CALCIUM METABOLISM - its importance in orthodontics

Physiological importance of calcium and its metabolism..orthodontic importance of calcium with the effect of calcium on bone and tooth movement.

1. CALCIUM METABOLISM LIJA JOHN 1st year MDS Department of orthodontics an d Dentofacial O rthopedics

2. CONTENTS Introduction Body content and Distribution Dietary sources Functions Calcium balance Calcium absorption and excretion Clinical importance Effect on tooth movement Conclusion References

3. INTRODUCTION Calcium, represented by the symbol Ca, atomic no 20, is a soft grey alkaline earth metal. In nature, it occurs mostly in soil systems as limestone (CaCO3), gypsum (CaSO4*2H2O) & fluorite (CaF2) In the body, it is the most abundant mineral. Average adult body (70 kg) contains approx. 1 kg of Ca. Dorozhkin SV. Calcium Orthophosphates: Occurrence, Properties and Major Applications. Bioceramics Development and Applications. 2014 Nov 19;2014.

4. Calcium is a nutrient that all living organisms need, including humans. It is the most abundant mineral in the body, and it is vital for bone health. Humans need calcium to build and maintain strong bones, and 99% of the body’s calcium is in the bones and teeth. 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.

5. BODY CONTENT AND DISTRIBUTION Dorozhkin SV. Calcium Orthophosphates: Occurrence, Properties and Major Applications. Bioceramics Development and Applications. 2014 Nov 19;2014

6. PLASMA CALCIUM (NON BONE) PERCENTAGE OF CALCIUM 10% 50% 40% Free or ionized calcium Protein bound (mainly albumin) Complex with anions- bicarbonates, citrates, phosphates, lactates Diffusible 50% Ca2+ ionized 10% combined with anions (citrate, phosphate) – non- dissociated Non- diffusible 40% combined with plasma proteins Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. Journal of internal medicine. 2015 Oct1;278(4):354- 68.

7. DIETARY SOURCES Milk, cheese, yoghurt Green leafy vegetables Fish eaten with bones like sardines and pilchards Nuts like almonds and peanuts Bread and anything made with fortifies flour Seeds like poppy, chia and sesame seeds.

8. REC O MME N DE D CALC I U M INTAKE Age Infants Amount of calcium Birth to six months 6 months to 1 year 400 mg 600 mg Children / young adults 1 – 10 years 11 – 24 years 800 – 1200 mg 1200 – 1500 mg Adult women Pregnant and lactating Over 65 yrs old 1200 – 1500 mg 1500 mg Adult men 25 – 64 yrs old Over 65 yrs old 1000 mg 1500 mg Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64.

9. FUNCTIONS Free ,ionized calcium is the biologically active form of calcium. Calcium serves many important biochemical functions . The plasma concentration of calcium is maintained at 9- 11 mg %. Formation of teeth and bones - Calcium is the most vital component of bone. Bones, which are in a dynamic state, serve as the reservoir of Ca. Ca along with Phosphates, is required for the formation of hydroxyapatite.

10. Intracellular signaling - Calcium regulates the activity of a number of intracellular proteins in response to second messenger IP3. Activation of enzymes : Calcium ions are needed for the direct activation of enzymes such as lipase, ATPase and succinate dehydrogenase. Calmodulin mediated action of Ca ⁺⁺ : Calmodulin (mol.wt 17000) is a calcium binding regulatory protein. Ca- calmodulin complex activates certain enzymes ..E.g. adenylate cyclase, Ca ions dependent protein kinase

11. Blood clotting - Several steps in the cascade of blood clotting process are dependent on Calcium ion. Muscle contraction and relaxation- Calcium ions react with troponin C to trigger muscle contraction. Calcium also activates ATPase, increases the interaction between actin and myosin.

12. Transmission of nerve impulse - Ca 2+ is necessary for the transmission of the nerve impulse. Endocrine system - All process that involve exocytosis (e.g hormone secretion) require calcium. Cardiovascular system - Ca regulates the membrane potential and contraction of muscle cells.

13. Contact inhibition – Ca is involved in cell to cell contact and adhesion of cell in tissues. Calcium may also be required for cell to cell communication. Membrane integrity and plasma membrane transport – Permeability and transport of water and several ions across the cell membrane are influenced by calcium . Release of hormones : The release of certain hormones like insulin, PTH, calcitonin from the endocrine glands is facilitated by Ca ⁺⁺ .

