that they begin to discharge spontaneously,

BONE AND PARATHYROID METABOLISM

CALCIUM
Dr. Labrador
Normal Values: 9.4 mg/dl or 2.4 mmol/L initiating trains of nerve impulses that pass
 Hypercalcemia - CNS DEPRESSION to the peripheral skeletal muscles
 Hypocalcemia -CNS STIMULATION  9.4 mg/dL to 6 mg/dL - lethal at 4 mg/dL
 Seizures
Total Body Calcium  Increasing excitability in the brain
 ECF - 0.1%  Laboratory animals
 Cells - 1%  Marked dilatation of the heart
 Bones - 98.9% (largest reservoir of calcium)  Changes in cellular enzyme activities
 Increased membrane permeability in some
 Complexed - 10% cells
 Protein-bound - 40%  Impaired blood clotting
 Ionized - 50%
 Carpopedal spasm
CALCIUM in Plasma  Tetany in the hand
 Usually occurs before tetany develops in
With anions Nondiffusible most other parts of the body
(41%) thru
membrane
HYPERCALCEMIA
Protein-bou Diffusible Unionized
 Abnormal neurologic function that involves
nd (9%)
muscle weakness, depression, confusion, coma
Ionized Diffusible Ionized  Gastrointestinal disturbances
(50%) Functional  EKG abnormalities (shortening of QT interval)
Normal levels: 1.2 mmol/L or 2.4 mEq/L  Kidney abnormalities: kidney stones
One half of total plasma Ca concentration  Cause CNS depression
PHOSPHATE  Sluggish reflexes
 Lack of appetites, constipation-depressed
contractility of GIT muscles
Forms Concent Acidic Basic  Symptoms at 12 mg/dL-15 mg/dL
ration  Calcium crystals at 17 mg/dL
HPO4 1.05 Increased decreased
mmol/L INTESTIAL ABSORPTION AND FECAL EXCRETION OF CA
H2PO4 0.26 Decreased Increased
mmol/L  Normal intake: 1000 mg/day each for calcium
and phosphorus = approx. 1 liter of milk
 Divalent cations such as calcium ions are poorly
absorbed from the intestines
HYPOCALCEMIA  Vitamin D promotes calcium absorption by the
Difficulty in determining levels of each intestines
NV: 3-4 mg/dL (adults): 4-5 mg/dL (children)  About 35% (350 mg/day) of the ingested calcium
usually is absorbed
 Nervous system excitement and tetany  Ca remaining in the intestine excreted in the
 Increased neuronal membrane permeability to feces
sodium ions, allowing easy initiation of action  Additional 250 mg/day of calcium enters the
potentials. intestines via secreted gastrointestinal juices and
 Tetany sloughed mucosal cells
 50% below normal level  About 90% (900 mg/day) of the daily intake of
 Peripheral nerve fibers become so excitable Ca excreted in the feces
 Intestinal absorption occurs very easily
 A small portion excreted in the feces in
combination with nonabsorbed Ca
 Almost all the dietary phosphate absorbed into
the blood fro the gut and alter excreted in the
urine
RENAL EXCRETION OF Ca
 About 10% (100mg/dL) of the ingested Ca
excreted in the urine
 About 41% of the plasma Ca is bound to plasma
proteins and is therefor not filtered by the
glomerular capillaries
 The rest is combined with anions such as
phosphate (9%) or ionized (50%) and is filtered
through the glomeruli into the renal tubules.
RENAL EXCRETION OF PHOSPHATE
 Controlled by an overflow mechanism
 When phosphate concentration in the plasma
is belwo the critical value of about 1 mmol/L,
all the phosphate in the glomerular filtrate is
reabsorbed and no phosphate is lost int the
urine
 But above this critical concentration, the rate
of phosphate loss is directly proportional to
the additional increase.
 Thus, the kidneys regulate the phosphate
concentration in the extracellular fluid by
altering the rate of phosphate excretion in
accordance with the plasma phosphate
concentration and the rate of phosphate
filtration by the kidneys
 PTH can greatly increase phosphate
excretion by the kidneys
 PTH plays an important role in the control of
plasma phosphate concentration as well as
Ca concentration
BONE
 Composed of a tough organic matrix greatly
strengthened by deposits of Ca salts
 Average compact bone by weight is approx. 30%
matrix, 70% salts
 Newly formed bone - higher percentage of
