METABOLISME

TULANG
(MODUL 1.3)
DWI NGESTININGSIH
Bones
99% of the Calcium in our bodies is found in our
bones which serve as a reservoir for Ca2+
storage.
10% of total adult bone mass turns over each
year during remodeling process
During growth rate of bone formation exceeds
resorption and skeletal mass increases.
Linear growth occurs at epiphyseal plates.
Increase in width occurs at periosteum

Once adult bone mass is achieved equal rates of

formation and resorption maintain bone mass
until age of about 30 years when rate of
resportion begins to exceed formation and bone
mass slowly decreases.
Bone can be classified based on both
anatomy and structure anatomic
long bones
flat bones

structure
macroscopic level
cortical
cancellous
microscopic level
lamellar
woven bone
Bone composition

The matrix
40% organic
Type 1 collagen (tensile strength)
Proteoglycans (compressive strength)
Osteocalcin/Osteonectin
Growth factors/Cytokines/Osteoid
60% inorganic
Calcium hydroxyapatite

The cells
osteo-clast/blast/cyte/progenitor
Bone Composition
 Structure of Bones
Haversian canals within lamellae
Types of Bone Cells
There are 3 major types of bone cells:

Osteoblasts are the differentiated bone forming

cells and secrete bone matrix on which Ca2+ and
PO43- precipitate.

Osteocytes, the mature bone cells are enclosed in

bone matrix.

Osteoclasts is a large multinucleated cell derived

from monocytes whose function is to resorb bone.
Inorganic bone is composed of hydroxyapatite and
organic matrix is composed primarily of collagen.
Bone Formation
Active osteoblasts synthesize and extrude
collagen

Collagen fibrils form arrays of an organic

matrix called the osetoid.

Calcium phosphate is deposited in the

osteoid and becomes mineralized

Mineralization is combination of CaPO4, OH-,

and H3CO3 hydroxyapatite.
Mineralization
Requires adequate Calcium and phosphate
Dependent on Vitamin D
Alkaline phosphatase and osteocalcin play

roles in bone formation

Their plasma levels are indicators of

osteoblast activity.
Control of Bone Formation and Resorption

Bone resorption of Ca2+ by two mechanims:

osteocytic osteolysis is a rapid and
transient effect and osteoclastic resorption
which is slow and sustained.

Both are stimulated by PTH. CaPO4

precipitates out of solution id its solubility is
exceeded. The solubility is defined by the
equilibrium equation: Ksp = [Ca2+]3[PO43-]2.
In the absence of hormonal regulation
plasma Ca2+ is maintained at 6-7 mg/dL by
this equilibrium.
 Peak bone mass occurs between ages 16 and 25
greater in men and African Americans

Bone loss bone mass decreases 0.3 to 0.5% per

year
bone mass decreases 2-3% per year for

untreated women during the 6th-10th years after

menopause

markers of increased bone resorption

urinaryhydroxyproline
pyridoline cross-links
markers for increase bone formation
serum alkaline phosphatase
Osteocytic Osteolysis
Transfer of calcium from canaliculi to
extracellular fluid via activity of osteocytes.
Does not decrease bone mass.
Removes calcium from most recently

formed crystals
Happens quickly.
Bone Resorption
Does not merely extract calcium, it destroys
entire matrix of bone and diminishes bone
mass.

Cell responsible for resorption is the

osteoclast.
Bone Remodeling
Endocrine signals to resting osteoblasts generate
paracrine signals to osteoclasts and precursors.
Osteoclasts resorb and area of mineralized bone.
Local macrophages clean up debris.
Process reverses when osteoblasts and precursors

are recruited to site and generate new matrix.

New matrix is minearilzed.
New bone replaces previously resorbed bone.
Osteoclasts and Ca2+ Resorption
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
Others by RANKL, and this
Mineralization leads to cells
Activation of differentiation to
osteoclasts via RANKL osteoclasts
production
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
Calcium, Bones and Osteoporosis
The total bone mass of humans peaks at 25-
35 years of age.
Men have more bone mass than women.
A gradual decline occurs in both genders
with aging, but women undergo an
accelerated loss of bone due to increased
resorption during perimenopause.
Bone resorption exceeds formation.
Calcium, Bones and Osteoporosis
Reduced bone density and mass: osteoporosis

Susceptibility to fracture.

Earlier in life for women than men but eventually

both genders succumb.

