RANIA AHMEDENDOCRINE

August 15 ,2012

Objective

Calcium homeostasis PTH structure and functionCaSR structure and actions Vitamin D metabolismCalcitonin

CALCIUM HOMEOSTASISSerum 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.

Calcium Metabolism40 % bound to plasma proteins , albumin10 % 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 .

Calcium MetabolismBased 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.

PTH

EmbryologyThe 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

Anatomy Number of glands: can vary from 4-6 They measure 6 x 4 x 2 mm in maximum diameter

and weigh 25 - 40 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 .

Parathyroid Hormone peptide hormonesecreted 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

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

PTH ReceptorsPTH1R 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.

Action of PTH : CalciumPTH acts to increase the plasma Ca2+

concentration in three ways :1.It stimulates bone resorption, resulting in the

release of calcium phosphate.2.It enhances intestinal Ca2+ and phosphate

absorption by promoting the formation of calcitriol (1,25 dihydroxycholecalciferol)within the kidney.

3.It augments active renal Ca2+ reabsorption.

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

Effects of PTH on Bone• Increase bone turnover, osteoclastic bone

resorption and new bone formationIntermittent PTH administration has anabolic

activity on boneEnhanced mineralization, recruitment of

osteoblasts and reduction of apoptosisContinous administration/secretion results in

bone resorptionOsteoclast activation occurs secondarily to

osteoblast recruitment

Renal Actions of PTHStimulate Ca reabsorption Inhibits proximal and distal reabsorption

of phosphateStimulate Synthesis of 1,25-OH-Vitamin D

PTH homeostasis

Calcium-ion Sensing Receptor (CaSR)A G-protein coupled

receptorLocated 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

Calcium sensing receptorsAllows the parathyroid gland to detect

changes in Ca concentrationActions aim to normalize serum calcium

concentrationDecrease in serum Ca concentration is a

potent stimulus for PTH release

Effects of CaSR on PTHIn hypercalcemia, CaSR acts to:

Increase intracellular calciumDecrease PTH productionDecrease PTH secretionIncrease PTH degradation and promotes

urinary Ca2+ excretionIn chronic hypocalcemia, CaSR affects:

PTH gene expression Parathyroid cell proliferation

Renal Effects of CaSRCaSR expressed heavily in the thick

ascending limb of the Loop of Henle.CaSR also expressed in the

collecting duct.

– 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

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

Disorders of extracellular calcium-sensing by the calcium-sensing receptor (CaSR)

Inactivating Mutations of CaSR: Familial Hypocalciuric HypercalcemiaAutosomal dominant condition resulting in partial

CaSR function lossAbout 200 mutations have been identifiedMutated 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

Activating Mutations of CaSR: Autosomal Dominant Hypocalcemia • Caused by activating mutation of CaSRCaSR 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

Vitamin DLipid 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%).

Vitamin DVitamin 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.

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

Action in Intestine1,25 (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.

Action in BoneVitamin 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.

Action in KidneyThe 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 .

Denosumab in postmenopausal women with osteoporosisHuman 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.

Mechanism of actionDenosumab 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.

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.

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.

CAlCITONINCalcitonin 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.

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.