matrix in relation to salts
 Functions:
 Structural
 Major role in Ca, Phosphorus, Magnesium
homeostasis (reservoir)
 Source of numerous growth factors,
cytokines, prostaglandins involved in bone
formation and resorption
 5-10% (ground substance)-controls Ca
deposition
 90-95%-(collagen)-strength
 Collagen
 Provides tensile and compressional strength
 Ground substance
 Composed of extracellular fluid plus
proteoglycan, especially chondroitin sulfate
and hyaluronic acid
 The precise function of each of these are not
known, although they do help control the
deposition of Ca salts.
 Bone salts
 Mainly Ca and phosphate
 Hydroxyapatite-major crystals
 Magnesium, sodium, potassium and carbonate
 Believed to be conjugated to the
hydorxyapatite crystals rather than organized
into distinct crystals of their own
 Contain a type of exchangeable Ca that is always
in equilibrium with Ca ions in ECF
 Osteoblasts-bone deposition
 Osteoclasts-bone reabsorption
TENSILE AND COMPRESSIONAL STRENGHT OF BONE
 These combined properties plus the degree of
bondage between the collagen fibers and the
crystals provide a bony structure that has both
extreme tensile strength and extreme
compressional strength.
 Collagen fibers of bone
 Have great tensile strength
 Ca salts
 Have great compressional strength
 Hydroxyapatite
 Does not precipitate in extracellular fluid
despite supersaturation of Ca and phosphate
ion
 Pyrophosphate-prevent precipitation
 Fail to precipitate in normal tissues except in
bone despite the state of supersaturation of
the ions
BONE REMODELING
 Occurs through coordinated coupling of bone
resorption and bone formation in bone
 remodeling units (osteons)
 3-8 months
 10% total bone mass/year
 Bone ordinarily adjusts its strength in proportion
to the degree of bone stress (bone thicken when
subjected to heavy loads)
 Even the shape of the bone can be rearranged for
proper support of mechanical forces by
deposition and absorption of bone in accordance
with stress patterns.
 Old bone becomes relatively brittle and weak,
new organic matrix is needed as the organic
matrix degenerates so the normal toughness of
bone is maintained
 Bones of children-rapid rates of deposition and
absorption
 Bones of the elderly - rates of deposition and
absorption are slow
Ca PRECIPITATION IN NONOSSEOUS TISSUES UNDER
ABNORMAL CONDITIONS
 Ca salts almost never
 precipitate in normal tissues besides except in
abnormal conditions
 Precipitate in arterial walls-arteriosclerosis
(arteries become bonelike tubes)
 Calcium salts deposits in degenerating tissues or
in old blood cells
EXCHANGEABLE CALCIUM
 Present in bones
 Always in equilibrium with the Ca ions in the
extracellular fluids
 Within 30 minutes - 1 hour or more, Ca ion
concentration returns to normal
 Provides a rapid buffering mechanism to keep
the calcium ion concentration in the extracellular
fluids from rising to excessive levels or falling to
very low levels under transient conditions of
excess or decreased availability of Ca.
RATE OF BONE DEPRESSION BY BONE "STRESS"
 Bone is deposited in proportion to the
compressional load that the bone must carry.
 Bone of athletes-heavier than those of
nonathletes
 One leg in a cast-the bone of the leg in the cast
becomes thin, as much as 30% decalcified within
a fe weeks; the opposite bone remains thick and
normally calcified.\
 Therefore, continual physical stress stimulates
osteoblastic deposition and calcification of bone
 Bone stress also determines the shape of bones
under certain circumstances
 If a long bone of the leg breaks in it center and
then heals at an angle, the compression stress on
the inside of the angle causes increased
deposition of bone, and increased absorption
occurs on the outer side of the angle where the
bone is not compressed
REPAIR OF FRACTURE ACTIVATES OSTEOBLASTS
 Osteoprogenitor cells
 Bones stem cells in the surface tissue lining
bone
 Callus-new organic matrix followed shortly
by the deposition of Ca salts