14. CALCIUM BALANCE Defined as the net gain or loss of calcium by the body over a specified period of time. The overall calcium homeostasis (calcium balance) or the normal daily calcium turnover is maintained by an interplay of following processes. Absorption of ingested calcium. Exchange of calcium between bone and ECF. Secretion of calcium from ECF. Excretion of calcium in feces and urine. Positive calcium balance in growing children Negative calcium balance in aging adults

15. CALCIUM ABSORPTION Calcium is taken through dietary sources as calcium phosphate, carbonate, tartrate and oxalate. It is absorbed from the gastrointestinal tract in to blood and distributed to various parts of the body. ACTIVE TRANSCELLULAR ABSORPTION Two mechanisms have been proposed for the absorption of calcium by gut mucosa: Simple Diffusion. An active transport process, involving energy and calcium pump.

16. While passing through the kidney, large quantity of calcium is filtered in the glomerulus. From the filtrate, 98 to 99% of calcium is reabsorbed in the renal tubules in to blood and only small quantity is excreted through urine. In the bone, the calcium may be deposited or resorbed depending upon the level of calcium in the plasma. Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64.

17. FACTORS PROMOTING Ca ABSORPTION Acidic environment (low pH) Vitamin D ( through its active form calcitriol) PTH, by increasing the synthesis of calcitriol Amino acids lysine and arginine Lactose FACTORS INHIBITING Ca ABSORPTION Alkaline conditions (high pH) Free fatty acid, particularly when fat absorption is impaired. Phytates and oxalates High content of dietary phosphates High contents of dietary fibers

18. CALCIUM EXCRETION Calcium is excreted in the urine, bile, and digestive secretions. The renal threshold for serum Ca is 10 mg/dl. A large amount of calcium is filtered in kidneys ,but 99% of the filtered calcium is reabsorbed (PCT- 60%, ascending loop of henle and distal tubule). STOOL Unabsorbed calcium in the diet 60 – 70% URINE 50- 200 mg/day SWEAT 15 mg/day

19. Daily turnover rates of Ca in an adult Intake 1000mg. Intestinal absorption 350mg Secretion in GI juice 250mg Net absorption over secretion 100mg Loss in the faeces 200mg Excretion in the urine 80-100mg Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64.

20. CALCIUM HOMEOSTASIS Calcium homeostasis refers to the regulation of concentration of calcium ions in extracellular matrix. Various hormones involved in the regulation of metabolism of these minerals include: Calcitropic hormones – Parathyroid hormone(PTH), calcitonin, and cholecalciferol (Vit D 3 ), which are primarily concerned with regulation. These hormones act on three organ systems- bones, kidneys, and intestinal tract to maintain Ca levels. Parathyroid hormone related protein (PTHrP )- it acts on the PTH receptor and is important skeletal development in utero. Other hormones – glucocorticoids, growth hormones, oestrogens.

21. CALCITRIOL The physiologically active form of vit.D is a hormone, namely calcitriol or 1,25-dihydroxycholecalciferol. Calcitriol induces the synthesis of a specific calcium binding protein in the intestinal cells. This protein increases the intestinal absorption of calcium as well as phosphate. Thus blood Ca level is increased by calcitriol. Calcitriol stimulates calcium uptake by osteoblasts of bone and promotes calcification or mineralization (deposition of calcium phosphate) and remodelling . DAILY REQUIREMENT Adults – 2.5mg Lactating mother Pregnancy Adolescents Infants 5mg Cline J. Calcium and vitamin d metabolism, deficiency, and excess.Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64.

22. 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 Combined weight of 130mg with each gland weighing between 30- 50mg. Plasma half life – 20- 30 minutes. Plasma concentration – 10- 50ug/ml.

23. ACTIONS OF PTH The main function is to increase the level of Ca in plasma within the critical range of 9 to11 mg%. Parathormone inhibits renal phosphate reabsorption in the proximal tubule and therefore increases phosphate excretion Parathormone increases renal Calcium re absorption in the distal tubule, which also increases the serum calcium. Net effect of PTH ↑ serum calcium ↓ serum phosphate STIMULATION FOR PTH SECRETION The stimulatory effect for PTH secretion is low level of calcium in plasma. 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 Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64.

24. PTH exerts its action on 3 independent tissues- bone, kidneys and intestine. Action on bone- PTH causes decalcification of bone ,a process carried out by osteoclasts. This is brought out by PTH stimulated increased activity of the enzymes pyrophosphatase and collagenase. These enzymes result in bone resorption . Decalcification ultimately leads to an increase in the blood Ca level. The action of PTH on bone is quantitatively very significant to maintain Ca homeostasis. Action on kidney- PTH increases the Ca reabsorption by kidney tubules and at the same time it diminishes phosphate reabsorption. This is most rapid action of PTH to elevate blood Ca levels. PTH promotes the production of calcitriol(1,25 DHCC) in kidneys which further helps in calcium absorption in intestine and bone. Action on intestine - The action of PTH on the intestine is indirect. It increases the intestinal absorption of Ca by promoting the synthesis of calcitriol

25. CALCITONIN Minor regulator of calcium & phosphate metabolism Secreted by parafollicular cells or C- cells of thyroid gland. Also called as thyrocalcitonin. Single chain polypeptide Molecular weight 3400 Plasma concentration – 10- 20ug/ml ACTION OF CALCITONIN Net EFFECT of calcitonin - decreases Serum Ca Target site – On bone- decreased ability of osteoclasts to resorb bone On kidney- inhibits the reabsorption of Ca from renal tubules- ↑ Ca excretion 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

26. EFFECTS OF OTHER HORMONES ON CALCIUM METABOLISM 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 Stimulates stomatomedin C which acts on cartilage to increase the length of bones TESTOSTERONE Testosterone causes differential growth of cartilage resulting to differential bone development Acts on cartilage & increase the bone growth.

