Pathophysiol ogy of Calcium, Phosphate Homeostasis Bone Structure Functions Maintain, Support, Site of Muscle Attachment (Locomotion ) Protective

for Vital Organs, Marrow Metabolic (Reserve of Ions)(Especially Calcium, Phosp hate) (Maintain Serum Homeostasis) Bone Structure Bone Cells Osteoblast Osteocytes Osteoclasts Matrix Organic Inorganic Collagen (95%) Calcium, Phosp hate Ground Substances (5%) Hydroxyapatite (Ca10 (PO4 )6 (OH)2 ) • Keratine Sulfate • Chondroitin Sulfate

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Anatomy

Abnormalities Serum Concentration of 2 Minerals (especially Calcium) Serum Ca2+ Abnormally ↓ Abnormally ↑ Renal Failure Malignancy Hypoparathyroidism 1° Hyperparathyroidism Bone Density ↓ ↑ Osteoporosis Paget’s Disease Osteomalacia Osteopetrosis Major Regulating Organ System (Especially Parathyroid Gland, Kidney, GIT) GIT ↓ Ca2+ Absorption ↑ Ca2+ Absorption Malabsorptive Vitamin D Intoxication Milk-Alkali Syndrome Kidney Fail to Excrete Overexcrete Underexcrete Overexcrete Ca2+ Ca2+ Phosphorus Phosphorus Hypercalcemic Nephrolithiasis Renal Failure Renal Tubular disorders Disorders Body Distribution of Calci um, Phosphate Calcium Phosphate Total Body Calcium (1kg) Total Body Phosphate (700g) • Bone, Teeth (99%) • Bones, Teeth (85%) • Blood, Body Fluids Intracellular • Soft Tissues (15%) Calcium (1%) • ECF (0.1%) Normal Plasma Calcium Plasma Phosphate exists • 2.2 – 2.6 mmol/L • Inorganic Phosphate Ions Daily Recommended Intake (Adult) (HPO4 2- , H2 PO4- ) (Largely) • 1000 – 1500 mg • Bound to Proteins (10%) Ionized Ca2+ (Biologically Active) • Freely Diffusible, Equilibrium with Distribution of Calcium in Body Intracellular, Bone Phosphate (Remainder) Recommended Ph osphate Intake (Adult) – 700 mg Infants, Young Childre n ↑ Phosphate (influe nce of GH, ↑ Skeletal Growth Rate)
Neonates < 7 y/o < 15 y/o Adult s 1.2 – 2.8 mmol/L 1.3 – 1.8 mmol/L 0.8 – 1.3 mmol/L 0.6 – 1.25 mmol/L

Bone Structure Osteoblast (Bone Formation) 3 Steps in Bone Formation Process • Production of Extracellular Organic Matrix • Mineralization of Matrix to form Bone • Remodelling by Resorption, Refor mation Bone formation actively fixes circulating calcium in its mineral form (removing it from bloodstream)

Osteoclast (Bone Resorption) Release Calcium into Systemic Circulation Actively unfixes the calcium ↑ Circulating Calcium Levels

Peak Bone Mass Schematic Representation Crossover of Formation/ Resorption occurs during 4th Decade In Osteoporosis, Accelerated Loss of Bone (↑ Resorption, ↓ Formation) Equilibrium of Bone Tissue Balance between • Osteoclastic Resorption (of existing bone) • Osteoblastic Formation (of new bone) 3 Major Influences on Equilibrium • Mechanical Stress (Stimulating Osteoblastic Activity) • Calcium, Phosp hate level in ECF • Hormones, Local Factors (Influencing Res orption, Formation)

Importance • Constituent of Cell Membranes (affe ct permeability, electrical) • ↓ Ca2+ in ECF o ↑ Permeability o ↑ Excitability of Cell Membrane
(↓ Ca2+ i n ECF - ↑ Excitabil ity of Nerve T issue, Stimulate Muscle Contraction) (Ca2+ - Coup ling Factor betwee n Excitation, Contraction of Actomyosin)

• Influence Cardiac Contractility, Automaticity (via Slow Ca2+ channels in Heart) • Release of Preformed Hormones in Endocrine Cells, Release of ACh at Neuromuscular Junctions • MOA of Hormones within Cells (cyclic AMP, cAMP) 2° intracellular messenger • Adhesive (Enzyme, Blood Coagulation)

