Calcium and phosphate METABOLISM

Calcium and phosphate

1. good morning

2. Calcium & phosphorous metabolism Dr. D.V.S. REVATH VYAS PG 1 ST YEAR DEPT OF ORAL MEDICINE AND RADIOLOGY

3. - INTRODUCTION -CALCIUM REGULATION IN BODY -CALCIUM METABOLISM -FACTORS REGULATING CALCIUM METABOLISM -TOOTH MINERALISATION CONTENTS

4. CONTENTS -PHOSPHOROUS REGULATION IN BODY -PHOSPHOROUS METABOLISM -FACTORS REGULATING PHOSPHOROUS METABOLISM -APPLIED ASPECTS

5. The rigidity of skeleton which provides support and protection for soft tissues , muscle contraction , the hardness and fitness of the teeth , the stability of the cell membranes , as activator of many hormones and last but not the least the heart beat it self, is dependent on CALCIUM. With its myriads of functions and complex mechanisms of control, calcium in both ionized and unionized form is arguably one of the most important body components . INTRODUCTION

6. CALCIUM Symbol : Ca Atomic number: 20 Atomic weight: 40.078g Group number : 2 Group name: Alkaline earth metal Colour : Silvery white Classification: Metallic

7. 1% of total body calcium

8. TOTAL BODY CALCIUM 1100-1200gms(1.5 % of body weight ) 99% in the skeleton 4-5gms in soft tissue 1gm in ECF NORMAL SERUM CALCIUM 8.8-10.4mg% PLASMA CALCIUM occurs in 2 forms Diffusible : 5.36mg% or 54-55% Ionized 47% Non-ionized 5 % Non diffusible : 4.64mg% or 45-46% MOST ABUNDANT MINERAL OF OUR BODY

9. ESTIMATION OF CALCIUM CONCENTRATION Ionized Ca concentration can be estimated from routine laboratory tests, usually with reasonable accuracy eg : plasma Ca is often low - Hypoalbuminemia plasma Ca increases - Multiple myeloma Measured total plasma Ca decreases or increases by about 0.8 mg/ dL (0.20 mmol /L) for every 1-g/ dL decrease or increase in albumin

10. 8-ounce glass of milk = 300mg of calcium 2 ounces of Swiss cheese = 530mg of calcium 6 ounces of yogurt = 300 mg of calcium 2 ounces of sardines with bones = 240mg of calcium 6 ounces of cooked turnip greens = 220mg of calcium 3 ounces of almonds = 210mg of calcium “ Avoid foods causing calcium loss.. For example excess salt and caffeine ”

11. ADULT MALES AND FEMALES ….800mg WOMEN DURING PREGNANCY AND LACTATION ….1200mg INFANTS UNDER 1 YEAR ….360-540mg CHILDREN(1-18 YEARS) ….800-1200mg DAILY REQUIREMENTS OF CALCIUM . Dietary calcium intake is inversely related to body weight and body fat mass. It has the potential to increase faecal fat excretion to an extent that could be relevant for prevention of weight (re-)gain. (Nutrition Reviews. 66(10):601-605, October 2007 )

12. Factors Increasing Absorption : - Calcitriol - Paratharmone - Acidity (Low PH) - Growth Hormone - Pregnancy, Lactation - Lactose, Arginine, Lysine Factors Decreasing absorption : - Oxalates & phytates – form Ca salts - High dietary fats & fibers  formm Ca soaps - Phosphates Alkalinity - Chronic renal failure ( impaired activity of vitamin – D)

13. CALCIUM REGULATION IN THE BODY

14. - Before the fifth month of IUL very little calcium is found in the fetus because bone formation is only starting. -60% of the total deposition occurs in the last trimester which is the period of rapid and extensive ossification

15. - One year old baby contains about 100 g of calcium, a gain of 70 g over the total calcium content at birth. - The adult human weighing 70 kg contains about 1.2 to 1.4 kg of calcium that is 1.5% of the body weight, 99% of which is present in bones and teeth. Mature fetus contains about 30 g of calcium which constitutes about 3 to 4% of maternal calcium Much greater drainage occurs after birth during lactation