27. INSULIN It is an anabolic hormone which favors bone formation 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

28. DECREASED SERUM Ca: Renal failure. Hypoparathyroidism. Vit D deficiency. Tetany. Malabsorption syndrome. INCREASED SERUM Ca: Hyperparathyroidism. Hypervitaminosis (Vit D). Multiple myeloma. Sarcoidosis. Thyrotoxicosis. Milk alkali syndrome. Infantile hypercalcemia SYMPTOMS OF CALCIUM - PHOSPHORUS IMBALANCE Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

29. CLINICAL IMPORTANCE HYPOPARATHYROIDISM- HYPOCALCEMIA HYPERPARATHYROIDISM- HYPERCALCEMIA METABOLIC BONE DISEASES- RICKETS OSTEOMALACIA OSTEOPOROSIS

30. HYPOPARATHYROIDISM- HYPOCALCEMIA HYPOCALCEMIA- A decrease in total plasma calcium concentration below 8.8 mg/dL (2.20 mmol/L) in the presence of normal plasma protein concentration. CLASSIFICATION Etiology- HEREDITARY ACQUIRED TRUE HYPOPARATHYROIDISM (Def of PTH) CHRONIC RENAL FAILURE LACK OF VITAMIN D PSEUDOHYPOPARATHYROIDISM (PTH ineffective)

31. Results from a deficiency in or absence of PTH. Hypocalcemia and Hyperphosphatemia and is often associated with chronic tetany. Hypoparathyroidism usually results from the accidental removal of or damage to several parathyroid glands during thyroidectomy. Transient hypoparathyroidism is common after subtotal thyroidectomy. Permanent hypoparathyroidism occurs in fewer than 3% of expertly performed thyroidectomies . Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

32. CAUSES Accidental removal of gland during surgery occasionally from autoimmune destruction of the gland. Congenital absence of the gland Atrophy of the gland- Idiopathetic Pseudohypoparathyroidism

33. CLINICAL SIGNS & SYMPTOMS Hyperactive reflexive Spontaneous muscular contractions Convulsions Laryngeal spasm CLINICAL FEATURES ARE DEVELOPMENTAL ANOMALIES INCLUDES short stature Short metacarpal or metatarsal bones Mental retardation

34. ORAL MANIFESTATIONS: Enamel hypoplasia and dental dysplasia Dryness of the mucous membranes Angular cheilitis Circumoral paresthesia Disturbances in tooth eruption Root defects Hypodontia and impacted teeth Large pulp chambers were observed in the deciduous teeth and the permanent teeth, Thickening of the lamina dura was observed in the permanent teeth. Radiographic features Enamel hypoplasia External root resorption Delayed eruption Root dilaceration

35. PSEUDOHYPOPARATHYROIDISM It is the result of defective G protein in kidney and bone, which causes end-organ resistance to PTH. There is hypocalcemia and hyperphosphatemia that is not correctable by administration of exogenous PTH. Circulating endogenous PTH levels are elevated. Albright’s hereditary osteodystrophy- Abnormalities of skeletal development are seen in some patients with pseudohypoparathyroidism. Shortening of the metacarpal bones that can occur in patients with Albright’s syndrome or in patients without abnormalities of calcium or parathyroid hormone Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

36. TETANY Hypoparathyroidism causes hypocalcemia by decreasing the resorption from bones. This causes neuromuscular hyperexcitability resulting in hypocalcemic tetany Tetany occurs if the plasma calcium level falls below 6mg% from its normal value of 9.4mg% and it is usually lethal at about 4mg/dl. Tetany is a condition characterized by hyperexcitability of nerves and skeletal muscles resulting in muscular spasm in feet and hand. The increased excitability results in convulsive muscle contractions

37. Causes of Tetany Hypocalcemia : extracellular calcium maintains membrane integrity and excitability .when the ionic calcium is reduced to < 50% ,cell membrane becomes more permeable resulting in series of action potential. Hypomagnesaemia : causes tetany, because Mg ions are also associated with neuromuscular irritability. Alkalosis : reduces ionic calcium leading to tetany

38. Clinical features Signs and symptoms depend on the age of the patient: In children, characteristic triad is seen Carpopedal spasm – it is peculiar attitude of hands in tetany. The flexion at the elbow and wrist joint. Laryngeal stridor – Severe contractions of the laryngeal muscles occurs, leading to laryngeal stridor and this causes respiratory arrest and death. Visceral features – intestinal cramps, bronchospasm Convulsion and even death .

