Disorders of Calcium Metabolism Flashcards
What are the biological functions of calcium?
-Intracellular Ca2+ is maintained at very low
concentrations (less than 1 μmol/L).
=Reversible increases allow Ca2+ ions to bind to
proteins to influence many key cell processes (proliferation, cell migration and differentiation and apoptosis)
-Extracellular Ca2+ is present at much higher
concentration (about 1 mmol/L).
=To allow normal bone mineralisation
=To maintain normal activity of excitable tissue (neuromuscular tissues have contractility)
What phase of blood is extracellular calcium measured in?
-Liquid (non-cellular) phase of blood i.e. either
o Serum (the liquid phase obtained after blood has
clotted) OR
o Plasma (the liquid phase of non-clotted blood where
the blood sample taken includes an anti-coagulant)
Describe plasma (or serum) calcium (what are the components and concentration)
The concentration measured in plasma (or serum) is within a well defined normal range
• This range is typically 2.1-2.6 mmol/L
• This calcium concentration is made up of 2 components:
o Ionised Ca2+ which is physiologically active
o Ca2+ which is ‘bound’ mainly to albumin and
is not physiologically active
• It is the ionised Ca2+ which is actively regulated
What is the link between albumin and calcium?
- Albumin is the major Ca2+ binding protein in plasma (or serum)
- Abnormal albumin concentration (which is quite common, more likely down than up in infection/inflammation/malignancy) will alter the Ca2+ bound
- Measuring both albumin and total calcium is required to assess extracellular ionised Ca2+ status
How does albumin affect interpretation of plasma calcium?
- Ionised calcium constant
- Bound calcium not constant
- Albumin not constant (less= less capacity to bind calcium)
Describe calcium balance
-Net absorption and excretion both 5mmol/24h
=Diet 25 mmoles
=10 mmoles absorbed from gut
=5 mmoles excreted, other excreted through kidneys
=Bone exchange and turnover (dynamic organ)
How does calcium balance alter throughout life?
- Growth (new bone formation) requires a positive Ca2+ balance
- Adulthood would ideally be associated with neutral balance (Ca2+ in = Ca2+ out)
- The ageing process is associated with a slow phase of negative Ca2+ balance leading to loss of bone density (may lead to osteoporosis)
- Bone loss accelerated after menopause
What is the morphology and function of bone?
• The skeleton makes up ±17% by body weight
• Bone functions
o Support of the body
o Protection of organs
o Leverage system for movement
o Site for haematopoiesis
o Endocrine function (fibroblast growth factor-23;
osteocalcin= basal metabolic rate)
o Regulation of mineral homeostasis
• Bone morphology
o Trabecular Bone (narrow rods, internal)
o Cortical Bone (thicker, outside, strength)
What are the types of bone cells?
- Osteoblasts= cells that make bone
- Osteoclasts= cells that resorb bone
- Osteocytes= most abundant cell type in bone, mechanosensor cell
Describe bone formation by osteoblasts
- Ob precursor
- Ob (osteoblast)
- Osteoid (uncalcified bone matrix, fibrils and collagen, adjacent to osteoblast)
- Calcified bone matrix (phosphate)
- Cell process from osteocyte
- Osteocyte (internal, cell processes for pressure sensing)
Describe bone matrix mineralisation
• Several day delay before osteoid mineralises
• Skeleton contains ~98% of body calcium
• Mineral component is hydroxyapatite: Ca10(PO4)6(OH)2
o Tiny crystals surround collagen fibres
o Provides rigidity, resistance to compression
• Mineralisation of osteoid dependent on calcitriol (active vitamin D);
o Deficiency results in failure to mineralise
o Leads to rickets in children, osteomalacia in adults
• Full mineralisation takes several months
Describe the role of Alkaline phosphatase (ALP) in mineralisation
• Expressed on surface of differentiated osteoblasts; also released into extracellular fluid and circulation (bone formation marker), liver function test
• Releases inorganic phosphate ions (PO4 3-) from diverse molecules (hydrolysis)
• ALP promotes mineralisation (i.e., precipitation of calcium phosphate/ hydroxyapatite) in 2 ways:
o by increasing the local concentration of inorganic phosphate ions
o by hydrolysing pyrophosphate, a key endogenous inhibitor of mineralisation
What is the role of osteoclasts in bone resorption?
