Hormones In Calcium And Bone Metabolism Flashcards
A normal adult body contains about
1kg of Ca
70kg indiv = 1,000g Ca
1% in soft tissues and extracellular fluids
Approx. 99% is present in the skeleton as
Hydroxyapatite (Ca10(PO4)6(OH)2)
A normal diet provides how much Ca per day
20-2000mg with an ave of 1000mg Ca per day
Approx. How much is absorbed, in majority in ileum bcs of its large absorptive surface
300g
Secreted into the intestinal tract in bile, pancreatic juice and intestinal secretions so that the net absorption of Ca equals about
175mg/day
The conc of Ca in plasma ave about
9.4mg/dL
Normally varying between 9 and 10 mg/dL
This is equivalent to about 2.4mmol of Ca per liter
The Ca present in plasma is present in 3 forms:
(1) 40% (1mmol/L) of Ca is combined w the plasma CHONs = nondiffusible form thru capillary mem
(2) 10% Ca (0.2 mmol/L) diffusible thru the cap mem but is combined w other subs of the plasma and interstitial fluids (citrate and phosphate) Not ionized
(3) 50% Ca is both diffusible and ionized (1.2 mmol/L or 2.4 mEq/L) divalent
The skeleton also serves as a storage depot for phosphorus and contains about how much of the total body phosphorus?
80%
The plasma conc of total Ca (ionized and non) is about
10mg/dL
Equivalent to 5mEq/L or 2.5mmol/L
Ca is present in plasma as
A. Ionized or free (45%)
B. Complexed w HPO4^2-, HCO3- or citrate ion (10%)
C. Bound to CHON (45%)
Sum of ionized and complexes Ca constitutes the diffusible fraction (55%) of Ca
The protein-bound form constitutes the nondiffusible fraction (45%)
Regulates the serum-ionized Ca conc
PTH, Calcitonin, Vit D
Distribution (mmol/L) of Ca in normal human plasma
Total diffusible
Ionized Ca
Complexed to HCO3, Citrate etc
Total diffusible = 1.34
Ionized Ca = 1.18
Complexed to HCO3, Citrate etc = 0.16
Total nondiffusible (protein bound)
Bound to albumin
Bound to globulin
Total nondiffusible (protein bound) = 1.16
Bound to albumin = 0.92
Bound to globulin = 0.24Total plasma Ca
2.50mmol/L
This represents the Ca pool that is not readily exchangeable and it is not available for rapid mobilization
Larger Ca pool
This represents the Ca pool that is readily exchangeable bcs it’s in physiochemical equilibrium w the ECF
The pool consists of Ca phosphate salts and provides an immediate reserve for sudden decreases in bld Ca2+
Smaller Ca pool
When the pH of ECF becomes more acidic, there is a
Relative increase in H2PO4 and decrease in HPO4-
The ave total quantity of inorganic phosphorus represented by both phosphate ions is
4mg/dL
Varying between normal limits of 3-4mg/dL in adults and 4-5mg/dL in children
Total body phosphorus is
500-800g (16.1-25.8 mol), 85-90% of wc is in the skeleton
Total plasma phosphorus is abt
12 mg/dL
with 2/3 of total in organic compounds and remaining inorganic phosphorus mostly in PO4^3-, HPO4^2- and H2PO4-
When Ca intake is high, 1,25-dihydroxycholecalciferol levels fall bcs of
Increased plasma Ca
Relationship of Ca absorption and Ca intake
Inverse
Increase absorption
Increase CHON diet in adults
Ca absorption is also decreased by subs that form
Insoluble salts w Ca (e.g phosphates and oxalates or by alkalis)
Enters the intestines via secreted GI juices and sloughed mucosal cells
An additional 250mg/day of Ca
How much of daily intake of Ca is excreted in the feces
90% (900mg/day)
Pi is absorbed in the duodenum and small intestine by
Active transport and passive diffusion
It is linearly proportionate to dietary intake
Absorption of Pi
Ingested Ca excreted in urine
10% or 100mg/day
How many percent of plasma Ca is bound to plasma proteins and not filtered by the glomerular capillaries, the rest is combine d w anions s/a phosphate (9%) or ionized (50%) and is filtered thru the glomeruli into tye renal tubules
41%
Amount of phosphorus normally entering bone is about
3mg (97 umol/kg/d), w an equal amt leaving via reabsorption
% if filtered Pi us reabsorbed
85-90%
Proximal tubule accounts for most of the reabsorption, and is inhibited by PTH
Active transport
Renal phosphate excretion is ctrlled by an overflow mechanism this is when
