1. Calcium..PTH .. CaSR Vitamin D
RANIA AHMED
ENDOCRINE
August 15 ,2012

2. Objective Calcium homeostasis PTH structure and function
CaSR structure and actions
Vitamin D metabolism
Calcitonin

3. CALCIUM HOMEOSTASIS
Serum calcium concentrations are normally maintained within the very narrow range that is required for the optimal activity of extracellular and intracellular processes.
Intracellular :
secretion ,differentiation , proliferation , motility ,and cell death.
Extracellular:
»hormones secretion
»excitation-contraction
»synaptic transmission
»platelet aggregation and coagulation.

6. Calcium Metabolism 40 % bound to plasma proteins , albumin
10 % bound to small anions such as phosphate and citrate
50% Ionized state
Concentration of ionized ca 1.25±0.07mmol/L,
It is the ionized ca that is regulated in extracellular fluid .

7. Calcium Metabolism
Based on a balance between intestinal absorption, bone mineralization and demineralization, and urinary filtration and reabsorption.
Major direct regulators:
Dietary intake
Parathyroid hormone (PTH)
1,25 (OH)2-cholecalciferol
Calcitonin.

9. PTH
PTH

10. Embryology The parathyroid glands develop at 6 weeks.
Superior parathyroid glands develop with the thyroid gland from the fourth branchial pouch and are residing lateral and posterior to the upper pole of the thyroid at the level of the cricothyroid cartilage.
Inferior parathyroid glands descend with the thymus from the third branchial pouch and migrate to the level of the aortic arch or, rarely, fail to migrate, remaining in the high neck
parathyroid glands typically located posterolateral to the thyroid

12. Anatomy Number of glands: can vary from 4-6
They measure 6 x 4 x 2 mm in maximum diameter and weigh mg each.
Arterial supply: inferior thyroid artery
venous drainage: inferior, middle, superior thyroid veins
Adult parathyroid gland:
50% parenchyma 50% fat
cell types:
chief cells
oxyphil cells
Both types make Parathyroid hormone .

13. Parathyroid Hormone peptide hormone secreted by chief cells
half-life is only 10 minutes.
Increased by: low serum calcium
Decreased by:
high serum calcium,
low magnesium,
High 1,25 dihydroxy vitamin D

14. Parathyroid Hormone
PTH is synthesized in the parathyroid gland as a precursor hormone,preproparathyroid hormone, which is cleaved first to proparathyroid hormone and then to the final 84-amino-acid PTH.
Secreted PTH has a half-life of 2 to 4 minutes.
In the liver, PTH is metabolized into the active N-terminal component and the relatively inactive C-terminal fraction

15. PTH Receptors
PTH1R expressed in bone and kidney, and also present in breast ,skin ,heart ,blood vessels and pancreas
PTH1R binds intact PTH and N-terminal residues.
Activation of PTH1R activates multiple cellular pathways and release intracellular calcium stores.
PTH2R expressed in the CNS,CVS ,GIT, lung and testes
PTH2R selectively binds PTH only.
C-PTHRs which present in bone with specificity to carboxyl-terminal region of PTH, PTH 7-84 and shown to possess hypocalcemic activity ,that is reserved by PTH1-34and PTH 1-84.

16. Action of PTH : Calcium
PTH acts to increase the plasma Ca2+ concentration in three ways :
It stimulates bone resorption, resulting in the release of calcium phosphate.
It enhances intestinal Ca2+ and phosphate absorption by promoting the formation of calcitriol (1,25 dihydroxycholecalciferol)within the kidney.
It augments active renal Ca2+ reabsorption.

