This document discusses calcium and phosphate metabolism and bone physiology. It begins by describing the functions and importance of calcium and phosphate in the body. The majority of calcium is stored in the bones, while calcium levels in blood and extracellular fluid are tightly regulated. Several hormones, including PTH, vitamin D, and calcitonin help regulate calcium levels. PTH and vitamin D work to increase calcium levels by promoting bone resorption and intestinal absorption, while calcitonin decreases calcium levels by inhibiting bone resorption. The kidneys also play an important role in calcium regulation through hormone-modulated reabsorption and excretion.

1. BY
DR. NUSRAT TARIQ
ASSOCIATE PROFESSOR
M.I.M.D.C
PHYSIOLOGY OF CALCIUM AND
PHOSPHATE METABOLISM
AND BONE PHYSIOLOGY

2. LEARNING OBJECTIVES
By the end of the lecture you should be able to :
1. Describe functions, distribution and
metabolism of calcium in human body.
2. Describe Bone physiology.
3. Explain hormonal regulation of calcium
metabolism

3. Physiological importance of
Calcium
• Calcium salts in bone provide structural integrity of
the skeleton
• Calcium ions in ECF and ICF are essential for:
– Neuoromuscular excitability
– Contraction of skeletal ,smooth & cardiac muscle
– Blood coagulation
– Hormonal secretion
– Enzymatic regulation

4. Physiological importance of
Phosphorous
Phosphorous is an essential mineral necessary
for:
• ATP,
• cAMP second messenger systems

5. CALCIUM CONCENTRATION IN ECF
ECF CALCIUM CONCENTRATION = 9.4 mg/dl
= 2.4 mmol/L
CALCIUM: – 1100 gm.
– 1.5% OF BODY WEIGHT

6. Distribution

7. 1. Skeleton (99%)
a. Rapidly Exchangeable
reservoir.
b. Stable calcium

8. 2-Blood (1%) 9 – 10 mg%, 2.4 mmol per liter.
Present in three forms in the plasma:
50% ( 1.2 mmol/L) Diffusible and in ionized form (the physiologically active
form)
41% ( 1 mmol/L) bound to proteins (predominantly albumin) so not
diffusble
09% ( 0.2 mmol/L) Diffusble but complexed with anions (citrate, sulfate,
phosphate) so not ionized
Most of the calcium in the body exists as the mineral
hydroxyapatite, Ca10(PO4)6(OH)2.

10. Absorption and Excretion of Calcium and
Phosphate
• Intestinal Absorption of Calcium and Phosphate
• Fecal Excretion of Calcium and Phosphate
• Renal Excretion of Calcium and Phosphate

12. HORMONAL REGULATION OF
CALCIUM METABOLISM
PTH
VITAMIN D
CALCITONIN

13. ORGANS INVOLVED IN REGULATION
OF CALCIUM METABOLISM
BONE
PARATHYROID GLAND
KIDNEY

14. CALCIUM AND BONE
• 99% of Calcium is found in the bone.
• Most is found in hydroxyapatite crystals.
• Very little Ca2+ can be released from the
bone– though it is the major reservoir of Ca2+
in the body.

15. Structure of bones
Haversian canals within lamellae

16. Composition of Compact Bone
1. Organic Matrix (30%) –organic bone
- 90 to 95 % collagen fibers
- 05 to 10 % is ground substance ( composed of ECF plus
proteoglycans esp. chondroitin sulfate and hyaluronic acid
2. Bone Salts (70) –Inorganic bone
- crystalline salt is composed principally of calcium and
phosphate, known as Hydroxyapatite Ca10(PO4 )6(OH)2
Magnesium, sodium, potassium, and carbonate ions
are also present

17. Tensile and Compressional Strength of Bone
• Collagen fibers of bone have great tensile
strength
• Calcium salts have great compressional
strength

18. Bone cell types
Three types of bone cells:
• Osteoblasts:
Differentiated bone forming cells secrete bone matrix
on which Ca++ and PO precipitate.
• Osteocytes:
Mature bone cells enclosed in bone matrix.
• Osteoclasts:
Large multinucleated cell derived from monocytes
function is to resorb bone..

19. Bone calcification
• Active osteoblasts synthesize and extrude
collagen molecules.
• Collagen fibrils form arrays of an organic
matrix called the osetoid.
• Calcium phosphate is deposited in the osteoid
and becomes mineralized
• Mineralization is combination of CaP04, OH-,
and H2CO3
– hydroxyapatite.

20. Mineralization
• Requires adequate Calcium and phosphate
• Dependent on Vitamin D
• Alkaline phosphatase and osteocalcin (bone
gamma-carboxyglutamic acid-containing
protein) play roles in bone formation
• Their plasma levels are indicators of
osteoblast activity.

