Calcium and phosphorus levels in the blood are regulated by the same hormonal system. Calcium and phosphorus levels react in opposite ways, as blood calcium levels rise, phosphate levels fall and vice versa. The major sources of calcium include dairy products, leafy greens, fish, and nuts. Calcium is important for bone mineralization, muscle function, blood clotting, and many other processes. Phosphorus also plays important roles and its levels are regulated by parathyroid hormone and calcitriol. Imbalances in calcium and phosphorus can lead to disorders.

1. 1

2.  Calcium and phosphorus
 Body distribution are almost similar
 React in opposite ways
 As blood calcium level rises, Phosphate level falls
 Regulation is by same hormonal system
2

3. Different Forms of Calcium
Most of the calcium in the body exists as the mineral
hydroxyapatite, Ca10(PO4)6(OH)2.
 Calcium in the plasma:
45% in ionized form (the physiologically active form)
45% bound to proteins (predominantly albumin)
10% complexed with anions (citrate, sulfate, phosphate)
 Both total calcium and ionized calcium measurements are
available in many laboratories

4. Distribution

5. source
 Calcium is found in milk and dairy products
 Green leafy vegetables
 Seafood
 Almonds
 Blackstrap molasses
 Broccoli
 Enriched soy and rice milk products, figs
 Soybeans and tofu

6. Circulating Calcium
 Ionized calcium (free calcium)
 Responsible for calcium function
 Can be directly measured
 Hypoalbuminemia
 Total Ca++ may be low
 But conc. of Ca++ is usually normal
 Acidosis – favours ionization
 Alkalosis – disfavours ionization
 Hyperventilation precipitates tetany and laryngospasm in
Calcium deficiency
6

7. Biological functions of Calcium
 Bone and teeth mineralization
 Regulate neuromuscular excitability
 Excitation contraction coupling of all types of muscles
 Controls impulse generation in heart
 Blood coagulation
 Secretory processes
 Membrane integrity
 Plasma membrane transport
 Enzyme reactions
 Release of hormones and neurotransmitters
 Intracellular second messenger

8. Absorption of Calcium
 Absorption is taking place from the first and second part of duodenum
against concentration gradients
 Absorption required a carrier protein , helped by Ca-dependent ATPase
 Increased absorption-
 Calcitriol , active form of Vit-D
 PTH
 Acidic pH
 Lys and Arg
 Inhibiting absorption -
 Phytic acid
 Oxalates
 Phosphate
 Mg
 Caffeine

9. Excretion of calcium
 Ionized calcium is totally filtered at the glomerulus and most of it
is reabsorbed in the tubules
 Vit D and PTH increase, while calcitonin decreases tubular
reabsorption of Ca2+
 Half of Ca excreted through the urine and half in faeces
 Same amount absorbed from intestine
 Thiazide diuretics hinder calcium excretion by facilitating
tubular reabsorption
9

10. Preparations
 Calcium carbonate (40% Ca)
 Calcium citrate (as tetrahydrate, 21% Ca2+)
 Calcium gluconate (9% Ca)
 Calcium lactate: (13% Ca)
 Calcium dibasic phosphate (23% Ca)
 Calcium chloride (27% Ca)
10

11.  Calcium chloride (27% Ca):
 Freely water soluble, but
irritant
 Tissue necrosis on IM or IV
(extravasation)
 Orally also irritant
 Calcium gluconate (9 % Ca):
 0.5 gm/1 gm tabs and 10%
injections
 Non irritant (preferred)
 Calcium lactate
 Orally non irritant
 Calcium dibasic phosphate
(23% Ca)
 Insoluble
 But with HCl form soluble
salts
 Calcium chloride
 Insoluble and no irritant –
antacids
11

12.  HYPOCALCEMIA
 Low blood calcium concentration
 Increased neuromuscular excitability, muscle spasm,
tetany and cardiac dysfunction
 HYPERCALCEMIA
 A concentration of blood calcium higher than normal
 Diffuse precipitation of calcium phosphate in tissue
 Leading to widespread organ dysfunction and damage
12

