Calcium Metabolism

Dr.AMMAR JAWAD
MBChB, MPH
 Calcium metabolism
• What is the recommended daily intake?
• 1000mg
• What is the plasma concentration?
• 2.2-2.6mmol/L
 Role of Calcium in Hormone
Secretion
• Secretion of peptide hormones is
often dependent upon influx of
calcium into the cell.
- Influx of calcium results in cell
depolarization.
 Role of Calcium in Bone Formation

• Adequate calcium supply is required for bone

formation, as calcium and phosphate are the
minerals which make up bone.
• Bone is mineralized by the precipitation of
calcium and phosphate in a basic
environment.
• Without calcium, have decreased bone
mineralization and strength.
 Role of Calcium in Muscular
Contraction
• Increased free cytoplasmic calcium binds with
troponin to cause muscle contraction.
 Role of Calcium in Neuronal
Excitation
• Changes in extracellular calcium
concentrations influence the resting
membrane potential of cells.
• Abnormally low calcium levels result
in increased permeability of neuronal
membranes to sodium, resulting in
hyperexcitability of neurons.
 Role of Calcium in Blood Clotting

• Calcium is required for proper

functioning of clotting factors.

• Thus, regulation of calcium levels

is critical for the function of many
systems!
 Osteoblast and Osteoclast
Function
• Osteoblasts • Osteoclasts
• Bone formation • Bone resorption
• Synthesis of matrix – Degradation of
proteins proteins by enzymes
– Type I collagen – Acidification
– Osteocalcin • RANK is activated by
– Others RANKL, and this
• Mineralization leads to cells
• Activation of osteoclasts differentiation to
via RANKL production osteoclasts
 Bone Remodeling
• Osteoclasts dissolve
bone
– Large multinucleated
giant cells
• Osteoblasts produce
bone
– Have receptors for
PTH, CT, Vitamin D,
cytokines, and growth
factors
– Main product is
collagen
• When osteoblasts
become encased in
bone, they become
osteocytes
 BONE PHYSIOLOGY

• BONE IS A RESERVOIR OF CALCIUM,

CALCIUM BEING REQUIRED TO MAKE AND
MAINTAIN THE SKELETON. TO BE AN
EFFECTIVE RESERVOIR FOR THE
MAINTAINANCE OF NORMAL BLOOD
CALCIUM, CALCIUM MUST BE ABLE TO BE
INCORPORATED INTO, AND LIBERATED
FROM, BONE ON SHORT NOTICE.
BONE PHYSIOLOGY, cont.
• BONE TURNOVER: A COUPLED PROCESS
OF BONE FORMATION AND BONE
RESORPTION (BREAK DOWN)
– TAKES PLACE THROUGHOUT LIFE
– SHIFT TOWARD FORMATION OR
RESORPTION REMOVES Ca FROM BLOOD
OR PUTS Ca INTO BLOOD,
RESPECTIVELY, AND CORRESPOND-
INGLY AFFECTS BONE MASS.
 BONE PHYSIOLOGY, cont.:
BONE TURNOVER

