcium and phosphorus
intakes in preterm infants after hospital discharge.
Few data are available about the optimal length, quantity and
methods of providing supplemental minerals for preterm infants .
The determination of ALP and of P seems to be useful in assessing
the risk of metabolic bone disease and serum analysis need to be
performed periodically in order to assess response to nutritional
treatment.
Through DEXA and quantitative
ultrasound it is also possible to determine
the state of bone mineralization and
therefore to plan a nutritional
intervention.
Most common sites:
• Ribs
• Radius ulna
• Femur
Koo WWK et al J Pediar Orthop 9:326,1989
Fracture Incidence in Low Birth Weight Infants
Article:
EARLY NEONATAL HYPOCALCEMIA IN INFANTS BORN TO MOTHERS
WITH HIGH PREVALENCE OF HYPOVITAMINOSIS D AND RELATION TO
BIRTH SIZE
A. Soliman, Emad Shatla, A. Adel
ABSTRACT: Conclusion
This high incidence of neonatal hypocalcemia necessitates vitamin
D supplementation to pregnant women in this population with high
prevalence of vitamin D deficiency.
Archives of Disease in Childhood 10/2014; · 2.91 Impact Factor
Radiological manifestations of Neonatal Rickets
Ashraf Soliman, Husam Salama, Emad Shatla, Elsaid Bedair
Article: Clinical, biochemical, and radiological
manifestations of vitamin D deficiency in newborns
presented with hypocalcemia
Indian journal of endocrinology and metabolism. 07/2013;
17(4):697-703.
• Emad Shatlaᶦ , A.Soliman².
• INCIDENCE OF EARLY NEONATAL HYPOCACEMIA IN
INFANTS BORN IN QATAR TO MOTHER WITH HIGH
PREVELENCE OF HYPOVITAMINOSIS D AND ITS RELATION
TO ANTHROPOMETRIC DATA.
• 27th international congress of pediatrics Melboume, Australia 2013;
August: 24-29.
Guidelines for the Treatment
of Osteopenia of PrematurityPrescribe:
Elemental calcium 2.5 - 4 mmol/kg/day and
Elemental phosphate 2 - 3 mmol/kg/day to be given in divided doses.
Ensure an adequate intake of calcium and phosphate from feeds
fortified breastmilk / preterm formula .
Weekly monitoring for infants .
Weekly bloods including bone profile for all preterm. If persistently
rising alkaline phosphatase (>500IU/L) despite prophylaxis, consider
calculating the urinary tubular reabsorption of phosphate (TRP). If
TRP >95%, this suggests that phosphate supplementation is still
insufficient and increasing or adding phosphate supplementation is
appropriate .
TRP % = (1 - ( Urine phosphate / Urinary Creatinine ) x ( Plasma
Creatinine / Plasma phosphate )) x 100 .
An adequate nutritional intake of calcium, phosphorus
and vitamin D and passive physical exercise may prevent
abnormal bone-remodelling activity during first weeks of
life and may optimize growth potential of preterm infants.
It is important to recognize the biochemical signs
of osteopenia in an early stage in order to be able to precociously
implement the dietary intake and reduce the risk of bones fractures.
Conclusion
98% of the calcium and 80% of the phosphorus in the body are in the
skeleton.
The metabolic homeostasis of calcium, phosphorus,
and magnesium and mineralization of the skeleton are complex.
Belkacemi L, Bedard I, Simoneau L, Lafond J. Calcium channels,transporters and exchangers in placenta: a review. Cell Calcium2005;37:1e8.Stauffer TP, Hilfiker H, Carafoli E, Strehler EE. Quantitativeanalysis of alternative splicing options of human plasmamembrane calcium pump genes. J Biol Chem1993;268:25993e6003.Glazier JD, Atkinson DE, Thornburg KL, et al. Gestationalchanges in Ca2þ transport across rat placenta and mRNA forcalbindin9K and Ca(2þ)-ATPase. Am J Physiol1992;263:R930e5.Kip SN, Strehler EE. Vitamin D3 upregulates plasma membraneCa2þ-ATPase expression and potentiates apico-basal Ca2þ fluxin MDCK cells. Am J Physiol Renal Physiol 2004;286:F363e9
References
Kovacs CS. Skeletal physiology: fetus and neonate. In:Favus MJ, editor. Primer on the Metabolic Bone Diseases andDisorders of Mineral Metabolism. 5th ed. Washington: ASBMR;2003. p. 65e71.Care AD, Caple IW, Abbas SK, Pickard DW. The effect of fetalthyroparathyroidectomy on the transport of calcium across theovine placenta to the fetus. Placenta 1986;7:417e24.Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC,Kronenberg HM. Parathyroid hormone-related peptide(PTHrP) regulates fetal-placental calcium transport througha receptor distinct from the PTH/PTHrP receptor. Proc NatlAcad Sci USA 1996;93:15233e8.Kovacs CS, Manley NR, Moseley JM, Martin TJ,Kronenberg HM. Fetal parathyroids are not required to maintainplacental calcium transport. J Clin Invest 2001;107:1007e15.Ardawi MS, Nasrat HA, HS BAA. Calcium-regulatinghormones and parathyroid hormone-related peptide in normalhuman pregnancy and postpartum: a longitudinal study. Eur JEndocrinol 1997;137:402e9.
