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Calcium and bone metabolism
Atif Hassan Khirelsied , B.Sc., M.Sc., Ph.D.
Department of Biochemistry, Faculty of Mediciney
International University of Africa, Khartoum, Sudan
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Learning objectives
By the end of this lecture the student should be able to:able to:
1. Outline the importance of calcium and phosphate in p p pthe body function.
2. Describe the mechanisms maintaining calcium and phosphate homeostasis.
3. Identify the most common abnormalities associated ith l i d h h t t b liwith calcium and phosphate metabolism.
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Biochemical importance of calcium
Calcium is essential element in the human body, it is necessary for several biological processes such as :necessary for several biological processes such as :
1. Bone mineralization.
2. Muscle contraction.
3 N i l t i i3. Nerve impulse transmission.
4. Exocytosis and chemotaxis.
5. Membranes integrity and permeability.
6. Formation of the mitotic spindle during cell division.
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Biochemical importance of calcium (continued):
7 Hormone and neurotransmitter secretion7. Hormone and neurotransmitter secretion.
8. Intracellular signaling.
9. Enzymes activity.
10 Bl d l i10.Blood coagulation.
11.Control of blood pressure, regulates heart rhythm .
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The distribution of calcium in the human body
• There is 1 Kg of calcium in the human body, forming 2% of body weight.body weight.
• About 99% of body calcium exist in bonesAbout 99% of body calcium exist in bones.
• About 1% is distributed in cells and body fluidsAbout 1% is distributed in cells and body fluids.
ResorptionNote
b f bExtracellular Calcium
About 1% of bone calcium is free exchangeable.
Calcification
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Body content and tissue distribution of calcium and phosphorus in a healthy adultphosphorus in a healthy adult
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Levels of calcium in cells and plasma
Calcium concentration mg/dl mmol\L
Total (plasma) 8.5 – 10.3 2.1 – 2.6
Ionized (plasma) 4.25 – 5.25 1.01 – 1.3
Intracellular 10‐5 – 10‐4 (0.1 μmol/L.)
Note:• Total plasma varies with albumin levels. • Ionized calcium varies with the plasma pH.
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Circulating calcium exists in three forms.
• Level of ionized calcium• Level of ionized calcium depends on pH
• Albumin is the main calcium• Albumin is the main calcium binding protein.
• Anions are mainly citrate and oxalate.oxalate.
Source: Textbook of medical physiology / ArthurSource: Textbook of medical physiology / Arthur C. Guyton, John E. Hall.—11th ed.
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Daily exchanges of calcium between different tissue compartments
From: Medical Physiology, Rhoades, and Tanner,
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The factors regulating plasma calcium levels
1. Dietary calcium (availability).
2. Parathyroid hormone.
3. Vitamin D.
4 Calcitonin4. Calcitonin.
5. Other hormones.
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The parathyroid hormone
• Parathyroid hormone (PTH), also called parathormone or parathyrinparathyrin.
I i l id• It is a polypeptide containing 84 aa, secreted by the chiefsecreted by the chief cells of the parathyroid glandsglands
Source: Textbook of medical physiology / Arthur C. Guyton, John E. Hall.—11th ed.
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The physiological effects of the PTH
• PTH ↑ calcium and ↓phosphate levels.
• PTH action is mediated through several body tissues, as:In the bones
↑ l d↓ bl i i– ↑osteoclasts and ↓osteoblasts activity.– ↑bone resorption.I th kidIn the kidneys
– ↑ phosphate excretion (phosphaturia)
↓ calcium excretion in urine– ↓ calcium excretion in urine
– ↑ Vitamin D activation In the intestinesIn the intestines
– Through vitamin D, ↑ calcium and phosphate absorption.
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Effects of parathyroid hormone(PTH) on calcium and phosphatemetabolism.
From: Medical Physiology, Rhoades, and Tanner,
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Vitamin D
• Ergocalciferol (D2): Produced by UV irradiation of plants ergosterol.
Ch l l if l (D3) P d d i th• Cholecalciferol (D3): Produced in the skin keratinocytes by UV irradiation of 7‐dehydrocholestrol7 dehydrocholestrol
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Vitamin D
Source: Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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Factors regulating the activation of vitamin D
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Vitamin D metabolism
Vitamin D metabolism is both regulated by and regulates calcium homeostasis.
l l d h b d hCalcitriol acts to reduce its own synthesis by inducing the 24‐hydroxylase and repressing the 1‐hydroxylase in the kidneykidney.