16. TYPES OF CALCIUM Calcium in plasma 3 forms: Ionized (50%) Nonionozed (8-10%) Calcium bound to plasma protein (40-42%) Calcium in bones: 2 forms: Rapidly exchangeable calcium Slowly exchangeable calcium

17. ABSORPTION & EXCRETION OF CALCIUM IN BODY 35-40% of average daily dietary Ca is absorbed from gut, mainly duodenum and first half of jejunum by a carrier mediated active transport under the influence of vitamin D After oral administration absorption is completed within 4hrs

18. 1000 mg/day

19. INCREASED BY DECREASED BY Acidity in stomach Calcium phosphate ratio Hypocalcemia during pregnancy & lactation Vitamin D 3- (1, 25-DHCC) Parathyroid hormone Lactose Intestinal alkalinity Excess of oxalate Excess of phytic acid Hypercalcemia Fats Alcohol and smoking Lack of exercise Emotional stability Glucocorticoids FACTORS AFFECTING CALCIUM ABSORPTION FROM GIT

20. EXCRETION As calcium is both filtered and reabsorbed but not secreted, the rate of renal calcium excretion is calculated as Renal calcium excretion= calcium filtered – calcium reabsorbed 99% of filtered calcium ( Glomerulus ) is reabsorbed by the tubules, 1% gets excreted 65% is reabsorbed in proximal tubules, 25-30% in loop of henle and 4-9% in distal and collecting tubules Daily loss of Ca in sweat is about 15mg.

21. FACTORS CONTROLLING EXCRETION Calcium concentration in the body PTH (loop of henle and distal tubules) Plasma concentration of phosphate ↓CALCIUM EXCRETION ↑ PTH ↓ Extracellular fluid volume ↓ Blood pressure ↑ Plasma phosphate ↑CALCIUM EXCRETION ↓ PTH ↑ Extracellular fluid volume ↑ Blood pressure ↓ Plasma phosphate

22. HORMONES INFLUENCING CALCIUM ABSORPTION GROWTH HORMONE “PROLACTIN (Prolactin has been shown to stimulate intestinal calcium absorption, increase bone turnover, and reduce renal calcium excretion)” Canadian Journal of Physiology & Pharmacology. 85(6):569-581, June 2007) GLUCOCORTICOIDS

23. FUNCTIONS OF CALCIUM Bone and teeth formation Neuronal activity Muscle activity Cardiac activity Cell division and growth Blood coagulation Excitability of nerves and muscles Maintains integrity of cell membrane

24. Constituent of bone and teeth Calcium and phosphorous are the principal constituent minerals of bone and teeth. They occur in the bone matrix, enamel, dentin and cementum of teeth mainly as rod shaped or platelet shaped crystals of calcium hydroxyapatites . These give the hardness, strength and concrete like elastic modulus to these tissues

25. Physiology of bone Bone is composed of tough organic matrix that is greatly strengthened by deposits of calcium salts Average compact bone contains by weight about 30% matrix and 70% salts Organic matrix of bone:

26. BONE SALTS The crystalline salts deposited in the organic matrix of bone are composed principally of calcium and phosphate. The major crystalline salt is known as hydroxyapatite [Ca 10 (PO4) 6 (OH) 2 ].

27. Bone is constantly being reabsorbed and reformed, under the cellular control…. Osteoblasts Osteocytes Osteoclasts .

28. Neuronal activity

29. Excitation-contraction coupling of all types of muscles THE ATTACHMENT OF CALCIUM TO TROPONIN AND MOVEMENT OF TROPONIN-TROPOMYSIN COMPLEX RESULTING IN EXPOSURE OF BINDING SITES ON ACTIN MYOSIN CROSS BRIDGING CAUSING A POWER STROKE

30. Muscle contraction

31. Membrane permeability Ca2+ reduces membrane permeability to ions and water, probably by binding with calmodulin of cell membranes and consequently changing the conformation and hydration of membrane proteins.