13. PHOSPHORUS
13

14. FUNCTIONS OF PHOSPHORUS
 Bone & Teeth formation (as calcium phosphate salts)
 Constituent of ATP, GTP, UTP, creatine phosphate etc.
 Required for the formation of phospholipids,
phosphoproteins
 P is a component of DNA-essential for cell growth &
differentiation
 Maintenance of acid base equilibrium
 Needed for the activation of certain proteins & enzymes
 For microbial protein synthesis in rumen
 Increase fertility, calving rates, growth rates
 Appetite control, efficiency of feed utilization

15. METABOLISM OF PHOSPHORUS
ABSORPTION-
Principally in the proximal small intestine
Adequate vit D is needed for Ca & P metabolism
ABSORPTION IN RUMINENTS
 Dephosphorylation & hydrolysis of phytate in ingested
grains & seeds by microbial phytases
 This is largely incorporated into microbial protein
15

16. ABSORPTION IN NON RUMINANTS
 Non ruminants can free most of the phytate from organic
complexes in the feed during digestion
 Sodium dependent transporters for phosphate have been
identified in the jejunal mucosa & kidneys of poultry
 Measurable absorption of P from the large intestine in pigs
16

17. RECYCLING & EXCRETION
 Copious secretion of P in saliva-adds greatly to the flow of P into the
rumen
 Faeces provides the primary route for excreting absorbed P on forage
based diets
 Faeces thus contain unabsorbed P from saliva
Excretion in pigs & poultry-Urine is the major route
Excretion in horse
Excrete excess absorbed P via faecal rather than urinary route
17

18. 18

19. PREVENTION & CONTROL OF P DEPRIVATION
Dietary supplementation
• Provide P licks in troughs or boxes
• P can also be provided directly in salt blocks & a simple 1:1
mixture of DCP
• Mineral supplements, including urea phosphate, monoammonium
phosphate, magnesium phosphate & tri calcium phosphate
• DCP given to poultry
• Microbial phytase can be added to cereal oil seed meal diets to
make grain P more digestible
The most efficient procedure-p given as fertilizer &
additional P given directly.

20. PHOSPHORUS TOXICITY
Livestock generally tolerate excessive P intakes-excretion of
excess P via urine.
 High P intakes predispose animals to urinary calculi
 Diets rich in magnesium predispose to Phosphatic calculi
because magnesium phosphates are integral to growth of
calculus)
 Dietary excess of P predispose broilers to tibial
dyschondroplasia. Unless excess calcium is also fed
 In horse, feeding excess P in diets low in Ca can cause
secondary hyperparathyroidism.

21. NUTRITIONAL SECONDARY HYPERPARATHYROIDISM
(Osteodystropha fibrosa/ Big head disease/Bran disease)
• Diets containing low levels of Ca & excess of P(feeding brans alone)
• Reported in horses, monkeys, rabbits, birds, primates, carnivores
Excess P Intestinal Ca absorption deceases
Hypocalcemia Release of parathormone
Mobilization of bone Ca
Fibrous Connective tissue invades the bone
Enlargement of bones
occurs in facial bones(horses, monkeys)

22. Hormone regulation of calcium
metabolism
Parathyroid hormone
(PTH)
Organ-target: bones, kidneys
Function of PTH - Increase of Ca
concentration in plasma
Mechanisms:
1. Releasing of Са by bones
(activation of osteoclasts –
resumption of bones)
2. Increase of Са reabsorbing in
kidneys
3. Activation of vit. Dз synthesis
and increase of absorption
in the intestine
Vitamin D
Calcitonin
Secreated from C cells of
thyroid
Organ-target - bones
Function - Decrease of Ca
concentration in
plasma
MOA :
 Direct inhibition of
osteoclast
 Promote diposition of
calcium into bone

23. 23

24. 24

25. 25

26. PARATHYROID HORMONE
(Parathormone)
 PTH is a single chain 84 amino acid polypeptide, MW 9500
 It is synthesized as prepro-PTH
 The excess amino acids are split off in two steps and it is then
stored in intracellular vesicles
 Secretion of PTH is regulated by plasma Ca2+ concentration
through a calcium-sensing receptor (CaSR)
 That is a G-protein coupled receptor on the surface of
parathyroid cells
26