Reduced risk:
Calcium in the diet
habitual exercise
avoidance of smoking and alcohol intake
avoid drinking carbonated soft drinks
Osteoclast Mediated Bone Resorption
PTH and
Osteoblastogenesis
Osteoclastogenesis
Osteoclastogenesis: RANKL,
RANK, and OPG
Osteoblasts activate osteoclasts, formation of a
multinuclear cell

The molecular participants in this pathway are the

membrane-associated protein named RANKL (receptor
activator of nuclear factor kappa B ligand,) a member
of the tumor necrosis factor family of cytokines
Its cognate receptor is RANK; TRAF, TNF receptor
associated factors
Mediates activation of NF-kappa-B by unknown
mechanism

OPG (osteoprotegerin) is a soluble "decoy" receptor

for RANKL
 RANKL is expressed on the surface of
osteoblastic stromal cells

By binding to RANK, its receptor, on osteoclast

precursors, RANKL enhances their recruitment
into the osteoclastogenesis pathway in the
physiology of bone metabolism

RANKL also activates mature osteoclasts to

resorb bone

RANKL is a factor through which osteoblasts

regulate osteoclasts, and bone formation is
coupled to bone resorption
RANK and RANKL
Bone turnover

What happens to bone.

in youth?
aged 20-40s?
aged 40+?
aged over 70?
Factors affecting
bone turnover
 Calcium
Bone acts as reservoir for 99% of bodies
calcium
400 mg /day of calcium is released from bone
Function
calcium has a wide range of function including
muscle function
nerve function
clotting mechanisms
Forms of calcium
plasma calcium (<1% of total body calcium)
may be free or bound to albumin
 Regulation
absorption in the duodenum by regulated by 1,25-(OH)2-
vitamin D3
PTH
kidney resorbs 98% of calcium (60% in the proximal tubule)

Dietary requirements
2000 mg/day for lactating women
1500 mg/day for pregnant women, postemenopausal woman,
and patients with a healing bone fracture
1300 mg/day for adolescents and young adults
750 mg/day for adults
600 mg/day for children

Dysfunction
hypercalcemia
hypocalcemia
 Calcium and the Skeleton

A, absorption is stimulated by Vit D; S: secretion

GF: glomerular filtration; TR: tubular
reabsorption of Ca2+ is stimulated by PTH
Calcium in Blood and Bone
Ca2+ normally ranges from 8.5-10 mg/dL in
the plasma.

The active free ionized Ca2+ is only about

48% 46% is bound to protein in a non-
diffusible state while 6% is complexed to
salt.

Only free, ionized Ca2+ is biologically active.

Calcium and Bone
99% of Ca is found in the bone. Most is
found in hydroxyapatite crystals.

Very little Ca2+ can be released from the

bone though it is the major reservoir of
Ca2+ in the body.
Calcium Turnover in Bones
80% of bone is mass consists of cortical bone
for example: dense concentric layers of
appendicular skeleton (long bones)

20% of bone mass consists of trabecular bone

bridges of bone spicules of the axial skeleton
(skull, ribs, vertebrae, pelvis)

Trabecular bone has 5 X greater surface area,

though comprises lesser mass.

Because of greater accessibility trabecular

bone is more important to calcium turnover
Phosphate
Functions
key component of bone mineral
important in enzyme systems and molecular
interactions
Forms
85% is stored in the bone
Regulation
plasma phosphate is mostly unbound and reabsorbed
by the kidney
may be excreted in urine
Dietary intake
1000-1500 mg/day
Phosphate Turnover
Phosphorous in Blood and Bone
PO4 normal plasma concentration is 3.0-4.5
mg/dL. 87% is diffusible, with 35%
complexed to different ions and 52%
ionized.

13% is in a non-diffusible protein bound

state. 85-90% is found in bone.