32. Blood coagulation

33. factors REGULATING CALCIUM METABOLISM Vitamin D Calcitonin Parathyroid hormone

34. PARATHORMONE - it provides a powerful mechanism for controlling extracellular calcium and phosphate concentrations Secreted by Chief cells of parathyroid gland

35. On blood calcium level: Increases bone resorption / absorbtion 2. Increases renal Ca ++ absorption in distal tubules 3. Increases absorption of intestinal Ca ++ On blood phosphate level: Stimulates resorption of phosphate from bone Increases urinary excretion Increases absorption of phosphate from GIT through calcitriol ACTIONS OF PTH

36. ↓ BONE RESORPTION ↑ URINARY LOSS ↓ 1,25,(OH) 2 D PRODUCTION ↓ NORMAL BLOOD CALCIUM ↑ ↑ BONE RESORPTION ↓ URINARY LOSS ↑ 1,25,(OH) 2 D PRODUCTION SUPPRESS PTH RISING BLOOD CALCIUM FALLING BLOOD CALCIUM STIMULATE PTH ↑ ↑ ↑ ↑

37. ON BONE: - RAPID PHASE - SLOW PHASE ON KIDNEYS: ON GASTROINTESTINAL TRACT

38. Role of PTH in the activation of VITAMIN D VITAMIN D IS A HORMONE BY CLASSIC CRITERIA: MADE IN ONE PLACE (OR SEQUENTIALLY SEVERAL PLACES!), AND ACTING IN OTHER DAILY DIETARY ALLOWANCE RECOMMENDED: - From infancy till puberty is 10 mcg of cholecalciferol (400 IU of vitamin D) - In young adulthood, its 7.5 mcg - After 25 yrs, 5 mcg required Pregnancy and lactation 10 mcg

39. ACTIVATION Of VITAMIN D OCCURS IN TWO STEPS

40. BONE STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO MOBILIZE CALCIUM KIDNEY IT INCREASES RE-ABSORPTION OF Ca FROM DCT & INCREASES RE-ABSORPTION OF PHOSPHATE ION FROM PCT

41. ACTIONS OF 1,25-Dihydroxycholecalciferol 1.Increases absorption of Ca from intestine 2.Increases synthesis of Ca induced ATPase in the intestinal epithelium 3.Increases synthesis of alkaline phosphatase in the intestinal epithelium 4.Increases absorption of phosphate from intestine.

42. Role of Ca ion in regulating 1,25 Dihydroxycholecalciferol ca ion 25 Dihydroxycholecalciferol ca ion - PTH secretion

43. Regulation of PTH secretion: Blood level of calcium: -inversely proportional conditions when PTH secretion decreases Blood level of phosphate: - directly proportional

44. CALCITONIN It is a 32 amino – acid polypeptide, secreted from clear cells or parafollicular cells of thyroid glands therefore also, known as THYROCALCITONIN It is not secreted until the plasma calcium exceeds 9.5mg/dl Normal secretion is 0.5mg/day; half life less than 15 mins ; molecular weight 3000; Normal plasma level 0.2ngm/ml

45. ACTIONS ON BLOOD CALCIUM LEVEL- It reduces the blood calcium concentration ON BONE Stimulates osteoblastic activity Inhibits osteoclastic activity Increases excretion of Ca through urine Inhibits reabsorption of Ca from renal tubules ON GIT Inhibits intestinal absorption of Ca ++ and PO 4 --- ON KIDNEYS

46. ON BLOOD PHOSPHATE LEVEL- On bones: Inhibits resorption of phosphate from bone On kidneys: Increases excretion of phosphate through urine

47. PTH 1,25-DHCC CT ON BONE Bone resorption increases Mobilize Ca & P Bone resorption decreases ON GIT Ca & P absorption increases Ca & P absorption increases Ca & P absorption decreases ON KIDNEY P absorption decreases Ca reabsorption increases Ca resorption increases 1,25-DHCC decreases Ca & P excretion increases ON S.Ca+2 Increases Increases Decreases ON S.PO4-3 Decreases Increases Decreases

