Calcium homeostasis is regulated by a complex interplay of organs and hormones. Calcium levels in the blood are tightly controlled within a narrow range through intestinal absorption, renal excretion, and bone deposition and resorption. The parathyroid hormone (PTH), vitamin D, and calcitonin work together to increase blood calcium when it is low and decrease it when high. PTH stimulates bone resorption and renal reabsorption of calcium. Vitamin D facilitates intestinal calcium absorption and renal reabsorption. Calcitonin inhibits bone resorption, slightly lowering blood calcium levels. Together this endocrine system maintains calcium balance and distribution in the body.

1. ©dharmdmd@gmail.com
Calcium Homeostasis
Dr Dharmendra
Dept of Physiology
AFMC

2. Sequence of Presentation
2
Introduction
History & Comparative Physiology
Calcium: Metabolism & Role
Regulation of Ca++ Levels:
Parathyroid Hormone (PTH)
Vitamin D
Calcitonin
Applied Aspects
Conclusion

3. Introduction
3
•Ca++ is a chemical element, an alkaline earth metal
•5th most abundant element
•An essential dietary element for human life
•As an electrolyte, Ca++ plays vital role in the
physiological and biological processes
•Both Intracellular and Extracellular functions

4. •Ca++ outside cells are important for maintaining the
potential difference across excitable CM as well
proper bone formation.
•Regulation of Ca++ in blood occurs within narrow
limit
•Organ Ca homeostasis
•Target organs : bones, kidneys, intestines
•Endocrine Ca homeostasis
•Three hormones primarily regulate Ca++
metabolism
4

5. •Primary process for release of Ca into circulation
• Ca GI absorption and bone resorption
•Primary process for removal of Ca from blood
• Ca Renal excretion and bone formation
•Phosphate metabolism is closely linked
•Multiple disorders
5

6. Historical Aspects
• 1808- Humphry devy
• Isolated from oxide and named it
• 1883- Sydney Ringer:
• Ist to reveal importance of Ca++
1888- Role in cellular Adhesion
• 1888- Alexis Hartmann
• Ringer solution- modified to ‘Ringer Lactate Solution’ or
‘Hartmann's solution’
• 1927- Heilbrum- roll in clotting
1940
NT
1970
Ca channels
1993
CaSR
6

7. Comparative Physiology
7
•Calcitonin/ PTH/ Vitamin D:
• Fish, Reptiles, Birds and Mammals
• Same functions as in humans
• Fish rich source of Vit D
• Salmon Calcitonin

8. Calcium: Metabolism
Distribution of Ca:
• Average human body – 1000 to 1100 gm
• 99% - skeleton
• 0.9% - intracellular
• 0.1%- ECF (one gram)
• Three forms in plasma:
• Normal value – 9.4 mg/dl (2.4 mmol/l)
• Total diffusible (ionic)- 5.3 mg/dl
• Total nondiffusible (protein-bound)- 4.6 mg/dl
• Ca estimation: Corrected Ca (mg/dl)= measured total Ca+.8 (4-Albumin)
8

9. Calcium: Metabolism
• Overview of calcium exchange between different tissue
compartments
(90%)
Rapid exchange
9
Exchangable &
Stable form
(10%)
(98–99%)

10. Calcium: Metabolism- Organ Ca homeostasis
10
Target organs:
1. Intestine- Ca absorption
2. Kidney- Ca excretion
3. Bone- uptake & release of Ca
•Plasma Ca conc depends on net effect of these
organ physiology

11. Organ Ca homeostasis: GI Absorption
11
• Mainly Small intestine- duodenum /proximal jejunum
• Absorption and fecal excretion
• Fractional absorption stimulated by- 1,25 DHCC
• Brush border : active, carrier mediated energy dependent
• Active transport transcellular route
• Passive & bulk flow paracellular route

12. Organ Ca homeostasis: GI Absorption
• TRPV5/6- ‘Transient Receptor Potential Vanilloid Type 5/6 ’
• 1,25-DHCC- increases the expression of all these proteins
• PTH- 1 α hydroxylase enzyme
/NCX1
12

13. 13
Organ Ca homeostasis: Renal excretion
(98–99%)

14. Renal Ca reabsorption
PCT- Passive paracellular pathway
TAL- Both paracellular & transcellular
pathway
14

15. Organ Ca homeostasis: Bone
15
• Accretion & resorption are in balance
• Bone remodeling can be modulated
• Chronic Ca & Pi dysregulation or H dysregulation
• Pathological changes
• Chemical Composition:
• Mineral salts - 35% (Ca++ & phosphates, Ratio: 1.3 to 2)
• Organic matrix - 20%
• Water – 45%
• Amorphous(CaHPo4) compounds –loosely bound-1% of
bone Ca++ - easily exchangeable – First line of Defense

