1. Metabolic Bone Diseases METAOLC BONE DISEASES are diseases of bones caused by disturbances in metabolism of bones in metabolism of bones & is characterized by a decrease in bone density & bone strength either by Increasing bone resorption Increasing bone resorption Or: Decreasing bone formation Or: Decreasing bone formation Or: Both Or: Both

2. Blood Calcium Homeostasis & Metabolic Bone Diseases

3. Biological Roles of Calcium 1- Calcium in Bone : Calcium is a major & essential component of bone Generally, bone is specialized mineralized connective tissue that contains: 1- Cells: osteoblasts & osteoclasts 2- organic matrix: materials like collagen type I & others proteoglycans Calcium 3- mineral: hydroxy apatite (Calcium + Phosphorous) Role of calcium in bones: Role of calcium in bones: Mechanical role 1- Mechanical role (it gives bone its hardness, tolerability, strength etc..) Material of turnover in skeleton 2- Material of turnover in skeleton (bone resporption & bone formation= remodelling) 5% per year of adult skeleton Reservoir for calcium to help stabilize extracellular calcium ions Ca2+ 3- Reservoir for calcium to help stabilize extracellular calcium ions Ca2+ Calcium gets out from bones to blood & reverse to correct decrease or increase in Ca2+ in blood 2- Calcium located in other extracellular locations: normal excitability of nerves & muscles 1- Extracellular calcium ions Ca2+ should be maintained within narrow limits as this is necessary for normal excitability of nerves & muscles. blood clotting mechanisms 2- Extracellular Ca2+ is essential for blood clotting mechanisms. Calcium ions inside cells (cytosolic) is much less than extracellular Ca2+ So, cells have transport systems to maintain this difference. Accordingly: increased intracellular calcium is a signal for some biological activity of cells

4. 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

5. Calcium in Blood

6. Regulation of Calcium Metabolism Calcium Homeostasis Calcium in plasma of blood 1- Ionized (Ca2+) 2- Bound with plasma proteins (albumin) 3- Complexed with citrate Ionized calcium Ca2+ is the physiologically important component So, Ca2+ in blood is regulated mainly by: 1, 25 dihydroxycholecalcefrol (1, 25 DHCC) 1- 1, 25 dihydroxycholecalcefrol (1, 25 DHCC) Parathyroid hormone (PTH) 2- Parathyroid hormone (PTH) Calcitonin hormone 3- Calcitonin hormone 1 & 2 increase Ca2+ in blood 3 decreases Ca2+ in blood 1, 2 & 3 regulate calcium metabolism through 3 organs 1- Bones 2- Intestines 3- Kidneys

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

8. Organ Calcium Homeostasis

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

10. 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)

11. 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

12. 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

13. Function of Vitamin D The overall function of 1,25 DHCC is to maintain adequate plasma levels of calcium this function is achieved by intestine increasing uptake of calcium by the intestine kidney Increase calcium reabsorption by the kidney stimulating resorption of bone (when necessary) in EMERGENCY HYPOCALCEMIA stimulating resorption of bone (when necessary) in EMERGENCY HYPOCALCEMIA

14. Vitamin D deficiency calcium of bone is mobilized outside bone with demineralization of bone Rickets Osteomalacia Rickets (in children) Osteomalacia (in adults)

15. Rickets Continued formation of the collagen matrix BUT BUT With incomplete mineralization Soft Bones with Bone Deformity Osteomalacia Demineralization of preexisting bones with Increased Susceptibility to Fractures (due to weakness of bone)

16. Rickets & Osteomalacia Rickets & Osteomalacia Rickets & Osteomalacia are metabolic bone diseases occurring calcium content 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:  Nutrional Vitamin D deficiency (vitamin D3)  Poor exposure to sun light 2- Impaired vitamin D metabolism: 2- Impaired vitamin D metabolism:  Renal Rickets: chronic renal failure causes deficiency of 1 hydroxylase of the kidney  Hypoparathyroidism: causing decrease in activity of 1 hydroxylase  Hypoparathyroidism: causing decrease in activity of 1 α hydroxylase  Genetic defects in vitamin D metabolism (defect in its activation)  Genetic defects of vitamin D receptors II. Calcium Deficiency (nutritional or defect in intestinal absorption)

17. 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

18. Laboratory Investigations for the Diagnosis of Rickets & Osteomalacia 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)

19. Parathyroid Hormone (PTH) secreted in response to al fall in plasma Ca2 The active hormone is secreted in response to al fall in plasma Ca2+ with a result in Ca2+ increase in plasma. On bone: On bone: PTH stimulates bone resorption by osteoclasts On kidney: On kidney: PTHcalcium 1- PTH increases reabsorption of calcium from kidney tubules. PTHphosphorous 2- PTH decreases phosphorous reabsorption from kidney tubules. PTH 3- PTH promotes activity of 1  hydroxylase of the kidney (with more hydroxylation of 25 hydroxycholecalciferol. (25 HCC) to 1,25 DHCC vitamin D (activation of vitamin D) intestinal which increases intestinal absorption of calcium so, action on intestine is indirect (via Vitamin D)

20. Hypoparathyroidism Deficiency or absence of parathyroid hormone (PTH) Causes Causes: Surgically removed by mistake during thyroidectomy Surgically removed by mistake during thyroidectomy Destruction of the glands by auto-immune process Destruction of the glands by auto-immune process Pseudohypoparathyroidism: receptors for PTH fail to respond to PTH Pseudohypoparathyroidism: receptors for PTH fail to respond to PTH Biochemical Effects: Hypocalcemia 1- Hypocalcemia Hyperphosphatemia 2- Hyperphosphatemia Deficiency of blood levels of 1, 25 DHCC : not 3- Deficiency of blood levels of 1, 25 DHCC : 25 HCC is not hydroxylated to 1, 25 DHCC

21. HyperparathyroidismCauses: Parathyroid adenoma Diffuse hyperplasia of parathyroid glands Biochemical Effects: 1- Hypercalcemia 2- Hypophosphatemia 3- Hypercalcuria (increased excretion in urine to reduce blood calcium) 4- Increased markers of bone resorption Clinical features of hyperparathyroidism Manifestations of hypercalcemia Generalized muscular weakness Generalized muscular weakness Neurological symptoms: inability to concentrate, confusion Neurological symptoms: inability to concentrate, confusion Anorexia, nausea, vomiting, constipation Anorexia, nausea, vomiting, constipation Polyuria & polydepsia Polyuria & polydepsia Calcium stones in kidney Calcium stones in kidney ECG changes: Shortened Q-T interval & bradycardia ECG changes: Shortened Q-T interval & bradycardia

22. 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

23. 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

24. Main Causes of Osteoporosis 1- Increased Bone Resorption Estrogen deficiency (as in menopause) Hyperparathyroidism (activation of osteoclasts) Hyperthyroidism (increase proteolysis) Hypogonadism (low testosterone which is an anabolic hormone) 2- Decrease Bone Formation 2- Decrease Bone Formation Liver disease (low protein production) Age over 50 3- Both Hypercortisolism (as Cushing’s syndrome)

25. Risk Factors of 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 1-Bone Mass Density (BMD): Dual Energy X-ray Absorptiometry (DXA) is highly recommended to evaluate bone density evaluate bone density 2- Vitamin D level in blood is checked 3- Secondary endocrinal causes of osteoporosis are checked (T3, T4, PTH, Cortisol, Testosterone) 4- Biochemical Bone Markers (not of great help)