21. CONTROL OF BONE FORMATION
AND RESORPTION
• Bone resorption of Ca++ by two mechanims:
 osteocytic osteolysis is a rapid and transient effect
 osteoclasitic resorption which is slow and sustained.
Both are stimulated by PTH.
In the absence of hormonal regulation plasma Ca++ is
maintained at 6-7 mg/dL by this equilibrium.

22. Osteocytic osteolysis
• Transfer of calcium from canaliculi to ECF via
activity of osteocytes.
• Does not decrease bone mass.
• Removes calcium from most recently formed
crystals
• Happens quickly.

23. Bone resorption
• Does not merely extract calcium, it destroys
entire matrix of bone and diminishes bone mass.
• Cell responsible for resorption is the osteoclast.

24. Osteoclasts and Ca++ resorption

25. Deposition of Bone by the Osteoblast
Absorption of Bone by the Osteoclast
Deposition and Absorption of Bone
The Osteoclast send out villus-like projections toward the
bone.
The villi secrete:
1. proteolytic enzyme released from lysosome of the
osteoclast
2. several acids including lactic acid and citric acid,
released from the mitochondria and secretory
vesicles

26. Bone remodeling
• Endocrine signals to resting osteoblasts generate
paracrine signals to osteoclasts and precursors.
• Osteoclasts resorb an area of mineralized bone.
• Local macrophages clean up debris.
• Process reverses when osteoblasts and precursors
are recruited to site and generate new matrix.
• New matrix is minearilzed.
• New bone replaces previously resorbed bone.

29. Hormone Regulation Of
Calcium Metabolism

30. Hormonal Regulation Of
Calcium Metabolism
Vitamin D
PTH
Calcitonin

31. Organs involved in regulation of
calcium metabolism
Bone
Parathyroid gland
Kidney

32. Vitamin D
• Vitamin D is a lipid soluble hormone
that binds to a typical nuclear
receptor
• Because it is lipid soluble, it travels in
the blood bound to hydroxylated a-
globulin.

34. Synthesis of Vitamin D
• Humans acquire vitamin D from two sources.
 produced in the skin (keratinocytes)by UV
radiation
 ingested in the diet.
• Vitamin D is not a classic hormone because it is
not produce and secreted by an endocrine
“gland.” Nor is it a true “vitamin” since it can be
synthesized de novo.

35. • PTH stimulates vitamin D synthesis. In the winter or
if exposure to sunlight is limited then dietary vitamin
D is essential.
• Vitamin D itself is inactive, it requires modification to
the active metabolite, 1,25-dihydroxy-D.
• The first hydroxylation reaction takes place in the
liver yielding 25-hydroxy D.
• Then 25-hydroxy D is transported to the kidney
where the second hydroxylation reaction takes place.
Synthesis of Vitamin D

36. • The mitochondrial P450 enzyme 1a-hydroxylase
converts it to 1,25-dihydroxy-D, the most potent
metabolite of Vitamin D.
• The 1a-hydroxylase enzyme is the point of regulation
of D synthesis.
• Feedback regulation by 1,25-dihydroxy D inhibits this
enzyme.
• PTH stimulates 1a-hydroxylase and increases 1,25-
dihydroxy D.
Synthesis of Vitamin D

37. • 25-OH-D3 is also hydroxylated in the 24 position
which inactivates it.
• If excess 1,25-(OH)2-D is produced, it can also be 24-
hydroxylated to remove it.
• Phosphate inhibits 1a-hydroxylase and decreased
levels of PO4 stimulate 1a-hydroxylase activity
Synthesis of Vitamin D

38. Vitamin D
• Vitamin D, after its activation to the hormone
1,25-dihydroxy Vitamin D3 is a principal
regulator of Ca++.
• Vitamin D increases Ca++ absorption from the
intestine and Ca++ resorption from the bone .

42. Vitamin D action
“Hormonal” Effect of Vitamin D to Promote Intestinal
Calcium Absorption.
• The main action of 1,25-(OH)2-D is to stimulate
absorption of Ca2+ from the intestine.
• 1,25-(OH)2-D induces the production of calcium
binding proteins which sequester Ca2+, buffer high
Ca2+ concentrations that arise during initial
absorption and allow Ca2+ to be absorbed against a
high Ca2+ gradient

43. Vitamin D Promotes Phosphate
Absorption by the Intestines.
Vitamin D Decreases Renal
Calcium and Phosphate Excretion.

44. Vitamin D Actions on Bones
• Another important target for 1,25-(OH)2-D is the
bone.
• Osteoblasts, but not osteoclasts have vitamin D
receptors.
• 1,25-(OH)2-D acts on osteoblasts which produce a
paracrine signal that activates osteoclasts to resorb
Ca++ from the bone matrix.
• 1,25-(OH)2-D also stimulates osteocytic osteolysis.

