LECTURE 5

Calcium homeostasis
 Calcium functions
• Major structural element in the vertebrate
skeleton (bones and teeth) in the form of
calcium phosphate (Ca10(PO4)6(OH)2 known
as hydroxyapatatite
• Key component in the maintenance of the cell
structure
• Membrane rigidity, permeability and viscosity
are partly dependent on local calcium
concentrations
Calcium plays important regulatory roles in
the body
A passive role:
- As a cofactor for many enzymes (e.g. Lipase) and
proteins
- As component in the blood clotting cascade
An active role: as an intracellular signal
- In the relaxation and constriction of blood vessels
- In cell aggregation and movement
- In muscle protein degradation
- In secretion of hormones as insulin
- In cell division
- In nerve impulse transmission
Calcium Metabolism
Summary of calcium balance
Calcium and Bones Endocrine Controls
• The hormones involved in calcium metabolism
in general & in bone in particular include the
protein parathyroid hormone & the modified
steroid calcitriol (1α,25 – dihydroxy vitamin D3;
1α,25 – dihydroxycholecalciferol), which both
promote the movement of calcium ion into
circulation, & the counter-balancing protein
hormone calcitonin, which promotes a decrease
in circulating calcium.
 What is the role of
Parathyroid hormone (PTH)
in Calcium homeostasis?

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 Parathyroid
glands

Parathyroid hormone (PTH), an 84 amino acid-long

protein, is produced by processing of a longer
translation product by the parathyroid glands
which are embedded in the thyroid tissues in many
vertebrate species.
PTH is secreted by the chief cells of the parathyroid gland
Secreted in response to decreasing ionized Ca++
 Parathyroid hormone ….
• Provides powerful mechanism for controlling
extracellular calcium and phosphate
concentrations by regulating intestinal
reabsorption, renal excretion and exchange
between the extracellular fluid and bone of the
two ions
• Causes increased osteoclast maturation and
thus increased bone resorption
• Causes increased Vitamin D activation in the
kidney
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What is the role of Vitamin D
in Calcium homeostasis?
 Vitamin D
• Lipid soluble vitamin
• Precursors:
– Cholecalciferol in the skin (produced by UV radiation)– Vit D3
– Ergocalciferol from diet – Vitamin D2

• Both get hydrolyzed in the liver to 25-hydroxyvitamin

D3
• Then, in the kidney, get hydrolyzed again to 1,25-
hydroxyvitamin D

• This last step is under the control of parathyroid

hormone
Guyton & Hall Textbook of Medical physiology, 11th ed.; J.E.Hall; Chapter 79
Synthesis of Vitamin D
Vitamin D
activity:
• Increased gut
absorption of
calcium

• Increased
reabsorption
of calcium in
the distal
nephron
 What is the role of
Calcitonin during
Calcium homeostasis?

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 Calcitonin
• Product of
parafollicular C cells
of the thyroid
• 32 aa
• Inhibits osteoclast
mediated bone
resorption
– This decreases serum
Ca2+
• Promotes renal
excretion of Ca2+
 Calcitonin…

• Not critical for calcium homeostasis.

• Removing the thyroid causes no

major alteration in calcium
homeostasis.

Endocrine Physiology, 3rd ed. P.E. Molina; Chapter 5 (Via CIAP)

Disorders of Calcium

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 Hypocalcemia
• Condition in which the calcium level
below the normal level

• Caused by low level of PTH , low level

of magnesium, deficiency of vitamin D

• The kidney dysfunction plays a role in

hypocalcemia – explain?
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 Causes of the hypocalcemia
• Decreased GI Absorption
• Poor dietary intake of calcium,impair
absorption
• Increased Urinary Excretion
• Decreased Bone Resorption/Increased
Mineralization
• Low PTH
• PTH resistance
• Vitamin D deficiency.
 Complication of hypocalcemia
• Tetany: condition of mineral imbalance in
the body that results in severe muscle
spasms.
• Usually occurs when the concentration of
calcium ions (Ca2+) in extracellular fluids
below normal
 Treatment of hypocalcemia
• Calcium carbonate, which is the least
expensive and has the most elemental
calcium
• Calcium citrate, which is the most easily
absorbed
• Calcium phosphate, which is also easily
absorbed and doesn’t cause constipation
• Calcium supplements are available in liquid,
tablet, and chewable forms
 Hypercalcemia
• Total calcium over 2.6 mmol/L
• Ionized calcium over 1.23 mmol/L