39. Hypocalcemic tetany in the hand, called carpopedal spasm. Tetany in the hand, which usually occurs before tetany develops in most other parts of the body. Adult patients have following features : Paresthesias , i.e tingling sensation in the peripheral parts of limbs Carpopedal spasm are less common Laryngeal stridor and convulsion are very rare.

40. Latent tetany Hypocalcemia causes hyperexcitability even before the onset of tetany. This condition is called latent tetany. Signs of latent tetany : Trousseau ’ Sign- carpopedal spasm is developed by applying pressure . Chvostek’s Sign –tapping at the angle of the jaw causes twitching of the muscles of the face on the same side due to the stimulation of the facial nerve . Erbs Sign- the skeletal muscles become more excitable to mild electrical stimulus .

41. CHVOSTEK’S SIGN TROUSSEAU’S SIGN CARPOPEDAL SPASM ACCOUCHER’S HAND

42. CAUSES OF HYPOCALCEMIA Vitamin D deficiency- Vitamin D deficiency may result from inadequate dietary intake or decreased absorption due to hepatobiliary disease or intestinal malabsorption. It can also occur because of alterations in vitamin D metabolism as occurs with certain drugs (phenytoin, phenobarbital, and rifampin) or lack of skin exposure to sunlight. The latter is an important cause of acquired vitamin D deficiency in northern climates among people wearing dress that covers them completely IDIOPATHIC HYPOPARATHYROIDISM It is an uncommon condition in which the parathyroid glands are absent or atrophied. It may occur sporadically or as an inherited condition. RENAL TUBULAR DISEASE Including Fanconi's syndrome due to nephrotoxins such as heavy metals and distal renal tubular acidosis, can cause severe hypocalcemia due to abnormal renal loss of Ca and decreasing renal conversion to active vitamin D.

43. HYPOPROTEINEMIA Can reduce the protein- bound fraction of plasma Ca. Hypocalcemia due to diminished protein binding is asymptomatic. Since the ionized Ca fraction is unaltered, this entity has been termed factitious hypocalcemia. HYPERPHOSPHATEMIA Also causes hypocalcemia by one or a variety of poorly understood mechanisms. Patients with renal failure and subsequent phosphate retention are particularly prone to this form of hypocalcemia. DRUGS Associated with hypocalcemia include those generally used to treat hypercalcemia anticonvulsants (phenytoin, phenobarbital) and rifampin, which alter vitamin D metabolism.

44. MAGNESIUM DEPLETION Occurring with intestinal malabsorption or dietary deficiency can cause hypocalcemia. Relative PTH deficiency and end- organ resistance to its action occur with magnesium depletion, resulting in plasma concentrations of < 1.0 mEq/L (< 0.5 mmol/L); repletion of magnesium improves PTH levels and renal Ca conservation ACUTE PANCREATITIS Causes hypocalcemia when Ca is chelated by lipolytic products released from the inflamed pancreas SEPTIC SHOCK May be associated with hypocalcemia due to suppression of PTH release and conversion of 25(OH)D3 to 1,25(OH)2D3.

45. SYMPTOMS

46. TREATMENT Intravenous Calcium gluconate SEVERE SYMPTOMATIC CASES Calcium carbonate Vitamin D ASYMPTOMATIC CASES

47. Emergency treatment : calcium gluconate inj 0.23mmol Ca/ml Dose : 10ml iv in first instance Oral calcium tablets Calcium gluconate 54mg Ca/tab Calcium gluconate 90mg/tab Sandoz calcium 400mg /tab Sandoz calcium 135mg /tab Long term treatment : vitamin D therapy Treatment of alkalosis – Re-expand volume with Normal Saline ( Primary Therapy) Supplement with Potassium to treat hypokalemia H+ blockers or PPIs if vomiting, to prevent further losses in H+ ions Discontinue diuretics Acetazolamide. (Monitor for hypokalemia) Treatment of underlying cause of hypocalcemia

48. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

49. HYPERPARATHYROIDISM- HYPERCALCEMIA Increased secretion of PTH is called hyperparathyroidism . This results in hypercalcemia. This is of three types : Primary hyperparathyroidism- due to tumour in one or more parathyroid glands. Secondary hyperparathyroidism – due to the physiological compensatory hypertrophy of parathyroids in response to hypocalcemia that occur in chronic renal failure. Tertiary hyperparathyroidism – hyperplasia of all the parathyroid glands develop due to chronic secondary hyperparathyroidism.