Importance • Bones, Teeth • Phospholipids (cell membranes ) • 1° Anions in ICF (Metabolism of Proteins, Fats, Carbohydrates) • Metabolic Processes (ATP) • Muscle, Neurologic Function, 2,3-DPG in RBC • Maintain Acid-Base balance through action as Urinary Buffer (Excrete ↑ Daily Acid Load)

Bone Resorption Calcium. Ileum Less in Duodenu m Absorption is a Linear Function of Dietary Pi Intake Intestinal Absorption in 2 Routes • Cellular mediated Active Transport mechanism • Diffusional Flux (Paracellular Shunt Pathway) Regulation – Calcitropic Hormones Increased Absorption • Vitamin D • PTH Excretion Filtered (90%) Proximal Tubule (90% Reabsorbed ) Active Passive H2 PO4 HPO4 2Distal Tubule (10% Reabsorbed) Regulation • Diet • Calcitropic Hormones ↑ Excretion ↓ Excretion PTH Vitamin D CT . Remove it from Blood ) Small Intestine Bone Kidney Calcium Absorption 1° in Duodenum • 15 – 20% Absorption • Duodenum > Jejunum > Ileum • Adaptive changes o ↓ Dietary Ca2+ o Age o Pregnancy o Lactation Mechanism of GI Ca2+ Absorption • Active Transport across Cell • Transcellular Transport • Endocytosis.com | Medicine Homeostasis (Balance between Input. P Output Amount Ingested Amount Secreted into GIT Amount Mobilized from Skeletal Pool Urinary Excretion Deposition in Bone Balance of Bone Formation. Excretion 3 Organs (Calcium. Output from ECF ) Ca. P Input Ca. Ph osphate) (Sup ply to Blood.jslum. Exocytosis Ca (CaBP Complex) Absorption of Ca2+ from GIT Excretion Daily Filtered Load – 10gm Filtered Calcium (98%) are reabsorbed along renal tubule 2 General Mechanisms • Active – Transcellular • Passive – Paracellular Reabsorption (Proximal Tubule. Loop of Henle ) • Filtered Load (70%) • Mostly Passive • Inhibited by Furosemide Distal Tubule Reabsorption • Filtered Load (10%) • Regulated Stimulated Inhibited PTH CT Vitamin D Thiazides Phosphate (Pi) Absorption Greatest in Jejunum. Phosp hate Absorption.

com | Medicine Major Mediators of Calcium. Phosphate Balance Parathyroid Hormone Calcitriol (PTH) (active form of Vit D3) Role Stimulates GI Absorption of both • Stimulate Renal Reabsorption of Ca2+ Calcium. Magnesium 1° Function Prevent Hypercalcemia after ingestion of meal Disruption of Homeostasis Failure to achieve. Phosp hate Stimulates Bone • Stimulate Bone Resorption Resorption Net Effect • Inhibit Bone Formation. restore homeostasis (result in death) • Injury • Illness • Disease Disruption of Ca2+ Homeostasis Disruption of Phos phate Homeostasis Hypocalcaemia Hypophosphatemia Hypercalcaemia Hyperphosphatemia . Phosp horus. Phosp hate Stimulates Renal • Inhibit Renal Reabsorption of Reabsorption of Phosphate Calcium. • ↑ Serum Calcium Mineralization • ↑ Serum Phosphate • Stimulate Calcitriol Synthesis Net Effect • ↑ Serum Calcium • ↓ Serum Phosphate Regulation • ↓ Serum [Ca2+] (↑ PTH Secretion) • ↑ Serum [Ca2+] (↓ PTH Secretion) Overview of Calcium-Phosphate Regulation Calcitonin Exact role Unknown Does not seem to be involved in homeostasis of Calcium. Ph osphate Hypercalcemia of Hypermagnesemia stimulates secretion ↓ Plasma Calcium (by ↓ Bone Resorption ) ↑ Reabsorption of Calcium.jslum.