16. Organ Ca homeostasis: Bone
Structure: Two types
• Compact or Cortical (75%)
• Outer layer
• Nutrients by Canaliculi/Haversian Canals
• Low surface to volume ratio
• Collagen arranged in circles -Osteons
• Trabecular or Spongy (25%)
• Lie inside the compact bone
• Made up of spicules
• High surface to volume ratio
• Nutrients diffuse through ECF
16

17. Organ Ca homeostasis: Bone
17
In adult- Bone remodeling involve:
1. Destruction of preformed bone with release of
Ca, Pi & hydrolysed fragments of protein metrix
(osteoid) into blood.
2. New systhesis of osteoid at the site of resorption
with subsequent calcification
Cell types: 02 major class
•Osteoblasts
•Osteoclasts

18. Organ Ca homeostasis: Bone
•Osteoblast regulation of osteoclast differentiation
and function.
After 2 wks
18

19. •osteoid (eg. Osteocalcin & ALP)- promote
calcification
Calcium phosphate
Hydroxyappetite crystals
Lamellae
Haversian Lacunae
Haversian system (osteon)
19

20. PTH
PTH/PTHrP
Sustained PTH- bone turnover & resorption
Intermittent low dose PTH- promote OB survival &
bone anabolic function
OB
20

21. Endocrine Ca homeostasis: PTH
•PTH & 1,25 DHCC = calciotropic Hormone
Synthesis:
•Two distinct cells:
•Chief Cells- prominent ER,
golgi appt – secrete PTH
• Oxyphil Cells
•Target organs
•Net effect- S. Ca, S. Pi
21

22. 22
Endocrine Ca homeostasis: PTH
Actions of PTH:
>Bone:
• Increased resorption of bone, Growth & development of cartilage
• Rapid and slow phase
>Kidney:
1. Ca resorption & Pi resorption
2. Hyperphosphaturia
3. Increased urinary excretion of Hydroxyproline
4. Increased conversion of 25-HCC to 1,25 DHCC
>Intestine: indirect action
>Other actions:
• Activation of Adenyl Cyclase in target tissues
• Brain , placenta , Teeth

23. 23
Endocrine Ca homeostasis: PTH
Mechanism of Action :
• 3 different receptors
• PTH1 (PTHrP receptor)
• PTH2: brain,placenta, kidney
• CPTH
• CPTH – acts at carboxyl terminal
• PTHrP:
• Produced by many tissues
• Marked homology bw PTH &
PTHrP
• Similar receptors
• On Osteoblast & PCT, DCT- for
PTH

24. 24
Endocrine Ca homeostasis: PTH
Regulation;
Major regulator:
• Ca++ ion
concentration
Minor regulator:
• Vit D
•Decreased
Ca++/Increased PTH
•Increased
Ca++/Decreased PTH
CaSR- PLC-IP3/DAG- IC Ca
CaSR

25. 25
Endocrine Ca homeostasis: Vit D
Synthesis:
•Vit D3- by UV irradiation of 7-dehydrocholesterol in
skin
•Indirect inhibition by Ca++
•Target organ: intestine, bone, kidney
parathyroid gland

26. 26
Vitamin D
metabolism
PCT
PCT
Ca

27. Effect of plasma calcium conc on
1,25 DHCC
Effect of Vit D3 intake on 1,25 DHCC
27

28. Endocrine Ca homeostasis: Vit D
28
Mechanism of Action:
Intestine:
1. 1,25 DHCC affects Ca++ absorption and transport
2. Act via Calbindin- D proteins
3. Intestinal epithelium – Calbindin D 9k
4.Also increases number of Ca++-ATPase/TRPV6
Kidney: Facilitates Ca++ resorption in kidneys via TRPV5
• Ca++ acts as transport mediator for phosphate
Bone:
• Increases synthetic activity of Osteoblasts
• Stimulate termination of OC differentiation
• Necessary for normal calcification of matrix

29. GI Absorption
• TRPV5/6- ‘Transient Receptor Potential Vanilloid Type 5/6 ’
• 1,25-DHCC- increases the expression of all these proteins
• PTH- 1 α hydroxylase enzyme
/NCX1
29

