Calcium Balance and homeostasis

1. Parathyroid Hormone,
Calcitonin, and
Vitamin D
Dr. Sai Sailesh Kumar G
Professor
Department of Physiology
NRIIMS
Email: dr.goothy@gmail.com

2. 1. The response to thyroid hormone is detectable within a few
minutes after its secretion. (True or false?)
2. Insulin is the only hormone that can lower blood glucose levels.
(True or false?)
3. Which of the following hormones does not exert a direct
metabolic effect?
a. epinephrine
b. growth hormone
c. aldosterone
d. cortisol
e. thyroid hormone

3. What are the consequences of diabetes mellitus?

4. What hormones are secreted by the adrenal cortex?

5. Case study
 Najma G. sought medical attention after her menstrual periods ceased
and she started growing excessive facial hair. Also, she had been
thirstier than usual and urinated more frequently. A clinical evaluation
revealed that Najma was hyperglycemic. Her physician told her that
she had an endocrine disorder dubbed “diabetes of bearded ladies.”
What underlying defect do you think is responsible for Najma’s
condition?

6. Case study
 Achard-Thiers Syndrome
 Rare disorder
 Seen in post menopausal women
 Type II diabetes mellitus and signs related to over production of
androgens

7. Case study
 A 27-year-old female presented with a compliant of gain in weight of
approximately 10 kg over 1 year. She also complained of increased
blood loss during her periods. There has been increase in acne and
growth of facial hair on chin and upper lips. She said she feels
depressed and unhappy due to her present condition. Recently she
had a constant pain in her back with difficulty in walking.

8. Case study
 Physical examination
 Pulse 80/min, BP 130/90 mmHg, FBS 156 mg/dL
 Moon like face
 Fragile skin
 Buffalo hump
 Purple striae on abdominal wall

9. Case study
 A lady is receiving very large dosage of cortisol like drug to treat
her arthritis. What will happen to the secretion of cortisol? What
will happen if such therapy is suddenly stopped? What happens
if the patient is exposed to stress or infection?

10. Introduction
 Extracellular fluid calcium concentration is normally regulated
precisely
 it seldom rises or falls more than a few percent from the normal value
of about 9.4 mg/dl
 This precise control is essential because calcium plays a key
role in many physiological processes

11. Introduction
 contraction of skeletal, cardiac, and smooth muscles
 blood clotting
 transmission of nerve impulses
 …………
 Excitable cells such as neurons are sensitive to changes in
calcium ion concentrations

12. Functions of calcium
 Neuromuscular excitability
 Even minor variations in the concentration of free ECF calcium
can have a profound and immediate effect on the sensitivity of
excitable tissues

13. Functions of calcium
 Increases in calcium ion concentration above normal (hypercalcemia)
cause progressive depression of the nervous system
 Decreases in calcium concentration (hypocalcemia) cause the
nervous system to become more excited

14. Functions of calcium
 Decrease in the free calcium
 Increases sodium permeability
 Influx of sodium
 Moves RMP close to threshold
 Even an ineffective stimulus can bring tissue to threshold
 If severe enough, spastic contraction of the respiratory muscles results in
death by asphyxiation

15. Functions of calcium
 Hypercalcemia (elevated blood Calcium) is also life threatening
 because it causes cardiac arrhythmias
 and generalized depression of neuromuscular excitability

16. Functions of calcium
 Excitation–contraction coupling in cardiac and smooth muscle
 Action potential
 increases calcium permeability
 Entry of ECF Calcium into cardiac and phasic smooth muscle cells
 triggers the contractile mechanism

17. Functions of calcium
 Excitation–contraction coupling in cardiac and smooth muscle
 Calcium is also necessary for excitation–contraction coupling in
skeletal muscle fibers
 but in this case the calcium is released from intracellular calcium
stores in response to an action potential

18. Note
 Rise in cytosolic calcium within a muscle cell causes contraction
 Increase in free ECF calcium decreases neuromuscular
excitability and reduces the likelihood of contraction

