1. Calcium and Vitamin D Metabolism and Related Diseases1

2. Objectives Calcium functions and metabolism
Vitamin D functions and metabolism
Vitamin D and calcium homeostasis
Regulation of vitamin D synthesis
Hypocalcaemia and hypercalcaemia
Biochemistry, types and diagnosis of:
Rickets and osteoporosis 2

3. Introduction Bone is a specialized mineralized connective tissue
osteoclasts mobilize minerals
osteoblasts control mineralization of the newly synthesized matrix
calcium and phosphate in the form of hydroxyapatite and small amount of hydroxide and carbonate)
Bone is a specialized mineralized connective tissue containing cellular elements (osteoblasts , bone forming and osteoclasts , bone resorption) , organic matrix ( eg. type I collagen, proteoglycan), and inorganic minerals (calcium and phosphate in the form of hydroxyapatite and small amount of hydroxide and carbonate)
Calcium is tightly regulated with Phosphorous in the body.

4. CALCIUM Calcium is the most abundant mineral in the body:
(1 kg) in a 70 kg man.
~99% of the body’s calcium is present in the bone, where it is combined with phosphate .
Calcium is the most prevalent mineral in the body where a 70 Kg adult about 25,000 mmol ( 1Kg) of calcium is present , where 99% is present in bone ( mainly While 1% is present in tissues and body fluids ( ECF 1mmol/L , ICF 100 nmol/L )

5. Biological function of calcium
Total Calcium
 99 % in bone
ICF
1 %
Clotting
Excitability of nerve & muscle
Bone formation
Reservoir for ECF [Ca2+]
Metabolic regulation for action of hormones & enzyme activation
ECF
Physiologically, calcium is classified as either extracellular or intracellular. The skeleton is a major reservoir for providing calcium for both the exracellular and the intracellular pools

6. Calcium homeostasis
The concentration of calcium, P & Mg in the plasma depend on:
Net effect of bone mineral deposition and resorption
Intestinal absorption
Renal excretion

7. Calcium balance: In adults: normally, calcium intake = output .
In infancy and childhood: input > output  positive balance , due to active skeletal growth.
In old age: calcium output > input  negative balance; marked in women after menopause,  postmenopausal osteoporosis.

8. Sources of calcium: Excellent: milk, cheese, yoghurt;
Fair (legumes, vegetables)

9. The ionized fraction is the biologically active fraction

10. PTH 1,25 DHCC Calcitonin Regulation of Calcium Plasma [Ca2+]
is regulated by:

11. Parathyroid hormone (PTH)
PTH is the principal acute regulator of plasma [Ca2+].
PTH is a key regulatory hormone of calcium metabolism. Within the parathyroid glands PTH is transcribed as a 115 polypeptide and processed to form 84 amino acid polypeptide. The biological activity of PTH is contained within the 36 amino acid fragment of the molecule located at the N – terminal end
Regulation of Secretion:
↓serum Ca ↓IC Ca2+ in PTG ↑cAMP ↑secretion of PTH
Mild ↓ serum Mg ↑PTH
Marked ↓ serum Mg ↓PTH

12. Vitamin D A group of sterols with a hormone-like function.
Calcitriol (1, 25 diOH cholecalciferol = 1, 25 diOH D3) is the biologically active molecule.
Vitamins D2 & D3
Preformed Vitamin D in the diet: they are needed only in exposure to sunlight is limited.
They are also available as supplement
They are NOT biologically active
They are activated in vivo to the biologically active form
Recommended dietary allowance (RDA): 5 mg cholecalciferol = 200 IU of vit D3 (or more)

14. D2, plant source D3, animal source: fatty fish, liver, egg yolk
Lippincott’s Illustrated Reviews, Biochemistry, 4th Edition, Champe, Harvey and Ferrier

15. Vitamin D metabolism
Cholecalciferol is derived from 7- dehydrocholesterol in the skin by sunlight
In liver:
Cholecalciferol is converted to 25- hydroxycholecalciferol by the enzyme 25- hydroxylase
In kidneys:
The 1-alpha-hydroxylase enzyme converts
25-hydroxycholecalciferol to 1,25- dihydroxycholecalciferol (biologically active)
Active vitamin D is transported in blood by gc- globulin protein 15

16. 25.Hydroxycholecalciferol (calcidiol), 1,25 dihydroxycholecalciferol ( calcitriol)16

