2. Scenario
A 50 year old female has had three vertebral fractures. She has also had a number of kidney stones. Routine labs revealed hypercalcemia.

3. Effects of Parathyroid Hormone on Bone Mineral Metabolism

4. Lecture Objectives At the end of the lecture students will be able to
Define the importance of calcium in bone mineral metabolism
Explain the action of Parathyroid Hormone on gut, bone and kidney.
Describe the role of 1,25-dihydroxy vitamin D and calcitonin in calcium homeostasis
List the symptoms of hyper and hypoparathyroidism

5. Physiological Importance of Calcium
Ca salts in bone provide structural integrity of the skeleton.
Ca ions in extracellular and intracellular fluids is essential for biochemical processes like:
Neuoromuscular excitability and signal transduction
Blood coagulation
Hormonal secretion
Enzymatic regulation
Neuron excitation

6. Three Forms of Circulating Ca2+

7. Regulation of Calcium
The important role that calcium plays in so many processes dictates that its concentration, both extracellularly and intracellularly, be maintained within a very narrow range.
This is achieved by an elaborate system of controls

8. Calcium and phosphorous
Calcium is tightly regulated with Phosphorous in the body.
Phosphorous is an essential mineral necessary for ATP, cAMP second messenger systems, and other roles
Ca2+ normally ranges from mg/dl in the plasma.
PO4 normal plasma concentration is mg/dl.

9. Extracellular Calcium
When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increase permeability of neuronal membranes to sodium.
Hyperexcitability causes tetanic contractions
Hypocalcemic tetany

10. Bone Composition

11. Bones
99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca++ storage.
10% of total adult bone mass turns over each year during remodeling process
During growth rate of bone formation exceeds resorption and skeletal mass increases.
Once adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resorption begins to exceed formation and bone mass slowly decreases.

12. Bone cell types
Osteoclasts (bone cells) remodel the bone by dissolving or resorbing bone
Osteoblasts (bone forming cells) synthesize new bone to replace the resorbed bone
Found on the outer surfaces of the bones and in the bone cavities
Osteocytes the mature bone cells are enclosed in bone matrix.

13. Bone formation Active osteoblasts synthesize and extrude collagen
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 H3CO3– hydroxyapatite.

14. Osteoblast and Osteoclast Function
Osteoblasts
Bone formation
Synthesis of matrix protein
Mineralization
Osteoclasts
Bone resorption
Degradation of proteins by enzymes
Acidification

16. Calcium, bones and osteoporosis
The total bone mass of humans peaks at years of age.
Men have more bone mass than women.
A gradual decline occurs in both genders with aging, but women undergo an accelerated loss of bone due to increased resorption during perimenopause.
Bone resorption exceeds formation.

17. Calcium, bones and osteoporosis
Reduced bone density and mass: osteoporosis
Susceptibility to fracture.
Earlier in life for women than men but eventually both genders succumb.
Reduced risk:
Calcium in the diet
habitual exercise
avoid drinking carbonated soft drinks

18. Vertebrae of 40- vs. 92-year-old women
Note the marked loss of trabeculae with preservation of cortex.

19. Calcium Homeostasis 1. Parathyroid Hormone 2. Calcitonin 3
Calcium Homeostasis 1. Parathyroid Hormone 2. Calcitonin 3. 1,25-dihydroxy vitamin D

20. Calcium regulates PTH

21. Key Organs Involved
Gut
Bone
Kidneys

22. Parathyroid
glands
Parathyroid glands which are embedded in the thyroid tissues in many vertebrate species.

23. PARATHYROID HORMONE
A polypeptide secreted from the parathyroid glands in response to a decrease in the plasma concentration of ionized calcium

24. Parathyroid Hormone Structure
Parathyroid hormone (PTH), an 84 amino acid-long polypeptide

25. Regulation of PTH
PTH secretion responds to small alterations in plasma Ca2+ within seconds.
An acute decrease of Ca results in marked increase of PTH mRNA increase of PTH synthesis
PTH secretion also is stimulated by low levels of 1,25-dihydroxy vitamin D

26. PTH increases Ca concentration by:
1: Action on the Bone
Increased PTH secretion leads to an increase in bone resorption by stimulating osteoclasts and promotes the release of calcium and phosphate into the circulation

27. PTH increases Ca concentration by:
2: Action on the Kidney
At the kidney, PTH acts to limit calcium excretion at the distal convoluted tubule via an active transport mechanism. It augments renal calcium reabsorption
PTH also inhibits phosphate reabsorption (at the Proximal convoluted tubule) and bicarbonate reabsorption.

