Bone Calcium & Phosphate Metabolism PDF

# Bone: Calcium & Phosphate Metabolism ## Important Minerals - **Macro Elements** - Calcium - Magnesium - Phosphorus - Sodium - Potassium - Chloride - Sulfur - **Trace Elements** - Iron - Iodine - Copper - Manganese - Zinc - Molybdenum - Se...

# Bone: Calcium & Phosphate Metabolism ## Important Minerals - **Macro Elements** - Calcium - Magnesium - Phosphorus - Sodium - Potassium - Chloride - Sulfur - **Trace Elements** - Iron - Iodine - Copper - Manganese - Zinc - Molybdenum - Selenium - Fluoride Calcium and phosphorous individually have their own functions and together they are required for the formation of hydroxyapatite and physical strength of the skeletal tissue. ## Calcium - Most abundant mineral in many animals and in the human body. - Ancient Romans prepared lime- calcium oxide. 975 AD -plaster of Paris (calcium sulfate) was used for setting broken bones. - Sir Humphry Davy Isolated calcium (1808) - Calcium: Ca-20, 40.078 ## Phosphorus - It is the second most abundant essential mineral in the human body after calcium. - In human body Phosphorus is present as phosphates (compounds containing the phosphate ion, $PO_4$3-) - The first form of elemental phosphorus to be produced was white phosphorus, in 1669 by Greek. Hennig Brand(1669) discovered. ## Role of Calcium in Body - Affects nerve and muscle physiology - Intracellular signal transduction pathways. - Co-factor in blood clotting cascade. - Constituent of bone and teeth. - Major structural element in the vertebrate skeleton (bones and teeth) in the form of calcium phosphate ($Ca_5(PO_4)_3(OH)$), known as hydroxyapatatite - Maintain all cells and connective tissues in the body. - Essential component in production of enzymes and hormones that regulate metabolism ## Role of Phosphate - Key constituent of bone and teeth. - Component of intra cellular buffering. Forms energy rich bonds in ATP. - Forms co-enzymes. - Regulates blood and urinary pH - Forms organic molecules like DNA & RNA - Cellular energy metabolism. - Constituent of macro molecules like nucleic acids, phospholipids and phosphoproteins. ## Distribution **Total Calcium** - 1000-1500gm - (1.5% of the body weight) - 99% - Bones - 1% - ECF, Plasma **Total Phosphorus** - 500-800gm - 80-90% - Bones, Teeth - 10% - RBC, Plasma ## Plasma Calcium and Phosphate **Normal Plasma Levels** - 9-11mg/dl (calcium) - 2.5-4.5mg/dl (phosphorous) - Ionized - 5 mg/dl - Unionized - 4mg/dl - Organic - 0.5-1mg/dl - Inorganic - Adults: 3-4mg/dl - Children: 5-6mg/dl ## Calcium Phosphate Ratio - Calcium: Phosphate ratio normally is 2:1 - Increase in plasma calcium levels causes corresponding decrease in absorption of phosphate. - This ratio is always constant. ## Sources of Calcium **Best Source** - Hard cheese - Milk - Dark green leafy vegetables **Fair Source** - String beans - Eggs - Bread **Good Source** - Ice-cream - Broccoli - Baked beans - Dried legumes - Dried figs **RDA of calcium** - Average adult: 800mg/day - Infants: < 1yr: 360-540mg - 1-10 yr: 800mg - 11-18yr: 1200mg - During pregnancy & lactation: 1200mg/day ## Sources of Phosphate **Rich Source** - Milk - Meat - Fish - Poultry - Eggs **Moderate Sources** - Cereals - Pulses - Nuts - Legumes - Meat **RDA of Phosphates** - Adults: 800-1200mg/day - Infants: 240mg/day - During pregnancy & lactation: 1200mg/day ## Absorption and Excretion of Calcium and Phosphate - 35-40% of average daily dietary calcium is absorbed mainly from the duodenum and first half of jejunum transport under the influence of vitamin D. Additionla 25% of Ca enters the intestine via secreted gastrointestinal juices and sloughed mucosal cells. Thus about 90% of daily intake of calcium is excreted in faeces ## Phosphorus Absorption - 50-70% - absorbed - Small intestine - soluble inorganic phosphate - Except the portion