19. Functions of calcium
 Stimulus–secretion coupling
1. Appropriate stimulation
2. increased permeability to calcium
3. entry of calcium into secretory cells
4. triggers the release of the secretory product by exocytosis
 secretion of neurotransmitters by nerve cells and for secretion of
hydrophilic hormones by endocrine cells

20. Functions of calcium
 Excitation–secretion coupling
1. In pancreatic beta cells
2. membrane depolarization
3. calcium entry from the ECF
4. leads to insulin secretion

21. Functions of calcium
 Maintenance of tight junctions between cells
 Calcium forms part of the intercellular cement that holds particular
cells tightly together

22. Functions of calcium
 Clotting of blood
 Calcium serves as a cofactor in several steps of the cascade of
reactions that leads to clot formation

23. Functions of calcium
1. intracellular Calcium serves as a second messenger in many
cells
2. Involved in cell motility and cilia action
3. Calcium in bone and teeth is essential for the structural and
functional integrity of these tissues

24. Introduction
 Only about 0.1 percent of the total body calcium is in the extracellular
fluid
 About 1 percent is in the cells and its organelles
 Rest is stored in bones
 Bones can serve as large reservoirs

25. Introduction
 85 percent of the body’s phosphate is stored in bones
 14 to 15 percent is in the cells
 less than 1 percent is in the extracellular fluid

26. Introduction
 The calcium in the plasma is present in three forms
 About 41 percent (1 mmol/L) of the calcium is combined with the
plasma proteins and in this form is non-diffusible through the
capillary membrane

27. Introduction
 The calcium in the plasma is present in three forms
 about 9 percent of the calcium (0.2 mmol/L) is diffusible through
the capillary membrane but is combined with anionic substances
of the plasma and interstitial fluids (citrate and phosphate, for
instance) in such a manner that it is not ionized

28. Introduction
 The calcium in the plasma is present in three forms
 50 percent of the calcium in the plasma is both diffusible through
the capillary membrane and ionized.

29. Hormones
 Three other hormones
 parathyroid hormone
 calcitonin
 vitamin D
 control calcium and phosphate metabolism

30. Introduction
 These hormonal agents concern themselves with regulating
plasma Calcium
 in the process, plasma phosphate is maintained

31. Control of calcium metabolism
 Includes
 Regulation of calcium homeostasis
 Regulation of calcium balance

32. Control of calcium metabolism
 Regulation of calcium metabolism depends on hormonal control of
exchanges between the ECF and three other compartments
 Bone
 kidneys
 intestine

33. Calcium homeostasis
 Immediate adjustments required to maintain a constant free plasma
calcium concentration on a minute-to-minute basis
 This is largely accomplished by rapid exchanges between bone
and ECF
 and to a lesser extent by modifications in urinary excretion of calcium

34. Calcium balance
 More slowly responding adjustments required to maintain a constant
total amount of calcium in the body
 Control of calcium balance ensures that calcium intake is
equivalent to calcium excretion over the long term (weeks to
months).

35. Calcium balance
 Calcium balance is maintained by adjusting the extent of
intestinal calcium absorption and urinary calcium excretion

36. Parathyroid hormone
 Parathyroid hormone, the principal regulator of calcium metabolism
 acts directly or indirectly on all three of these effector sites
 Bone, kidney and intestine
 It is the primary hormone responsible for maintaining calcium
homeostasis and is essential for maintaining calcium balance

37. Vitamin D
 Vitamin D also contributes in important ways to calcium balance

38. Parathyroid hormone
 Calcitonin, is not essential for maintaining either calcium homeostasis
or balance
 It serves a backup function during the rare times of extreme
hypercalcemia

39. Parathyroid hormone
 Parathyroid hormone (PTH) is a peptide hormone secreted by the
parathyroid glands
 Four rice grain–sized glands located on the back surface of the
thyroid gland, one in each corner
 Like aldosterone, PTH is essential for life

41. Parathyroid hormone
 The overall effect of PTH is to increase the calcium concentration of
plasma
 Prevents hypocalcemia
 What happens if PTH is absent?