27.  Hypocalcemia is a principal factor regulating PTH
synthesis & release, mediated through activation of
adenylate cyclase & subsequent increase in cAMP level
 Agents that increase cAMP cause PTH release
 Prolonged hypocalcaemia causes hypertrophy and
hyperplasia of parathyroids
27

28.  Changes in phosphate concentration in plasma affect PTH
secretion indirectly by altering Ca2+ concentration
 The active form of vit. D calcitriol inhibits expression of PTH
gene in parathyroid cells reducing PTH production
 PTH is rapidly degraded in liver and kidney
 Its plasma t½ is 2–5 min
28

29. PTH Action
NORMAL BLOOD Ca
RISING BLOOD Ca
FALLING BLOOD Ca
SUPPRESS PTH
STIMULATE PTH
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
29

30. ACTIONS
 PTH increases plasma calcium levels by:
Bone
 Increases resorption of calcium from bone
 By increasing the number of bone remodeling units
and activating osteoclasts
 Bone resorption followed by new bone formation
 Increased bone formation occurs when PTH is given
intermittently and in low doses
30

31. PTH receptor  G protein coupled receptor on activation increases
cAMP formation & intracellular Ca++ in target cells, in bone target
cells are osteoblast
31

32. Kidney
 Increases calcium reabsorption in the distal tubule and provides
moment to moment regulation of calcium excretion
 It also promotes phosphate excretion which tends to supplement
the hypercalcaemic effect
 Grossly increased plasma calcium level occurring in
hyperparathyroidism overrides the direct action on tubules
and calcium excretion in urine is actually increased
 The converse occurs in hypoparathyroidism
 PTH enhance the 1α hydroxylation of 25-OHD to generate
calcitriol
32

33. Intestines
 No direct effect on calcium absorption but increases it
indirectly by enhancing the formation of calcitriol (active
form of vit D)
 Calcitriol then promotes intestinal absorption of calcium
PTH decreases calcium levels in milk, saliva and ocular lens
This may be responsible for development of cataract in
hypoparathyroidism
33

34. Mechanism of action
 The PTH receptor is a G protein coupled receptor
 Which on activation increases cAMP formation and intracellular
Ca2+ in target cells
 In bone, the target cell is the osteoblast because PTH receptors are
not expressed on the surface of osteoclasts
 Acting on the osteoblast, PTH induces a factor ‘Receptor for
activation of nuclear factor- Kappa B-ligand’ (RANKL)
 Which diffuses and combines with RANK on osteoclast precursors
and transforms them into osteoclasts as well as activates osteoclast
34

35.  Formation of the remodeling pit is followed by
osteoblastic deposition of new bone into it
 PTH enhances proliferation and differentiation of
preosteoblasts and deposition of osteoid as well
 Bone resorption predominates when high
concentrations of PTH are present continually
 Intermittent exposure to low concentrations has the
opposite effect
35

36. Hormonal regulation of bone
remodeling unit
36

37. Hypoparathyroidism
 Low plasma calcium levels
 Tetany, convulsions, laryngospasm, paresthesias,
cataract and psychiatric changes
 Pseudohypoparathyroidism occurs due to reduced
sensitivity of target cells to PTH caused by a mutant G
protein that couples PTH receptor activation to cAMP
generation in target cells
37

38.  PTH is not used in hypoparathyroidism because plasma
calcium can be elevated
 Kept in the normal range more conveniently by vit D
therapy
 Teriparatide This recombinant preparation of 1–34
residues of amino terminal of human PTH has been
recently introduced for the treatment of severe
osteoporosis
38

39. Mechanism of action:
 Stimulates new bone formation on trabecular and
cortical bone surfaces by preferential stimulation of
osteoblastic activity over osteoclastic activity.
 It is the only agent which stimulate new bone formation
 Plasma half life is 1 hr
 Bone forming action predominant over bone resorption
 Side effects: Occasional headache and nausea
39
rParathyroid hormone [rPTH(1-34)
Teriparatide]

40. Hyperparathyroidism
 It is mostly due to parathyroid tumour
 It produces
 Hypercalcaemia, decalcification of bone—deformities
and fractures (osteitis fibrosa generalisata)
 Metastatic calcification, renal stones, muscle weakness,
constipation and anorexia
40