• SKELETAL MASS IN THE HUMAN REACHES

A PEAK AT ABOUT AGE 30
– PRIOR TO THAT, AS SKELETAL MASS IS
INCREASING, BONE FORMATION EXCEEDS
BONE RESORPTION.
– AT PEAK BONE MASS, THE TWO PROCESSES
ARE EXACTLY MATCHED
– AFTER THE AGE OF PEAK BONE MASS,
SKELETAL MASS IS LOST FOR THE REST OF
LIFE
 BONE PHYSIOLOGY, cont.
• BONE FORMATION IS MEDIATED BY
OSTEOBLASTS
• BONE RESORPTION IS MEDIATED BY
OSTEOCLASTS
• PNEMONIC: OSTEOBLASTS BUILD;
OSTEOCLASTS, WELL, THEY DON’T
MEASUREMENT OF BONE
TURNOVER
• THE COUPLED PROCESS OF BONE
TURNOVER CAN BE MEASURED BY:
– MARKERS OF OSTEOBLAST METABOLISM
• SERUM BONE-SPECIFIC ALKALINE PHOSPHATASE
• SERUM OSTEOCALCIN
– MARKERS OF OSTEOCLAST METABOLISM
• URINE PRODUCTS OF BONE COLLAGEN BREAKDOWN
– HYDROXYPROLINE
– N-TELOPEPTIDES
– PYRIDINIUM CROSSLINKS
BONE PHYSIOLOGY, cont.
• WHEN THE COUPLED PROCESS OF BONE
TURNOVER (FORMATION AND RESORPTION) IS
SHIFTED IN FAVOR OF RESORPTION, THERE IS
RELATIVE OR NET BONE LOSS. THIS OCCURS IN A
VARIETY OF CONDITIONS:
– age
– menopause in women or hypogonadism in men
– glucocorticoid therapy
– hyperparathyroidism (primary of secondary)
– defects in organ physiology (GI, RENAL, BONE)
– others (medications, genes, comorbid conditions, etc.)
 CALCIUM PHYSIOLOGY:
BLOOD CALCIUM

• CALCIUM FLUX INTO AND OUT OF BLOOD

– “IN” FACTORS: INTESTINAL ABSORPTION,
BONE RESORPTION
– “OUT” FACTORS: RENAL EXCRETION, BONE
FORMATION (Ca INCORPATION INTO BONE)
– BALANCE BETWEEN “IN” AND “OUT” FACTORS
• ORGAN PHYSIOLOGY OF GUT, BONE, AND KIDNEY
• HORMONE FUNCTION OF PTH AND VITMAMIN D
CALCIUM HOMEOSTASIS
DIETARY CALCIUM
THE ONLY “IN”
BONE
DIETARY HABITS, ORGAN,
ENDOCRINE
SUPPLEMENTS
BLOOD CALCIUM
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY KIDNEYS
ORGAN PHYS.
ENDOCRINE PHYSIOLOGY
ENDOCRINE PHYS.

URINE
THE PRINCIPLE “OUT”
 Intake, Storage and Excretion of
Calcium
• Calcium is the most abundant mineral in the
body.
• The amount of calcium in the body is a
balance between intake, storage, and
excretion.
• This balance is controlled by transfer of
calcium between three organs: intestine,
bone, and kidney.
 Intake of Calcium
• About 1000 mg of calcium is ingested per day.
• About 200 mg of this is absorbed into the body.
• Absorption occurs in the small intestine, and requires
vitamin D
 Storage of Calcium
• The primary site of storage is our bones (about 1000 grams).
• Some calcium is stored within cells (endoplasmic reticulum
and mitochondria).
• Bone is produced by osteoblast cells which produce collagen,
which is then mineralized by calcium and phosphate
(hydroxyapatite).
• Bone is remineralized (broken down) by osteoclasts, which
secrete acid, causing the release of calcium and phosphate
into the bloodstream.
• There is constant exchange of calcium between bone and
blood.
 Excretion of Calcium

• The major site of calcium excretion in the

body is the kidneys.
• The rate of calcium loss and reabsorption at
the kidney can be regulated.
• Regulation of absorption, storage, and
excretion of calcium results in maintenance of
calcium homeostasis.
 Endocrine Factors Regulating
Calcium Homeostasis
• There are three main hormones which regulate
calcium balance:
calcitonin
parathyroid hormone
vitamin D

• In addition, other factors influence bone and

calcium metabolism.
 Role of Calcitonin in Calcium
Homeostasis

• Calcitonin is produced from the parafollicular

cells of the thyroid gland (also called clear
cells).
• It is composed of 32 amino acids, derived
from a prohormone.
 Actions of Calcitonin
• The major action of calcitonin is on bone
metabolism.
• Calcitonin inhibits activity of osteoclasts, resulting
in decreased bone resorption (and decreased
plasma calcium levels).
calcitonin (-)
osteoclasts: destroy bone to
release calcium

