BONE PHYSIOLOGY

AND
METABOLISM
PRESENTED BY-
Dr ROCHANA MAHESH
1 ST YEAR PG
CONTENTS
◦BONE PHYSIOLOGY
Introduction
Development of bone
Classification Gross bone histology
Composition Blood supply
Functions of bone Nerve supply
Alveolar Bone
Structure of bone Modeling and Remodeling
Bone cells Clinical correlation
Regulation of bone cell formation Conclusion
 INTRODUCTION
◦ Bone is a highly vascular, living, constantly changing, mineralized connective tissue

◦ Morphologically, bone tissue appears to be under control of bone cells

◦ It’s surfaces are developed by active and resting osteoblasts and osteoclasts and it is
permeated by an interconnected canalicular system in which osteocytes are found

◦ Bone is a tension adapted tissue and tension on the periosteum will result in the
differentiation of osteoblasts from the periosteal cells and leads to formation of new
bone.

◦ On the other hand, pressure on the periosteum will cause vascular occlusion and may
produce bone resorption
CLASSIFICATION OF BONE

◦ Based on Shape :

a) Long bones

b) Short bones

c) Flat bones

d) Irregular bones

e) Sesamoid bone
◦ Based on development

a) Endochondral bones Eg: Condyle

b) Intramembranous bone Eg: Skull

◦ Based on microscopic structure

a) Immature/ Woven bone

b) Mature bone

- Compact bone

- Cancellous bone
COMPOSITION

◦Bone is a specialized mineralized connective tissue consisting of 33%

organic matrix, 28% Type 1 collagen and 5% non collagenous proteins,
including osteonectin, osteocalcin, bone morphogenetic proteins, bone
proteoglycan and bone sialoprotein.

◦This inorganic matrix is permeated by hydroxyapatite, which makes up

the remaining 67% of bone.
 BONE

MATRIX CELLS

OSTEOPROGINATO
ORGANIC (33%) INORGANIC
R
(67%)
OSTEOCYTE

NON COLLAGENOUS (5%) HYDROXYPETITE OSTEOBLAST

COLLAGENOUS
(28%) (CALCIUM & PHOSPHORUS)
OSTEOCLAST
OSTEOCALCIN
TYPE 1 COLLAGEN
SIALOPROTEIN
OSTEONECTIN
BONE MORPHOGENIC PROTEIN
BONE PROTEOGLYCAN
Collagen
◦Type 1 collagen > 95% - Principal collagen in mineralized bone

◦Alveolar bone contains type I , type V, type III and type XII collagen

◦Sharpeys fibers contain type III collagen with type I collagen

◦Type III and XII collagen fibers are produced by fibroblast during the
formation of pdl

◦Type I, V and XII collagen are expressed by osteoblasts

Noncollagenous proteins
◦Endogenous proteins – bone cells, albumin-blood

◦Osteocalcin: First noncollagenous protein to be recognized aka Bone Gla

protein

◦It is a glycoprotein- osteoblasts and regulated by vitamin D3 and

parathyroid hormone

◦Osteopontin and Bone Sialoprotein demonstrated in alveolar bone

◦Osteonectin : Bound to Collagen and hydroxyapatite crystals

◦ Proteoglycans are also present in the bone matrix

◦Lysyl oxidase and tyrosine rich acidic matrix proteins

(TRAMP) are the component of demineralized bone and dentin
matrix

◦TRAMP, aka dermatopontin, binds decorin and TGF- beta

◦Bone matrix also contains proteases, protease inhibitors and

cytokines secreted by osteoblasts, that regulate cell metabolism

◦These cells secrete several BMPs ( Bone Morphogenic Proteins)

FUNCTIONS OF BONE
◦Support : Forms supporting framework, giving shape and rigidity to the
body

◦Protection : Serves to protect the soft and delicate tissues of the body

Eg: Skull protects the brain

◦Locomotion : Forms a system to which the voluntary muscles are

attached

◦Manufacturing of RBCs : RBCs are manufactured in red bone marrow

which is situated in spongy tissue at the ends of long bones
STRUCTURE OF BONE
◦The structure of bone may be analyzed by considering parts of long bone

◦A typical long bone consists of the following parts:

a)Diaphysis ( growing between) – Bone’s shaft or long body ie main

portion of bone

b)Epiphysis (growing over) – These are the distal and proximal ends of
the bone
Epiphysis

Metaphysis

STRUCTUR
E OF LONG
BONE
Diaphysis
◦The metaphysis in mature bone is where the diaphysis joins the
epiphysis

In a growing bone each metaphysis includes an epiphyseal plate a layer

of hyaline cartilage that allows the diaphysis to grow.