42. Parathyroid hormone
1) In the complete absence of PTH
2) death ensues within a few days
3) usually because of asphyxiation caused by hypocalcemic spasm of
respiratory muscles

43. Parathyroid hormone
 By its actions on bone, kidneys, and intestine
 PTH raises plasma calcium concentration
 when it starts to fall
 so hypocalcemia and its effects are normally avoided
 This hormone also lowers plasma phosphate concentration

44. Bone continuously undergoes remodeling
 99% of the body’s Calcium is in bone
 the skeleton serves as a storage depot for calcium
 Bone is a living tissue composed of an organic extracellular
matrix or osteoid
 made hard by hydroxyapatite crystals consisting primarily of
precipitated calcium phosphate salts

45. Bone continuously undergoes remodeling
 Normally, Ca3(PO4)2 salts are in solution in the ECF
 but conditions within bone are suitable for these salts to precipitate
(crystallize) around the collagen fibers in the matrix

46. Bone continuously undergoes remodeling
 By mobilizing some of these Calcium stores in bone, PTH raises
plasma calcium concentration when it starts to fall

47. Bone continuously undergoes remodeling
 Bone deposition (formation) and bone resorption (removal) normally
go on concurrently so that bone is constantly being remodeled
 Through remodeling, the adult human skeleton is completely
regenerated an estimated every 10 years

48. Bone continuously undergoes remodeling
 Bone remodeling serves two purposes:
 (1) it keeps the skeleton appropriately “engineered” for maximum
effectiveness in its mechanical uses
and
 (2) it helps maintain the plasma calcium level

49. PTH raises plasma Ca+2 by withdrawing Ca21
from the bone bank
 PTH uses bone as a “bank” from which it withdraws Calcium as
needed to maintain plasma Calcium level
 PTH has two major effects on bone that raise plasma Calcium
concentration

50. PTH raises plasma Ca+2 by withdrawing Ca21
from the bone bank
 First
 it induces a fast Calcium efflux into the plasma from the small labile
pool of Calcium in the bone fluid

51. PTH raises plasma Ca21 by withdrawing Ca21
from the bone bank
 Second
 by stimulating bone dissolution
 it promotes a slow transfer into the plasma of both Calcium and
Phosphate from the stable pool of bone minerals in bone itself

52. PTH raises plasma Ca+2 by withdrawing Ca21
from the bone bank
 PTH exerts its effects via cAMP
 The earliest effect of PTH is to activate membrane-bound Calcium
pumps
 located in the plasma membranes of the cytoplasmic extensions of
osteocytes and osteoblasts

53. PTH raises plasma Ca+2 by withdrawing Ca21
from the bone bank
 These pumps promote movement of Calcium, without the accompaniment
of Phosphate
 Movement of Calcium out of the labile pool across the bone membrane
accounts for the fast exchange between bone and plasma
 Because of the large surface area of the bone membrane, small
movements of Calcium across individual cells are amplified into large
Calcium fluxes between the bone fluid and plasma

54. PTH raises plasma Ca+2 by withdrawing Ca21
from the bone bank
 After Calcium is pumped out, the bone fluid is replenished with
Calcium from partially mineralized bone along the adjacent bone
surface
 PTH draws Calcium out of the “quick-cash branch” of the bone
bank and rapidly increases plasma Calcium without breaking down
mineralized bone itself

55. PTH’s chronic effect is to promote localized
dissolution of bone
 Dietary Calcium deficiency
 chronic hypocalcemia
 PTH stimulates localized dissolution of bone
 promoting a slower transfer into the plasma itself both Calcium and
Phosphate from the minerals within the bone itself

56. PTH’s chronic effect is to promote localized
dissolution of bone
 Osteoblasts have PTH receptors
 but osteoclasts do not
 PTH promotes localized bone dissolution by acting on osteoblasts
 causing them to secrete RANKL (receptor activator of NFkB)
 thereby indirectly stimulating osteoclasts to gobble up bone