Decreased
resorption
 Minor Actions of Calcitonin

• Calcitonin may also have minor effects on the kidney:

- increased calcium excretion
- increased H+ secretion/K+ retention
- increased production of active form of vitamin D
 Regulation of Calcitonin Release
• Calcitonin release is stimulated by increased
circulating plasma calcium levels.
• Calcitonin release is also caused by the
gastrointestinal hormones gastrin and
cholecystokinin (CCK), whose levels increase
during digestion of food.

food
(w/ calcium?)

gastrin, CCK

increased decreased bone

calcitonin resorption
 Parathyroid Hormone
• Parathyroid hormone (PTH) is produced by the
four parathyroid glands, on the posterior aspect
of the thyroid gland.
 PTH is composed of 84 amino acids, formed
from a prohormone.

 It is THE MAJOR regulator of calcium

homeostasis in humans.
 Actions of PTH: Bone
• PTH acts to increase degradation of bone
(release of calcium).
- causes osteoblasts to release cytokines, which
stimulate osteoclast activity
- stimulates bone stem cells to develop into
osteoclasts
- net result: increased release of calcium from
bone
- effects on bone are dependent upon presence
of vitamin D
 Actions of PTH: Kidney
• PTH acts on the kidney to increase the reabsorption of
calcium (decreased excretion).
• Also get increased excretion of phosphate (other
component of bone mineralization), and decreased
excretion of hydrogen ions (more acidic environment
favors dimineralization of bone)
• ALSO, get increased production of the active metabolite
of vitamin D3 (required for calcium absorption from the
small intestine, bone demineralization).

• NET RESULT: increased plasma calcium levels

 Regulation of PTH Secretion
• PTH is released in response to changes in
plasma calcium levels.
- Low calcium results in high PTH release.
- High calcium results in low PTH release.

• Also, vitamin D inhibits PTH release (negative

feedback).
 The Role of Vitamin D in Calcium
Homeostasis
• The active metabolite of vitamin D is required for
efficient absorption of calcium in the small intestine
(major effect).
• In addition, vitamin D may have a minor effect on
bone resorption (and is required for the effects of
PTH on bone).
FUNCTION OF VITAMIN D
• TISSUE SPECIFICITY
– GUT
• STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM
AND PHOSPHATE IN THE SMALL INTESTINE (PRINCIPALLY
DUODENUM)
– BONE
• STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS
• STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO
MOBILIZE CALCIUM
– PARATHYROID
• INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK
REGULATION)
 Sources and Metabolism of Vitamin
D
• The production of the active metabolite of vitamin
D requires the actions of three major organ
systems, the skin, liver, and kidney.
• Vitamin D3 (cholecalciferol) is produced in the
skin upon exposure to the sun. It is also found in
milk and other foods.
• Cholecalciferol then is hydroxylated in the liver,
to form 25-hydroxycholecalciferol.
• 25-hydroxycholecalciferol is then 1-hydroxylated
in the kidney to form the active metabolite, 1,25-
dihydroxycholecalciferol (calcitriol).
VITAMIN D SYNTHESIS

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL VITAMIN D3 25(OH)VITAMIN D

25-HYDROXYLASE 1-HYDROXYLASE
h

VITAMIN D3 25(OH)VITAMIN D 1,25(OH)2 VITAMIN D

(ACTIVE METABOLITE)

TISSUE-SPECIFIC VITAMIN D RESPONSES

VITAMIN D
• THE BODY CAN SUPPLY ITS OWN
VITAMIN D VIA THE SYNTHETIC
PATHWAYS SHOWN ABOVE.
ALTERNATIVELY, VITAMIN D MAY BE
SUPPLIED BY VITAMIN D - ENRICHED
FOODS. THE CLASSIC EXAMPLES
ARE MILK AND MULTIPLE VITAMINS.
Regulation of Vitamin D Metabolism