of phosphate that is excreted in combination with non absorbed calcium - Almost all dietary phosphate is absorbed from the gut and later excreted in urine ## Renal Excretion of Calcium and Phosphate - 10% - urine - 41% - bound to protein and cannot be filtered - Rest is filtered through glomeruli ## Renal Handling of Calcium - Different segments of the nephron are tasked with calcium reabsorption. - 60-70% proximal convoluted tubule - 20% cortical segments of the loop of Henle - 10% distal convoluted tubule - 5% collecting duct ## Phosphorous Excretion - Is excreted primarily through Urine. - Almost 2/3rd of the total phosphorous that is excreted is found in the urine as phosphate of various cations. - Phosphorous found in the faeces is the non absorbed form of phosphorous. ## Factors Controlling Absorption **Factors Inhibiting** - Phylates and oxalates - High dietary phosphate - Free fatty acids - High pH - High fiber diet **Factors Promoting** - Vitamin D - Para thyroid hormone - Low pH - Lactose - Amino acids like lysine and arginine ## pH of Intestine - Acidic pH in the upper intestine (deodenum) increases calcium absorption by keeping calcium salts in a soluble state. - In lower intestine since pH is more alkaline, calcium salts undergoes precipitation ## Phytic Acid and Phytates: - Present in oatmeal meat and cereals and are considered anti-calcifying factors as they combine with calcium in the diet thus forming insoluble salts of calcium. ## Oxalates: - Present in spinach and rhubarb leaves. They form oxalate precipitates with calcium present in the diet thus decreasing their availability ## Fats: - Combines with calcium and form insoluble calcium, thus decreasing calcium absorption ## Bile Salts: - Increases calcium absorption by promoting metabolism of lipids. ## Protein and Aminoacids: - Increases calcium absorption as protein forms soluble complexes with calcium and keeps calcium in a form that is easily absorbable. ## Carbohydrates: - Lactose promotes calcium absorption by creating the acidity in the gut as they favours the growth of acid producing bacteria. ## Amount of Dietary Calcium and Phospates - Rottenson -1938-amount of calcium stored in body is directly proportional to amount of calcium absorbed in body - Increased level of calcium and phosphate in diet increases their absorption however up to a certain limit. This is because the active process of their absorption can bear with certain amounts of load beyond which the excess would pass out into faeces. ## Pregnancy and Growth: - During later stages of pregnancy, greater amount of calcium absorption is seen. - 50% of this calcium is used for the development of fetal skeleton and the rest is stored in the bones to act as a reserve for lactation. - This is due to the increased level of placental lactogen and estrogen which stimulates increased hydroxylation of vitamin D. - In growth there is a increased level of growth hormone. GH acts by increasing calcium absorption. It also increases the renal excretion of calcium and phosphates. ## Hormonal Control of Calcium & Phosphate Metabolism - Three hormones regulate calcium and phosphate metabolism: - Vitamin D - PTH - Calcitonin ## Vitamin D - Cholecalciferol / D3 - Ergocalciferol / D2 - Can be called as hormone as it is produced in the skin when exposed to sunlight. - Vitamin D has very little intrinsic biological activity. Vitamin D itself is not a active substance, instead it must be first converted through a succession of reaction in the liver and the kidneys to the final active product 1, 25 di hydroxycholecalciferol ## Action of Vitamin D - **On Bone:** In the osteoblasts of bone calcitriol stimulates ca intake for deposition as $CaPO_4$ - **On Kidney:** It is involved in minimizing the excretion of ca&p through kidney by decreasing their excretion and