41. Treatment
is surgical removal of the parathyroid tumour
 When this is not possible—low calcium, high
phosphate diet with plenty of fluids is advised
Cinacalcet:
 It activates the Ca2+ sensing receptor (CaSR) in the
parathyroids and blocks PTH secretion
 It is indicated in secondary hyperparathyroidism due
to renal disease and in parathyroid tumour
41

42. Vitamin D
 The body can supply its own Vitamin D via the
synthetic pathways
 D3 : cholecalciferol : synthesized in the skin
 under the influence of UV rays
 D2 : calciferol: present in irradiated food yeasts, fungi,
bread, milk
 D1 : mixture of antirachitic substances found in Food
42

43. Vitamin D synthesis
43

44. VITAMIN D SYNTHESIS
SKIN LIVER KIDNEY
7-DEHYDROCHOLESTEROL
VITAMIN D3
VITAMIN D3
25(OH)VITAMIN D
u
25-HYDROXYLASE
25(OH)VITAMIN D
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
1a-HYDROXYLASE
TISSUE-SPECIFIC VITAMIN D RESPONSES 44

45. Vit D should be considered a hormone
(a) It is synthesized in the body (skin); under ideal
conditions it is not required in the diet
(b) It is transported by blood, activated and then acts on
specific receptors in the target tissues
(c) Feedback regulation of vit D activation occurs by plasma
Ca2+ level and by the active form of vit D itself
45

46. Actions of calcitriol
 Enhancement of absorption of Ca and PO4 from intestine
 By increasing the synthesis of calcium channels and a carrier
“calcium binding protein (CaBP)” or calbindin
 Analogous to stroid hormones – binds to cytoplasmic vit
D receptor (VDR)-translocation-increased synthesis of
mRNA-regulation of protein synthesis
 Activation of VDR also promotes endocytotic capture of
Calcium and transport across the duodenal mucosa
46

47. 47

48.  Calcitriol also enhances recruitment and differentiation
of osteoclast precursor for remodelling – resorption of
Calcium and PO4 from bone
 Mature osteoclasts lack VDR
 Induces “receptor for acivaton of nuclear factor-kB-ligand
(RAANKL)” in osteoblasts and activates osteoclasts indirectly
 Also enhances tubular reabsorption of Calcium and
phosphate in the kidney
48

49. Pharmacokinetics
 Absorbed from intestine in presence of Bile salts mainly by
lymphatics
 D3 is better absorbed than D2
 Binds to alpha-globulin (DBP) and stored in fatty tissues
for many months
 Hydroxylated in the liver excreted through bile
 Malabsorption and steatorrhoea interfere with absorption
 Half life varies from 1 – 18 days
49

50. Vitamin D deficiency
•Deficiency of vitamin D leads to:
 Rickets in small children.
 Osteoporosis
50

51. Clinical manifestation
1. Osseous changes:
1) Head: frontal bossing, box like skull
2) Teeth: delayed eruption with abnormal order
3) Chest: rachitic rosary, pigeon chest
4) Spinal column: scoliosis, kyphosis, and lordosis
5) Extremities: bowlegs
6) Rachitic dwarfism
2. Muscular system: potbelly, late in standing and walking
3. Motor development: delayed
4. Other nervous and mental symptoms
51

52. 52

53. Vit D - Uses
 Prophylaxis and treatment of rickets & osteomalacia :
 Oral/IM injection every 2-6 month interval
 Metabolic Rickets
 Vit D resistant rickets: PO4 with high doses of calcitriol
 Vit D dependent rickets
 Renal rickets
 Senile or postmenopausal osteoporosis
 Hypoparathyroidism: calcitriol/alfacalcitriol
 Fanconi like syndrome
53

54. Treatment
1. Food and nursing care
2. Prevention of complications
3. Special therapy
1) Vitamin D therapy
2) Vitamin D analogues
54

55. Vitamin D analogues
 Vitamin D and metabolites
Cholecalciferol, Ergocalciferol, Calcitriol, Calcidiol
 Synthetic analogue of vitamin D
Alfacaccidol, Paricalcitol, Calcipotirol, Tacalcitol
 Miscellaneous agents
Cod liver oil and halibut liver oil
55

