1. Hormonal Regulation of Calcium Balance

2. Introduction
Adequate amounts of calcium in its ionized form, Ca+2, are needed for normal function of all cells
Body calcium ultimately is derived from the diet, and daily intake usually is offset by urinary loss
The skeleton acts as a major reservoir of calcium and can buffer the concentration of calcium in extracellular fluid by taking up or releasing calcium phosphate

3. Different Effects of Calcium
Calcium enters into a wide range of cellular and molecular processes
Changes of its concentration within cells regulate:
enzymatic activities
and fundamental cellular events as
muscular contraction
Secretion
and cell division
calcium and calmodulin also act as intracellular mediators of hormone action

4. Different Effects of Calcium
In the extracellular compartment,
calcium is vital for blood clotting
calcium may act in a hormone-like way as an extracellular regulator of a variety of cellular responses through stimulation of membrane calcium receptors
basic mineral of bones and teeth
Its concentration in extracellular fluid must be maintained within narrow limits
Deviations in either direction are not readily tolerated and, if severe, may be life-threatening

5. Distribution of Calcium in the Body
The adult human body contains approximately 1,000 grams of calcium, about 99% of which is sequestered in bone, primarily in the form of hydroxyapatite crystals (Ca10(PO4)6 (OH)2)
In addition to providing structural support, bone serves as an huge reservoir for calcium salts
Each day about 600 milligrams of calcium is exchanged between bone mineral and the extracellular fluid
Most of the calcium that is not in bone crystals is found in cells of soft tissues bound to proteins within the sarcoplasmic reticulum, mitochondria, and other organelles

6. Distribution of Calcium in the Body
Resting concentration of free calcium in cytosol at low levels of about 0.1 μM
Cytosolic calcium can increase ten fold or more
The concentration of calcium in interstitial fluid is:
mainly of free, ionized calcium
10% is complexed with such anions as citrate, lactate, or phosphate
Total calcium in blood plasma is normally about 10 mg/dL
twice that of interstitial fluid
because calcium is avidly bound by albumin and other proteins

7. Calcium Balance
Normally, adults are in calcium balance; that is, on average, daily intake equals daily loss in urine and feces
Except for lactation and pregnancy, deviations from balance reflect changes in the metabolism of bone
Immobilization of a limb, bed rest and malignant disease are examples of circumstances that produce negative calcium balance
Whereas growth of the skeleton produces positive calcium balance

9. Intestinal Absorption
Calcium is taken up along the entire length of the small intestine, but uptake is greatest in the duodenum and jejunum
Absorption of calcium requires metabolic energy and the activity of specific carrier molecules in the luminal membrane
Calcium is carried down by its concentration gradient into the cytosol of intestinal epithelial cells and is extruded from the basolateral surfaces in exchange for sodium, which must then be pumped out at metabolic expense
Overall transfer of calcium from the intestinal lumen to interstitial fluid proceeds against a concentration gradient

10. Bone
Crystallization or solubilization of bone mineral is determined by physicochemical equilibria related to the concentrations of calcium, phosphate, hydrogen, and other constituents in bone water
The fluxes of calcium and phosphate into or out of the bone extracellular fluid involve active participation of the cells of the bone membrane (endosteum, periosteum, osteocytes)
Hormones regulate the calcium concentration in the extracellular fluid compartment and the mineralization of bone by regulating the activities of these cells

11. Bone

12. Bone Osteoblasts are the cells responsible for formation of bone
During growth or remodeling of bone, some osteoblasts become entrapped in matrix and differentiate into osteocytes
Osteoclasts are responsible for bone resorption

13. Kidney
Ionized and complexed calcium pass freely through glomerular membranes
Normally 98 to 99% of calcium filtered by the glomeruli each day is reabsorbed by the renal tubules
two-thirds of the reabsorption occurs in the proximal tubule
Much of the remaining calcium is resorbed in the loop of Henle
Reabsorption of calcium in the area of the junction of the distal convoluted tubules and the collecting ducts is governed by an active, process
Active transport of calcium in this region is the principal target of hormonal regulation of calcium excretion

14. Phosphorus Balance
Because of their intimate relationship, the fate of calcium cannot be discussed without also considering phosphorus
Calcium usually is absorbed in the intestines accompanied by phosphorus,
and deposition and mobilization of calcium in bones always occurs in conjunction with phosphorus
About 90% of the 500 to 800 g of phosphorus in the adult human is deposited in the skeleton
Much of the remainder is incorporated into organic phosphates distributed throughout soft tissues in the form of phospholipids, nucleic acids, and soluble metabolites

15. Phosphorus Balance
The concentration of inorganic phosphate in blood is about 3.5 mg/dL
About 55% is present as free ions
about 35% is complexed with calcium or other cations
and 10% is protein-bound
Phosphate concentrations are not tightly controlled and may vary widely under such influences as diet, age, and sex
Ionized and complexed phosphate pass freely across glomerular and other capillary membranes

16. Parathyroid Glands and Parathyroid Hormone
Parathyroid hormone (PTH) is the principal regulator of the extracellular calcium pool
It increases the calcium concentration and decreases the phosphate concentration in blood by various direct and indirect actions on
bone, kidney, and intestine
In its absence, the concentration of calcium in blood, and hence interstitial fluid, decreases dramatically over a period of several hours while the concentration of phosphate increases