• PTH increases 1-hydroxylase activity, increasing

production of active form.
• This increases calcium absorption from the
intestines, increases calcium release from bone, and
decreases loss of calcium through the kidney.
• As a result, PTH secretion decreases, decreasing 1-
hydroxylase activity (negative feedback).
• Low phosphate concentrations also increase 1-
hydroxylase activity (vitamin D increases phosphate
reabsorption from the urine).
 Regulation of Vitamin D by PTH and
Phosphate Levels

PTH

1-hydroxylase

25-hydroxycholecalciferol 1,25-dihydroxycholecalciferol

increase
Low phosphate phosphate
resorption
Box 5.28: Vitamin D deficiency
Box 5.28: Vitamin D deficiency
 Other Factors Influencing Bone and
Calcium Metabolism
• Estrogens & Androgens: both stimulate bone
formation during childhood and puberty.
• Estrogen inhibits PTH-stimulated bone
resorption.
• Estrogen increases calcitonin levels
• Osteoblasts have estrogen receptors, respond
to estrogen with bone growth.
• Postmenopausal women (low estrogen) have
an increased incidence of osteoporosis and
bone fractures.
 Influences of Growth Hormone
• Normal GH levels are required for skeletal growth.
• GH increases intestinal calcium absorption and renal
phosphate resorption.
• Insufficient GH prevents normal bone production.
• Excessive GH results in bone abnormalities
(acceleration of bone formation AND resorption).
 Effects of Glucocorticoids

• Normal levels of glucocorticoids (cortisol) are

necessary for skeletal growth.
• Excess glucocorticoid levels decrease renal calcium
reabsorption, interfere with intestinal calcium
absorption, and stimulate PTH secretion.
• High glucocorticoid levels also interfere with growth
hormone production and action, and gonadal steroid
production.
• Net Result: rapid osteoporosis (bone loss).
 Influence of Thyroid Hormones

• Thyroid hormones are important in skeletal growth

during infancy and childhood (direct effects on
osteoblasts).
• Hypothyroidism leads to decreased bone growth.
• Hyperthyroidism can lead to increased bone loss,
suppression of PTH, decreased vitamin D
metabolism, decreased calcium absorption. Leads to
osteoporosis.
 Effects of Diet
• Increasing dietary intake of calcium may prevent
osteoporosis in postmenopausal women.
• Excessive sodium intake in diet can impair renal
calcium reabsorption, resulting in lower blood calcium
and increased PTH release. Normally, PTH results in
increased absorption of calcium from the GI tract (via
vitamin D). But in aging women, vitamin D production
decreases, so calcium isn’t absorbed, and PTH instead
causes increased bone loss.
• High protein diet may cause loss of calcium from bone,
due to acidic environment resulting from protein
metabolism and decreased reabsorption at the kidney.
 Effects of Exercise

• Bone cells respond to pressure gradients in laying

down bone.
 Lack of weight-bearing exercise decreases bone
formation, while increased exercise helps form bone.
 Increased bone resorption during immobilization may
result in hypercalcemia
CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS

BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION

RISING BLOOD Ca

NORMAL BLOOD Ca
FALLING BLOOD Ca

BONE RESORPTION
STIMULATE PTH
URINARY LOSS
1,25(OH)2 D PRODUCTION
CIRCULATING CALCIUM,
• IONIZED CALCIUM (FREE CALCIUM)
– RESPONSIBLE FOR CALCIUM FUNCTION
– CAN BE DIRECTLY MEASURED
Three Forms of Circulating Ca2+
HYPOCALCEMIA
• THE STATE OF BLOOD CALCIUM
BELOW THE NORMAL RANGE
– MOST ACCURATELY ASSESSED WITH
IONIZED CALCIUM
– TOTAL CALCIUM CANNOT BE
ACCURATELY INTERPRETED WITHOUT
KNOWING SERUM ALBUMIN
– FAIRLY UNCOMMON
 Phosphate metabolism
• Normal plasma concentration?
• 0.9-1.3 mmol/L
• Absorption and excretion?
• Gut and kidneys
• Regulation
• Not as closely regulated as calcium but
PTH most important