17. Regulation of PTH Secretion: Calcitriol & Ions
Calcitriol (1,25-OH-Vit D)
Binds to the intracellular vitamin D receptor and inhibits PTH gene expression
Inhibits parathyroid cell proliferation
Magnesium
Maintains normal parathyroid secretory response
Hypomagnesemia impairs response to PTH and its release  hypocalcemia
Phosphate
Hyperphosphatemia stimulates PTH secretion
Stimulates parathyroid growth

18. Effects of PTH on Bone
Increase bone turnover, osteoclastic bone resorption and new bone formation
Intermittent PTH administration has anabolic activity on bone
Enhanced mineralization, recruitment of osteoblasts and reduction of apoptosis
Continous administration/secretion results in bone resorption
Osteoclast activation occurs secondarily to osteoblast recruitment

19. Renal Actions of PTH Stimulate Ca reabsorption
Inhibits proximal and distal reabsorption of phosphate
Stimulate Synthesis of 1,25-OH-Vitamin D

20. PTH homeostasis
PTH Homeostasis

22. Calcium-ion Sensing Receptor (CaSR)
A G-protein coupled receptor
Located on the cell surfaces of parathyroid and renal tissues, Also in thyroidal C cells, brain cells & GI tract
Mediates the effects of Ca on target tissues & acts as a first-messenger

23. Calcium sensing receptors
Allows the parathyroid gland to detect changes in Ca concentration
Actions aim to normalize serum calcium concentration
Decrease in serum Ca concentration is a potent stimulus for PTH release

24. Effects of CaSR on PTH In hypercalcemia, CaSR acts to:
Increase intracellular calcium
Decrease PTH production
Decrease PTH secretion
Increase PTH degradation and promotes urinary Ca2+ excretion
In chronic hypocalcemia, CaSR affects:
PTH gene expression
Parathyroid cell proliferation

26. Renal Effects of CaSR
CaSR expressed heavily in the thick ascending limb of the Loop of Henle.
CaSR also expressed in the collecting duct.

27. Located on the basolateral aspect of cells
Elevated serum Ca inhibits reabsorption of filtered Ca, Mg and NaCl
Located on the apical aspect of cells
Inhibits ADH action  inhibits concentration of urine and results in isotonic polyuria

28. Disorders with parathyroid-specific decrease in sensitivity to Ca2+
Disorders of extracellular calcium-sensing by the calcium-sensing receptor (CaSR)
Disorders with generalized decrease in sensitivity to Ca2+ (affecting all CaSR-expressing tissue)
1. Familial hypocalciuric hypercalcemia (FHH)
2. Neonatal (NHPT) and neonatal severe hyperparathyroidism (SHPT)
3. Familial isolated hyperparathyroidism caused by CaSR mutations
4. Autoimmune hypocalciuric hypercalcemia
Disorders with parathyroid-specific decrease in sensitivity to Ca2+
1. Primary hyperparathyroidism
2. Severe uremic secondary and tertiary hyperparathyroidism
Disorders with generalized increase in sensitivity to Ca2+
1. Autosomal dominant hypoparathyroidism (ADH) due to activating CaSR mutations
2. ADH with features of Bartter's syndrome
3. Hypoparathyroidism due to activating antibodies to the CaSR

29. Inactivating Mutations of CaSR: Familial Hypocalciuric Hypercalcemia
Autosomal dominant condition resulting in partial CaSR function loss
About 200 mutations have been identified
Mutated CaSR less sensitive to Ca therefore
higher concentrations required to decrease PTH release from parathyroid glands
In the kidney, defect results in increased tubular Ca and Mg reabsorption
Net result is hypercalcemia, hypocalciuria, hypermagnesemia, inappropriately normal or high PTH

30. Activating Mutations of CaSR: Autosomal Dominant Hypocalcemia
Caused by activating mutation of CaSR
CaSR more sensitive to serum calcium levels therefore PTH release inhibited at lower serum Ca levels
In the kidneys, reabsorption of Ca inhibited at lower serum Ca levels
Net result is hypocalcemia, hypercalciuria and inappropriately low or normal PTH

31. Vitamin D
Lipid soluble compounds with a four-ringed cholesterol backbone.
SOURCES — Food and Sunlight.
Ultraviolet light photoisomerize provitamin D to vitamin D3 (cholecalciferol) in the skin from 7-dehydrocholesterol
Vitamin D transported in the blood principally bind to DBP (85%) and albumin (15%).