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Physiological effects of vitamin D
• Vitamin D ↑ the absorption of dietary calcium, phosphate and magnesium.
• It ↑ the expression of a number of calcium binding proteins in the intestine. p
• Promotes bone mineralizationPromotes bone mineralization .
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Effects of vitamin D on calcium and phosphate metabolism.
From: Medical Physiology, Rhoades, and Tanner,
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Calcitonin
• Is a 32‐amino acid polypeptide produced by the
parafollicular cells (C cells) of the thyroid glandparafollicular cells (C‐cells) of the thyroid gland.
• Secretion is stimulated by raised blood calcium levels.
• CT decreases blood calcium basically by:
1. Promoting bone mineralization, stimulates osteoblasts
and inhibits osteoclastsand inhibits osteoclasts.
2. Decrease calcium absorption in the intestine
3. Increases calcium urinary excretion
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Effects of calcitonin (CT) on calciumand phosphate metabolismand phosphate metabolism.
From: Medical Physiology, Rhoades and TannerRhoades, and Tanner,
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Hypocalcemia
• Decrease of plasma level of calcium (< 8.5 mg/dl).
• Characterized by muscle cramps, tetany, twitching and tingling of the fingers.g g g
• Caused by renal failure or by parathyroidectomy.
Hypocalcemic tetany in the hand, called carpopedal spasm
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Causes of hypocalcemia
Lack of ParathyroidHormone
Lack of vitamin D Increased calcium complexation
Parathyroidectomy Dietary deficiency Bone hunger (afterParathyroidectomy Dietary deficiency Bone hunger (after parathyroidectomy)
Hereditary Malabsorption Rhabdomylosis hypoparathyroidism
Pseudo‐hypoparathyroidism
Lack of sun exposure Acute pancreatitis hypoparathyroidism
Hypomagnesemia Defective metabolism Tumor lysis syndrome (hyperphospahtemia)
Anticonvulsnat therapy Malignancy (increased osteoblastic activity)
Liver diseasesLiver diseases
Renal diseases
Vitamin D resistant rickets
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Rickets
Rickets is a disorder caused by a lack of vitamin D, calcium, or phosphate.
Bowed legs
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Causes of rickets
• Dietary deficiency of vitamin D or calcium.
• Defective activation of vitamin D due to:• Lack of exposure to sun shine• Lack of exposure to sun shine• Liver disease • Renal disease• Celiac disease (autoimmune, gluten in wheat).
• Vitamin D‐dependent rickets = autosomal recessive enzyme defect of 1‐OHase
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Osteomalacia
• Is the softening of bones in adults caused by deficient mineralization.
• Characterized by:Diffuse body pains, Muscle weaknessMuscle weakness, Fragility of the bones.
• Caused by insufficient bone mineralization due to: Nutritional deficiency of calcium Defective metabolism of vitamin D Hypophosphatemia
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Hypercalcemiayp
• Increased plasma level of ionized calcium.
• Characterized by neurological signs (hyporeflexia, l h )lethargy or coma).
• When Ca2+ is deposited in the inner medulla of the• When Ca2+ is deposited in the inner medulla of the kidney, ADH resistance develops with polyuria and polydipsia.polydipsia.
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Causes of hypercalcemia
Excess ParathyroidHormone
Excess vitamin D Increased bone resorption
Primary Vitamin D intoxication Metastatic osteolclasticPrimary hyperparathyroidism
Vitamin D intoxication Metastatic osteolclastictumors
Tertiary Sarcoidosis and Humoral hypercalcemiahyperparathyroidism granulomatous disease
Pseudo‐hypoparathyroidism
Severe hypophosphatemia PTH related proteinhypoparathyroidism
Increased intestinal b ti
Decreased renal excretion Impaired bone f tiabsorption formation
Vitamin D intoxication Familaial hypocalciurichypercalcemia
Aluminum intoxication yp
Milk alkali syndrome Thiazides Low turnover bone disease
Corticosteroids
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Phosphate Metabolism
Atif Hassan Khirelsied , B.Sc., M.Sc., Ph.D.