Phosphate conc in plasma is below the critical value of abt 1mmol/L
The rate of phosphate loss is directly proportional to the additional increase thus kidneys regulate the phosphate conc in ECF by altering rate of phosphate excretion
Above critical conc
Ca doesn’t require an active transport process bcs the conc gradient across the membrane is
larger for Ca than for any other ion
Ca conc in ICF is
10-70 mmol/L
Ca in ECF is
10^-3 mol/L (actual value is 2.5x10^-3 mol/L)
The Ca gradient from outside to inside the cell is on the order of
10,000 to 1
Ca is bound to cell surfaces and has a role in
Stabilization of membrane and intracellular adhesion
Chronic hypocalcemia or hypophosphatemia greatly decreases
Bone mineralization
Causes NS excitement and tetany
- increase neuronal mem permeability to Na, easy action potentials
Hypocalcemia
At plasma Ca conc about 50% below normal, the peripheral nerve fibers become so excitable that they begin to
Discharge spontaneously
Elicit tetanic muscle contraction
Tetany in hand
Occurs before tetany in other body parts develop
Carpopedal spasm
Occurs when bld conc of Ca falls from its normal lvl of 9.4mg/dL wc is only 35% below normal Ca conc and usually lethal at about 4mg/dL
Tetany
When lvl of Ca in body fluids rises above normal, the ND depress and reflex are sluggish
Decrease QT interval
Lack appetite
Constipation
Depressed contractility of muscle walls of GI
Depressive effects begin to appear when the blood Ca rises above
12mg/dL
Marked: 15mg/dL
Ca rises above ___ in bld, Ca phos crystals ppt
17mg/dL
Exchangeable Ca salts in bones are
Amorphous Ca phos compounds
- mainly CaHPO4
The quantity of these salts that is available for exchange is abt 0.5 to 1% of the tCa salts of the bone
Total of 5-10g Ca
Within 3-5 mins after an cute increase in Ca ion conc, the rate of PTH secretion
Decreases
Relationship of PTH and Calcitonin
Inverse
Causes rapid deposition of Ca in bones
Inc in Calcitonin
Can cause a high Ca conc to return to normal perhaps considerably more rapidly than can be achieved by the exchangeable Ca-buffering mechanism alone
Excess Ca
Ca regulation involves 3 tissues, 3 hormones and 3 cell types
3 tissues: bone, intestine, kidney
3 hormones: PTH, calcitonin, activated vit D3
3 cell types: osteoblasts, osteocytes, osteoclasts
When plasma Ca falls
PTH secretion increases
Hypercalcemic hormone
PTH
Hypocalcemic hormone
Calcitonin
A 32 AA residue polypeptide secreted by the parafollicular (C) cells of thyroid gland
Calcitonin
As plasma Ca increases
Calcitonin secretion increases
Calcitonin release is stimulated by
Pentagastrin
A secosteroid containing 27 C atoms wc makes it the largest steroid hormone
Vit D3 (cholecalciferol)
The major bld form of vit D
Prevent rickets
Calcidiol (25-hydroxyvitamin D3) 25-hydroxycholecalciferol
Another active metabolite of vit D
On a molar basis, it is 100x more potent than calcidiol
Calcitriol (1,25-dihydroxyvitamin D3) 25-dihydroxycholecalciferol
Inhibits bone resorption and increases the amount of Ca in urine
Calcitonin
Acts on one of the PTH receptors and is important in skeletal dev in the uterus
PTHrP
lower plasma Ca lvls by inhibiting osteoclast formation and activity but over long pds they cause osteoporosis by decreasing bone formation and increasing bone resorption
Glucocorticoids
They decrease bone formation by
inhibiting protein synthesis in osteoblasts
they decrease absorption of Ca and PO4^3- from the intestine and increase the renal excretion of these increases the secretion of ions
Increases Ca excretion in the U but it also increases intestinal reabsorption of Ca and this effect may be greater than the effect on excretion w a resultant positive Ca balance
GH
generated by the action of GH stimulates CHON synthesis in the bone
IGF-I
may cause hypercalcemia, hypercalciuria and sometimes osteoporosis
Thyroid hormone
prevents osteoporosis probably by direct effect on the osteoblasts
estrogen
increases bone formation and there is significant bone loss in untreated diabetes
Insulin
is found in the form of hydroxyapatite crystals
Bone Ca