57. PTH’s chronic effect is to promote localized
dissolution of bone
 PTH also transiently inhibits the bone-forming activity of the
osteoblasts

58. PTH’s chronic effect is to promote localized
dissolution of bone
 Continuous PTH secretion over months or years eventually leads
 to the formation of holes throughout the skeleton
 which are filled with very large, overstuffed osteoclasts

59. PTH’s chronic effect is to promote localized
dissolution of bone
 PTH promotes dissolution of Ca3(PO4)2 crystals in bone
 to harvest their Calcium content
 both Calcium and Phosphate are released into the plasma
 An elevated plasma PO4 is undesirable
 but PTH deals with this dilemma by its actions on the kidneys

61. PTH acts on the kidneys
 PTH promotes Calcium conservation and Phosphate elimination by the
kidneys during urine formation
 Under the influence of PTH
 the kidneys can reabsorb more of the filtered Calcium
 so less Calcium escapes into the urine
 This effect increases plasma Calcium
 Decreases urinary Calcium losses

62. PTH acts on the kidneys
 PTH decreases Phosphate reabsorption
 thus increasing urinary Phosphate excretion
 As a result
 PTH reduces plasma Phosphate at the same time it increases
plasma Calcium

63. PTH acts on the kidneys
 The third important action of PTH on the kidneys is to enhance
the activation of vitamin D by the kidneys

64. Regulation of PTH
 PTH secretion increases when plasma Calcium falls and decreases when
plasma Calcium rises
 this relationship forms a simple negative-feedback loop for controlling PTH
secretion without involving any nervous or other hormonal intervention
 The secretory cells of the parathyroid glands are directly and exquisitely
sensitive to changes in free plasma Calcium

65. Hyper secretion of PTH
 Hyperparathyroidism
 Caused by a hypersecreting tumor in one of the parathyroid glands
 characterized by hypercalcemia and hypophosphatemia
 The affected individual can be asymptomatic or symptoms can be severe,
depending on the magnitude of the problem

66. Hyper secretion of PTH
 Hypercalcemia reduces the excitability of muscle and nervous tissue
 leading to muscle weakness
 neurologic disorders
 including decreased alertness, poor memory, and depression
 Cardiac disturbances may also occur

67. Hyper secretion of PTH
 Excessive mobilization of Calcium and Phosphates from skeletal stores
leads to thinning of bone
 which may result in skeletal deformities and increased incidence of
fractures

68. Hyper secretion of PTH
 An increased incidence of Calcium containing kidney stones occurs
 because the excess quantity of Calcium being filtered through the
kidneys may precipitate and form stones
 These stones may impair renal function
 Passage of the stones through the ureters causes extreme pain
 Because of these potential multiple consequences, hyperparathyroidism
has been called a disease of “bones, stones, and abdominal groans.”

69. Hyper secretion of PTH
 hypercalcemia can also cause
 Peptic ulcers
 Nausea
 constipation

70. Hypo secretion of PTH
 Hypoparathyroidism, used to be the inadvertent removal of the
parathyroid glands
 during surgical removal of the thyroid gland (to treat thyroid disease)
 If all the parathyroid tissue was removed, these patients died, of course,
because PTH is essential for life
 surgeons are careful to leave parathyroid tissue during thyroid removal

71. Hypo secretion of PTH
 Rarely, PTH hyposecretion results from an autoimmune attack against
the parathyroid glands
 Hypoparathyroidism leads to hypocalcemia and hyperphosphatemia
 increased neuromuscular excitability from the reduced level of free
plasma calcium
 In the complete absence of PTH, death is imminent

72. Hypo secretion of PTH
 With a relative deficiency of PTH, milder symptoms of increased
neuromuscular excitability become evident
 Muscle cramps and twitches occur from spontaneous activity in the
motor nerves
 whereas tingling and pins-and-needles sensations result from
spontaneous activity in the sensory nerves
 Mental changes include irritability and paranoia