Department of Biochemistry, Faculty of Mediciney
International University of Africa, Khartoum, Sudan
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The role of phosphates in the human body
Phosphorus plays an important role in several aspects of
p p y
cellular metabolism, including :
• Calcium phosphate, hydroxyapatite (bone)
• Adenosine triphosphate (energy metabolism,)
• 2,3‐diphosphoglycerate (oxygen transport).
Ph h li id i ll b• Phospholipids in cell membranes.
• Nucleotides (nucleic acids)
• Creatine phosphate (muscle).
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The distribution of phosphates in the human bodyp p y
• An average adult human contains about 0.7 kg of phosphorus.
• About 80% of the body phosphorus is present in bones and teethand teeth.
• About (10.9%) in the viscera, (9%) in the skeletal muscle ,About (10.9%) in the viscera, (9%) in the skeletal muscle , and only 0.1% is in the extracellular fluids.
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Phosphorus
• The physiologic concentration of serum phosphorus in
normal adults ranges from 2.5 to 4.5 mg/dL (0.80–1.44
mmol/L)mmol/L).
• A diurnal variation occurs in serum phosphorus, the lowest
concentration occurring between 8 AM and 11 AM.
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The control of phosphates levels in the human body
The major determinants of serum phosphorus concentration j p p
are:
1. Dietary intake
2. Gastrointestinal absorption p
3. Urinary excretion
4. Shifts between the intracellular and extracellular
spaces.p
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Daily exchanges of phosphorus between different tissue compartments.
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The role of kidney in the control of phosphate
• Phosphate is freely filtered across the glomerules of
which 80% is reabsorbed in the proximal tubules.
• Several factors, primarily dietary intake of phosphorus
and PTH decreases the renal phosphate reabsorption.
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Decreased reabsorption Increased reabsorption
Factors regulating renal reabsorption of phosphateDecreased reabsorption Increased reabsorption
High phosphate diet Low phosphate diet
PTH or related peptides Growth hormone, insulin
Glucocorticoids 1, 25 (oh) vitamin D
Chronic metabolic acidosis Chronic metabolic alkalosis
Acute respiratory acidosis High calcium diet
Calcitonin , Thyroid hormone
Fasting High potassium diet
H k l i h l i St i l i *Hypokalemia , hypercalcemia Stanniocalcin*
Diuretics
Phosphatonin*
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The phosphatonin (newly discovered protein)
• Phosphatonin also called fibroblast growth factor 23 (FGF 23)
p p ( y p )
• Phosphatonin, also called fibroblast growth factor‐ 23 (FGF‐23)
• Has been identified as the last member of FGF family.Has been identified as the last member of FGF family.
• Is produced by bone and acts on kidneys through a specific receptor system.
• Reduces serum phosphate level by suppressing renal• Reduces serum phosphate level by suppressing renal phosphate reabsorption and intestinal phosphate absorption.
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Hypophosphatemia
• Is the serum phosphate level below 0.80 mmol/L.
yp p p
• Serum phosphate of 0.32‐ 0.65 mmol/L is moderate hypophosphatemia and < 0 32 mmol/L is severehypophosphatemia and < 0.32 mmol/L is severe hypophosphatemia
• Could result from:1. internal redistribution of phosphorous, 2. increased urinary excretion3. decreased intestinal absorption.
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Major causes of hypophosphatemia
Internal redistribution
Decreased intestinal absorption
Increased urinary excretion
Increased insulin,
ti l l
Inadequate intake
Primary and secondary hyperparathyroidism
particularly during refeeding
Antacids containing aluminum or
Vitamin D deficiency or resistance
g aluminum or magnesiumAcute
respiratory Fanconi’s syndrome
alkalosis
Hungry bone syndrome
Steatorrhea and chronic diarrhea
Miscellaneous: • osmotic diuresissyndrome chronic diarrhea • osmotic diuresis,• proximally acting
diuretics, acute volume expansion
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The clinical symptoms of hypophosphatemia
H l i i d i d i i
y p yp p p
• Hypercalciuria and increased urinary magnesium excretion.
• Proximal myopathy, dysphagia and ileus (bowel obstruction))
• Cardiac and respiratory disorders
• Hemolysis, thrombocytopenia.
• Metabolic acidosis.
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Hyperphosphatemia
R lt f
Hyperphosphatemia
• Results from:
I Increased phosphate that exceeds the renalI. Increased phosphate that exceeds the renal excretory ability.
II. Decreased urinary excretion of phosphate.
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Thanks