1. Calcium Metabolism, Homeostasis & Related Diseases

2. Objectives of Lectures By the end of these lectures, students should be able to: Calcium  Recall Calcium Sources, Distributions & Functions Homeostasis of Calcium  Understand Organ & Endocrinal Homeostasis of Calcium with recognition of the roles of: - Vitamin D - Parathyroid Hormone (PTH) - Calcitonin Hormone Causes of Hypocalcaemia & Hypercalcemia  Verify Main Causes of Hypocalcaemia & Hypercalcemia Metabolic diseases of bone:  Recognize the biochemical and Clinical Interrelations of Metabolic diseases of bone: - Rickets & Osteomalacia - Osteoporosis

3. Components of Bones Bone is a specialized mineralized connective tissue containing: Cellular Elements 1- Cellular Elements: Osteoblasts - Osteoblasts (bone forming cells) Osteoclasts - Osteoclasts (bone resorping cells) Organic Matrix 2- Organic Matrix Proteins - Proteins: Type I Collagen Proteoglycan Inorganic Minerals - Inorganic Minerals: Calcium & Phosphate Others - Others: small amount of hydroxide & carbonate Calcium is tightly regulated with phosphorous in the body Calcium is tightly regulated with phosphorous in the body

4. Calcium  Calcium is the most abundant mineral in the body: about 1 kg in a 70 kg man  ~ 99% of the body’s calcium is present in the bone where it is combined with phosphate

5. Dietary Sources of Calcium  RichMilkmilk products  Rich: Milk, milk products as cheese & yoghurt  Fair :  Fair : Legumes, vegetables

6. Total Calcium Of the Body  99 % in bone ICF 1 % Blood Clotting Excitability of Nerve & Muscle Bone Formation Reservoir for ECF [Ca2+] Metabolic Regulation for Action of Hormones & Enzyme Activation ECF Biological Functions of Calcium

7. Calcium in Blood

8. Organ Calcium Homeostasis

9. Organ Calcium Homeostasis cont. The concentration of calcium, phosphorous & magnesium in the plasma depends on ORGAN PHYSIOLOGY:  Net effect of bone mineral deposition & resorption  Intestinal absorption  Renal excretion

10. Blood [Ca 2+ ] is Regulated By: is Regulated By:  Parathyroid Hormone (PTH)  Active Vitamin D (Calcitriol or 1,25 DHCC)  Calcitonin Hormone

11. Vitamin D  A group of sterols with a hormone-like function. Sources of Vitamin D  Sources of Vitamin D 1- Skin synthesis (On Exposure to Sun Lights): 7 dehydrocholesterol vitamin D3 In the skin, 7 dehydrocholesterol is converted to vitamin D3 by exposure to sunlight 2- Diet: Vitamins D3) - Animal Source Cholecalciferol (Vitamins D3) Vitamin D2) - Plant Source: Ergocalciferol (Vitamin D2) NOT Vitamin D2 & D3 are NOT biologically active Activation of cholecalciferolvitamin D3) – Activation of cholecalciferol (vitamin D3) Cholecalciferol Cholecalciferol (Vitamin D3) is activated in the body to the biologically active liver form by two hydroxylations: first in the liver (at position 25) by 25 hydroxylase kidney & then in the kidney at positions 1 by 1 α hydroxylase  Active Vitamin D 1, 25 dihydroxycholecalciferol (Calcitriol or DHCC) 1, 25 dihydroxycholecalciferol (Calcitriol or DHCC)

12. Vitamin D 2 plant source plant source Vitamin D3 animal source fatty fish Liver egg yolk 7-dehydrocholesterol In the skin DIET VITAMINs D SOURCES OF VITAMIN D SunRays

13. Vitamin D metabolism  Cholecalciferol (Vitamin D3)  Cholecalciferol (Vitamin D3) is derived from 7-dehydrocholesterol in the skin by sunlight or supplied in the diet  In liver: 25-hydroxycholecalciferol Cholecalciferol is converted to 25-hydroxycholecalciferol (25-HCC) by the enzyme 25 hydroxylase  25-hydroxycholecalciferol  25-hydroxycholecalciferol is the predominant form of vitamin D blood in blood 25-hydroxycholecalciferol storage  25-hydroxycholecalciferol is the main storage form of vitamin in the body  In kidneys: The 1 α hydroxylase enzyme converts 25 hydroxycholecalciferol to 1,25-dihydroxycholecalciferol 1,25-dihydroxycholecalciferol (1, 25 DHCC or Calcitriol) biologicallyactive form of vitamin D which is the biologically active form of vitamin D

14. Functions of Vitamin D Active vitamin D (1, 25 DHCC or Calcitriol) regulates calcium levels in the body (calcium homeostasis) Through:  Increasing absorption of calcium by the intestine  Minimizing loss of calcium by kidney bone (when necessary)  Stimulating resorption of bone (when necessary)

16. Mechanism of Action of Vitamin D Mechanism of Action of Vitamin D

17. Parathyroid hormone (PTH)

18. Functions of Parathyroid Hormone (PTH)  The active hormone is secreted in response to al fall in plasma Ca2+ resulting in in Ca2+ increase in blood.  On bone: resorption by osteoclasts PTH stimulates bone resorption by osteoclasts resulting in release of calcium ions from bones to blood in cases of hypocalcemia  On kidney: PTHreabsorption of calcium 1- PTH increases reabsorption of calcium from kidney tubules. PTHactivity of 1  hydroxylase 2- PTH promotes activity of 1  hydroxylase of the kidney (with more hydroxylation of 25 hydroxycholecalciferol (25 HCC) to 1,25 DHCC vitamin Dintestinal (activation of vitamin D) which increases intestinal absorption of calcium So, action of PTH on intestine is indirect (via Vitamin D)