48. Applied physiology – Disorders of parathyroid glands ( two types ) HYPOPARATHYROIDISM -causes: Parathyroidectomy Thyroidectomy Deficiency of receptor for PTH HYPERPARATHYROIDISM Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism

49. Hypoparathyroidism - Hypocalocemia Hypocalcemic tetany : signs and symptoms 1. hyper- reflexia and convulsions 2. carpopedal spasm 3. laryngeal stridor 4. cardiovascular changes 5. other features Late or subclinical tetany : 1. trousseau’s sign 2. chvostek’s sign 3. erb sign

50. Hyperparathyroidism- hypercalcemia signs and symptoms: 1. depression of the nervous system 2. sluggishness of reflex activities 3. reduced ST segment and QT interval in ECG 4. lack of appetite 5. constipation Parathyroid function tests: Measurement of blood Ca level Chvostek’s sign and trousseau’s sign for hypoparathyroidism

51. CALCIUM AND DENTAL CARIES if it occurs when teeth are still forming, following abnormalities may occur: -Enamel hypoplasia - Poorely mineralised dentin -Malformed teeth -Elongated pulp chambers - Anodontia or impacted teeth

52. CALCIUM AND SALIVA Calcium content of submandibular saliva is almost double the parotid content. This probably contributes to marked prevalence of calculus on lingual aspect of mandiblular incisors Concentration of calcium lessens as salivary flow increases. This probably results from the increased parotid contribution in rapid salivary flow rates - Principal salivary calcium phosphates salts are dicalcium phosphate dihydrate , octacalcium phosphate, tricalcium phosphate and hydroxyapatite

53. Phosphorous Symbol : P Atomic number : 15 Atomic mass: 30.97376amu Melting point : 44.1 o C (317.25K, 111.38 o F) Boiling point : 280.0 o C (553.15K, 536.0 o F) Colour Classification: Non-metal : White

54. PHOSPHOROUS Key element in all the known forms of life Plays a major role in biological molecules such as RNA and DNA Main structural component of all the cellular membranes Living cells also utilize phosphate to transport cellular energy via ATP Average person contains little less than 1 kg of phosphorous, about 3quater present in bones and teeth in form of apatite crystal

55. PHOSPHATE METABOLISM It is found in ATP, cAMP , 2, 3-DPG ( diphosphoglyceric acid) Total body phosphate is 500-600gms, 80-85% is in skeleton Remaining is in intracellular phosphate pool. Serum inorganic phosphate level: In adults: 2.5-4mg% In children: 5-6mg%

56. Sources of Phosphorus

57. Phosphorus: Requirements Adequate Intake 0-6 months 100 mg/day 6-12 months 275 mg/day Estimated Average Requirements 1-3 years 380 mg/day 4-8 years 405 mg/day 9-18 years 1,055 mg/day 19-70+ years 580 mg/day Pregnant & Same as for nonpregnant & lactating women nonlactating women Reference : Dietary Reference Intakes , Food and Nutrition Board, National Academy of Sciences-Institute of Medicine, 1997

58. Distribution Total phosphate:500-800 mg Bones and teeth 80-85 % Inorganic (0.5-1mg/dl) (Adults:3-4mg/dl) ( children:5-6mg/dl ) Normal plasma levels: 2.5-4.5 mg/dl Organic

59. Phosphate Absorption Mechanism– co-transport Na P is absorbed in duodenum and other parts of small intestine by active transport and passive diffusion.

60. DISTRIBUTION AND FATE Approximately 3mg/kg/day of Phosphorous enters the bone . In plasma is filtered in glomeruli of which 85-95% gets reabsorbed actively in PCT. Its excretion in urine is: INCREASED BY: Vitamin D excess; hyperparathyroidism; high phosphate diet. DECREASED BY: GH, during lactation; hypoparathyroidism ; low phosphate diet.