◦The articular cartilage is a thin layer of hyaline cartilage covering the

epiphysis where bone forms an articulating joint with another bone This
reduces friction, absorbs shock at freely movable joints
◦Periosteum : Tough sheath of dense irregular connective tissue that sum
the bone surface where it is not covered by articular cartilage

◦Medullary cavity : Marrow cavity is the space within diaphysis that

contains fatty yellow bone marrow in adults

◦Endosteum : Thin membrane that lines medullary cavity Contains bone

forming cells and connective tissue
CELLS OF BONE TISSUE
 Osteoprogenitor cells
◦Derived from stem cells

◦Differentiate into 4 types of cells

◦Comprise periosteal and endosteal cells

◦Flattened or squamous cells, light staining,

elongated or ovoid nuclei, cytoplasm

acidophilic or basophilic
 Osteoblasts
◦Mononucleated cells

◦Synthesizes collagenous and non collagenous bone

matrix proteins

◦Produce organic matrix of bone (osteoid)

◦Arise from pluripotent stem cells

◦Exhibit high levels of alkaline phosphatase on the

surface of their plasma membrane

◦Plump, cuboidal cells or slightly flattened cells

◦Type I collagen is the dominant component of the bone matrix

◦Type V collagen and proteoglycans and non collagenous proteins are

present in small amounts

◦They secrete a number of cytokines and growth factors that help in

regulating cellular function and bone formation
◦IGF-I + TGF –β + Platelet derived growth factor = Increase rapidity of
bone formation and bone repair

◦Parathyroid hormone, 1,25- dihydroxy vitamin D , Calcitonin, Estrogen

and Glucocorticoids = Bone metabolism

◦Parathyroid hormone + Vitamin D = a) Bone resorption

( at high concentration )

b) Bone formation

( at lower concentration )
◦Leptin, a circulating hormone –

a) Can promote and inhibit the differentiation of osteoclasts

b) Promote the initiation and differentiation osteoprogenitor cells and

stimulate osteoblasts to make a new bone
 Bone lining cells
◦Derived from osteoblast
◦Communicate by gap junctions
◦ Bone lining cells prevent the direct interaction between osteoclasts and
bone matrix, when bone resorption should not occur, and also
participates in producing osteoprotegerin (OPG) and the receptor
activator of nuclear factor kappa-B ligand (RANKL)
Stained with toluidine blue showing a portion of a bony trabecula (B). Osteoblasts (Ob) and bone
lining cells (BLC)
 Osteocytes
◦The osteocytes are located within lacunae surrounded by mineralized
bone matrix, wherein they show a dendritic morphology

◦More rapid bone formation more osteocytes are present per unit volume

◦As a general rule, Embryonic (woven) bone have more osteocytes than
does lamellar bone
Silver impregnation method. The cytoplasmic Scanning electron micrograph showing two osteocytes
processes of the osteocytes (Ot) surrounded by bone matrix
 Osteoclasts
◦ Multinucleated giant cells

◦Derived from fusion of mononuclear hematopoietic progenitor

cell

◦Large in size

◦Rest in Howship’s lacunae

◦Numerous lysozymes
◦ Howship’s lacunae – Shallow troughs with an irregular shape reflecting
the activity and mobility of osteoclasts during active resorption

◦ Ruffled border- Adjacent to the tissue surface, cell membrane of the

osteoclast is thrown into myriad of deep folds

◦ Clear or sealing zone – attaches cells to the mineralized surface but also
isolates a microenvironment between them and the bone surface

◦ Lamina limitans – electron-dense , interfacial matrix layer observed

between sealing zone and calcified tissue surface

◦ Functional secretory domain – collection site of vesicles

◦ Basolateral surface – regulatory surface for receiving messages from

neighboring cells
 Osteoclasts (Oc and
Oc1) are observed in a
resorbing bone
lacuna.
Formation of Osteoclast
◦Multinucleated giant cells are derived from hemopoietic cells of
monocyte macrophage lineage