Neoplasms, multiple myeloma, renal

dysfunction

Treatment: diuretics to increase the renal

clearance of calcium calcitonin and
bisphosphonates
 Causes of hypercalcemia
• Excessive PTH
– Primary hyperparathyroidism eg. adenoma, hyperplasia of gland
– Tertiary hyperparathyroidism, eg. long term stimulation of
parathyroid gland in chronic renal failure
– Paraneoplastic PTHrP production (solid tumours)
• Excessive activated Vitamin D
– Sarcoidosis, silicosis, tuberculosis, lymphomas
– Vitamin D intoxication
• Neoplasia, lytic bone lesions
• Excessive calcium intake, eg. calcium antacids
• Bone resorption due to immobilization
• Hyperthyroidism, antiestrogen therapy, lithium therapy,
thiazides
Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL,
Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
 Consequences of hypercalcemia

• Metastatic calcification
• Renal stones
 Diagnostic aids for hypercalcemia
• Is it the albumin? What’s the corrected Ca++
• PTH levels, or PTH related peptide (PTHrP) levels

• Vitamin D levels

• Phosphate and magnesium are done routinely with

calcium

• What is the renal function

• Has anything happened to the neck?

Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J:
Harrison's Principles of Internal Medicine, 17th ed.
 Management of mild hypercalcemia

• Consider not doing anything

• Consider stopping calcium replacement
• Consider stopping thiazides (used to treat hypertension)
• Consider giving a different variety of resonium
(ion-exchnange resin)

• Rehydration (hypercalcemia inevitably leads to

dehydration by polyuria)
• Loop Diuretics if volume already normal

Khosla Sundeep, "Chapter 47. Hypercalcemia and Hypocalcemia" (Chapter). Fauci AS, Braunwald E, Kasper DL,
Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th ed.
 Management of severe hypercalcemia

• GOALS:
– Decrease bone resorption
– Increase calcium excretion
– Then, deal with the primary pathology, if
possible

Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
 Management of severe hypercalcemia

• Rehydrate aggressively WHILE giving loop

diuretics
• Aim for a daily urine output of 4-5 litres
• If there are no kidneys to work with, go with
dialysis.

• Infusion of bisphosphonates: pamidronate,

zolendronate, etidronate…
• Takes 1-3 days to reach maximum effect

Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
 Specific strategies in the
management of hypercalcemia

• Chloroquine for sarcoidosis- reduces serum vitamin D levels

• Ketoconazole is also for sarcoidosis-induced

hypercalcemia and vitamin D intoxication

• Hydrocortisone for myeloma, granulomae, Vitamin D intoxication

Oh’s Intensive Care Manual, 6th ed. B. Venkatesh; Chapter 54 Acute Calcium Disorders
 Abnormal management of hypercalcemia
• Gallium Nitrate known to inhibit bone resorption by altering the
structure of hydroxyapatite, equivalent efficacy to pamidronate but
horribly nephrotoxic in 12.5%

• Calcitonin was more popular before bisphosphonates

– For some reason, salmon calcitonin is more powerful than human calcitonin

• Plicamycin (“mithramycin”)- chemotherapy agent, also happens to

lower calcium levels. Pamidronate = more effective, better tolerated

• Disodium Ethylenediaminetetraacetic acid: EDTA

– 15-20mg/kg acts as a calcium chelator, very rapidly lowers calcium
levels;  cardiotoxicity and nephrotoxicity

– Yes it’s the same stuff they put in purple top blood tubes
Degenerative Bone Disease & Treatment

Osteoporosis
• Decreased bone mass
• Decreased mineral deposition
• Increased bone resorption

• Treatment: Bisphosphonates, estrogen

Degenerative Bone Disease & Treatment…

Paget’s Disease
Excess of bone destruction and
unorganized bone formation and repair.

• Hyperactive bone metabolism

• Fragile bone and microfractures

• Treatment: Calcitonin, bisphosphonates

 What are Bisphosphonates?
• Pyrophosphate is a normal by-product of
metabolism. Bisphosphonates are analogues of
pyrophosphate which have potent inhibitory
effects on bone resorption
• They are effective drugs in bone disorders
characterized by increased bone resorption,
such as Paget's disease and osteoporosis
• Bisphosphonates adsorb very effectively to
hydroxyapatite, the crystalline form of calcium
and phosphate in bone.
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 Bisphosphonates…

Called
Bisphosphonates
because they have
two phosphonate
(PO(OH) ) groups.

The are poorly absorbed, not metabolized, excreted

in urine.
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Next lecture…

Pancreatic and GI tract hormones

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