o Multinucleate, motile bone-resorbing cells
o Formed by fusion of promonocytic precursors present in marrow and circulation
o “Ruffled border” adjacent to bone surface secretes H+
and enzymes
o Express high levels of carbonic anhydrase II required for H+ generation
Describe the role of RANK-RANKL in osteoclast biology and function
-Bone marrow stromal cell (expresses RANKL) communicates with osteoclast precursor through RANK-RANKL interaction ligands
=Activation of osteoclast precursor
=Mature osteoclast
How do osteoclasts resorb bone?
- Pits on flat surface of bone
- Osteoclast highly motile
What clues indicate osteopetrosis?
• Also known as: ‘Marble bone disease’/ stone bone • Inherited bone disease =shorter • Increased bone mass • Caused by dysfunctional osteoclasts =flat pits
What is the cause of osteopetrosis?
-Failure of matrix degradation by osteoclasts
=CA 2 mutations (carbonic anhydrase)
=TCIRG1 mutations (proton pumps through ruffled border)
=CLCN7 mutations (chloride channel defects, so no HCl)
=Cat K mutations (other protein pumps)
Overview of bone remodelling cycle
- Quiescence of lining cells
- Osteoclast resorption (10 days)
- Osteoblast reversal (osteoblast lays down new osteoid)
- Osteocytes= formation
- Mineralisation 3 months
=4-6 months
Why do we need bone metabolism?
o To grow
o Respond to altered mechanical requirements
o Repair damage (macro / micro fractures)
o Maintenance (failure prevention)
o Calcium deficit
• Skeleton is renewed every ± 7 years
• In health, bone formation and resorption are
balanced
• For bone growth, formation exceeds resorption
Describe bone turnover and metabolism in disease
• Pathological imbalance between formation and
resorption leads to disease
• Most common bone diseases reflect this
imbalance
• Osteoporosis (late stages in life, oestrogen influence, smoking, reduced bone density)
o Most common cause: low oestrogen after menopause
o Main cause of bone loss: increased bone resorption
• Paget’s disease
o Due to overactive osteoclasts (thickened bone, skull can affect neuro-processes, hearing problems and pain)
How is ionised Ca2+ regulated?
• This regulation is endocrine, requiring the
participation of 2 key hormones called
parathyroid hormone (PTH) and calcitriol which
show typical endocrine feedback loops
• PTH is a peptide hormone
• Calcitriol is a steroid hormone which is
synthesised from dietary factor (vitamin D)
• The principal organs involved are gut, bone and
kidney (liver and skin)
What is the physiology of PTH?
• A peptide hormone required for the minute-byminute regulation of ionised calcium levels in
blood
• PTH is secreted as a single chain polypeptide
(84 amino acids) from the parathyroid glands
• PTH secretion is increased in response to falling
Ca2+ and its actions are directed at restoring
Ca2+ levels
• Rising Ca2+ feeds back to the parathyroid glands
and suppresses PTH secretion (negative
feedback loop)
How is PTH secretion regulated?
• PTH secretion is tightly
regulated to maintain Ca2+ in physiological range
• Calcium receptors on cell
sense Ca2+ levels to regulate PTH secretion
• G-protein coupled receptor is activated by binding of calcium
What are the actions of PTH?