◦Earliest identifiable hematopoietic precursor that can form osteoclast is

the granulocyte- macrophage colony forming unit (CFU-GM)

◦The early precursor cells proliferate and differentiate to form post mitotic
committed precursor cells
◦ These committed precursor then differentiate and fuse to form
multinucleated giant cells

◦These are activated to form bone resorbing osteoclast

◦The formation of osteoclast requires the presence of RANK ligand

( receptor activator of nuclear factor kB) and M-CSF (macrophage colony
stimulating factor)

◦These two membrane bound proteins are produced by neighboring

stromal cells and osteoblasts, thus requiring direct contact between
these cells and osteoclast precursors.
◦M-CSF acts through its receptor on osteoclast precursors c-Fms
( colony stimulating factor 1 receptor) and thereby provides signals
required for proliferation

◦RANKL has been implicated in the fusion of osteoclast precursor into

multinucleated giant cells

◦Their differentiation into mature osteoclasts, their attachment to bone

surface and their activation to resorb bone
◦It recognize RANKL, and blocks their
interaction between RANK and RANKL,
leading to inhibition of osteoclasts
differentiation and activation

◦The balance between RANKL-RANK

signaling and the levels of biologically
active OPG, regulates development and
activation of osteoclast and bone
metabolism
 Regulation of bone cell
formation
◦ Bone forming cells have a mesenchymal origin, whereas that of
osteoclast is hematopoietic.

◦Two transcription factors essential for osteoblast differentiation from

mesenchymal stem cells and their function – Runx2 and Osterix

◦Runx2- a) involved in osteoblast differentiation

b)Control the maturation of osteoblasts and their transition into osteocytes

◦Osterix may play an important role in directing precursor cells away
from the chondrocyte lineage and toward osteoblast lineage.

◦Stromal cells in the marrow cavity and osteoblasts modulate the

differentiation of osteoclasts via a secreted molecules and via direct cell-
cell interaction

◦The receptor activated nuclear factor kB(RANK) and its ligand (RANKL)
play major role in controlling osteoclastogenesis
BONE DEVELOPMENT
◦Endochondral bone formation

◦Intramembranous bone formation

◦Sutural bone growth

 Endochondral bone
formation
◦Endochondral bone formation uses hyaline cartilage as blue print
Histogenesis of hyaline cartilage
◦During hyaline cartilage development, mesenchymal cells retract their
cytoplasmic extensions and assume a round shape, becoming more
tightly packed and forming a mesenchymal condensation or pre cartilage
condensation
◦The increased cell to cell contact stimulates cartilage differentiation,
which progresses from the center outward

◦Cell at the condensation core are the first to become chondroblasts

and secrete cartilage matrix

◦After it is surrounded by cartilage matrix chondroblast is termed as

chondrocyte

◦Peripheral mesenchyme condenses around the developing cartilage mass

to form the fibroblast containing, dense regular connective tissue of
the perichondrium
◦In this type of osteogenesis, the bone formation is preceded by formation
of a cartilaginous model which is subsequently replaced by bone

◦Mesenchymal cells become condensed at the site of bone formation

◦Some mesenchymal cells differentiate into chondroblasts and lay down

hyaline cartilage

◦The cartilage is surrounded by membrane called perichondrium. This is

highly vascular and contains osteogenic cells.
◦The intercellular substance surrounding the cartilage cells becomes
calcified due to the influence of enzyme alkaline phosphatase secreted
by the cartilage cells

◦Thus the nutrition to the cartilage cells is cut off leading to their death.
This results in formation of empty spaces called primary areolae

◦The blood vessels and osteogenic cells from the perichondrium invade
the calcified cartilaginous matrix which is now reduced to bars or walls
due to eating away of the calcified matrix

◦This leaves large empty spaces between the walls called secondary
areolae
◦The osteogenic cells from the perichondrium become osteoblast
and arrange themselves along the surface of these bars of
calcified matrix

◦The osteoblasts lay down osteoid which later becomes calcified

to form a lamella of bone

◦Now another layer of osteoid is secreted and this goes on and on

◦Thus the calcified matrix of cartilage acts as a support for bone

formation
Intramembranous bone
formation

◦In this type of ossification, the formation of bone is not

preceded by formation of a cartilaginous model

◦Instead bone is laid down directly in a fibrous membrane

◦The intramembranous bone is formed in the following way:

 At the site of bone formation, mesenchymal cells become aggregated

 Some mesenchymal cells lay down bundle of collagen fibers

These osteoblasts secrete a gelatinous matrix called osteoid around the

collagen fibers

They deposit calcium salts into the osteoid leading to conversion of

osteoid into bone lamella
◦Now the osteoblasts move away from the lamella and a new layer
of osteoid is secreted which also gets calcified.