32. Vitamin D
Vitamin D2 is manufactured through the ultraviolet irradiation of ergosterol, it has a lower affinity than 25-hydroxyvitamin D3 for vitamin D-binding protein. Thus, 25-hydroxyvitamin D2 has a shorter half-life than 25OHD3
Production of 1,25(OH)2D in the kidney stimulated by PTH and IGF-1 and inhibited by FGF23 and high levels of calcium and phosphate.

34. VIT D Action
1,25-dihydroxyvitamin D binds to intracellular receptors VDR in target tissues and regulates gene transcription
Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
Stimulation of intestinal phosphate absorption, direct suppression of PTH release, regulation of osteoblast function, and allowing PTH-induced osteoclast activation and bone resorption
Production of 1,25(OH)2D in the kidney stimulated by PTH and IGF-1 and inhibited by FGF23 and high levels of calcium and phosphate

35. Action in Intestine
1,25 (OH)2D enhance the efficacy of small intestine to absorb calcium and phosphorus.
Both vitamin D and VDR are required for optimal absorption of calcium.
Vitamin D induce active cellular calcium uptake and transport mechanisms.
Calcium uptake is the rate limiting step in intestinal calcium absorption, which is highly dependent on vitD.
Vitamin D increase active phosphorus transport.

36. Action in Bone
Vitamin D is essential for the development & maintenance of mineralized skeleton.
Osteoblastic bone formation and osteoclastic bone resorption demand both vitamin D and VDR.
1,25(OH)2D VDR system is critical in PTH induced osteoclastogenesis.
1,25(OH)2D VDR increased the expression of RANKL on the surface of osteoblast ,RANK interaction with its receptor RANKL promotes maturation of osteoclast progenitor cell & mature osteoclast.
Vitamin D ,PTH and prostaglandin stimulate RANKL expression.

37. Action in Kidney
The kidney expresses VDR, and 1,25 (OH)2D stimulate Ca²-ATPase in distal tubule as well as 24,25(OH)2D production in the proximal tubule.
1,25 dihydroxyvitamin D decrease its own synthesis through negative feedback and decrease secretion and synthesis of PTH.
1,25 dihydroxyvitamin D increase expression of 25-hydroxyvitamin D-24-hydroxylase to catabolize 1,25(OH)2D to the water-soluble ,biological inactive calcitroic acid .

39. Denosumab in postmenopausal women with osteoporosis
Human monoclonal antibody to RANK ligand [RANK-L])
Approved for the treatment of postmenopausal osteoporosis in June 2010, and is highly effective in reducing the risk of vertebral, nonvertebral, and hip fracture risk.

40. Mechanism of action
Denosumab binds to osteoblast-produced RANK-L, thereby preventing RANK-L from binding to the osteoclast receptor, RANK. By preventing RANK-L from binding to RANK, there is less osteoclast differentiation and activity so that bone resorption decreases.

42. Denosumab
'FREEDOM' 5-year data indicates continued safety and efficacy, and will be extended.
Denosumab offers a highly effective and safe parenteral therapy for osteoporosis and is being studied long term with the extension of the FREEDOM trial, and in other osteoporotic states - in men and glucocorticoid-induced osteoporosis.
Dose of 60 mg by subcutaneous injection every 6 months.

44. The results of the pivotal registration fracture trial with denosumab versus placebo (‘FREEDOM’). Over 3 years denosumab (60 mg as a subcutaneous injection every 6 months) significantly reduced the incidence of vertebral, nonvertebral and hip fractures compared with placebo [Cummings et al. 2009].
Composite measurement excluding pathological fractures and those associated with severe trauma, fractures of vertebrae, skull, face mandible, metacarpals, fingers and toes.

45. CAlCITONIN Calcitonin is a 32-amino-acid peptide
Calcitonin secreted by parafollicular C cells of the thyroid.
Secretion of calcitonin is under the control of ionized ca.
CaSR expressed on C cell of thyroid ,high extracellular calcium increase secretion of calcitonin.
Hypocalcaemia inhibit calcitonin secretion.

46. Action of CALCITONIN
Osteoclast and proximal renal tubule cells express calcitonin receptors.
In the bone calcitonin inhibit osteoclastic bone resorption.
In the kidney calcitonin inhibits the reabsorption of PO4 and increase renal excretion of calcium.

48. THANK YOU