50. PRIMARY HYPERPARATHYROIDISM Tumor of one of PTH gland.- single adenoma Adenomas are located at inferior portion of parathyroid gland Mostly seen in women than men & children Extreme osteoclastic activity in bones Elevates Ca ion conc. in ECF which depresses phosphate ions. MEN I (Wermer's syndrome) consists of hyperparathyroidism and tumors of pituitary and pancreatic islet cells, often associated with peptic ulcer and gastric hypersecretion. (Zollinger – Ellison syndrome) MEN II - carcinoma of the thyroid

51. ORAL MANIFESTATIONS Dehydration Mandibular or maxillary tumors of the bone, which on biopsy display a brown tumor of von Recklinghausen Increased incidence of tori; Reduction in cortical bone content leading to osteoporosis BROWN TUMOR On occasion, a patient with undiagnosed hyperparathyroidism presents with a lytic lesion that may be mistaken for a tumor. These lesions are termed "Brown Tumors" due to the presence of old hemorrhage in the lesion.

52. Normal trabecular pattern is lost & replaced by granular or ground glass appearance. Moth- eaten like appearance of jaw bones Teeth are mobile and migrate. Lamina dura diminished or completely absent in 10% of cases. According to Schour and Massler, malocclusion caused by a sudden drifting with definite spacing of the teeth may be one of the first signs of the disease.

53. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

54. Osteitis Fibrosa Cystica The unique bone involvement in hyperparathyroidism is osteitis fibrosa cystica. In the past osteitis fibrosa cystica occurred in 10 to 25 percent of patients with hyperparathyroidism. Histologically the pathognomonic features are a reduction in the number of trabeculae and increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship’s lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissues. Loss of lamina dura of the teeth is less specific. Tiny “punched out” lesions may be present in the skull, producing the so called salt and pepper appearance . Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

55. SECONDARY HYPERPARATHYROIDISM Vitamin D deficiency Chronic renal disease Hypocalcemia, hyperphosphatemia & increased serum alkaline phosphatase

56. TERTIARY HYPERPARATHYROIDISM Parathyroid tumor develop from long standing secondary hyperparathyroidism. Serum calcium is increased Phosphorus is normal to increased Alkaline phosphatase is increased Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56 .

57. HYPERCALCEMIA Elevated serum calcium level up to 12- 15 mg/dl Classification of Causes of Hypercalcemia PTH related i) Primarily hyperparathyroidism Solitary adenoma Multiple endocrine neoplasia ii) Lithium therapy iii) Familial hypocalciuric hypercalcemia Vit D related i) Vit D intoxication ii) Increased 1,25 DHCC, sarcoidosis. iii) Idiopathic hypercalcemia of infancy Malignancy related i) Solid tumor with metastasis ii) Solid tumor with humoral mediation of hypercalcemia

58. Signs and Symptoms

59. TREATMENT OF HYPERCALCEAMIA Emergency treatment : The solution of IV infusion contains a mixture of mono and dihydrogen phosphate so that pH is 7.4. 500ml of this solution should be infused over 4 to 6 hours. Long term phosphate treatment : Oral phosphate is given as diphosphate. Choice depends upon serum phosphate levels. Dose 100 to 300ml per day in divided doses Phosphate sandoz tablet Phosphorous :500mg Na: 21 mmol K : 3mmol Dose: 1 to 6 tab daily Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

60. METABOLIC BONE DISEASES RICKETS Occurs in children between 6 months to 2 years of age. Affects long bones Lack of calcium causes failure of mineralization resulting into formation of cartilaginous form of bone. Most critical area that gets affected is the center endochondral ossification at the epiphyseal plate.

61. CLINICAL FEATURES Bony defects Craniotabes – earliest lesion seen in infants. It refers to small rounded areas in the membranous bones of the skull which yield under pressure Widening of wrist Collapse of chest wall Ricket rosary- beading of the costochondral junction of ribs Frontal bossing Harrison’ sulcus- indentation of lower ribs Bowing of legs pelvic deformities

62. General features Respiratory and gastrointestinal infections Developmental milestones are delayed Tetany and convulsions – marked hypocalcemia Biochemical changes Low levels of plasma calcium and phosphate Serum alkaline phosphatase level are high due to increased osteoblastic activity Plasma 1,25- DHCC is low

63. ORAL MANIFESTATIONS Developmental abnormalities of dentin and enamel Delayed eruption Misalignment of teeth in the jaw High caries index Enamel hypoplasia

64. TYPES OF RICKETS NUTRITIONAL RICKETS VITAMIN D RESISTANT RICKETS VITAMIN D DEPENDENT RICKETS ONCOGENOUS RICKETS

65. NUTRITIONAL RICKETS Primarily, Vitamin D deficiency due to poor dietary intake Vegetarian diet(cereals, vegetables, fruits). Non- vit D supplemented formulations for children. Children with chronic diarrhea or malabsorption disorders e.g cystic fibrosis. Exclusive breastfed infants in mothers with poor uv light exposure or mother with vit D deficiency Dark skin infants at higher risk. Premature infants on parenetal nutrition. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