The empirical chemical formula for this substance is Ca10(PO4)6(OH)2 or {(ICa3PO4)2}3
Hydroxyapatite crystals
Fluoride ion can replace the OH- group and form
fluoroapatite {(Ca3PO4)2}3 CaF2
Ca:Phos ratio in bone is
1.7:1
A large SA is provided by the microcrystalline structure of bone; it is estimated to be
100 acres in human
over 90% of organic matrix is
collagen
bone is composed of tough organic matrix that is grealy strengthened by
deposits of Ca salts
early dev, bone exists as
osteoid - an organic, unmineralized matrix surrounding the bone cells that deposited it
embryonic germ layer that gives rise to cartilage, bone and muscle
Mesoderm
can differentiate as bone cells including:
- cells that deposit dentin in teeth
- cartilage and bone of the head
Neural crest cells
are highly differentiated cells that nonmitotic in their differentiated state
osteoblasts
- secrete and synthesize collagen
- cont abundant alk phos
- derived fr BM mesenchyme
become buried in bone matrix
has osteolytic activity
no longer syn collagen
osteocytes
large, multinucleated cells containing numerous lysosomes
they mediate bone resorption at bone surfaces
contain acid phos
are stimulated by PTH and form significant amounts of lactic and hyaluronic acids
osteoclasts
Might cause bone dissolution via an increased local conc of H+ wc solubilizes bone mineral and increases the activity of enz that degrade matrix
Derived from circulating monocytes
Osteoclasts
Stimulate osteoblasts
PTH 1,25-dihydroxycholecalciferol IL-1 T3, T4 HGH, IGF-1 PGE2 TNF Estrogen
Inhibit osteoblasts
Corticosteroids
Stimulate osteoclasts
PTH
1,25-dihyxycholecalciferol
IL-6, IL-11
Inhibit osteoclasts
Calcitonin Estrogen (by inhibiting production of certain cytokines) TGF-B IFN-a PGE2
Arise from the fourth brachial/pharyngeal pouch in conjunction w the ultimobrachial bodies
Superior parathyroid glands
Arise from the third brachial/pharyngeal pouches in conjunction w the thymus
Inferior parathyroid glands
Are more constant in position and lie at the level of the middle of the posterior border of the thyroid gland
Superior parathyroid glands
Close proximity to the cricothyroid membrane, entrance of the recurrent laryngeal nerve and usually cephalad to the
Superior thyroid glands
Variable in location than the superior glands
2cm in diameter centered on point that is on the posterolateral aspect of the lower pole of thyroid glands
Two inferior parathyroid glands
Removal of half the parathyroid glands usually causes
No major physiologic abnormalities
However, removal of 3 of the 4 normal glands
Causes transient hypoparathyroidism
If the parathyroid glands were accidentally removed during surgery, the person would suffer from
Tetany, a severe convulsive disorder
The parathyroid glands are ovoid bodies measuring about
6mm long in their greatest diameter
3mm wide
2mm thick
Approx. 40mg
Serve mainly to support the parenchyma consisting of cords or clusters of epithelial cells surrounded by reticular fibers
Septa
Major fxnal parenchymal cells of parathyroid glands are the slightly eosinophilic-staining
Chief cells
is synthesized in ribosomes of the RER to form proparathyroid hormones and a polypeptide
Preproparathyroid hormone
Probably present inactive phases of single cell type with chief cells being the actively secreting phase
Intermediate cells
Usually supply arterial blood to the parathyroid glands but they may be supplied by the superior thyroid arteries, thyroidea ima, esophageal arteries
Inferior thyroid arteries
Parathyroid veins drain into the plexus of veins on the
Anterior surface of the thyroid gland and trachea
Nerves of the parathyroid glands are derived from the thyroid branches of the
Cervical sympathetic ganglia
Polypeptide chain of 115 AA
Preprohormone
With 90AA
Prohormone
The final hormone has a molecular weight of about
9,500
The normal plasma lvl of intact PTH of
10-55pg/mL
PTH half-life
10 minutes
Doesn’t bind bind PTHrP and found in the brain, placenta and pancreas
Second receptor, PTH2 (hPTH2-R)
Reacts w the carboxyl terminal rather than the amino terminal of PTH.