61. DAILY REQUIREMENT OF PHOSPHOROUS EXCRETION OF PHOSPHOROUS It is excreted in urine and feaces Urine phosphate constitutes about 60% of total excretion and rest is excreted in feaces . Infant 240 - 400mg Children 800 - 1200mg/day Adults 800mg/day Pregnancy & Lactation 1200mg/day

62. IN BONE STRUCTURAL COMPONENT INTERMEDIATE METABOLISM GENETIC MATERIAL FUNCTIONS OF PHOSPHOROUS

63. Important Functions to note are……….. Gives rigidity to bones and teeth Helps in regulation of pH of blood In regulation of glycolysis and energy metabolism Forms a part of DNA, RNA, Phospholipids & nucleotides.

64. PHOSPHATE TURNOVER

65. Overview of Phosphate Balance

66. Conditions arising from disruption / irregularities of phosphate metabolism

67. Etiologies of Hyperphosphatemia Increased GI Intake : Fleet’s Phospho -Soda Decreased Urinary Excretion : Renal Failure Low PTH ( hypoparathyroidism ) Thyroidectomy Autoimmune hypoparathyroidism Cell Lysis : Rhabdomyolysis Tumor lysis syndrome

68. Etiologies of Hypophosphatemia Decreased GI Absorption Decreased dietary intake Diarrhea / Malabsorption Phosphate binders (calcium acetate, Al & Mg containing antacids) Decreased Bone Resorption / Increased Bone Mineralization Vitamin D deficiency / low calcitriol Hungry bones syndrome Osteoblastic metastases

69. Increased Urinary Excretion Elevated PTH (as in primary hyperparathyroidism) Vitamin D deficiency / low calcitriol Fanconi’s syndrome Internal Redistribution (due to acute stimulation of glycolysis ) Refeeding syndrome (seen in starvation, anorexia, and alcoholism) During treatment for Diabetic keto acidosis Etiologies of Hypophosphatemia

70. Applied physiology

71. Rickets Age Site Pathology - calcium phosphate

72. Dental findings in Rickets Rickets causes hypoplasia or hypocalcification

73. Pigeon chest deformity

74. Rachitic rosary

75. Knock knees and bow legs

76. Harrisons sulcus & lumbar lordosis

77. OSTEOMALACIA OR ADULT RICKETS The amount of mineral accretion in bone per unit bone matrix is deficient due to inadequate absorption of Ca and decreased amount of phosphorous owing to deficiency of vitamin D&C in diet. Disease is limited to females, usually after multiple pregnancies &lactation but symptoms tend to clear up after lactation is completed. The bones especially pelvic girdle, ribs & femur become soft, painful & deformed.

78. PSEUDOHYPOPARATHYROIDISM The patients have normal parathyroid glands, but they fail to respond to parathyroid hormone or PTH injections Autosomal dominant Symptoms and signs Hypocalcemia Hyperphosphatemia Characteristic physical appearance: short stature, round face, short thick neck, obesity, shortening of the metacarpals Resistance to parathyroid hormone

79. Symptoms begin in children of about 8 years Tetany and seizures Hypoplasia of dentin or enamel and delay or absence of eruption occurs in 50% of people with the disorder Rx: Vitamin D and calcium Adequate amount of phosphorous in diet

80. PSEUDOHYPOPARATHYROIDISM Pseudohypoparatyhroidism - induced dental anomalies - ENAMEL HYPOPLASIA -DENTIN DYSPLASIA -SHORT BLUNTED ROOTS -IMPACTED TEETH -ALTERED TOOTH ERUPTION PATTERN -PARTIAL ANODONTIA Elfin facies