66. Cupping of proximal tibia Bowing of lower limbs Cupping of metaphysis of distal radius/ulna Flaring of metaphysis

67. VITAMIN D RESISTANT RICKETS Also referred as X- linked hypophosphatemia. Non- nutritional rickets. Some mothers of affected siblings manifest the disease features. Autosomal dominant and sporadic case may occur. Renal tubular disorder leading to excessive loss of phosphorus MANIFESTATIONS No profound myopathy, rachitic rosary, tetany,or enamel defects. Radiographic findings : Metaphyseal widening and fraying. Cupping of metaphysis of proximal and distal tibia, distal femur, radius and ulna

68. Oral Manifestations Histological evidence of widespread formation of globular, hypocalcified dentin, with clefts and tubular defects occurring in the region of pulp horns. Periapical involvement of grossly normal appearing deciduous and permanent teeth, followed by the development of multiple gingival fistulas. Abnormal cementum and the alveolar bone pattern Lamina dura is frequently absent or poorly defined.

69. Radiographic features: Dental radiographs reveal hypocalcification of teeth and the presence of large pulp chambers and alveolar bone loss.

70. VITAMIN D DEPENDENT RICKETS Also known as Pseudo vitamin D deficiency OR Hypocalcemic Vitamin D resistant Rickets. Two types exist: Type 1.( VDDR1) Type 2.(VDDR2)

71. ONCOGENOUS RICKETS (Primary hypophosphatemic Rickets) Rickets due to a mesenchymal tumor . Mostly benign. Occur in sites difficult to detect e.g nasal antrum, pharynx, small bones of the hands etc. May be associated with other syndromes like Neurofibromatosis. They elaborate massive amounts of F6F23 gene, which impairs hydroxylation of 25- (OH)D And impairing PO4 reabsorption. Remission occurs on tumor excision.

72. Treatment Oral therapy : Vitamin D- 0.5- 1g/24 hr for children 2- 4 yrs 1- 4g/24 hr for children > 4 yrs. For patients requiring parenteral administration of phosphate, an initial phosphate dose of 0.08 mmol per kg body weight may be given over six hours. The dose may be increased to 0.16 mmol per kg if a patient has serious clinical manifestations. With early diagnosis and compliance, limb deformity can be minimized. Corrective osteotomy for deformed limbs should be delayed till radiological healed rickets is noted and serum alkaline phosphatase levels are normal. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

73. OSTEOMALACIA Softening of bones due to defective mineralization (Ca and PO4). Also due to excessive resorption of bones in hyperparathyroidism. Common cause is vit.D deficiency. Main causes Inadequate Ca absorption Phosphate deficiency due to renal losses Other causes Renal tubular acidosis Malabsorption syndrome. Malnutrition during pregnancy. Hypophosphatemia. Tumor induced osteomalacia. Drugs- anticonvulsants, anti TB, Steroids, glucocorticoids

74. Clinical features Pain and Chronic fatigue, starting insidiously. Proximal muscles weakness. Waddling gait. Deformed pelvis and exaggerated lordosis. Bowing of Lower limbs Biochemical features are similar to Rickets except in renal osteodystrophy where serum phosphate is high.

75. Radiographic features Pseudofractures -Common on scapula, medial femoral cortex and pubic rami. Biconcave vertebral bodies. Femoral neck fractures Oncogenic osteomalacia caused by phosphaturic mesenchymal

76. CONTENTS Osteoporosis Effect on tooth movement Conclusion References

77. OSTEOPOROSIS Osteoporosis is characterized by a reduction of bone mass per unit volume with normal ratio of bone matrix and minerals Pathogenesis It develops due to mismatch between bone resorption remodelling process; the bone resorption is excess. and bone Aetiology After a 45 yrs of age, all begin to lose bone mass progressively as they grow older. In males, bone loss is usually less significant . After menopause, women have rapid bone loss because of estrogen deficiency.

78. Factors contributing to development of osteoporosis: Lack of physical stress on the bones because of inactivity. Malnutrition. Lack of vitamin C. Postmenopausal lack of estrogen secretion. Old age in which growth hormone and other growth factors diminish greatly.

79. Characteristic features Bone density is reduced . In radiographs, the affected bones shows clear glass appearance (ground glass appearance seen in osteomalacia). In severe cases, bone resorption may lead to cyst formation. (osteitis fibrosa cystica) Incidence of fractures is increased at distal forearm, vertebral bodies and hips . Biochemical changes – serum calcium and phosphorus is normal. There may be increased urine excretion of calcium and hydroxyproline .