30. Endocrine Ca homeostasis: Vit D
30
Regulation:
•PTH
•Feedback - Ca++ and PO4
3+ levels
•High levels Ca-
• inhibit 1,25 DHCC production
• More 24,25 DHCC produced (Inactive form)
•Promotes mineral precipitation on collagen fibrils
•Low levels Ca-
• stimulates more PTH – more 1α hydroxylase

31. • Regulation:
• A new protein called – α Klotho :
• Important role in calcium and phosphate homeostasis
• Stabilizes membrane proteins TRPV5/NaK ATPase.
• Enhances activity of, Fibroblast Growth Factor 23
(FGF23)
• FGF23 decreases renal NaPi-IIa and NaPi-IIc expression
• Inhibits the production of 1 -hydroxylase, reducing 1,25-
DHCC
31

32. Endocrine Ca homeostasis: Calcitonin
Synthesis:
• Release in response of increase Ca
Action:
• Inhibits resorption of bones- Ca, Pi
• Reduces levels of Calcium and Phosphates:
• Inhibits activity of Osteoclasts
• Increasing efflux of calcium from kidneys
• Increased mitochondrial uptake of calcium
• Overall Minor Role:
• Post Thyroidectomy – Normal levels of Ca++ and bone density
• Medullary Ca Thyroid-Very high calcitonin – No effect on Ca++
32

33. •In renal failure:
• calcitonin
•Regulation:
Bone-
• Ca
• Same by CaSR
• Similar PTH/PTHrP receptors
• ECF Ca--- calcitonin
• Act on Osteoclast
•Kidney- inhibit reabsorption 33

34. Interplay of Ca++, PTH & Calcitonin
34

35. 35
Effect of other Hormones on Ca++
• Glucocorticoids :
Bone:
• inhibiting osteoclast formation and activity.
• Osteoporosis - inhibits protein synthesis in osteoblasts.
Intestine:
• decrease the absorption of Ca2+ and PO4 3–
Kidney:
• Decrease reabsorption
• Growth hormone:
• increases intestinal absorption of Ca2+
• IGF-I stimulates protein synthesis in bone
• Estrogens:
• prevent osteoporosis - inhibits stimulation of osteoclasts
• Increase Ca absorption & reabsorption
• Insulin: increases bone formation - bone loss in untreated diabetes.

36. 36
Role of Calcium
• Main component of Bony Skeleton (99%)
• Excitation-Contraction coupling
• Stabilization of Cell Membrane
• Release of Neurotransmitters at synaptic vesicle
• Secretion from Endocrine/Exocrine glands
• Secondary massenger
• Synthesis of Nucleic Acids
• Activation/Regulation of enzymes
• Blood Clotting
• Teeth

37. 37
Applied Aspects
1. Hypercalcemia/Hyperpatathyroidism
• GI absorption/Renal reabsorption/Bone resorption
• Calcification in soft tissue
• Bone demineralization
• Osteoporosis
• FBHH- CaSR mutation
2. Hypocalsemia/Hypoparathyroidism
• Bone /kidney
• Alkalosis
• No bone demineralization
• Teteny/carpopedal spasm/trousseau’s sign/chvostic sign
• Laryngospasm
• First degree HB

38. Integrated response to a hypocalcemic challenge.
38

39. Applied Aspects
39
3. Vitamin D deficiency:
• Defective bone mineralization
• Ca– PTH
• Child- Rickets
• Adult- Osteomalasia
4. Osteoporosis:
• Mutation OPG….. Highly overactive OC
5. Osteopetrosis:
• Mutation in RANK/RANKL gene

40. Applied Aspects
40
6. Hypervantilation:
• Decrease PTH
7. Paget disease:
• Increase bone resorption followed by new bone
formation
• Excessive bone turnover by increase OC actvity
• Bone deformity
• Raised ALP & Osteocalcin

41. Applied Aspects
41
8. Renal osteodystrophy
9. Neuromuscular junction
10. Pseudohyperparathyroidism
11. Significant tissue damage
12.Drugs: loop diuretics/thiazides/CaSR modified &
blocker
13. ECG changes
14. Effect of microgravity

42. Conclusion
42
• Calcium plays a very IMPORTANT role in metabolic
processes of almost all body cells
• Necessary for normal Skeletal Bony Growth
• Levels are maintained in a narrow range
• Right conc. depends upon interplay of Ca absorption from
intestine, bone uptake/ release and renal excretion
• All the above are regulated in concert by PTH, Vit D &
Calcitonin
• Many disorders are linked with dysfunction

43. 43