Calcium &
& Bone
Bone Homoeostasis
Homoeostasis
Calcium
Unde
Unde
from the
the mec
mec
from
John AA Eisman
Eisman
John
Director,Osteoporosis
Osteoporosis and
andBone
BoneBiology
Biology Program,
Program,
Director,
GarvanInstitute
Instituteof
ofMedical
Medical Research;
Research;
Garvan
Endocrinologist,
St
Vincent's
Hospital;
Endocrinologist, St Vincent's Hospital;
Professor
(Conjoint)
(Conjoint),
University
of
New
South Wales
Wales
Professor (Conjoint),
(Conjoint) University of New South
Consultingand
andResearch
ResearchSupport
Supportfrom
from
Consulting
Amgen,deCode,
deCode,Eli
EliLilly,
Lilly,GE-LUNAR,
GE-LUNAR,
Amgen,
MerckSharp
Sharpand
andDohme,
Dohme,Novartis,
Novartis,
Merck
sanofi-Aventis,
S ii
sanofi-Aventis,
fifiAA titi Servier
SServier
99 percent of the calcium in our
bodies is in our bones.
Bones allow you to move.
Locomotion depends on an
intact skeleton.
Protection
Protection
Garvan
GarvanI nstitute
I nstituteofofMedical
MedicalResearch
Research
Calcium
Calcium && Bone
Bone Homoeostasis
Homoeostasis
Calcium
Calcium
Calcium
Serum
Serum
–– 2.2
2.2--2.6
2.6 mmol/l
mmol/l
–– 40%
protein
40% proteinbound
bound (esp
(esp Albumin)
Albumin)
–– 15%
complexed
to
anions
15% complexed to anions
++
–– 45%
45%ionised
ionised == free/bioactive
free/bioactive == ECF
ECF Ca
Ca++
•• Extracellular
EExtracellular
llll ll flfluid
E tt
fl id
fluid
id
– 1.3 - 1.5 mM
– 1.3 - 1.5 mM
• Intracellular
• Intracellular
– microMolar
– microMolar
Half is bound to albumin.
Calcium
Calcium
–– Serum
Serum
–– Calcium
C
C ll ii
Calcium
and
crit
Inside cells is a very constant and crit
– Ionised
levels of calcium. 1000 times – Ionised
»» neur
less than extracellular
neu
» mus
component.
» mus
» exoc
» exo
» clott
» clott
» intra
» intra
Garvan I nstitute of Medical Research
Calcium
Garvan I nstitute of Medical Research
– Serum levels remarkably constant (over many years)
– Calcium in bone mineral = major body store and critical component for bone
strength. 99.something percent. Critical component of skeletal strength.
– Ionised calcium critical biological roles in:
» neural function
» muscular contraction
» exocrine gland function – eg. gut excretions.
» clotting
» intra-cellular second messenger – micromolar levels can be intracellular
messaging.
Garvan I nstitute of Medical Research
Garvan I nstitute of Medical Research
Calcium Homoeostasis
Diet – dairy, some vegetables
and in other
Calcium
countries, some foods are calcium
content
supplements.
Sources:
Mainly
y dairy,
y, vegetables
g
& fortified foods
of
Mineral supplements
We will have low calcium intake.
Can only
some
absorb 30% from diet.
Absorption:
foods
30% or less in adulthood (~ 60% in neonate)
Green leafy vegetables have relatively high
part passive
Calcium Vitamin D
Calcium,
calcium levels. Have oxylate
in them –
part driven by active form of vitamin D hard to absorb from gut. and Osteoporosis
Requires adequate magnesium levels
id for
f GPs
GP 2nd ed
d
AG
Guide
Excretion:
Tofu can have calcium with Published
it, but it by
doesn’t naturally.
O t
Osteoporosis
i Australia
A t li
I t ti l secretions
Intestinal
ti
Obligatory urinary loss
Skin surface
~300md/day
Garvan I nstitute of Medical Research
We lose a certain amount of calcium
everyday. Minium excretion is 300 mg.
Phosphate Homoeostasis
Sources:
Most foods - protein, cereals, grains
Absorption:
Well absorbed
E
Excretion:
ti
High renal filtration
Tubular reabsorption
Regulated by
PTH
& FGF 23
Active tubular secretion
Phosphate
Homoeostasis
Garvan I nstitute of Medical Research
Sources: Most foods - protein, cereals, grains - in all protein foods.
Absorption: Well absorbed, unlike calcium
Excretion: High renal filtration – we have to get rid of it, because we have more
than we need.
Tubular reabsorption – modest resorption - Active tubular secretion
Regulated by PTH & FGF 23
Major component of skeletal mineral with calcium  hydroxyapatite
In extreme cases where the body can’t retain phosphate you can get
mineralization of the skeleton. Occurs in leakage from kidney.
Phos
Serum le
Major co
wit
Protein f
Energy m
DNA (all
Garvan I nstitute of Medical Research
Protein function, activation/inactivation
Energy metabolism (e.g. ATP)
DNA (all nucleotides)
Vitamin D
Fat soluble vitamin – a misnomer because we can make it our self, we just can’t
make enough of it. Effect on sunlight on cholesterol derivatives.
Stored in adipose tissue and muscle.
Main source from sunlight (D3) - needs to have enough skin exposed and rays
strong enough. Most of us should have sub-optimal levels.
Some foods D2 and D3 – if the food is animal source it is D3 (derived from
cholesterol) and D2 from plant ergosterol.
25-hydroxylated in liver (25 hydroxy-vitamin D)
Circulates bound to serum D-binding protein
Renal conversion to 1,25-dihydroxy
Vitamin D 24-hydroxylation  Degradation
Intracrine role of tissue 1-hydroxylases
Rickets – vitamin D deficiency due to lack of sun exposure and success of slip
slop slap campaign.
Calcium and Phosphate
p
Homoeostasis


