1. RACHITIS, VITAMIN D RICKETSIA, OSTEOMALACIA
EKA AGUSTIA RINI
RACHITIS, VITAMIN D RICKETSIA, OSTEOMALACIA

4. RICKETS
Disorder of mineralization of the bone matrix / osteoid in growing bone
Involved : growth plate
Newly trabecular formed
Cortical bone
Osteomalacia
After cessation of growth
Involves only a bone, not the growth plate

5. Risk factors Living in northern latitudes (>30o);
Dark skinned children;
Decreased exposure to sunlight
Maternal vitamin D deficiency;
Diets low in calcium, phosphorus and vit. D
Prolonged parenteral nutrition in infancy with an inadequate supply of intravenous calcium and phosphate;
Intestinal malabsorption

6. Defective production of 1,25(OH)2D3
Hereditary type I vitamin D-resistant (or dependent) rickets (mutation which abolishes activity of renal hydroxylase);
Familial (X-linked ) hypophosphataemic rickets – renal tubular defect in phosphate transport;
Chronic renal disease;
Fanconi syndrome (renal loss of phosphate)
Target organ resistance to 1,25(OH)2D3- hereditary vitamin D-dependent rickets type II (due to mutations in vitamin D receptor gene).

7. Calcium homeostasis - PTH action
-ve feedback
PTH
Decreased
Ca Clearance
1,25-(OH)2D
Increased
Resorption
Increased
Ca Absorption
Serum
Ca2+

8. Vitamin D Metabolism Skin 25-OH-D3 (calcidiol) VitD3
7 Dehydrocholesterol
Skin
VitD3 (cholecalciferol)
25-OH-D3
(calcidiol)
VitD3
Calcium absorption 
1,25-(OH)2-D3
(calcitriol)
25-OH-D3
(calcidiol)
Resorption 

9. PTH Response to Hypocalcemia
-ve feedback
Plasma
Ca2+
PTH 
Plasma
Ca2+
Renal Excretion 
H2PO4-
1,25-(OH)2D 
Increase
Renal Excretion 
Ca2+
GIT absorption 
Ca2+
Resorption 

10. Role of Calcium Bone Growth Blood Clotting
Maintenance of trans membrane potential
Cell replication
Stimulus-contraction & stimulus-contracting coupling
Second messenger process

11. Intestine: Increases calcium binding protein
Active transport in the jejunal cells
Phosphorus ions absorption through specific phosphate carrier
Alkaline phosphatase (AP) synthesis
ATP-ase sensibility to calcium ions

12. Factors in Calcium Homeostasis
Ca++ sensing receptor (CaSR) 
membrane protein that binds Ca++
determines the set-point for PTH secretion.
Parathyroid hormone (PTH)
84 amino acid peptide
 increases calcium concentration
 calcium reabsorption in the kidney
 calcium resorption from bone
 intestinal calcium absorption via  renal formation 1,25-diOH-D).

13. Factors in Calcium Homeostasis
Vitamin D (1,25-diOH-D).
 absorption / reabsorption of calcium (intestines, bone, and kidney).
Calcitonin.
32 amino acid peptide
Secretion  if serum calcium  (antagonist PTH)
inhibits osteoclast activity  bone calcium resorption 

14. Calcium metabolism Skeleton 25 mmol/day 25 Mol (99%) Gut Kidney
Plasma/ICF
2.20 mmol/L
(30mmol)
25 Mol (99%)
300 mmol/day
290 mmol/day
10 mmol/day
3 mmol/d
25 mmol/day
15 mmol/day
13 mmol/d

15. Calcium Distribution in Plasma
Ionised Calcium
~1.0 mmol/L
Total Calcium
~2.0 mmol/L
Bound Calcium
~0.95 mmol/L
Complexed Calcium
~0.05 mmol/L

16. Pathophysiology of Calcium
Disorders of homeostatic regulators
PTH
vitamin D
Disorders of the skeleton
bone metastases
Disorders of effector organs
gut - malabsorption
kidney
Diet

17. Breast milk contains 30-50IU/liter, cow’s milk 20-30IU/l, egg yolk contains 20- 50IU/10gr.
80% of the vitamin D is absorbed in the small intestine in the present of normal biliary secretion.
Vitamin D reaches the blood through thoracic duct along with chilomicrons.