◦Some of the osteoblasts get entrapped between two lamella

◦They are called OSTEOCYTES

 Sutural bone growth
◦Sutures play an important role in the growing face and skull

◦Found exclusively in the skull, sutures are the fibrous joints between
bones; however, sutures allow only limited movement.

◦Their function is to permit the skull and face to accommodate growing

organs such as the eyes and brain
◦Osteogenic layer- cambium

◦Inner leaf layer- capsule

◦Between these two layers is a loose cellular and vascular tissue

◦When two bones are separated E.g.: the skulls bones forced
apart by growing brain- bone forms at the sutural margins, with
successive waves of new bone cells differentiating from cambium

◦Sutures have same osteogenic potential as periosteum

Gross bone histology
◦Microscopic structure :

 The bone tissue consists of bone cells present in a bone matrix

The bone matrix or the intercellular substance is made of collagen fibers

and ground substance i.e.. Complex mucopolysaccharides

The inorganic or crystalline part of the bones comprises of

hydroxyapatite crystals

The bone cells are called osteocytes and are found occupying small
spaces in the matrix called LACUNAE
◦The lacunae are connected to one another by a system of canals called
CANALICULI

◦Some of the canaliculi open into certain canals that contain capillaries

◦This system of connected bone cells is the means by which nutrients are
distributed throughout the bone tissue

◦Mature bone is formed in thin layers called lamellae. The lamellae are
arranged in concentric circles called HAVERSIAN SYSTEM
◦The haversian system consists of concentric lamellae around a canal
called HAVERSIAN CANAL which contain capillary blood vessels

◦Haversian system consists of a central canal surrounded by concentric

circles of bony lamellae

◦The lamellae in turn are made of osteocytes found within empty spaces
called LACUNAE

◦A number of canaliculi are found radiating from the lacunae

◦Three distinct type of bony lamellae are found –
1. Circumferential lamellae
2. Concentric lamellae
3. Interstitial lamellae

◦ Circumferential Lamellae : Bony lamellae that surrounds the entire

bone, forming its outer perimeter
◦Concentric Lamellae : They form the bulk of the bone and form the
basic metabolic unit of the bone called osteon. The osteon is a cylinder
of bone found oriented along the long axis of the bone
◦Interstitial Lamellae : They are lamellae that are found between
adjacent concentric lamellae. They are thus fillers that fill the space
between the concentric lamellae
◦A number of canals are found in bone, containing blood vessels that
pass into the bone from the outside or from the bone marrow cavity.
These canals are called VOLKMANN’S CANALS

◦Branches of blood vessels from these canal may enter the smaller
haversian canals.

◦BONE MARROW is found occupying the center of the bone. It can be

two types-

 Red Bone Marrow

Yellow Bone Marrow

◦RED BONE MAROW

 They are found in most of the bones in young individuals

They help in formation of RBCs and WBCs

In adult most of the red bone marrow gets converted into yellow marrow

◦YELLOW BONE MARROW

 It is a fatty marrow that does not produce red and white blood cells
◦Types of Bone Tissue : Bone tissue is classified by its architecture as
spongy or compact by its fine structure as primary (woven) or secondary
(lamellar)

◦All bone tissue begins as primary bone, but nearly all is eventually
replaced by secondary bone
◦The distinction between intramembranous and endochondral bone is
based on histogenesis but is not microscopically detectable in mature
bone.