28. PTH and Kidney
PTH acts on the distal tubule

29. PTH increases Ca concentration by:
3: Action on the Gut
PTH also stimulates renal 1- Hydroxylase activity, leading to an increase in 1,25-dihydroxy vitamin D, which Stimulates the absorption of Ca in the intestine

30. 1,25-dihydroxy-Vitamin D3 UV Low plasma Ca++ increase kidney enzymes
Cholesterol precursor
7-dehydrocholesterol
Vitamin D3
25 Vitamin D3
1,25 Vitamin D3
-made in the liver, the skin, the liver, and the kidney
Liver: cholesterol precursor transformed to 7-dehydrocholesterol
Skin: UV transforms 7-dehydrocholesterol to Vit D3
Liver: Enzyme transforms Vit D3 to 25-OH-Vit D3
Kidney: Enzyme transforms 25-Vit D3 to 1,25 Vit D3
-lack of melanin pigment in Northen Europeans was thought to account for the lower light level: let more UV across the skin to ensure high enough levels of Vit. D3
-increases Ca++ uptake from the gut
-made from cholesterol…….acts like a steroid…..what kind of receptors? How would they act? (they increase transcription and translation of Ca++ transport proteins in the epithelial cells of the gut)
-minor roll: also acts to stimulate osteoclasts, (which would do what?) increasing Ca++ resorption from the bone
-control of secretion:
-low Ca++ levels causes increase of PTH, which increases enzymes in the kidney (more enzyme, more 1,25 Vit. D3)
1,25 Vitamin D3
Low plasma Ca++ increase kidney enzymes

31. 1,25-dihydroxy-vitaminD3 ( Calcitriol)
Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxy-D3 is one of the principal regulator of Ca++.
The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D3.
Then 25-hydroxy D3 is transported to the kidney where the second hydroxylation reaction takes place.

32. 1,25-dihydroxy-vitamin D3 promotes intestinal calcium absorption
1,25-dihydroxy-D3 acts via steroid hormone like receptor to increase transcriptional and translational activity
One gene product is calcium-binding protein (CaBP)
CaBP facilitates calcium uptake by intestinal cells
calbindin (calcium-binding protein) – regulated by the active form of vitamin D

33. 1,25-dihydroxy-Vitamin D Actions on Bones
Another important target for 1,25-(OH)2-D3 is the bone.
Osteoblasts, but not osteoclasts have vitamin D receptors.
1,25-(OH)2-D3 acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca++ from the bone matrix.
1,25-(OH)2-D3 also stimulates osteocytic osteolysis.

34. PTH functions to regulate calcium levels via its actions on three target organs, the bone, kidney, and gut.

35. Calcitonin
Parathyroid
glands
Calcitonin is produced by the parafollicular or C cells of the thyroid interstitium; these cells do not play a role in thyroid hormone production.

36. Calcitonin Calcitonin is a 32 amino acid peptide
Inhibits osteoclast mediated bone resorption
Promotes renal excretion of Ca2+

37. Calcitonin
The major stimulus of calcitonin secretion is a rise in plasma Ca2+ levels
PTH and vitamin D act to increase plasma Ca2+ only calcitonin causes a decrease in plasma Ca2+.
Calcitonin is a physiological antagonist to PTH with regard to Ca2+ homeostasis

38. PTH Actions
The overall action of PTH is to increase plasma Ca++ levels and decrease plasma phosphate levels.
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 reabosorptioin of phosphate (thereby stimulating its excretion).
PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D synthesis.

39. Disorders of the Parathyroid Glands

40. Hypofunction Hyperfunction hypocalciemia hyperphosphatemia
hypophosphaturia
tetanus
Hyperfunction
hypercalciemia
hypophosphatemia
hyperphosphaturia
osteoporosis
Accumulation of Са in tissues 40

41. Hyperparathyroidism
Enlargement of a single gland or parathyroid adenoma in approximately 80% of cases, multiple adenomas or hyperplasia in 15 to 20% of patients and parathyroid carcinoma in 1% of patients

42. Hyperparathyroidism Most people are asymptomatic
Classically affects skeleton, kidneys, and GI tract
Triad of complaints: bones, stones, and abdominal groans
Renal stones are most common single presenting complaint
Usually due to an adenoma (tumor)

43. Hyperparathyroidism
The disorder is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia
Most common complication are renal stones made of calcium phosphate
Most serious complication is the deposition of calcium in the kidney tubules resulting in impaired renal function

44. Normal bone
Hyperparathyroid

45. Primary Hyperparathyroidism
Calcium homeostatic loss due to excessive PTH secretion
Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue
Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption
Surgery is the most common treatment for primary hyperparathyroidism.