18. Calcium regulation in the blood is as follows:
Vitamin D2 in the food (exogenous) + vitamin D3 (skin, endogenous) =>liver microsomes
=>25(OH) D3 => Mitochondrial kidney tubules membrane activated 3 forms:
24,25 (OH)2 D3; 1,24,25 (OH)2 D3; 1,25 (OH)2 D3 !!! last more active.
In placental macrophage of pregnancy women are present 1,25(OH)2 D3

19. Serum calcium : narrow physiological range
Result of complex interaction process  vitamin D, parathyroid hormone (PTH), and the calcium sensing receptor.
Serum calcium
50% free (ionized)
40% protein bound (80% albumin & 20% globulin)
10% complexed (phosphate, citrate, bicarbonate, lactate)
Maintenance of serum calcium levels in the
physiological range is a complex process that
reflects the function of, and interaction between,
vitamin D, parathyroid hormone (PTH), and the
calcium sensing receptor.

20. Physiology of PTH Bone GIT Kidney
 Resorption: free Ca2+, orthophosphate, Mg, citrate, hydroxyproline,osteocalcin.
GIT
 Calcium absorption indirectly through vit D metabolism
Kidney
 phosphate excretion via proximal tubules
Inhibits bicarbonate reabsorption  metabolic acidosis  favours calcium ionization   bone resorption & dissociation of calcium from plasma protein binding sites

21. Causes of rickets Vit. D deficiency Lack of adequate sunlight
Unsupplemented breast-fed infant.
Total parenteral nutrition (TPN)
Ca deficiency
Lack of dietary Ca
Inadequate Ca in TPN
Phosphat def.
Breast-fed infant
Inadequate PO4 in TPN

22. Causes of rickets Vit. D deficiency Lack of adequate sunlight
Consumption of diet low in fortified foods
Unsupplemented breast-fed infant.
Total parenteral nutrition (TPN)
UV / increased sunlight exposure
Vit D2
Vit D2 for premature
Vit D2 in TPN / oral
Ca deficiency
Lack of dietary Ca
Inadequate Ca in TPN
Ca 700 mg/day
Ca in prmature / TPN
Phosphat def.
Breast-fed infant
Inadequate PO4 in TPN

23. CLINICAL MANIFESTATIONS
Rickets may develop in any age of an infant, more frequent at 3-6mo, early in prematures.
The first signs of hypocalcaemia are CNS changes- excitation, restlessness, excessive sweated during sleep and feeding, tremors of the chin and extremities.

24. Skin and muscle changes- pallor, occipital alopecia, fragile nails and hair, muscular hypotony,motor retardation.
Complications- apnoea, stridor, low calcium level with neuromuscular irritability (tetany).
CNS changes are sometimes interpreted as CNS trauma and the administration of the

26. ACUTE SIGNS Have acute and subacute clinical signs
Craniotabes – acute sign of rickets, osteolyses detected by pressing firmly over the occipital or posterior parietal bones, ping- pong ball sensation will be felt. Large anterior fontanella, with hyperflexible borders, cranial deformation with asymmetric occipital flattening.

27. SUBACUTE SIGNS
Subacute signs are all the following: frontal and temporal bossing
False closure of sutures (increase protein matrix), in the X-ray craniostenosis is absent.
Maxilla in the form of trapezium, abnormal dentition.

28. Late dental evolution, enamel defects in the temporary and permanent dentition.
Enlargement of costo-chondral junctions- “rickets rosary”
Thorax, sternum deformation, softened lower rib cage at the site of attachment of the diaphragm- Harrison groove.

30. Subacute signs Spinal column- scoliosis, lordosis, kyphosis.
Pelvis deformity, entrance is narrowed (add to cesarean section in females)
Extremities- palpated wrist expansion from rickets, tibia anterior convexity, bowlegs or knock kness legs.
Deformities of the spine, pelvis and legs result in reduced stature, rachitic dwarfism.
Delayed psychomotor development (heat holding, sitting, standing due to hypotonia).