56. TOXICITY
•Hypervitaminosis D
causes hypercalcemia, which manifest as:
• Nausea & vomiting
• Excessive thirst , polyuria & anorexia
• Severe itching
• Joint & muscle pains
• Disorientation & coma
• Calcification of soft tissue
– Lungs, heart, blood vessels
• Hypercalcemia
– Normal is ~ 10 mg/dl
– Excess blood calcium leads to stone formation in
kidneys
56

57. 57

58. Calcitonin
58

59.  Calcitonin, peptide hormone secreted by the Thyroid gland
 Tends to decrease plasma Ca concentration and, in general, has
effects opposite to those of PTH
 Parafollicular cells, or C cells, lying in the interstitial fluid
between the follicles of the thyroid gland
 32-amino acid peptide with a molecular weight of about 3400
59

60.  The primary stimulus for calcitonin secretion is increased
plasma Ca ion concentration
 Calcitonin decreases blood Ca ion concentration rapidly,
within minutes after injection of the calcitonin
60

61.  Inhibit bone resorption by direct action on Osteoclasts
 Also inhibits the proximal tubular reabsorption of calcium and
phosphate by direct action on kidney
 Action is mediated through G- protein coupled calcitonin
receptor & increased cAMP formation but target cells are
different from that of PTH
61

62. Calcitonin : Preparations
 Porcine (Natural) calcitonin:
 Antigenic
 Synthetic salmon calcitonin:
 More potent due to slower metabolism
 Synthetic human calcitonin:
 Calcitonin is given by SC/IM routes
 Salmon calcitonin is also available as nasal spray
62

63. Calcitonin-salmon
 Nasal Spray is a synthetic polypeptide of 32 amino acids in
the same linear sequence that is found in calcitonin of
salmon origin
• Mechanism of action:
• Causes inhibition of osteoclast function with loss of the ruffled
osteoclast border responsible for resorption of bone.
 Peak plasma concentrations of drug appear 35 minutes
after nasal administration.
 t 1/2 - 43 mins
63

64.  Advantage
 May provide analgesic
effect on bone pain
associated with
fractures
 Disadvantage
 Inconsistent effects on
BMD and fracture risk
64

65. • Hypercalcemia states (e.g associated with neoplasia)
• Pagets disease of bone
• Postmenopausal osteoporosis & corticosteroid induced
osteoporosis
• Salmon calcitonin is used as nasal spray along with Vit D
supplements
• Diagnosis of medullary carcinoma of thyroid
 Detection of high blood level of calcitonin is diagnostic of
this tumour which arises from the calcitonin producing
parafollicular cells of thyroid
Uses
65

66. Estrogen Replacement Therapy (ERT)
 Indication: Used to prevent and treat osteoporosis (FDA
indication is for prevention)
 Mechanism:
 ↓ osteoclast activity
 Acts on osteoblast to ↓ production of IL- 6
 ↑ production of osteoprotegerin,there by interfering with
recruitment of osteoclast precursors
66

67. Glucocorticoid-Induced
Osteoporosis
(1) Inhibit osteoblast function and ↑ osteoblast apoptosis
(2) Stimulation of bone resorption, probably as a secondary
effect
(3) Impairment of the absorption of calcium across the
intestine, probably by a vitamin D–independent effect
67

68. (4) Increase of urinary calcium loss and perhaps induction
of some degree of secondary hyperparathyroidism
(5) Reduction of adrenal androgens and suppression of
ovarian and testicular secretion of estrogens and
androgens
(6) Induction of glucocorticoid myopathy, which may
exacerbate effects on skeletal and calcium homeostasis
68

69. Treatment
 Only bisphosphonates have been demonstrated in
large clinical trials to reduce the risk of fractures in
patients being treated with glucocorticoids
 Thiazides reduce urine calcium loss, but their role
in prevention of fractures is unclear
69

70.  Controlled trials of hormone therapy have shown bone-sparing
effects, and calcitonin also has some protective effect in the
spine
 PTH has also been studied in a small group of women with
glucocorticoid-induced osteoporosis, where bone mass
increased substantially
70

71. Thank you
71