Calcitonin
Formation
PTH

Calcium
Absorption
p
Phosphate

Resorption
Filtration
1,25-OH2D
FGF 23
FGF-23
Garvan I nstitute of Medical Research
Reabsorption
p


Garvan I nstitute of Medical Research
Gained from diet, absorbed
into circulation.
Calcium-hydroxy-phosphate is
bone formation
Bone always undergoing
Ca
turnover – so there is always
removal of calcium, phosphate Form
and alkali from the skeleton.
In the kidney, both calcium and
Resorption
phosphate are very highly
filtered. It has a very active
reabsorption of calcium. 95 or
FGFFGF
more percent.
Only some phosphate is
reabsorbed.
Garvan I nstitute of Medical Rese
Parathyroid glands measure
the calcium level in the blood.
Low Calcium intake
 Low dietary calcium.
Calcitonin
Formation
PTH
Calcium
Absorption
p
Phosphate
Resorption
Filtration
1,25-OH2D
FGF 23
FGF-23
Reabsorption
p
 If calcium decreases, PTH goes
up, telling kidney to resorb
more calcium and makes more
D20.1.5 hydroxy.
 This drives calcium resorption
in the kidney.
 PTH also, chronically elevated
also enhances the removal of
calcium from the skeleton,
which is designed to return the
calcium level back to normal.
Garvan I nstitute of Medical Research





The only problem is that when you increase calcium resorption, you increase
phosphate absorption
When you increase skeletal resorption you increase phosphate removal into the
blood
PTH then tells the kidney to excrete all phosphate to get back to a normal
physiological state.
FGF23 – fibroblast growth factor 23, comes from the bone is produced by the
osteocytes and regulates both 1.25 production and renal reabsorption of
phosphate.
Abnormalities of it’s function or metabolism lead to altered pathological states.

Vitamin D deficiencyy
PTH
Calcitonin

Calcium
Formation
Absorption
p
Phosphate
Resorption
Filtration

1,25-OH2D
FGF 23
FGF-23
Reabsorption
p
Garvan I nstitute of Medical Research

Calcium and Phosphate
p
Homoeostasis
Calcitonin
Lack of vitamin D, you don’t
have enough active vitamin D
causing malabsorption of
calcium from the gut and the
calcium level tends to drop.
PTH will go up, can’t make
more 1.25 but can retain
calcium. Drives more
reabsorption and removal from
skeleton.
If there is not enough vitamin
D, and not enough calcium you
want calcium to be taken form
the skeleton. Because if you
didn’t you would die. It is a
trade off. You lose skeletal
mass.
Baby with rickets. Not proper
mineralisation of the bone,
splaying of the bone ends.
Femur bones are bowed, they
are soft due to lack of proper
mineralisation.
PTH
Calcium
Formation
Absorption
p
Phosphate
Resorption
Filtration
1,25-OH 2D
Phosphate
p
excess
FGF 23
FGF-23
Reabsorption
p
PTH
Garvan I nstitute of Medical Research
Calcitonin
Formation
Calcium
Absorption
p
Phosphate
Resorption
Filtration
1,25-OH2D
Quiescence
 Body will resorb less calcium
Activation
and phosphate from
the gut.
 This pushes the PTH
up and
Resorption
will drive phosphate
excretion and thereFormation
will be
production of FGF 23 to
further enhance excretion.
Mineralization
FGF 23
FGF-23
Reabsorption
p
Garvan I nstitute of Medical Research
Quiescence

Bone Remodeling
g
Lining cells
Quiescence

Activation
Osteoclasts
Resorption

Osteoblasts
Skeleton is always changing
and remodelling. Constantly
undergoing removal and
replacement.
Removal by osteoclasts,
removing damaged bone.
Then osteoblasts come and
replace it.
Formation
Mineralization
Mineralising bone
Quiescence
Bone structural unit

In age the osteoblasts can’t
keep up and you lose bone
mass.

A giant cell with a very large
skirt that settles on the bone. It
makes acid that dissolves the
calcium and produces enzymes
to degrade the protein.

Osteocytes get stuck in the
bone – they are the most
abundant cells in bone. They
put out sclerostin, which stops
bone formation.

PTH blocks this, allowing more
bone to be formed. high PTH
levels have a reverse effect,
enabling bone resorption.
Adapted from Compston 1996
Bone Cell Origins
Garvan I nstitute of Medical Research
LRP5 – lipoprotein receptor like
protein 5. Mutations in this gene
are very important in bone,
because if you have an activating
receptor you have very dense
bones, and inactivating mutation
results in a marked loss of bone.
Regulates bone mass.
If you want to have fine control,
you have to have these
accelerators and breaks in the
pathway. This ensures good
stability.
Hypophosphataemic
yp p
p
Rickets
Adults don’t get rickets
because the bone is already
mineralised. We get
osetomalatia instead.

Renal oseto-dystrophy relates
to impaired ability to excrete
phosphate and make vit. 1.25
D. number of different
potential changes in the bone.
X-link
PTH
Calcitonin
Formation

Calcium
Absorption
p
Phosphate
Resorption
Filtration
1,25-OH2D
FGF 23
FGF-23
Reabsorption
Garvan I nstitute of Medical Research
Ostep
p
Cortex
Trabeculae
Cortex
Trabec lae
Trabeculae
Ostepenia
p
Osteoporosis
p
Transition
Cortex
Trabeculae
Normal
Bone
remodeling
sites
Cortex
Trabec lae
Trabeculae
Perforations
Loss of trabecular connections
particularly with high bone turnover
Garvan I nstitute of Medical Research