The rest is in ATP, cAMP, and proteins

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
 PTH
Structure
84 amino acid peptide
Origin
synthesized and secreted from chief cells in the four
parathyroid glands

Net effect
increases serum Ca
decreases serum P

Regulatory cycle
decrease serum calcium > stimulates beta2receptors
to release PTH
 End organ action
bone
PTH stimulates osteoblastics toactivate osteoclasts and
increase resorption of bone
kidney
stimulates enzymatic conversion of 25-(OH)-vitamin
D3converted to1,25-(OH)2-vitamin D3(active hormone
form)
increases resorption of Ca in kindney
increase excretion of P from kidney
intestine
no direct action
indirectly increase Ca absorption by activating1,25-
(OH)2-vitamin D3
Dysfunction
PTH-related protein and its receptor have been
implicated in metaphyseal dysplasia
Calcitonin
Physiological role
Stimulates cAMP production in bone and

kidney
Potential treatment for hypercalcemia
Levels increased when serum Ca

>2.25mmol/L
Target organs

Bone - suppresses resorption

Kidney - increases excretion
 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+
Vitamin D (cholecalciferol)
Sources of vit D
Diet
u.v. light on precursors in skin
Normal daily requirement
400IU/day
Target organs
bone - increased Ca release
gut - increased Ca absorption
 Normal metabolism

Vit D

25-HCC (Liver)
Ca/PTH

1,25-DHCC 24,25-DHCC
(Kidney) (Kidney)
Vitamin D Metabolism
Transport and Metabolic Sequence
of Activation of Vitamin D
Proposed Mechanism of Action of
1,25-DihydroxyD3 in Intestine
Factors affecting bone turnover ( cont.)
Other hormones
Oestrogen
gut - increased absorption
bone - decreased re-absorption
Glucocorticoids
gut - decrease absorption
bone - increased re-absorption/decreased
formation
Thyroxine
stimulates formation/resorption
net resorption
Estrogen
Normal function
preventsbone loss by inhibiting bone resorption
alone, because bone formation and resorption are
coupled, it also indirectly decreases bone
formation

leads to an increase in bone density of the

femoral neck and reduces the risk of hip fracture

most important sex-steroid for peak bone mass

attainment in both men and women
 Therapeutic estrogen

outcomes
decreases bone loss if started within 5-10 years after onset of
menopause
significant side effects so risk/benefit ratio must be evaluated

secondary effects
increases risk of
heart disease
breast cancer
decreases risk of
hip fracture
endometrial cancer (if combined with cyclic progestin)

laboratory
will see a decreases in
urinary pyridoline
serum alkaline phosphatase
Steroids

Function

increase bone loss by

decrease Ca absorptionin intestine through a
decrease in binding proteins

decrease bone formation(cancellous more so

than cortical bone) by
decreasing collagen synthesis
inhibiting osteoblast activity
Thyroid Hormone

Function
regulates skeletalgrowth at the physisby
stimulating
chondrocyte growth
type X collagen synthesis
alkaline phosphatase activity
thyroid hormones increase bone resorption
and can lead toosteoporosis
large doses of therapeutic thyroxine can
mimic this process and cause osteoporosis
Growth Hormone

Function
increases serum calcium by
increased absorption in intestine
decreasing urinary excretion
function is interdependent with insulin,
somatomedins, and growth factors (TGF-B, PDGF,
mono/lyphokines)

Gigantism
oversecretion or increasedresponse to growth
hormone effecting the proliferative zone of the
growth plate
Factors affecting bone turnover (cont.)
Local factors
I-LGF 1 (somatomedin C)
increased osteoblast prolifn
TGF
increased osteoblast activity
IL-1/OAF
increased osteoclast activity (myeloma)
PGs
increased bone turnover
BMP
bone formation
Factors affecting bone turnover (cont.)

Other factors
Local stresses
Electrical stimulan
Environmental

temp
oxygen levels
acid/base balance
Vertebrae of 40- vs. 92-year-old
women
Note the marked loss of trabeculae with preservation of cortex.
Hormonal
Control of
Bones
Hormonal Control of Ca2+
Three principal hormones regulate Ca2+
and three organs that function in Ca2+
homeostasis.

Parathyroid hormone (PTH), 1,25-

dihydroxy Vitamin D3 (Vitamin D3),
and Calcitonin, regulate Ca2+ resorption,
reabsorption, absorption and excretion
from the bone, kidney and intestine. In
addition, many other hormones effect
bone formation and resorption.
Vitamin D
Vitamin D, after its activation to the
hormone 1,25-dihydroxy Vitamin D3 is a
principal regulator of Ca2+.

Vitamin D increases Ca2+ absorption from

the intestine and Ca2+ resorption from the
bone .
Synthesis of Vitamin D
Humans acquire vitamin D from two sources.
Vitamin D is produced in the skin by ultraviolet
radiation and ingested in the diet.