◦Compact bone is usually long (like a femur) and white

◦It is a hard bone, that makes up the outer covering of the bone

◦It is composed of multiple osteon unit that are bunched closely together
like stacked logs and thus is good at bearing weight in the long direction
◦Spongy bone is softer bone, with holes in it

◦It is found inside the bone

◦Individual osteon like struts (called trabeculae) branch in many

direction and interconnect

◦Thus, there are spaces created where red marrow exists

◦This kind of bone is good at handling stress from multiple

directions and is lighter weight
Histology of Woven and Lamellar
bone
◦Two types of bone can be identified microscopically according to the
pattern of collagen forming the osteoid ( collagenous support tissue of
type I collagen embedded in glycosaminoglycan gel ) :
◦Woven bone, which is characterized by haphazard organization of
collagen fibers and is mechanically weak
◦Lamellar bone, which has a regular parallel alignment of collagen into
sheets (lamellae) and is mechanically strong
◦Woven bone is produced when osteoblasts produce osteoid rapidly, which
occurs initially in all fetal bones ( but is later replaced by more resilient
lamellar bone)
◦ In adults woven bone is created after fractures or in Paget’s disease.
Woven bone is weaker with a smaller number of randomly oriented
collagen fibers, but forms quickly; it is for this appearance of the fibrous
matrix that the bone is termed woven

◦It is soon replaced by lamellar bone, which is highly organized in

concentric sheets with a much lower proportion of osteocytes to
surrounding tissue

◦After a fracture, woven bone forms initially and is gradually replaced by

lamellar bone during a process known as ‘ Bony substitution’.
Compared to woven bone, lamellar bone formation takes place more
slowly.
Blood supply of Bone
◦Arterial Supply
 The bone is supplied by periosteal
metaphyseal, epiphyseal arteries
◦Venous Drainage
 By periosteal, epiphyseal, metaphyseal
veins
Nerve supply of Bone
◦Nerves accompany the blood vessels that supply bone.

◦The periosteum is rich in sensory nerves, some of which carry

pain sensations

◦Nerves are specially sensitive to tearing and tension, which

explains the severe pain from fracture or bone tumor
ALVEOLAR BONE
◦The alveolar process bone may be defined as that part of the maxilla and
the mandible that forms and supports the sockets of the teeth

◦Functions of alveolar bone:

 Houses the roots of teeth

Anchors the roots of teeth to the alveoli, which is achieved by the

insertion of Sharpey’s fibers into alveolar bone proper

Helps to move the teeth for better occlusion

◦Helps to absorb and distribute occlusal forces generated during
tooth contact

◦Supplies vessels to periodontal ligament

◦Houses and protects developing permanent teeth, while supporting

primary teeth

◦Organizes eruption of primary and permanent teeth

 Development of alveolar
process
◦Near the end of 2nd month of fetal life, the maxilla as well as the
mandible forms a groove that is open toward the surface of the oral
cavity.

◦The tooth germs are also contained in this groove, which also includes
the alveolar nerves and vessels.

◦Gradually bony septa develops between the adjacent tooth germs, and
much later, the primitive mandibular canal is separated from the dental
crypts by a horizontal plate of bone
◦An alveolar process develops only during the eruption of the teeth

◦During growth part of alveolar process is gradually incorporated into the

maxillary and mandibular body while it grows at a fairly rapid rate at its
free borders

◦During this period a tissue may develop at the alveolar crest that
combines characteristics of cartilage and bone. It is called chondroid
bone

◦The alveolar process forms with the development and the eruption of
teeth
 Structure of alveolar bone
◦Alveolar bone proper- a thin lamella of bone that surrounds the root
of the tooth and gives attachment to principle fibers of the periodontal
ligament

◦Supporting alveolar bone- bone that surrounds the alveolar bone

proper and gives support to the socket

◦Bundle bone- it is that bone in which principle fibers of the periodontal

ligament are anchored
◦Lamina dura (LD) is a radiographic landmark viewed largely
on periapical radiographs. It is a thin layer of dense cortical bone, which
lines the roots of sound teeth.

◦Cribriform plate- The alveolar process is the lining of the tooth's socket
and referred to as the alveolus. The alveolar process is made up of compact
bone, it may also be called the cribriform plate as it contains various holes
where Volkmann canals pass from the alveolar bone and into the PDL.