17. Predominant form in plasma
VITAMIN D SYNTHESIS
SKIN
LIVER
KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
25(OH)VITAMIN D UV
25-HYDROXYLASE
1,25(OH)2 VITAMIN D
1a-HYDROXYLASE
Predominant form in plasma
ACTIVE METABOLITE
Active vitamin D is transported in blood by vitamin D-binding protein

19. Vitamin D functions
Regulates calcium and phosphorus levels in the body (calcium homeostasis)
Through:
Increasing uptake of calcium by the intestine
Minimizing loss of calcium by kidney
Stimulating resorption of bone when necessary
Deficiency of 1: 25-DHCC  defective bone mineralization. 19

20. Calcitonin Calcitonin is a peptide hormone
secreted by the parafollicular or “C” cells of the thyroid gland
released in response to high plasma calcium
Net result of its action   plasma calcium & phosphate

21. Calcitonin : Calcitonin   plasma [Ca2+] by:  osteoclast activity
The only Hypocalcemic hormone
Calcitonin   plasma [Ca2+] by:
 osteoclast activity
 renal reabsorption of calcium and phosphate.

23. Causes of hypocalcaemia:
Hypoprotenemia
Hypoparathyroidism
Vit D deficiency
Acute pancreatitis
Renal disease
Drugs as phenytoin and diphosphonates

24. Numbness around the mouth Cramps and tetany Laryngospasm Cataract
Symptoms:
Numbness around the mouth
Cramps and tetany
Laryngospasm
Cataract
When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increase permeability of neuronal membranes to sodium.

25. Causes of hypercalcaemia:
Artifact
Parathyroid disease, ( primary , tertiary hyperparathyroidism)
Malignant disease ( bone metastasis , multiple myeloma)
Drugs as lithium
Thyrotoxicosis

26. Biochemical bone diseases
Generalized defects in bone mineralization, frequently associated with abnormal calcium or phosphate metabolism, "biochemical or metabolic bone diseases".
Osteoporosis
Rickets
Osteomalacia
The most common

27. Osteomalacia and Rickets
Defective bone mineralization in adults
Rickets:
Defective bone and cartilage mineralization in children
Before introduction of vitamin D-supplemented milk, children with insufficient exposure to sunlight developed Vit D deficiency
Not common these days as foods (milk, oils) are now supplemented with vitamin D 27

28. Osteomalacia and Rickets, continued..
These conditions are due to:
Vitamin D deficiency
Impaired vitamin D metabolism
Calcium deficiency
Imbalance in calcium homeostasis 28

29. Osteomalacia and Rickets, continued..
Vitamin-D-dependent rickets types 1 and 2 (genetic disorders)
Rare bone diseases
Due to:
Defects in vitamin D synthesis: type 1 (can be overcome by high doses of Vit D)
Defects in vitamin D receptor: type 2 (cannot be overcome by high doses of Vit D, as the hormone is unable to act) 29

30. Clinical features Osteomalacia and Rickets, continued.. Rickets
Soft bones
Bone pain
Increased tendency of bone fractures
Skeletal deformity (bowed legs)
Muscle weakness
Dental problems
Growth disturbance
Osteomalacia
Soft bones
Bone pain
Bone fractures
Compressed vertebrae
Muscle weakness 30

31. 31

32. Osteomalacia and Rickets, continued..
Diagnosis
Serum calcium (hypocalcemia)
PTH secretion
 Alkaline phosphatase
 Serum levels of 25-hydroxycholecalciferol 32

33. Osteoporosis Reduction in bone mass per unit volume
Bone matrix composition is normal but it is reduced
Post-menopausal women lose more bone mass than men (primary osteoporosis) 33

34. 34

35. 35

36. Osteoporosis Secondary osteoporosis may be caused by: Drugs
Immobilization
Smoking
Alcohol
Cushing’s syndrome
Gonadal failure
Hyperthyroidism
GI disease 36

37. Osteoporosis, continued..
Diagnosis
Serial measurement of bone density
No specific biochemical tests to diagnose or monitor primary osteoporosis
Secondary osteoporosis (due to other causes) can be diagnosed by biochemical tests
The test results overlap in healthy subjects and patients with osteoporosis
Common biochemical tests:
Urinary Hydroxyproline (bone resorption)
Alkaline phosphatase (bone formation)
Osteocalcin (bone formation)
Biochemistry Diagnosis is Unremarkable in Osteoporosis 37

38. THANK YOU