80. Treatment Calcium intake should be increased Moderate exercise to prevent osteoporosis Estrogen treatment- for arresting the rapidly developing osteoporosis in women after menopause. Bisphosphonates such as etidronate are useful in osteoporosis. These inhibit the osteoclastic activity, increase the mineral content of bone. Fluoride has a little value in the treatment . Its action is to stimulate osteoblast, and making bone more dense

81. Comparison of the effects of 1,25 dihydroxycholecalciferol and prostaglandin E2 on orthodontic tooth movement This study compared the effects of local administrations of prostaglandin E2 (PGE2) and 1,25-dihydroxycholecalciferol (1,25-DHCC) on orthodontic tooth movement in rats. There was no significant difference in tooth movement between the PGE2 and the 1,25- DHCC groups. Both PGE2 and 1,25- DHCC enhanced the amount of tooth movement significantly when compared with the control group. The numbers of Howship’s lacunae and capillaries on the pressure side were significantly greater in the PGE2 group than in the 1,25-DHCC group. On the other hand, the number of osteoblasts on the external surface of the alveolar bone on the pressure side was significantly greater in the 1,25-DHCC group than in the PGE2 group. Thus, 1,25- DHCC was found to be more effective in modulating bone turnover during orthodontic tooth movement, because its effects on bone formation and bone resorption were well balanced. Am J Orthod Dentofacial Orthop 2004;125:607- 14

82. THE EFFECT OF ALTERED BONE METABOLISM ON ORTHODONTIC TOOTH MOVEMENT The purpose of this study was to determine how bone remodelling changes induced by nutritional hyperparathyroidism affect tooth movement through alveolar bone. The clinical data revealed more rapid tooth movement in the experimental animals who fed with a diet with decrease in the calcium (0.12 percent) to phosphorus (1.20 percent) ratio. . Laboratory data indicated that the hyperparathyroid animals had significantly decreased bone density as well as bone remodeling changes consistent with high PTH levels. These findings suggest that, in addition to applied force, tooth movement is dependent upon the state of calcium metabolism in alveolar bone. Am J Orthod Sept 1981 ; vol 80.3

83. Does common prescription medication affect the rate of orthodontic tooth movement? The Objective of the study was To systematically investigate and appraise the quality of the available evidence regarding the effect of commonly prescribed medications on the rate of orthodontic tooth movement. Twenty- seven animal studies, involving various pharmacologic and orthodontic interventions, were finally identified. The rate of orthodontic tooth movement was shown to increase after the administration of diazepam, Vitamin C and pantoprazole, while simvastatin, atorvastatin, calcium compounds , strontium ranelate, propranolol, losartan, famotidine, cetirizine, and metformin decreased the rate of orthodontic tooth movement. No interference with the rate of orthodontic tooth movement was reported for phenytoin, phenobarbital and zinc compounds, whereas, inconsistent or conflicting effects were noted after the administration of L- thyroxine, lithium compounds, fluoxetine and insulin. European Journal of Orthodontics, 2018, 649–659

84. PARATHYROID FUNCTION & ROOT RESOPRTION In addition to the applied force, tooth movement seems to depend upon calcium metabolism in alveolar bone. A study of Midgetts et al indicated that animals with hyperparathyroidism had significantly decreased bone density, as well as increased bone remodelling changes, thus increased orthodontic tooth movement. Goldie & King have shown that lactation coupled with Calcium deficient diet, will produce decreased bone density & increased tooth movement. Engstrom et al demonstrated that although the level of PTH in serum plays an important role in regulation of resorptive activity in bone, a change in serum level calcium is a determining factor for root resorption. Angle OrthodontistOct1994;Vol 64

85. THE EFFECT OF THYROID HORMONE, PROSTAGLANDIN E2 AND CALCIUM GLUCONATE ON ORTHODONTIC TOOTH MOVEMENT AND ROOT RESORPTION IN RATS. The aim of this study was to determine the effect of administration of thyroid hormone, prostaglandin E2, and calcium on orthodontic tooth movement (OTM) and root resorption in rats. The highest mean OTM was observed in the thyroxine and prostaglandin E2 group (Mean±SD = 0.7375±0.1359 mm) that was significantly different (p< 0.05). A significant difference (p< 0.05) in root resorption was observed between the prostaglandin E2 (0.0192±0.0198 mm(2)) and the other groups. It seems that the combination of thyroxine and prostaglandin E2, with a synergistic effect, would decrease the root resorption and increase the rate of orthodontic tooth movement in rats. Journal of Dentistry (Shiraz, Iran), 01 Mar 2015, 16(1 Suppl):35- 42 PMID: 26106633 PMCID: PMC4476115