46. Secondary Hyperparathyroidism
Secondary hyperparathyroidism occurs as a result of another disease that initially causes low levels of calcium in the body and over time, increased parathyroid hormone levels occur. This is due to chronic stimulation of the parathyroid glands by a chronic decrease in the ionic calcium level in the blood

47. Secondary Hyperparathyroidism
In pts with chronic renal failure
Deficiency of 1,25-dihydroxy vitamin D as a result of loss of renal tissue, low calcium intake, decreased calcium absorption, and abnormal parathyroid cell response
Normally treated medically

48. Congenital Hypoparathyroidism
Hypoplasia of the teeth, shortened roots, and retarded eruption

49. Hypoparathyroidism Deficient secretion of PTH which manifests itself
biochemically by hypocalcemia, hyperphospatemia
diminished or absent circulating PTH and , often causing
cramping and twitching of muscles or tetany.
The condition can be inherited, but it is also encountered
after thyroid or parathyroid gland surgery, and it can be
caused by immune system-related damage

50. Pseudohypoparathysoidism
A rare familial disorders with target tissue resistance to PTH. There is hypocalcaemia, hyperphosphataemia, with increased parathyroid gland function. There is also a variety of congenital defects in the growth and development of skeleton including:
Short statue
Short metacarpal and metatarsal bones

51. Pseudohypoparathyroidism
Elfin facies, short stature,
enamel hypoplasia

53. Hormonal Regulators Calcitonin (CT) Parathormone (PTH)
Lowers Ca++ in the blood
Inhibits osteoclasts and reabsorbtion through kidney
Parathormone (PTH)
Increases Ca++ in the blood
Stimulates osteoclasts
1,25 dihydroxy Vitamin D3
Increase Ca++ uptake from the gut

54. PRACTICE QUESTIONS

55. 1,25-dihydroxy vitamin D Calcitonin Parathyroid hormone
Q1. Secretion of which hormone is stimulated by hypercalciemia and it acts to lower the serum levels of calcium:
 1,25-dihydroxy vitamin D
Calcitonin
Parathyroid hormone
Thyroid hormone
Correct Answer: B
Explanation
1,25-dihydroxy vitamin D: It stimulates the absorption of Calcium in the intestine.
Calcitonin: It acts to decrease plasma Calcium levels.
Parathyroid hormone: It increases Calcium concentration by the action on gut, bone and kidney.
Thyroid hormone: Primarily responsible for regulation of body metabolism

56. Q2. Which hormone increases the resorption of bone by stimulating osteoclasts and promoting the reabsorption of calcium by the kidneys? a. 1,25-dihydroxy vitamin D b. Calcitonin c. Parathyroid hormone d. Thyroid hormone Correct Answer: C Explanation a. 1,25-dihydroxy vitamin D: It stimulates the absorption of Calcium in the intestine and Calcium resorption from the bone b. Calcitonin: It acts to decrease plasma Calcium levels. c. Parathyroid hormone: It increases Calcium concentration by bone resorption, renal reabsorption and act indirectly on intestine by stimulating1,25-dihydroxy vitamin D synthesis. d. Thyroid hormone: Primarily responsible for regulation of body metabolism.

57. Q3. The major effect of which hormone is a rapid fall in Calcium caused by inhibition of bone resorption:
1,25-dihydroxy vitamin D
Calcitonin
Parathyroid hormone
Thyroid hormone
Correct Answer: B
Explanation
a. 1,25-dihydroxy vitamin D: It stimulates the absorption of Calcium in the intestine.
b. Calcitonin: It inhibits osteoclast mediated bone resorption and promotes renal excretion of Calcium
c. Parathyroid hormone: It increases Calcium concentration by the action on gut, bone and kidney.
d. Thyroid hormone: Primarily responsible for regulation of body metabolism.

58. Q4. A 45 year old female has had three vertebral fractures
Q4.A 45 year old female has had three vertebral fractures. She has also had a number of kidney stones. Routine labs revealed hypercalcemia. Select the most likely diagnosis:
a. Hyperparathyroidism
b. Hypoparathyroidism
c. Osteomalacia
d. Ricket
Correct Answer: A
Explanation
A. Hyperparathyroidism: It is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia with renal stones made of calcium phosphate
B.Hypoparathyroidism: It is characterized by hypocalcemia, hyperphospatemia and diminished circulating PTH
C. Osteomalacia: It is the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D
D. Rickets: It is defective mineralization of bones due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium, potentially leading to fractures and deformity.

59. a. Hyperparathyroidism b. Hypoparathyroidism c. Osteomalacia d. Ricket
Q5. Which disorder is characterized by hypocalcemia, hyperphosphatemia?
a. Hyperparathyroidism
b. Hypoparathyroidism
c. Osteomalacia
d. Ricket
Correct Answer: B
Explanation
A. Hyperparathyroidism: It is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia with renal stones
B.Hypoparathyroidism: It is characterized by hypocalcemia, hyperphospatemia and diminished circulating PTH
C. Osteomalacia: It is the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D
D. Rickets: It is defective mineralization of bones due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium, potentially leading to fractures and deformity.