Third receptor
CPTH
The first 2 are serpentine receptors coupled to Gs and via this heterotrimetric G protein they activate
Adenylyl cyclaee
- increasing intracellular cAMP
In the parathyroid, its activation
Inhibits PTH secretion
Acts directly on the parathyroid glands to decrease preproPTH mRNA
1,25-dihydroxycholecalciferol
Stimulates PTH secretion by lowering plasma Ca and inhibiting the formation of 1,25-dihydroxycholecalciferol
Increased plasma phosphate
Required to maintain normal parathyroid secretory responses
Impaired PTH release along with diminished target organ responses to PTH account for the hypocalcemia that occasionally occurs in Mg deficiency
Magnesium
PTH action on bone is increased mobilization of Ca and Phos (i.e bone dissolution) from the
Nonreadily exchangeable Ca pool
The long term effects of PTH on bone remodeling, wc involves
Bone resorption and accretion
Stimulate bone syn
PTH
In adults, hematopoietic tissue is more abundant in
Trabecular bone
A mediator of bone resorption bcs PTH stimulates adenylyl cyclase in bone cells
cAMP
With the dissolution of stable bone, _____ is excreted in the urine. This forms tye basis for assessing collagen metabolism and thereby the relative rate of bone resorption
Hydroxyproline
Both active and passive transport but most of the intestinal absorption of Ca occurs via facilitated diffusion
Ca and Phos absorbed by intestine
They act synergistically to absorb Ca and Phos
PTH and calcitriol
Increased intestinal absorption of Ca promoted by PTH is mediated indirectly through the increased synthesis of
Acts on the intestine to promote the transport of Ca and Phos
Calcitriol
Increased intestinal absorption of Ca promoted by PTH is mediated indirectly through the increased synthesis of
Acts on the intestine to promote the transport of Ca and Phos
Calcitriol
PTH increases the renal threshold for Ca by
Promoting the active reabsorption of Ca by the distal nephron, including the distal tubule, cortical thick ascending limb of LoH, and connecting segment
PTH inhibits
The proximal tubular reabsorption of Ca
PTH inhibits
Phosphate reabsorption in the proximal tubules (lowers renal threshold for HPO4 wc leads to a phosphatase diuresis (phosphaturia))
Both increased PTH secretion and Phosphate depletion stimulate the formation of
Calcitriol via the activation of 1a-hydroxylase
The phosphaturic effect of PTH may be mediated by
cAMP, bcs PTH activates adenylyl cyclase in the renal cortex
PTH increases the urinary excretion of
Na, K and HCO3
PTH decreases the excretion of
NH4 and H
The unopposed effects of PTH on bone, intestines and kidney include
Hypercalcemia
Hypophosphatemia
Hypocalciuria
Hyperphosphaturia
32 AA polypeptide w an AT disulfide bridge linking positions 1 and 7 and an amidated carboxy terminus
MW 3400
Calcitonin
Syn in C cells or parafollicular cells of neuroendocrine origin
Loc: within thyroid gland but to a lesser extent the thymus gland
Calcitonin
Calcitonin half-life
<10
Serpentine receptors for calcitonin are in
Bones
Kidneys
Lowers the circulating Ca and Phosphate lvls
Calcitonin
Calcitonin exerts its calcium lowering effect by
Inhibiting bone resorption
This action is direct abd calcitonin inhibits the activity of
Osteoclasts in vitro
Calcitonin increases Ca excretion in
Urine
Serves as the second messenger for calcitonin action
cAMP
Synthesis and secretion qof calcitonin are ctrlled by the
conc of ionized serum Ca
Increase Ca 9mg/dL
Calcitonin secretion increases in a linear fashion
Decreased ionized Ca = increase PTH secretion to restore serum Ca =
Decrease calcitonin to remove a hypocalcemic effect
Inhibits osteoclastic activity
Antihypercalcemic effect is c/b principally by the direct inhibition of bone resorption
Calcitonin
Associated w an increase in alkaline phosphatase synthesis from the osteoclasts
Promotes urinary excretion of Ca , phosphate and Na
Inhibits renal 1a-hydroxylase activity
Calcitonin
Effects of calcitonin are most marked when the rates of bone turnover and osteoclast fxn are highest, as in the young or in dses such as
Paget’s dse
In the epidermis, the previtamin 7-dehydrocholesterol is transformed into the
Lipid-soluble vitamin D3
Teh plant sterol is transformed into Vit D2 (ergocalciferol) by irradiation and has been the main source of vit D that added to food (melk)