Hypercalcaemia Etiologies of Hypercalcaemia ↑ GI Absorption Milk-Alkali Syndrome ↑ Calcitriol Vitamin D Excess (Excess Dietary Intake. Head. Hypoalbuminemia. Citrate-Buffered Blood. (↓ Calcitriol) Malabsorption Hungry Bones Syndrome Syndromes) Osteoblastic Metastases ↓ Conversion of Vitamin D → Calcitriol (Liver Failure.55 mmol/L 1% Prevalence in General Population 1 – 4% Prevalence in Hospital Population Malignancy (common cause in Hospital Patient) 1° Hyperparathyroidism (commonest in General Population) Causes Hyperparathyroidism 1° Hyperparathyroidism 2° Hyperparathyroidism (Chronic Renal Failure.25 (OH ) 2 D3 (Anticonvulstant Drugs) Alkalosis. Chvostek’s Sign) CNS Altered Mood Impaired Memory Confusi on Convulsive Seizures GIT Diarrhoea Loose Stool Malabsorption Steatorrhea Skin Dry Skin Scaly Skin Dry Hair Overview of Calcium Balance . Radiographic Contrast Media) Signs. Granulomatous Diseases) ↑ PTH Hypophosphatemia ↑ Loss from Bone ↑ Net Bone Resorption ↑ PTH (Hyperparathyroidism) Malignancy (Osteolytic Metastases. Renal Failure. Feet) Hyperactive Reflexes Tetany (Trousseu’s Sign. Phosphates.25 (OH)2 D3 Intoxication Milk-Alkali Syndrome Signs. Hands.1 mmol/L Ionized Calcium) Common finding (5 – 8% of Hospitalized Patients) Majority due to ↓ Plasma Albumin (True Hypocalcemia is ↓ common) Causes of Hypocalcaemia ↓ PTH Hypoparathyroidism (Idiopathic.com | Medicine ↑ Urinary Excretion ↓ PTH (Thyroidectomy.2 mmol/L (< 1. Hyperphosphatemia. Vomiting Weight Loss Constipation Renal Polyuria Nephrolithiasis Nephrocalcinosis Renal Failure Skeletal Bone Resorption Formation of Bone Cysts Subperiosteal Erosion of Lone Bone Hypocalcaemia Serum Calcium Levels < 2. Hyperphosphatemia) jslum. Malabsorption Disease) Impaired 25-Hydroxylation in Liver (Alcoholic Liver Disease) Impaired Renal Hydroxylation (Chronic Liver Failure. Symptoms (Consequences of Hypocalcaemia) Cardiovascular ECG Changes Dysrhythmias Neuromuscular Paresthesias (Circumoral. Symptoms (Consequences of Hypocalcaemia) Cardiovascular Hypertension ECG Changes Dysrhytmias Neuromuscular Generalized Muscle Weakness Depressed Deep Tendon Refle xes Metastatic Calcification in Soft Tissue CNS Impaired Concentration Confusi on Altered State of Consciousness GIT Polydipsia Anorexia Nausea. Hypophosphatemic Ri ckets) Impaired Response to 1. Hypoparathyroidism. I131 Treatment. PTHrP Secreting Tumour) ↑ Bone Turnover Paget’s Disease Hyperthyroidism ↓ Bone Mineralization ↑ PTH Aluminium Toxicity ↓ Urinary Excretion Thiazide Diuretics ↑ Calcitriol ↑ PTH Hypocalcaemia Etiologies of Hypocalcaemia ↓ GI Absorp on ↓ Bone Resorption (↑ Mineralization) Poor dietary intake of ↓ PTH Calcium (Hypoparathyroidism) Impaired absorption PTH Resistance of Calcium (Pseudohyp oparathyroidism) Vitamin D Deficiency Vitamin D Deficiency (Poor dietary Intake. ↓ PTH. Autoimmune Hypoparathyroidism) PTH Resistance Vitamin D Deficiency (↓ Calcitriol) Hypercalcaemia Serum Calcium Levels > 2. Surgical) Hypomagnesemia Abnormal Metabolism of Vitamin D Deficiency (↓ Intake. Neck) Solid Tumour with Bone Metastasis (Carcinoma of Breast) Hematologic Malignancies (Multiple Myeloma. Loop Diuretics. Acute Pancreatitis Drugs (Chemotherapy. Acute Leukemia) Abnormal Vitamin D Metabolism Sarcoidosis Tuberculosis Endocrine Hyperthyroidism Adrenal Insufficiency Prolonged Immobilization Drugs Thiazide Diuretics Lithium Vitamin A Intoxication Vitamin D Intoxication 1. ↓ Sunlight Exposure. Vitamin D Malabsorption) Malignancies Solid Tumours without Bone Metastasis (Squamous Cell Carcinoma of Lu ng.