◦Interdental septum-The portion of alveolar bone between two adjacent

teeth is known as the interdental septum (or interdental bone). The
connected, supporting area of the jaw (delineated by the apexes of the
roots of the teeth) is known as the basal bone.
◦Supporting alveolar bone consists of 2 parts :

a) Cortical plates

b) Spongy bone
Age changes
◦In older individuals:
 Alveolar socket appear jagged and uneven
The marrow spaces have fatty infiltration
The alveolar process in edentulous jaws decreases in size
Loss of maxillary bone is accompanied by increase in size of the
maxillary sinus
Internal trabecular arrangement is more open, which indicates bone loss
The distance between the crest of the alveolar bone and CEJ increases
with the age- approximately by 2.81mm
MODELLING AND
REMODELLING OF BONE
BONE REMODELING

◦Bone remodeling is ongoing replacement of old bone tissue by

new bone tissue

◦Involves bone resorption i.e.. Removal of minerals and collagen

fibers from bone by osteoclasts and bone deposition ie addition
of minerals and collagen fibers to bone by osteoblasts
◦ During the process of bone resorption osteoclast attaches to bone
surface at endosteum or periosteum and forms a leak proof seal at
the edges of its ruffled border

◦Releases protein digesting enzymes and acids, resulting in

destruction of collagen fibers and loss of minerals

◦Working together osteoclasts carve out a small tunnel in the old

bone.

◦ As osteoclasts move through bone, leading edge of bone is cutting

cone, characterized by a scalloped array of Howship’s lacunae
◦ As these cells differentiate into osteoblasts , they produce a coating
called Cement or Reversal Line

◦On top of this cement line, osteoblasts lay down new bone matrix,
mineralizing it from outside in.

◦The area where active formation occurs is called Filling cone

◦During production and mineralization of organic matrix – there are

periods of activity and quiescence – resulting in formation of incremental
lines. Such lines in bone are called as Resting lines

◦In lamellar spongy bone- a half moon resorption cavity is created by

osteoclasts and then filled in with bone matrix by osteoblast
MODELLING AND REMODELLING
Both trabecular and cortical bones grow, adapt and turnover by
means of two mechanisms-

a)Bone Modeling: independent sites of resorption and formation

change the form of bone

b)Bone Remodeling : a specific, coupled sequence of resorption

and formation occurs to replace previously existed bone.

The biomechanical response to tooth movement involves an

integrated array of bone modeling and remodeling
◦Bone modeling is the dominant process of facial growth and adaptation
to applied loads such as head gear, RME and functional appliances

◦Modeling changes can be seen on cephalometric tracing but

Remodeling changes are only apparent at the microscopic levels

Both modeling and remodeling are controlled by an interaction of

metabolic and mechanical signals

◦Bone modeling is directly under the integrated biomechanical control of

functional applied loads and under hormonal influence particularly during
periods of growth and aging
CLINICAL CORRELATION

1) Intermittent VS Continuous mechanics

 Tooth movement is directly proportional to the number of hours the

force is applied.

Even when motivation and co-operation are optimal, the effectiveness of

therapy is in consistent
2) Differential Anchorage

 The density of alveolar bone and the cross sectional area of the
roots in the plane perpendicular to the direction of tooth
movement are primary consideration for assessing anchorage
potential

Anchorage Value : The volume of osseous tissue that must be

resorbed for a tooth to move a given distance is its anchorage
value
◦Mandibular molars are difficult to move when compared to
Maxillary molars because

 Thin cortices and trabecular bone of maxilla offer less resistance to

resorption than the thick cortices and more coarse trabeculae

The leading root of mandibular molars being translated mesially forms

bone that is far more dense than the bone formed by translating
maxillary molars
◦ There is change in trabecular pattern of bone in maxilla and
mandible because

 Maxilla transforms most of its force to the cranium

The mandible is subjected to substantial torsion and flexure caused by

muscle pull and masticatory function

Maxilla is loaded predominantly in compression and there is no major

muscle attachment
3) Rate of tooth movement

 The rate of tooth movement is inversely proportional to bone density

and the volume of bone resorbed

Maximal rate of translation of mid-root area trough dense cortical bone is

about 0.5mm per month for the first few months; the rate then declines
to 0.3mm per month until 1st molar site is closed
◦The 3 principle variables that determine rate of tooth movement are

1)Growth

2)Bone density

3)Type of tooth movement

◦During growth period there is increase in tooth movement

◦Increase in density slow is the tooth movement and vice versa

◦Bodily movement is difficult to produce when compared to tipping

movement
CONCLUSION
◦It is necessary to remember that such factors as hormones , vitamins ,
age and probably heredity may influence the resorption of bone.