oStimulates efflux of Ca2+ from bone
oStimulates renal tubular reabsorption of Ca2+
(distal tubule)
oStimulates formation of calcitriol (indirectly)
promoting intestinal absorption of Ca2+
oPromotes phosphate and bicarbonate loss from
the kidney (proximal tubule, inhibits reabsorption)
Describe calcium, PTH and vitamin D feedback loops
-Rising blood Ca2+
=Suppress PTH
=Decreased bone resorption, increased urinary calcium loss, decreased active vitamin D production
-Falling blood Ca2+
=Stimulate PTH
=Increased bone resorption, decreased urinary calcium loss, increased active vitamin D production
Describe calcitonin
• 32 amino acid polypeptide secreted in response to rising Ca2+ from parafollicular or C-cells of the thyroid gland
• Principal action is to reduce osteoclast activity
• No clear role in calcium homeostasis (e.g. neither total thyroidectomy nor calcitonin-secreting tumours alter calcium homeostasis)
• May be used therapeutically to treat high serum calcium levels
• Also serves as a ‘tumour marker’ (certain thyroid
tumours; some breast cancers)
Describe cholecalciferol
• Fat soluble vitamin (vitamin D)
• Steroid structure
• Produced endogenously by the action of UV light
on skin precursor, 7-dehydrocholesterol
• Dietary sources include oily fish, eggs, butter,
margarine (fortified)= 30%
• Cholecalciferol requires activation by liver and
kidney to produce the active hormone, calcitriol
Describe vitamin D physiology
• Calcitriol is a hormone: it is synthesised in one location (kidney) and acts at many sites
• Vitamin D is distinct from other “classical” vitamins, such as vitamin C, B vitamins, etc., which act as cofactors in biochemical reactions
• Calcitriol is required for the longer-term maintenance of calcium (and phosphate) levels
and is required for normal bone growth and mineralisation
How is vitamin D synthesised (precursor to D3)?
-The precursor for vitamin D synthesis is a sterol in the cholesterol biosynthetic pathway, 7- dehydrocholesterol which is found in skin
• Ultraviolet light (UVB) transforms 7- dehydrocholesterol to vitamin D3 (cholecalciferol)
How is vitamin D synthesised (D3 to 25(OH) vitamin D)?
• Vitamin D3 circulates to the liver, where the microsomal enzyme 25-hydroxylase hydroxylates
it to 25-hydroxy vitamin D (25(OH)vitamin D)= calcidiol
• 25-hydroxylase functions constitutively without
input from blood calcium status or PTH (all the time)
• 25(OH)vitamin D is the best screening test for
vitamin D adequacy
How is vitamin D synthesised (to active form)?
• 25(OH)vitamin D circulates to the kidneys where
it is hydroxylated by 1α-hydroxylase to 1,25(OH)2
vitamin D (calcitriol) = ‘active’ vitamin D
• Renal 1α-hydroxylase is regulated by PTH which
stimulates its activity. PTH is the principle physiologic regulator, although calcium can affect the activity
• Other hydroxylations possible (e.g. at the 24-
position= inactivates vitamin D)
Describe vitamin D metabolism
- 7-DHC= Vitamin D3= 25(OH)D3= 1,25(OH)D3
- Increases calcium and phosphate absorption in gut through calbindin
- Increases bone resorption
What is the mechanism of calcitriol action
• Calcitriol binds to a single vitamin D receptor (VDR)
• The VDR-calcitriol complex acts through a vitamin D-responsive element (new protein synthesis= gene transcription)
o In the intestine, a calcium-binding protein (calbindinD9k) is synthesised which promotes absorption of
both calcium and phosphate
o In bone, stimulates osteoblast differentiation and osteoclast activation via RANK ligand (RANKL)
formation in osteoblasts
What are the actions of calcitriol?
• Calcitriol promotes gut absorption of calcium and
phosphate (requires new protein synthesis)
• Calcitriol, in concert with PTH, stimulates osteoclasts and efflux of Ca2+ from bone
• Calcitriol, in concert with PTH, increases renal Ca2+ reabsorption
• Maintenance of both calcium and phosphate
levels essential for hydroxyapatite formation and normal bone mineralisation
• Calcitriol deficiency has major effects on bone
mineralisation (low calcitriol, high PTH- secondary hypoparathyroidism)