 Many bone surgeons use the phenomenon of
bone stress to accelerate the rate of fracture
healing
 Use of special mechanical fixation
apparatuses for holding the ends of the
broken bone together so that the patient can
continue to use the bone immediately
VITAMIN D
 Increase Ca absorption from the GIT
 Effects on bone deposition and absorption
 Not an active substance, has to be converted to
active form 1,25(OH)2D3.
 7-dehydrocholesterol
 Occurs primarily in keratinocytes
 7-DHC most abundant
 Pre vitamin D3
 Cleavage of carbon bonds between carbons 9
and 10
 Thermally labile previtamin D3
 Undergoes temp dependent rearrangement into
vitamin D3
 UV light also converts previtamin D3 to inert products
(lumisterol and tachysterol)
> Prolonged sun exposure does not cause vitamin D
intoxication
SYNTHESIS OF CALCITROL
 Not tightly regulated
 Reflects increases in vitamin D3 or ingestion of Vitamin
D or vitamin D deficiency
 Biologically inert
Vitamin D  concentrations for hydroxyapatite deposition into
Steps matrix
1. Cholecalciferol (vitamin D3) is formed in the skin
2. Vit D3 converted to 25(OH) cholecalciferol in the liver Actions of Vitamin D
First step in activation of cholecalciferol  Increase serum calcium
 Limited by negative feedback  Increase serum phosphate
Feedback Control  Normal bone mineralization
a) precisely regulates 25-hydroxycholecalciferol VITAMIN D DISORDERS
b) Conserved vit D stored in the liver for future use incr - increase
decr – decrease
3. Formation of 1,15(OH)2D3 in the kidneys and its Ca PO PTH
control by PTH Excess incr incr decr
 Proximal renal tubules Vitamin D
 Absence of kidneys cancels effects of vitamin D
Vitamin D decr decr incr
4. Ca ion concentration controls formation of deficiency
1,25(OH)2D3
Inversely affected by plasma Ca concentration PARATHYROID HORMONE
Reasons
 4 in humans
a) Ca ions has slight effect in prevention conversion of
 Located immediately behind the thyroid gland
25-dehydrocolecalciferol ----- 1,25(OH)2D3
(one behind each of the upper and lower poles)
b) At low Ca levels, PTH promotes conversion of
25-hydroxycholecalciferol ------ 1,25(OH)2D3  6 mm long, 3mm wide, 2 mm think
 Grossly dark brown fat
Actions
Histology
 Promote intestinal Ca absorption
Epithelial cells
 Promotes phosphate absorption by the GIT
- Chief
 Decreases renal Ca and phosphate excretion
- Oxyphil
 Effects on bone and ratio to PTH Stromal cells
Actions of Vitamin D on the Gut Parathyroid Hormone
 Increases intestinal absorption f Calcium and - Contains mainly chief cells that secrete PTH
Phosphorus - Oxyphil cells absent in humans and many animals
 Increases synthesis of calbindin(calcium binding - MW 9,500
protein
 Decreases renal Can ad Phosphate excretion Effects
- Weak effect - Increases Ca and PO absorption from the bone
- Decreases Ca excretion and increase phosphate
Vitamin D effects on bone and relation to PTH excretion by the kidneys
 Extreme amounts of Vit D causes absorption of - Increases intestinal absorption of Ca and PO
bone - Decreases Ca excretion and increases PO
 In the absence of Vit D PTH effects greatly excretion by the kidneys
reduced or prevented o Diminished proximal tubular reabsorption
 Effect of 1,25(OH)2D3 to increase Ca transport of phosphates
thru membranes o Increase renal tubular reabsorption of Ca
 Small amounts of vitamin D promotes bone
calcification PTH ACTIONS ON KIDNEYS CALCIUM AND
 Increase ca and phosphate absorption from GIT PHOSPHATE
 Effect of 1,25(OH)2D3 to increase Ca transport 1. Increases calcium reabsorption in ascending loop and
thru membranes (opposite effect) distal tubule
- BUT due to increase in filtered load
Direct effect: stimulates bone resorption hypercalciuria  kidney stones
 Synergistic with PTH 2. Decreases reabsorption of phosphate in proximal tubule
activates osteoclast via osteoblast  phosphaturia  decreases serum phosphate
Indirect effect: maintains normal ECF Ca and PO4 - Calcium phosphate ion product