19. Role of Parathyroid Hormone (PTH) in Hypocalcemia PTH is the principal acute regulator of blood [Ca 2+ ] PTH is a hypercalcemic hormone in case of hypocalcemia

20. Calcitonin Hormone Calcitonin hormone is : – Secreted by the parafollicular or “C” cells of the thyroid gland in response hypercalcemia – Released in response to high blood calcium (hypercalcemia) In cases of hypercalcemia, Calcitonin Hormone   blood [Ca2+] by: Osteoclast activity –  Osteoclast activity (preventing release of calcium to blood) Renal reabsorption of calcium –  Renal reabsorption of calcium Net result of its action   blood calcium CALCITONIN IS THE ONLY HYPOCALCEMIC HORMONE

22. HYPERCALCEMIA MAIN CAUSES of HYPERCALCEMIA Primary hyperparathyroidism : adenomas due to adenomas (single or multiple) of the parathyroid gld high  Blood PTH is high (or upper normal range *) high & low  Blood calcium is high & Blood phosphate is low high  Urine calcium & phosphorous are high (hypercalciuria & hyperphasphatruria)Tumors  Humoral hypercalcemia of malignancy due to PTHrP (PTH related protein) released by some kinds of tumor cells.  PTHrP is not responsive to negative feedback by calcium Hypervitaminosis D:  Excessive intake of vitamin D  Extrarenal hydroxylation of 25HCC as in granulmotaous diseases as sarcoidosis

24. HYPOCALCEMIA MAIN CAUSES of HYPOCALCEMIA  Hypoparathyroidism (  PTH)  Vitamin D deficiencies  Renal disease : low 1  hydroxylase activity & by hyperphosphaturia  Hypoalbuminemia: low blood albumin  Nutritional calcium deficiency  Intestinal disorders causing inadequate calcium or vit.D absorption

25. Metabolic Diseases of Bone: Rickets & Osteomalacia Rickets & osteomalacia calcium content Rickets & osteomalacia are metabolic bone diseases occurring due to poor mineralization (calcium content) of bone Causes of poor calcification of bones: I. Vitamin D deficiency 1- Deficiency of sources of vitamin D3: 1- Deficiency of sources of vitamin D3: BOTH: BOTH:  Nutrional Vitamin D deficiency (vitamin D3)  Poor exposure to sun light 2- Impaired vitamin D metabolism: 2- Impaired vitamin D metabolism:  Renal Rickets: deficiency of 1 hydroxylase of the kidney  Deficiency of parathyroid hormone : decrease activity of 1 hydroxylase  Deficiency of parathyroid hormone : decrease activity of 1 α hydroxylase  Genetic defects in vitamin D metabolism (defect in its activation)  Genetic defects of vitamin D receptors or abnormal ligand binding II. Calcium deficiency (nutritional or defect in intestinal absorption)

26. Metabolic Diseases of Bones RICKETS RICKETS Normal formation of the collagen matrix BUT Incomplete mineralization (poor calcification) Soft Bones Soft Bones CLINICALLY: Bone Deformity CLINICALLY: Bone DeformityOSTEOMALACIA Demineralization (poor calcification) of preexisting bones with CLINICALLY: More Susceptibility to Fracture Rickets & Osteomalacia

27. In Chronic Renal Failure Low activity of Renal 1  Hydroxylase Low activity of Renal 1  Hydroxylase Decreased ability to form the active form of vitamin D (1, 25 DHCC will be low) Treatment: 1,25 DHCC (Calcitriol) Renal Rickets Renal Osteodystrophy

28. Laboratory Investigations for the Diagnosis of Rickets & Osteomalacia Investigations to confirm the diagnosis of rickets: Investigations to confirm the diagnosis of rickets:   Blood levels of 25-hydroxycholecalciferol (25 HCC)   Blood calcium, (hypocalcemia)   Blood Alkaline phosphatase (ALP) Investigations to diagnose the cause of rickets:  Kidney function tests (KFT)  Blood 1, 25 dihydroxycholecalciferol (1, 25 DHCC)  Blood PTH  Others i.e. molecular genetics (if indicated)

29. Most adults Most prevalent metabolic bone disease in adults reduction in bone mass per unit volume It means reduction in bone mass per unit volume. bone matrix composition is normal, but it is reduced i.e. bone matrix composition is normal, but it is reduced Typically silentfracture Typically silent (without symptoms) until it leads to fracture at a degree of trauma that would not have caused a fracture in a non-osteoprotic skeleton. Fractures are called fragility or osteoporotic fractures) Most affected: vertebral compression (may be asymptomatic) & hip fractures (requires surgery in most cases) primary osteoporosis Post-menopausal women lose more bone mass than men (primary osteoporosis) Osteoporosis diagnosis is by dual energy x-ray absorpitometry (DXA) scan Osteoporosis diagnosis is by dual energy x-ray absorpitometry (DXA) scan not Lab diagnosis: not conclusive Metabolic Diseases of Bone: Osteoporosis

30. Metabolic Diseases of Bone Osteoporosis

31. Secondary Osteoporosis Risk Factors Secondary osteoporosis may be caused by reduced bone mass with increased consequent risk of fractures Risk Factors for osteoporosis:  Advanced age (esp. in females)  Certain Drugs  Family history of osteoporosis or fractures  Immobilization  Smoking  Excess alcohol intake  Cushing’s syndrome  Long term glucocorticoids therapy  Hyperparathyroidism  Hyperthyroidism  Vitamin D disorders  Certain malignancies In these cases, DXA is highly recommended to evaluate bone density