Calcium and Vitamin D Metabolism and Related Diseases 1

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

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.

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 )

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

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

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.

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

The ionized fraction is the biologically active fraction

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

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 Ca2+ --------- ↓IC Ca2+ in PTG --------- ↑cAMP---------- ↑secretion of PTH Mild ↓ serum Mg 2+ ---------- ↑PTH Marked ↓ serum Mg2+-------- ↓PTH

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)

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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