45. Vitamin D and Bones
• Proper bone formation is stimulated by 1,25-
(OH)2-D.
• In its absence, excess osteoid accumulates
from lack of 1,25-(OH)2-D repression of
osteoblastic collagen synthesis.
• Inadequate supply of vitamin D results in
rickets, a disease of bone deformation

46. SUMMARY OF FUNCTION OF VITAMIN D
• TISSUE SPECIFICITY
– GUT
• STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM AND PHOSPHATE
IN THE SMALL INTESTINE (PRINCIPALLY DUODENUM)
– BONE
• STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS
• STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO MOBILIZE
CALCIUM
– PARATHYROID
• INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK REGULATION)

47. PARATHYROID HORMONE

49. Parathyroid Hormone
• Synthesized and secreted by the parathyroid
gland which lie posterior to the thyroid glands.
• The blood supply to the parathyroid glands is
from the thyroid arteries.
• The Chief Cells in the parathyroid gland are
the principal site of PTH synthesis.

50. Synthesis of PTH
• PTH is translated as a pre-prohormone.
• Cleavage of leader and pro-sequences yield a
biologically active peptide of 84 aa.
• Cleavage of C-terminal end yields a
biologically inactive peptide.

51. Regulation of PTH
• The dominant regulator of PTH is plasma Ca2+.
• Secretion of PTH is inversely related to [Ca2+].
• Maximum secretion of PTH occurs at plasma
Ca2+ below 3.5 mg/dL.
• At Ca2+ above 5.5 mg/dL, PTH secretion is
maximally inhibited.

52. Calcium regulates PTH

53. Calcium
regulates
PTH
secretion

54. • PTH secretion responds to small alterations in plasma
Ca2+ within seconds.
• A unique calcium receptor within the parathyroid cell
plasma membrane senses changes in the
extracellular fluid concentration of Ca2+.
• This is a typical G-protein coupled receptor that
activates phospholipase C and inhibits adenylate
cyclase—result is increase in intracellular Ca2+ via
generation of inositol phosphates and decrease in
cAMP which prevents exocytosis of PTH from
secretory granules.
Regulation of PTH

55. • When Ca2+ falls, cAMP rises and PTH is
secreted.
• 1,25-(OH)2-D inhibits PTH gene expression,
providing another level of feedback control of
PTH.
• Despite close connection between Ca2+ and
PO4, no direct control of PTH is exerted by
phosphate levels.
Regulation of PTH

56. PTH actions
Action of PTH is to:
• increase plasma Ca++ levels
• decrease plasma phosphate levels.

57. PTH actions
PTH acts directly on:
• the bones to stimulate Ca++ resorption and
• kidney to stimulate Ca++ reabsorption in the distal
tubule of the kidney and to inhibit reabsorptioin of
phosphate (thereby stimulating its excretion).
PTH acts indirectly on:
intestine by stimulating 1,25-(OH)2-D synthesis.

58. ACTIONS OF PTH ON TARGET ORGANS
1. BONES OR SKELETON
Calcium and Phosphate absorption from bones
a. Rapid Phase – osteolysis
b. Slow Phase – activation of osteoclasts
1. immediate activation of osteoclasts that are already formed
2. formation of new osteoclasts from osteoprogenator cells
2. INTESTINES
Enhances both Ca and PO4 absorption from the intestines by increasing
formation of 1, 25 dihydroxycholecalciferol
3. KIDNEYS
a. Increased renal tubular reabsorption of calcium in the distal tubules and
collecting ducts
b. diminished proximal tubular reabsorption of PO4

59. 1. Blood Calcium and Phosphate
a. Hypercalcemia
b. Hypophosphatemia
2. Urine
a. Hypocalciuria
b. Hyperphosphatemia - phosphaturic

60. Cyclic Adenosine Monophosphate
Mediates the Effects of PTH

63. PTH,
Calcium &
Phosphate

64. Calcitonin
• Calcitonin is synthesized and secreted by the
parafollicular cells of the thyroid gland.
• They are distinct from thyroid follicular cells by their
large size, pale cytoplasm, and small secretory
granules.
• Calcitonin acts to decrease plasma Ca++ levels.
• While PTH and vitamin D act to increase plasma Ca++-
- only calcitonin causes a decrease in plasma Ca++.

65. • The major stimulus of calcitonin secretion is a
rise in plasma Ca++ levels
• Calcitonin is a physiological antagonist to PTH
with regard to Ca++ homeostasis
Calcitonin

66. • The target cell for calcitonin is the osteoclast.
• Calcitonin acts via increased cAMP
concentrations to inhibit osteoclast motility
and cell shape and inactivates them.
• The major effect of calcitonin administration is
a rapid fall in Ca2+ caused by inhibition of bone
resorption.
Calcitonin

67. • Chronic excess of calcitonin does not produce
hypocalcemia and removal of parafollicular
cells does not cause hypercalcemia. PTH and
Vitamin D3 regulation dominate.
• May be more important in regulating bone
remodeling than in Ca2+ homeostasis.
Calcitonin