17. Parathyroid Glands and Parathyroid Hormone
Human beings typically have four parathyroid glands, but as few as two and as many as eight have been observed
Each gland is a flattened ellipsoid measuring about 6 millimeters in its longest diameter
The aggregate mass of the adult parathyroid glands is about 120 milligrams in men and about 140 milligrams in women
These glands adhere to the posterior surface of the thyroid gland or occasionally are embedded within thyroid tissue

18. Parathyroid Glands and Parathyroid Hormone
Parathyroid glands are comprised of two cell types
Chief cells
predominate and are arranged in clusters or cords
They are the source of PTH and have all the cytological characteristics of cells that produce protein hormones:
rough endoplasmic reticulum, prominent Golgi apparatus, and some membrane-bound storage granules

19. Parathyroid Glands and Parathyroid Hormone
Oxyphil cells,
which appear singly or in small groups
are larger than chief cells and contain a remarkable number of mitochondria
have no known function
thought by some to be degenerated chief cells
Their cytological properties are not characteristic of secretory cells, but they are sometimes able to produce small amounts of PTH
Few oxyphil cells are seen before puberty, but their number increases thereafter with age

20. Biosynthesis, storage and secretion of PTH
PTH is a simple straight-chain peptide of 84 amino acids (expressed as a larger 115 amino acid preprohormone)
PTH then is packaged into secretory granules
Synthesis of PTH is regulated at both transcriptional and at posttranscriptional sites
Cyclic AMP, acting through the cyclic AMP response element binding protein (CREB), upregulates PTH gene transcription,
whereas vitamin D (and high levels of intracellular calcium) downregulates transcription

21. Biosynthesis, storage and secretion of PTH
Parathyroid cells are unusual in the respect that hormone degradation as well as synthesis is adjusted according to physiological demand
As much as 90% of the hormone synthesized may be metabolized within the chief cells, which cleave PTH into fragments at an accelerated rate when plasma calcium concentrations are high
The ratio of fragments to intact hormone released into the circulation increases when plasma calcium is high and decreases when it is low

22. Physiological Actions of PTH: Actions on Bone
Increases in PTH concentration in blood result in mobilization of calcium phosphate from the bone matrix due primarily, and perhaps exclusively, to increased osteoclastic activity
Although activity of all bone cell types is affected by PTH, it appears that only cells of osteoblastic lineage express receptors for PTH
Osteoclasts and their precursors are thus not direct targets for PTH
PTH acts on cells of osteoblastic
lineage to stimulate production of M-CSF (macrophage colony stimulating factor) and RANKL (receptor activator of N-kappa B ligand), which results in osteoclast formation and activation

23. Physiological Actions of PTH: Actions on Bone
With prolonged continuous exposure to high concentrations of PTH, as seen with hyperparathyroidism, osteoclastic activity is greater than osteoblastic activity, and bone resorption predominates
In addition to its critical role in maintaining blood calcium concentrations, PTH is also important for skeletal homeostasis
As already mentioned, bone remodeling continues throughout life
Remodeling of bone not only ensures renewal and maintenance of strength, but also adjusts bone structure and strength to accommodate the various stresses and strains of changing demands of daily living
Increased stress leads to bone formation strengthening the affected area,
and weightlessness or limb immobilization leads to mineral loss
Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood

24. Physiological Actions of PTH: Actions on kidney
In the kidney, PTH produces three distinct effects, each of which contributes to the maintenance of calcium homeostasis
In the distal nephron:
It promotes the reabsorption of calcium
In the proximal tubule:
It inhibits reabsorption of phosphate
Promotes hydroxylation, and hence activation of vitamin D
In producing these effects, PTH binds to G-protein coupled receptors in both the proximal and distal tubules and stimulates the production of cyclic AMP, diacylglycerol, and IP3

25. Physiological Actions of PTH: Effects on Intestinal Absorption
Calcium balance finally depends on intestinal absorption of dietary calcium
Calcium absorption is severely reduced in hypoparathyroid patients and dramatically increased in those with hyperparathyroidism
Intestinal uptake of calcium is stimulated by an active metabolite of vitamin D
PTH stimulates the renal enzyme that converts vitamin D to its active form, but has no direct effects on intestinal transport of either calcium or phosphate

26. Parathyroid hormone-related peptide (PTHrP)
Closely related to PTH
PTHrP bind with high affinity to the PTH receptor and therefore produce the same biological effects as PTH
Except during lactation little or no PTHrP is found in blood plasma of normal individuals
Found in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcemia
PTHrP thus appears to function in calcium homeostasis during lactation when secretion of milk may drain as much as 300 mg of calcium from the mother’s body each day
occasionally secreted by cancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma)

27. Regulation of PTH Secretion
Chief cells are exquisitely sensitive to changes in extracellular calcium and rapidly adjust their rates of PTH secretion in a manner that is inversely related to the concentration of ionized calcium
The resulting increases or decreases in blood levels of PTH produce either positive or negative changes in the plasma calcium concentration and thereby provide negative feedback signals for regulation of PTH secretion
The activated form of vitamin D, whose synthesis depends on PTH, is also a negative feedback inhibitor of PTH synthesis