Vitamin D is not a classic hormone because it is

not produce and secreted by an endocrine
gland. Nor is it a true vitamin since it can be
synthesized de novo.

Vitamin D is a true hormone that acts on distant

target cells to evoke responses after binding to
high affinity receptors
Synthesis of Vitamin D
Vitamin D3 synthesis occurs in keratinocytes in the
skin.

7-dehydrocholesterol is photoconverted to
previtamin D3, then spontaneously converts to
vitamin D3.

Previtamin D3 will become degraded by over

exposure to UV light and thus is not overproduced.

Also 1,25-dihydroxy-D (the end product of vitamin D

synthesis) feeds back to inhibit its production.
Synthesis of Vitamin D
PTH stimulates vitamin D synthesis. In the winter or
if exposure to sunlight is limited (indoor jobs!), then
dietary vitamin D is essential.

Vitamin D itself is inactive, it requires modification to

the active metabolite, 1,25-dihydroxy-D.

The first hydroxylation reaction takes place in the

liver yielding 25-hydroxy D.

Then 25-hydroxy D is transported to the kidney

where the second hydroxylation reaction takes
place.
Synthesis of Vitamin D
The mitochondrial P450 enzyme 1-hydroxylase
converts it to 1,25-dihydroxy-D, the most potent
metabolite of Vitamin D.

The 1-hydroxylase enzyme is the point of

regulation of D synthesis.

Feedback regulation by 1,25-dihydroxy D inhibits

this enzyme.

PTH stimulates 1-hydroxylase and increases

1,25-dihydroxy D.
Synthesis of Vitamin D
25-OH-D3 is also hydroxylated in the 24 position
which inactivates it.

If excess 1,25-(OH)2-D is produced, it can also by

24-hydroxylated to remove it.

Phosphate inhibits 1-hydroxylase and decreased

levels of PO4 stimulate 1-hydroxylase activity
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
1,25-
25-hydroxycholecalciferol
dihydroxycholecalciferol

increase
Low phosphate phosphate
resorption
Synthesis of
Vitamin D
Vitamin D
Vitamin D is a lipid soluble hormone that
binds to a typical nuclear receptor,
analogous to steroid hormones.

Because it is lipid soluble, it travels in the

blood bound to hydroxylated -globulin.

There are many target genes for Vitamin

D.
Vitamin D action
The main action of 1,25-(OH)2-D is to stimulate
absorption of Ca2+ from the intestine.

1,25-(OH)2-D induces the production of calcium

binding proteins which sequester Ca2+, buffer
high Ca2+ concentrations that arise during initial
absorption and allow Ca2+ to be absorbed
against a high Ca2+ gradient
Vitamin D promotes intestinal calcium
absorption

Vitamin D acts via steroid hormone like

receptor to increase transcriptional and
translational activity

One gene product is calcium-binding protein

(CaBP)

CaBP facilitates calcium uptake by intestinal

cells
Clinical correlate
Vitamin D-dependent rickets type II

Mutation in 1,25-(OH)2-D receptor

Disorder characterized by impaired

intestinal calcium absorption

Results in rickets or osteomalacia despite

increased levels of 1,25-(OH)2-D in
circulation
Vitamin D Actions on Bones
Another important target for 1,25-(OH) 2-D is the
bone.

Osteoblasts, but not osteoclasts have vitamin D

receptors.

1,25-(OH)2-D acts on osteoblasts which produce

a paracrine signal that activates osteoclasts to
resorb Ca++ from the bone matrix.

1,25-(OH)2-D also stimulates osteocytic

osteolysis.
Vitamin D and Bones
Proper bone formation is stimulated by
1,25-(OH)2-D.

In its absence, excess osteoid accumulates

from lack of 1,25-(OH)2-D repression of
osteoblastic collagen synthesis.

Inadequate supply of vitamin D results in

rickets, a disease of bone deformation
 Parathyroid Hormone
PTH is synthesized and secreted by the
parathyroid gland which lie posterior to the
thyroid glands.

The blood supply to the parathyroid glands is

from the thyroid arteries.

The Chief Cells in the parathyroid gland are

the principal site of PTH synthesis.

It is THE MAJOR of Ca homeostasis in humans.

TERIMA
KASIH
TUGAS :
Buatlah secara skematis hubungan antara

Ca, P, dan hormon-hormon yang berperan

pada metabolisme tulang