73. Hypo secretion of PTH
 hypocalcemia causes tetany
 It also occasionally causes seizures because of its action of increasing
excitability in the brain
 Tetany in the hand, which usually occurs before tetany develops in most
other parts of the body. This is called carpopedal spasm
 Tetany ordinarily occurs when the blood concentration of calcium falls
from its normal level of 9.4 mg/dl to about 6 mg/dl

76. Treatment for hypoparathyroidism
 PTH is occasionally used to treat hypoparathyroidism
 However, hypoparathyroidism is usually not treated with PTH because
this hormone is expensive
 its effect lasts for a few hours at most
 and the tendency of the body to develop antibodies against it makes it
progressively less and less effective

77. Treatment for hypoparathyroidism
 In most patients with hypoparathyroidism
 the administration of extremely large quantities of vitamin D
 to as high as 100,000 units per day
 along with intake of 1 to 2 grams of calcium
 keeps the calcium ion concentration in a normal range

78. Treatment for hypoparathyroidism
 At times, it might be necessary to administer 1,25-
dihydroxycholecalciferol instead of the nonactivated form of vitamin D
because of its much more potent and much more rapid action

79. Treatment for hypoparathyroidism
 However, administration of 1,25-dihydroxycholecalciferol can also cause
unwanted effects because it is sometimes difficult to prevent overactivity
by this activated form of vitamin D

80. Calcitonin
 Produced by the C cells of the thyroid gland
 Calcitonin has two effects on bone
 but in this case both effects decrease plasma Calcium levels
 Short term, calcitonin decreases Calcium movement from the bone fluid
into the plasma
 Long-term, calcitonin decreases bone resorption by inhibiting the
activity of osteoclasts via the cAMP pathway

81. Calcitonin
 The suppression of bone resorption reduces plasma Calcium
concentration and lowers plasma phosphate levels

82. Calcitonin
 Calcitonin also inhibits Calcium and Phosphate reabsorption from the kidney
tubules during urine formation, further reinforcing its hypocalcemic and
hypophosphatemic effects

83. Calcitonin
 Calcitonin has no effect on the intestine or on vitamin D

85. Calcitonin
 The primary regulator of calcitonin release is free plasma
Calcium concentration
 An increase in plasma Calcium stimulates calcitonin secretion
and a fall in plasma Calcium inhibits calcitonin secretion

86. Calcitonin
 Calcitonin plays little or no role in the normal control of Calcium
or Phosphate metabolism
 Although calcitonin protects against hypercalcemia, this condition
rarely occurs under normal circumstances

87. Vitamin D
 Cholecalciferol, or vitamin D, a steroid-like compound essential for Calcium
absorption in the intestine
 Vitamin D should be considered a hormone because the skin (specifically, the
keratinocytes) can produce it from a precursor related to cholesterol (7-
dehydrocholesterol) on exposure to sunlight.

88. Vitamin D
 Skin-produced vitamin D is subsequently released into the blood to act
at a distant target site, the intestine
 The skin, therefore, is actually an endocrine gland and vitamin D is a
hormone

90. Function of Vitamin D
 The most dramatic effect of activated vitamin D is to increase Calcium
absorption by the intestine
 Unlike most dietary constituents, dietary Calcium is not indiscriminately
absorbed by the digestive system
 In fact, the majority of ingested Calcium is typically not absorbed but is lost in
the feces
 More dietary Calcium is absorbed into the plasma under the influence of
vitamin D

91. Function of Vitamin D
 Independently of its effects on Calcium absorption, the active form of
vitamin D increases intestinal phosphate absorption
 vitamin D increases responsiveness of bone to PTH
 Thus, vitamin D and PTH are closely interdependent

92. Action of Vitamin D
 Vit D binds with nuclear vitamin D receptor (VDR)
 Hormone-receptor complex
 binding with the vitamin D–response element in DNA
 Protein synthesis
 Proteins exerts action