31. LABORATORY DATA
Serum calcium level (N= mmol/l). At the level <2.0mmol/l convulsions sets in.
Phosphorus normal ( mmol/l). Normal ratio of Ca : P= 2:1; in rickets become 3:1; 4:1.
Serum 25(OH)D3 (N=28+2.1ng/ml); and 1,25(OH)2D3(N= ng/ml)
Serum alkaline phosphatase is elevated >500mmol/l.
Thyrocalcitonin can be appreciated (N= pM/l)
Serum parathyroid hormone (N= pM/l)
In urine: Aminoaciduria >1.0mg/kg/day
Urinary excretion of 3’5’ cyclic AMP
Decreased calcium excretion (N=50-150mg/24h)

32. Radiological findings
Only in difficult diagnostic cases.
X-ray of the distal ulna and radius: concave (cupping) ends; normally sharply, Fraying rachitic metaphyses and a widened epiphyseal plate.
Osteoporosis of clavicle, costal bones, humerus.
Greenstick fractures.
Thinning of the cortex, diaphysis and the cranial bones.

33. EVOLUTION
The evolution is slow with spontaneous healing at the age of 2-3 years. If treated can be cured in 2-3mo with the normalization of the skeletal and the cellular system. Gibbous, palatal deformity and the narrow pelvis may persist.

34. DIFFERENTIAL DIAGNOSIS
Osteogenesis imperfecta, chondrodystrophy, congenital diseases- CMV, rubella, syphilis.
Chronic digestive and malabsorption disorders.
Hereditary Fanconi’s disease, phosphorus diabetes, renal tubular acidosis.

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36. Radiology Biochemistry Thinning of cortex Widening, cuping metaphyses
Decreased bone density
Biochemistry
Ca serum : low / N
ALP increased
PTH increased

37. PROPHILAXIS IN RICKETS
Specific antenatal prophylactic dose administration : IU/day of vitamin D3 solution at the 28-th week of pregnancy.
The total dose administered is IU. In term infants prophylactic intake of vitamin D2 700IU/d started at 10 days of age during the first 2 years of life; in premature the dose may increase to 1000IU/day.

38. PROPHILAXIS IN RICKETS
WHO recommendation for rickets prophilaxis in a children coming from unfavorable conditions and who have difficult access to hospitals is IU vitamin D2 i/muscular,
On the 7day, 2, 4, 6 month- total dose IU. In case of the necessary prolongation 700IU/day till 24mo are given.

39. SPECIFIC TREATMENT IN RICHETS
The treatment is with vitamin D3 depending on the grade.
In grade I IU/day for 4-6weeks, totally IU.
In grade II IU/day for 4-6 weeks, totally IU.
In grade III IU/day for 6-8 weeks, totally IU.

40. SPECIFIC TREATMENT IN RICHETS
Along with vitamin D, calcium is also administered (40 mg/kg/day for a term baby,
80 mg/kg/day for a premature baby); also indicate vitamin B&C preparations.
From the 7-th day of the treatment massage can be started. Intramuscular administration
of ATP solution in case of myotonia 1ml/day is preferred.

41. Vit D. def; TPN : 0,5 ug/kg/day Oral: 400-800 IU daily Ca deficiency;
Premature: mg/dl
Oral :200 mg/kg/day
IV : solution 20 mg/dl

42. RICKETS COMPLICATIONS
Rickets tetany in result of low concentration of serum calcium (<2mmol/l), failure of the PTH compensation and muscular irritability occur.
Hypervitaminosis D

43. HYPERVITAMINOSIS D
Symptoms develop in hypersensitivity to vitamin D children or after1-3mo of high doses intakes of vitamin D; they include hypotonia, anorexia, vomiting, irritability, constipation, polydipsia, polyuria, sleep disorder, dehydration. High serum level of acetone, nitrogen and
Ca>2.9mmol/l are found. Increase calcium concentration in urine may provoke incontinence, renal damage and calcification.