Effects
Increases intestinal absorptoion of CA and PO
- Increased formation of 1,25(OH)2D3 in the
kidneys
- Mediated by cAMP 2nd messenger mechanism
Days to weeks – increase proliferation of PTH
REGULATION OF PTH: PHOSPHATE
Increase phosphate 
Decrease in ionized calcium 
Increase in PTH secretion

PTH actions in the kidneys Effects of Calcitrol

1. Increased synthesis of 1,25(OH)2D (cacitrol) via o Decrease in PTH gene transcription
activation of 1a hydroxylase indirectly stimulates o Decrease in PTH secretion
intestinal absorption of Calcium o Decrease in PT cell proliferation
2. Decreases renal bicarbonate reabsorption non-gap
metabolic acidosis PARATHYRIOD HORMONE RELATED PROTEIN (PTHrP)
o Homologous to PTH and binds to PTH receptor
- Ca ion concentration controls PTH secretion with equivalent affinities
- Conditions causing hypertrophy of PT glands o Normal circulating level PTHrP ---- PTH
o Rickets o Vital functions in developmental (intrauterine,
o Pregnancy infancy) and at cell and tissue level (paracrine)
o Lactation o Major cause of hypercalcemia associated with
- Ca ion concentration controls PTH secretion malignancies (tumor production of PTHrP)
- Conditions causing diminished size of parathyroid
glands CALCITONIN
o Excess Ca in the diet
o Increased vit D in the diet\ o Peptide hormone secreted by the thyroid gland
o Bone absorption caused by factors other that o Decrease plasma Ca concentration
PTH o Has effects opposite to PTH
o Synthesis and secretion occur in the parafollicular
- Powerful mechanism for controlling ECF Ca and cells or C cells
phosphate concentrations by regulating: o Composed 0.1% of human thyroid gland
o Intestinal absorption o Remnants of ultimo brachial glands of lower
o Renal excretion animals
o Exchange between ECF and bones of these o 32-AA peptide
ions o MW 3,400
Intact PTH o Increased plasma Ca concentration stimulates
- 84 amino acids\ calcitonin secretion
- half life 2- 4 minutes o Decreases plasma Ca concentration
- cleared by liver and kidneys o Weal effect on plasma Ca concentration on adult
human
Actions of PTH o Secreted by parafollicular © cells of thyroid
o Increase serum calcium (neural crest) – 0.1 % of thyoid mass
o Decrease serum phosphate o Polypeptide 32 amino acids
o Increase 1,25(OH)2D
Increased plasma Ca concentration stimulates calcitonin
Regulation of PTH secretion secretion
- Plasma calcium level o 2nd hormonal feedback mechanism for Ca level
- Phosphate control
- Calcitrol o Relatively weak
- Magnesium o Works opposite that of PTH
TEMPORAL HIERARCHY OF PTH RESPONSE TO
HYPOCALCEMIA Decreases plasma Ca concentration
Sec – few min release of PTH  o Decrease absorptive activities of osteoclasts
o Decreases formation of new osteoclast
Min – 1 hour – intracellular PTH degradation
Weak effect on plasma Ca concentration in adult human
Hours to few days – increase PTH gene expression o Any initial reduction of Ca ion concentration
caused by calcitonin leads within hours to a
 powerful stimulation of PTH secretion ---
overrides the calcitonin effect
Action os Calcitonin
o Decrease serum calcium
o Decrease serum phosphate

Major effect – antagonizes effects of PTH on bone

- Decrease osteoclastic differentiation and activity
- Osteoclast receptors for calcitonin

1. Buffer function of exchangeable Ca in bones

- CaHPO4 (5-10 gm)
- 5% of all blood flows through the bones
- 50% of excess Ca in the ECF removed in 70 mins
- Mitochondria helps in maintaining Ca
concentrations

2. Hormonal control of Ca ion concentration

- Parathyroid and calcitonin hormonal systems
- Long term control resides in the PTH and vitamin
CLINICAL PRESENTATION OF PRIMARY
HYPO/HYPERPARATHYROIDISM

Ca PO Calcitrol
Hyperpara incr decr incr
Hypopara decr incr decr

Secondary Hyperparathyroidism

Rickets
- Vitamin D deficiency
- Occurs mainly in children who remain indoors
throughout winter
- Common in spring months
- Vit D Deficiency: Rickets
- Defective mineralization leads to profusion of
disorganize non mineralized cartilage, bonuy
abnormalities