enhancing reabsorption ## Parathyroid Hormone - Parathyroid hormone is one of the main hormones controlling $Ca^{+2}$ absorption. - It mainly acts by controlling the formation of 1,25 DHCC, which is active form of Vit. D, which is responsible for, increased $Ca^{+2}$ absorption. - Normal PTH level in serum: 10-60ng/L ## Parathyroid Hormone (PTH) - Secreted by parathyroid gland. Glands are four in number, present posterior to the thyroid gland. Formed from third and fourth branchial pouches. Histologically - two types of cells. - Chief cells (forming PTH) - Oxyphilic cells (replaces the chief cells, stores hormone) ## Action of PTH - The main function is to increase the serum calcium in the critical range of 9 to 11 mg. - Parathormone inhibits renal phosphate reabsorption from the proximal tubule and therefore increases the excretion of phosphate (Mg,H and, Na,K) - Parathormone increases renal calcium reabsorption from the tubule, which also increases the serum calcium. - Net Effect of PTH → ↑ serum calcium, ↓ serum phosphorus ## Stimulation for PTH secretion - The stimulatory effect for PTH secretion is low level of calcium in plasma. (Rapid phase, Slow phase) - Maximum secretion occurs when plasma calcium level falls below 7mg/dl. - When plasma calcium level increases to 11mg/dl there is decreased secretion of PTH ## Calcitonin - Minor regulator of calcium & phosphate metabolism - Secreted by parafollicular cells or C-cells of thyroid gland. Single chain polypeptide. - Plasma Concentration: 10-20ug/ml - Calcitonin is a Physiological Antagonist to PTH with respect to Calcium. With respect to Phosphate it has the same effect as PTH i.e. Plasma Phosphate level. ## Action of Calcitonin - Net effect of calcitonin → decreases Serum Ca. - Target site: Bone (osteoclasts), Kidney, Intestine. ## Influence of other Hormones: - Growth Hormone - Insulin - Testosterone & other Hormones - Lactogen & Prolactin - Steroids - Thyroid Hormones ## Growth Hormone - Increases the intestinal absorption of calcium and increases its excretion from urine. - Stimulates production of insulin like growth factor in bone which stimulates protein synthesis in bone. ## Insulin - It is an anabolic hormone which favors bone formation. ## Testosterone - Testosterone causes differential growth of cartilage resulting to differential bone development. - Acts on cartilage & increase the bone growth. ## Thyroid Hormone - In infants → stimulation of bone growth - In adults → increased bone metabolism → increased calcium mobilization ## Glucocorticoids - Anti vitamin D action, decrease absorption of calcium in intestine. - Inhibit protein synthesis and so decrease bone formation. - Inhibit new osteoclast formation & decrease the activity of old osteoclasts ## Concept of Calcium Balance - Defined as the net gain or loss of calcium by the body over a specified period of time. - Calculated by deducting calcium in faeces and urine from the calcium taken in diet. - Positive calcium balance in growing children. - Negative calcium balance in aging adults. ## Osteoporosis - An atrophy of bone. - Bone resorption > bone deposition - Calcium or hormonal deficiencies - Older people - women > 60yrs. - c/f: Loss of height - shortening of the trunk & collapse of the vertebrae. Deformed thoracic cage. Bone pain - due to fracture ## Radiographically: - Loss of'bone density - Thinning of cortex - Trabaculae - reduced ## Stages of Osteoporosis - Normal bone - Osteopenia - Osteoporosis - Severe Osteoporosis ## Rickets - Softening of the bones in children potentially leading to fractures and deformity. - Due to def. of vit.D causing deficiency in Ca & phosphate. - This is a bone disease that occurs in children, the bones become soft because of lack of a certain nutrient. ## Clinical Features - Femoral and tibial bowing - Growth retardation - Weakness - Tetany - Susceptibility to fracture - Irritability - Some studies shown that rickets during the time of tooth formation is the most common cause of enamel hypoplasia. Shelling & Anderson - in rachitic children: 43% of teeth showed hypoplasia. Type - pitting variety ## Ricket Weakness in Bones: - Prolonged rickets → increased PTH → increased osteoclastic activity → rapid osteoblastic activity ## Oral Manifestation: - Sir Edward Mellanby (1884-1955) - 1st to report the effect of rickets on the teeth. - Development abnormalities of dentine & enamel - Delayed eruption - Malalignment of the teeth in the jaws - High caries index - Abnormally wide predentine zone - Interglobular dentine - Many reports - rickets linked with hypoplasia ## Treatment: - Diet and sunlight. - Recommendations are for 400 international units (IU) of vitamin D a day for infants and children. Children who do not *get adequate amounts* of vitamin D are at increased risk of rickets. Vitamin D is essential for allowing the body to uptake calcium for use in proper bone calcification and maintenance. - According to the American academy of paediatrics (AAP), all infants, including those who are exclusively breast-fed, may need Vitamin D supplementation until they start drinking at least 17 US fluid ounces (500 ml) of vitamin D-fortified milk or formula a day ## Osteomalacia - Softening & distortion of skeleton - Oral manifestation: Taylor & day - 50% incidence of severe periodontitis in a series of 22 Indian women. ## Clinical Features: - Bone pain and tenderness - Peculiar waddling or "penguin" gait - Tetany - Greenstick bone fractures - Myopathy ## Oral Manifestation: - Severe Periodontitis - Thin or absent trabeculae - Loosened teeth - Weakened jaw bones ## Hypophosphatasia: - Def. of enzyme alkaline phosphatase - Excretion of phosphoethanolamine in the urine. - c/f: - **Infantile Form:** Severe rickets. Bone abnormalities. Failure to thrive. - **Childhood:** Loss of primary teeth. Increased infection. Growth retardation. Rachitic like deformation, lung., renal, Gl disorders - **Adult:** Spontaneous Fracture ## Oral Manifestations: - Premature Loss of primary teeth - Gingivitis ## Radiographic Features: - Hypocalcification - Large pulp chambers - Alveolar bone loss ## Hypocalcemia - < 8.8 mg/dl - < 8.5mg/dl - mild tremors - < 7.5mg/dl - life threatening condition will result - TETANY ## Causes: - Hypoparathyroidism - Vit. D deficiency - Increased calcitonin - Deficiency of calcium, magnesium - Hypoalbuminemia ## Symptoms: - Muscle cramps - Paresthesia - Neuromuscular irritability - Muscle twitching - Tetany - Seizures - Bradycardia ## Cats of Hypocalcemia: - C. convulsion - A. arrhythmias - T. tetany - S. spasm and stridor ## Hypercalcemia ## Causes: - Hyperparathyoidism - Thyrotoxicosis, addison's disease - Paget's disease - Dehydration - Milk - alkali syndrome - Drugs - thiazides ## Parathyroid Poisioning: - Ca >15 mg/dl - Ca-p crystals ## Symptoms: - Anorexia, nausea, vomiting - Polyuria, polydypsia - Confusion, depression, psychosis - Osteoporosis & pathological fracture - Renal stones - Ectopic calcification & pancreatitis - Increased serum alkaline phosphatase ## Management of Hypercalcemia - Adequate hydration, IV normal saline - Furosemide IV to promote calcium excretion - Steroids, if there is calcitriol excess - Definitive treatment for the underlying disorder ## Causes & Outcomes for Calcium Deficiency **Causes** - Gluten Induced Malabsorption - Vitamin D Deficiency - Antacid Medications - Diet High in Sugar - Chronic Steroid Use **Outcomes** - Calcium Deficiency - Muscle Spasms & Joint Pain - Bone Loss - Hormone Disruption - High Blood Pressure - Abnormal Blood Clotting - Prescription Pain Medications - Drugs for Bone Building - Hormone Prescription - Blood Pressure Medications - Blood Thinners