Ergosterol
In the liver, vit D3 is converted to calcidiol is converted to calcitriol by the action of
1a-hydroxylase
The reaction involves the rapid formation of previtamin D3 wc is converted more slowly to
vit D3 (cholecalciferol)
Normal plasma lvl if 25 hydroxycholecalciferol
30ng/mL
Normal 1-25dihydroxycholecalciferol
0.03ng/mL (approx. 100 pmol/L)
They are steroids in wc one of the rings has been opened
VitD2 and its derivatives are secosteroids
Increases the activity of 1a-hydroxylase and circulating 1,25-dihydroxycholecalciferol is increased during lactation
Prolactin
Increases total circulating 1,25-dihyroxycholecalciferol but this is probably dt a increase in the secretion of its binding protein w/o any steady state change in free, 1,25-dihydroxycholecalciferol
Estrogen
Associated w decreased circulating 1,25-dihydroxycholecalciferol and an increase incidence of osteoporosis
Hyperparathyroidism
Stimulate 1,25-dihy formation
GH, hCS and Calcitonin
Depresses prodxn of 1,25-dihy
Metabolic acidosis
The mRNAs that are produced in response to 1,25-dihy dictate the formation of a family of
Also members of trop C
Calbindin-D proteins
MW of 9000 and binds 2 Ca
Calbindin-D 9K
MW of 28,000 and binds 4 Ca even though it has 6 Ca binding sites
Calbindin-D 28K
Increase Ca absorption
Facilitates Ca reabsorption in the kidneys
1,25-dihy
Acts on bone, where it mobilizes Ca and PO4^3- by increasing the number of mature osteoclasts
Stimulates osteoblasts but net effect is still Ca mobilization
1,25-dihy
Promotes the distal tubular reabsorption of Ca
Calcitriol
Direct effect of calciferols on bone is
Resorption
Plays imp role in both bone absorption and bone deposition
Vit D
Signs of neuromuscular hyperexcitability appear
Full blown hypocalcemic tetany
Plasma phosphate lvls usually rise as the plasma Ca lvl fall after parathyroidectomy but rise doesn’t always occur
Hypoparathyroidism
A quick contraction of the ipsilateral facial muscles elicited by tapping over facial nerve at angle of jaw
Chvostek’s sign
Spasm of the muscles of the upper ex that causes flexion of the wrist and thumb w extension of the fingers
Trousseau’s sign
When the parathyroid gland are suddenly removed, the Ca lvl in bld falls from the normal 9.4mg/dL to
6-7mg/dL within 2-3 days and bld phosphate conc may double
Failure to absorb fat
Steatorrhea
Resulting from congenitally reduced absorption of phosphates by the renal tubules
Congenital hypophosphatemia
Inappropriate, excess PTH secretion
Primary hyperparathyroidism
Causes extreme osteoclastic activity in the bones
This elevates the Ca ion conc in the ECF while usually depressing the conc of phosphate ions bcs of increased renal excretion of phosphate
Hyperparathyroidism
The cystic bone dse of hyperparathyroidism
Osteitis fibrosa cystica
Important diagnostic findings in hyperparathyroidism
High lvl plasma alkaline phosphatase
Cause the plasma Ca lvl to rise to
12-15mg/dL
High lvls PTH as compensation for hypocalcemia rather than as primary abnormality
Secondary hyperparathyroidism
C/b vit D def or chronic renal dse
Sec hyperparathyroidism
Hypercalcemia by eroding bone
Local osteolytic hypercalcemia
Elevated circulating lvls of PTHrP
Humoral hypercalcemia of malignancy
A condition in wc there’s a chronic moderate elevation in plasma Ca bcs the feedback inhibition of PTH secretion by Ca is reduced
Familial benign hypocalciuric hypercalcemia
Indivs who r homozygous for inactivating mutations develop
Neonatal severe primary hyperparathyroidism
Indivs w activating mutations of the gene for the Ca receptor develop
Familial hypercalciuric hypocalcemia d/t increased sensitivity of parathyroid glands to plasma Ca
S&S hypercalcemic dse
Fatigue, lethargic, weak Confusion, coma Anorexia, nausea Abdominal pain, constipation Polyuria, polydipsia, nocturia Widespread soft tissue calcification
S&S hypocalcemia
Perioral parasthesias, tingling of fingers and toes Spontaneous tetany Chvostek's (+) Trousseau's (+) Rickets
Labs of hypercalcemic
Serum Ca >3mmol/L (12mg/dL) Cardiac arrhythmia (bradyarrhythmias or heart block)
Labs for hypocalcemic dse
Dec serum Ca of 0.2 mmol/L for every 10g/L decrease in albumin
Prolonged QT int and marked ST and QRS changes that mimic an MI