Insulin Infusion Severe Burns ↑ Urinary Loss Hyperparathyroidism Renal Tubular Disorders Signs.Hyperphosphatemia Etiologies of Hyperphosphatemia ↑ GI Intake Fleet’s Phospho-Soda ↓ Urinary Excretion Renal Failure ↓ PTH (Hypoparathyroidism) (Thyroidectomy. Alcoholism) During Treatment for DKA Hypophosphatemia Serum Phosphate Level < 0. Intestinal Absorption Excess use of Phosphate (containing Laxatives. HCO3.25 (OH)2 D3 Synthesis Metabolic Acidosis Respiratory Insufficiency Respiratory Acidosis Hypoxia Cardiomyopathy ↓ Cardiac Output Hypotension Overview of Phosphate Balance . Al. En dogenous ) Soft Tissue Calcification. Enemas) IV Phosphate Vitamin D Intoxication (Vitamin D Medication. Symptoms Hematologic Red Blood Cell Dysfun ction Hemolysis Leucocyte Dysfunction Platelet Dysfunction Muscle Weakness Rhabdomyolysis Skeletal Osteomalacia.com | Medicine Etiologies of Hypophosphatemia ↓ GI Absorption ↓ Dietary Intake (Rare in Isolation) Diarrhoea. Tetany Important Short-Term Consequence s Due to ↑ Pi load from any source (Exogenous.↓ Calcitriol Hungry Bones Syndrome Osteoblastic Metastases ↑ Urinary Excre on ↑ PTH (as in 1° Hyperparathyroidism) Vitamin D Deficiency. ↓ Renal Pi Excretion Hypophosphatemia jslum. Bones Respiratory Alkalosis Total Parenteral Nutrition (TPN) Diabetic Ketoacidosis Glucose. Mg2+ Excretion ↑ 1. Anorexia. Intestinal Absorption Deficiency of Dietary Phosphate Antacid Abuse Malabsorption States Vitamin D Deficiency Shift from ECF into Cells.5 mmol/L May be a consequences of • ↑ Intake of Pi • ↓ Excretion of Pi • Translocation of Pi (Tissue Breakdown → ECF) Causes of Hyperphos phatemia ↓ Renal Phosphate Excretion Renal Failure Hypoparathyroidism Endocrine Disorders (Acromegaly. Hyperthyroidism) Biphosph onate Therapy Redistribution ICF → ECF Chemotherapy for Neoplasm Respiratory. I131 Treatment for Graves Disease of Thyroid Cancer. ↓ Calcitriol Fanconi Syndrome Internal Redistribution (Due to Acute Stimulation of Glycolysis) Refeeding Syndrome (Starvation. 2° Hyperparathyroidism Long Term Conseque nces Due to Renal Insufficien cy. Symptoms Hypocalcemia. Adrenal Insufficiency. Metabolic Acidosis Rhabdomyolysis Hemolysis ↑ Intake. Malabsorption Phosphate Binders (Calciu m Acetate. Tuberculosis) Signs. Mg containing Antacids) ↓ Bone Resorption (↑ Bone Mineralization) Vitamin D Deficiency. Autoimmune Hypoparathyroidism) Cell Lysis Rhabdomyolysis Tumour Lysis Syndrome Hyperphosphatemia Serum Concentration of Inorganic Phos phorus > 1. Sarcoidosis.6 mmol/L Unusual unless there is • ↓ Oral Intake • Shift of Phosphate from ECF into Cells/ Bone • Excessive Renal Loss of Phosphate Causes of Hypophosphatemia ↓ Intake. Rickets CNS Irritability Paresthesias Dysarthria Confusi on Seizures Coma Renal ↑ Ca2+.

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