93. Vitamin D Deficiency
 Impaired intestinal absorption of Calcium
 PTH maintains the plasma Calcium level at the expense of the bones
 bone matrix is not properly mineralized because Calcium salts are not
available for deposition
 The demineralized bones become soft and deformed, bowing under the
pressures of weight bearing, especially in children
 This condition is known as rickets in children and osteomalacia in adults

95. Rickets
 The plasma calcium concentration in rickets is only slightly depressed
 but the level of phosphate is greatly depressed
 This phenomenon occurs because the parathyroid glands prevent the calcium
level from falling by promoting bone resorption every time the calcium level
begins to fall
 However, no good regulatory system exists for preventing a falling level of
phosphate, and the increased parathyroid activity actually increases the
excretion of phosphates in the urine

96. Osteomalacia—“Adult Rickets”
 serious deficiencies of both vitamin D and calcium occasionally occur as a result of
steatorrhea (failure to absorb fat)
 because vitamin D is fat-soluble and calcium tends to form insoluble soaps with fat
 consequently, in steatorrhea, both vitamin D and calcium tend to pass into the feces
 Under these conditions,
 an adult occasionally has such poor calcium and phosphate absorption that rickets
can occur
 Rickets in adults almost never proceeds to the stage of tetany

97. Renal rickets
 Renal rickets” is a type of osteomalacia that results from prolonged
kidney damage
 failure of the damaged kidneys to form 1,25dihydroxycholecalciferol, the
active form of vitamin D
 In patients whose kidneys have been removed or destroyed and who are
being treated by hemodialysis, the problem of renal rickets is often
severe

98. Renal rickets
 Another type of renal disease that leads to rickets and osteomalacia is
congenital hypophosphatemia
 resulting from congenitally reduced reabsorption of phosphates by the
renal tubules
 This type of rickets must be treated with phosphate compounds instead
of calcium and vitamin D, and it is called vitamin D–resistant rickets

99. Osteoporosis
 A decrease in bone density resulting from reduced deposition of the
bone’s organic matrix

101. Osteoporosis
 It is different from osteomalacia and rickets because it results from
diminished organic bone matrix rather than from poor bone calcification

102. Osteoporosis
 In persons with osteoporosis the osteoblastic activity in the bone is
usually less than normal, and consequently the rate of bone osteoid
deposition is depressed

103. Osteoporosis
 The many common causes of osteoporosis are
 (1) lack of physical stress on the bones because of inactivity
 (2) malnutrition to the extent that sufficient protein matrix cannot be
formed
 (3) lack of vitamin C, which is necessary for the secretion of intercellular
substances by all cells, including formation of osteoid by the osteoblasts

104. Osteoporosis
 (4) postmenopausal lack of estrogen secretion because estrogens
decrease the number and activity of osteoclasts
 (5) old age, in which growth hormone and other growth factors diminish
greatly, plus the fact that many of the protein anabolic functions also
deteriorate with age, so bone matrix cannot be deposited satisfactorily

105. Osteoporosis
 (6) Cushing syndrome,
 because massive quantities of glucocorticoids secreted in this disease
cause decreased deposition of protein throughout the body
 and increased catabolism of protein
 have the specific effect of depressing osteoblastic activity
 Thus, many diseases of deficiency of protein metabolism can cause
osteoporosis

106. Osteoporosis- Treatment
 Calcitonin (Miacalcin), slows osteoclast activity, is used to treat
advanced osteoporosis
 traditionally it had to be injected daily
 Now calcitonin is available in a more patient-friendly nasal spray
(Fortical)

107. Osteoporosis- Treatment
 Despite advances in osteoporosis therapy
 treatment is still often less than satisfactory
 and all the current therapeutic agents are associated with some undesirable
side effects
 Therefore, prevention is by far the best approach to managing this disease
 Continued physical activity throughout life appears to retard or prevent bone
loss, even in the elderly

108. THANK YOU