81. Osteoporosis

82. Osteoporosis

83. osteoporosis

84. PRIMARY HYPERPARATHYROIDISM Women (especially postmenopausal) are more commonly affected than men ( Scutellari et al, 1996). Causes SPORADIC ADENOMA(s) MOST COMMON CAUSE MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN-1): PARATHYROID TUMORS (AND PITUITARY AND PANCREAS) MEN-2a: PARATHYROID TUMORS, MEDULLARY THYROID CANCER (OR HYPERPLASIA), AND PHEOCHROMOCYTOMA FAMILIAL HYPERPARATHYROIDISM: 1 o HPT WITHOUT THE OTHER TUMORS SEEN IN MEN-1 OR MEN-2a FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCEMIA

85. Characterized by: ↑ serum Ca2+ ↓ serum phosphate ↑ urinary phosphate excretion ( phosphaturic effect of PTH) ↓ urinary Ca2+ excretion (caused by ↑ Ca2+ reabsorption ) ↑ urinary ( nephrogenous ) cAMP ↑ bone resorption Osteoblastic activity increases in an attempt to make for the resorbed bone. They secrete large quantities of alkaline phosphatase

86. Clinical features “Painful Bones , Renal Stones , Abdominal Groans , Psychiatric Moans ” Pain Due To # Of Bones Renal Stones ( Nephrolithiasis ) With Pain And Obstructive Uropathy GI Disturbances -Constipation, Pancreatitis, Nausea, Peptic Ulcrs CNS Alterations Including Depression, Lethargy And Seizures Neuromuscular Abnormality Including Weakness And Hypotonia

87. Metastatic calcifications seen in subcutaneous soft tissues, sclera, dura and region around joints Brown tumor Affect mandible, clavicles, ribs and pelvis Osteitis fibrosa cystica - develops from central degeneration and fibrosis of long standing brown tumor

88. Clinical picture of browns tumour

89. Brown tumour

90. Dental Features of Browns Tumour

91. Histo -pathological features of browns tumour

92. Radiological features First radiological sign is subperiosteal resorption of phalanges of index and middle fingers Unilocular or multilocular cystic radiolucencies in bone Generalized Attenuation or loss of lamina dura surrounding the teeth Decrease in trabecular density and blurring of normal trabecular pattern, giving ‘ground glass’ appearance

93. Granular appearance of skull in patient having renal osteodystrophy Solitary “punched out” radiolucency in calvarium represents a Brown tumour in secondary hyperparathyroidism

94. Generalized Loss Of Lamina Dura

95. Metastatic calcifications in hand and wrist of patient with primary hyperparathyroidism Detail of calcification adjacent to thumb

96. Right humerus shows coarse internal trabeculation in primary hyperparathyroidism

97. Osteitis fibrosa cystica : Multilocular radiolucencies in skull

98. Treatment: Hyperplastic parathyroid tissue or functional tumor is removed surgically to reduce PTH levels to normal

99. SECONDARY HYPERPARATHYROIDISM Secondary hyperparathyroidism results in excess secretion of parathyroid hormone due to parathyroid hyperplasia compensating for a metabolic disorder that has resulted in retention of phosphate or depletion of the serum calcium level ( Ganibegovic , 2000). Renal osteodystrophy refers to skeletal changes that result from chronic renal failure

100. In patients with secondary hyperparathyroidism caused by end stage renal disease, striking enlargement of jaw occurs Palatal enlargement is a characteristic of renal osteodystrophy associated with secondary hyperparathyroidism

101. Bone lesions in digits, clavicle Mottling of skull, erosion of the distal clavicle, rib fractures and necrosis of femoral head. Children show osteomalacia

102. Treatment Restriction of dietary phosphate Use of phosphate binding agents (calcium carbonate or calcium acetate) Use of calcimimetic agents like cinacalcet ( Nephrol Dial Transplant (2002) 17: 204-207) Treatment with an active vitamin D metabolite Synthetic salmon calcitonin can be used Renal transplant: An ideal treatment

103. REFERENCES Textbook of medical physiology by Guyton & Hall; 10th Edition The physiology & biochemistry of the mouth by G Neil Jenkins; 4th Edition Textbook of physiology by Prof. A. K. Jain Textbook of Endodontics - Ingle

104. Thank you…