86. THE EFFECT OF ALTERED BONE METABOLISM ON ORTHODONTIC TOOTH MOVEMENT The purpose of this study was to determine how bone remodeling changes induced by nutritional hyperparathyroidism affect tooth movement through alveolar bone. Radioimmunoassays during the experiment showed that the test animals had significantly elevated levels of parathyroid hormone, indicating a probable state of hyperparathyroidism. The clinical data revealed more rapid tooth movement in the experimental animals. Laboratory data indicated that the hyperparathyroid animals had significantly decreased bone density, as well as bone remodeling changes consistent with high PTH levels. These findings suggest that, in addition to applied force, tooth movement is dependent upon the state of calcium metabolism in alveolar bone. American Journal of Orthodontics , Volume 80, Issue 3 , September 1981:256- 262

87. BISPHOSPHONATES AS A RISK FACTOR FOR ADVERSE ORTHODONTIC OUTCOMES Bisphosphonates are a class of drugs commonly prescribed to treat osteoporosis. They act by decreasing the resorption of bone. Since tooth movement depends on bone remodeling, these drugs can impact orthodontic treatment. Among patients with extractions or initial spacing,there are higher odds of poor space closure and poor root parallelism at the end of treatment in those who took bisphosphonates. AJODO Nov 2012;142:625- 34

88. BMP2- Functionalized Biomimetic Calcium Phosphate Graft Promotes Alveolar Defect Healing During Orthodontic Tooth Movement in Beagle Dogs The histological sections of the bone defect showed more newly formed bone in the BioCaP group. The percentage of new bone formation in the BioCaP group was 1.61- , and 1.25- fold higher compared to the control and DBB (deproteinized bovine bone) group, respectively. After 8 weeks of OTM, the resorption rate of BioCaP was 1.42- fold higher compared to DBB. The root resorption index in the DBB group was 1.87- , and 1.39- fold higher compared to the control and BioCaP group, respectively. CBCT images showed 1.92- , and 1.36- fold higher bone mineral density in the BioCaP group compared to the control and DBB group, respectively. There was no significant difference in OTMamong the three groups. The distance between the enamel cementum and the crest of the alveolar ridge in the control group was 1.45- , and 1.69- fold higher compared to DBB and BioCaP group, respectively. Periodontal probing depth at week 8 was reduced in the BioCaP group compared to the control. IL- 1 b concentration in the gingival cervicular fluid was significantly lower in the BioCaP group compared to the control group at week 4 and 8. Front. Bioeng. Biotechnol. 8:517 Frontiers in Bioengineering and Biotechnology May 2020 | Volume 8 | Article 517 .

89. CONCLUSION Disturbances in calcium and phosphate intake, excretion and trans cellular shift result in deranged metabolism accounting for abnormal serum levels. As a result of the essential role played by these minerals in intra and extracellular metabolism, the clinical manifestations of related disease states are extensive. Orthodontics is a bone manipulative therapy and thus importance of calcium metabolism in orthodontics can never be denied. Thus, an understanding of the basic mechanism of calcium, phosphate metabolism and pathophysiology of various related disorders is helpful in guiding therapeutic decisions.

90. REFRENCES Review of medical physiology -William F Ganong 21 st edition Textbook of medical physiology- Arthur C Guyton 8 th edition Essentials of physiology for dental students- K.Sembulingam, Prema Sembulingam Harrison MR, Edwards PP, Klinowski J, Thomas JM, Johnson DC, Page CJ. Ionic and metallic clusters of the alkali metals in zeolite Y. Journal of Solid State Chemistry. 1984 Oct 31;54(3):330- 41.

91. Cline J. Calcium and vitamin d metabolism, deficiency, and excess. Topics in companion animal medicine. 2012 Nov 30;27(4):159- 64. Dorozhkin SV. Calcium Orthophosphates: Occurrence, Properties and Major Applications. Bioceramics Development and Applications. 2014 Nov 19;2014. Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. Journal of internal medicine. 2015 Oct 1;278(4):354- 68. Emkey RD, Emkey GR. Calcium metabolism and correcting calcium deficiencies. Endocrinology and metabolism clinics of North America. 2012 Sep 30;41(3):527- 56.

92. Efstratios Poumpros Angle OrthodontistOct1994;Vol 64. Lotwala RB, Geoffrey M, Greenlee, Susan M. Ott AJODO Nov 2012; 142:625- 34 Journal of Dentistry (Shiraz, Iran), 01 Mar 2015, 16(1 Suppl):35- 42 PMID: 26106633 PMCID: PMC4476115 American Journal of Orthodontics , Volume 80, Issue 3 , September 1981:256- 262 Mohsen Shirazivol Angle Orthodontist;Vol71,Dec2001,Pg.No.494-498 Bartzela T ,Motschall T, Jaap C. Malthad AJODO Jan 2009 ;135:16- 26)

93. THANK YOU