◦The orthodontic treatment is dependent on-

 Amount of force applied

Reaction of bone to orthodontic forces

Ultimate stability of bone

THANK YOU
 BONE
METABOLISM
PRESENTED BY-
ROCHANA MAHESH
1 ST YEAR PG
CONTENTS
BONE METABOLISM
 Growth hormone and IGF-1
Regulators of bone metabolism
 Thyroid hormone
 Calcium and phosphate balance  Estrogens, progesterone and
 Calcium and phosphate androgens
 Parathyroid hormone  Cortisol and related
 Calcitonin glucocorticoids
 Biomarkers
 Vitamin D
 Disorders of bone metabolism
 Fibroblast growth factor  Orthodontic considerations
 Conclusion
 References
REGULATORS OF BONE
METABOLISM
1. Calcium and phosphate balance
4. Estrogens, progesterone and
a) Calcium and phosphate androgens
b) Parathyroid hormone 5. Cortisol and related
c) Calcitonin glucocorticoids

d) Vitamin D 6. Mechanical strain

e) Fibroblast growth factor

2. Growth hormone and IGF-1

3. Thyroid hormone
CALCIUM AND PHOSPHATE BALANCE :
1. CALCIUM :-

• LOCATION –
-Most abundant among the minerals in the body.
- The total content of calcium in an adult is about 1 to 1.5kg (1.5%
body weight)
- As much as 99% of it is in the bones and teeth and a small fraction of
found outside the skeletal tissue.
- Normal Serum Calcium level is 9-11 mg/dl
• FUNCTIONS –
a) mineralization of bone
b) cell proliferation
c) cellular secretion
d) stability and permeability of cell
membranes
e) blood clotting
f) neural transmission
g) neuromuscular function
h) muscle contraction (including
cardiac muscle)
• FORMS OF CALCIUM –
- In bone,
A normal 70 kg adult contains between 700 and 1000 g of calcium with
over 99% in the skeleton in the form of hydroxyapatite
- In serum,
i.Ionized Calcium:
About 45-50% of total serum calcium is present
in the ionized form (physiologically active) as
Ca2+ ions. Ionized calcium is freely exchangeable
between the soft tissues, ECF and blood.
 ii.Protein Bound Calcium:
◦Nearly 45-50% of total serum calcium is bound to protein
(Albumin)

iii.Calcium Salts:
◦About 5-10% of calcium is present in the form of salts i.e.. bound
with citrate, bicarbonate and phosphate.
• REGULATION OF CALCIUM –

I. Absorption from the digestive tract

II. Resorption from bone
III. Resorption in the kidneys
I. Absorption from the digestive tract -

a) Active, transcellular absorption

-occurs only in the duodenum when calcium intake has been low
- involves import of calcium into the enterocyte, transport across the cell,
and export into extracellular fluid and blood
- only a limited amount of calcium can be absorbed
- at low levels of calcium intake, the active transport is extremely
important, because it can absorb a very high percentage of small amounts
of calcium.
b) Passive, paracellular absorption

- occurs in the jejunum and ileum, when dietary calcium levels have been
moderate or high

- ionized calcium diffuses through tight junctions into blood

- depends on having higher concentrations of free calcium in the intestinal

lumen than in blood

- Passive calcium transport is simply diffusion across the intestinal

mucosa.
II. Resorption from bone -

ECF contains about 1000mg of calcium which is in equilibrium with

calcium present in the bones and exchange between them occurs in two
ways.

a)Rapid exchange:
- Occurs between ECF and smaller (1% of total bony content) readily
exchangeable pool of bone calcium.
- A large amount of calcium (about 20,000mg) per day moves in and
out of the readily exchangeable pool.
b)Slow exchange:

◦- Occurs between the ECF and larger (99% of total bone content)
pool of stable calcium.

◦- This exchange is the one concerned with bone remodelling by

constant interplay of bone resorption and deposition.
III.Resorption in the kidneys –

• The amount of calcium excreted in

the urine usually ranges from 100 to
200 mg per 24 hours while 98%–99% of
the filtered load of calcium is
reabsorbed by the renal tubules.
• Calcium absorption proceeds
through both an active, transcellular
pathway and by a passive
paracellular pathway.
◦Vitamin D and parathyroid hormone (PTH) help regulate how
much calcium is absorbed and how much calcium the kidneys eliminate.
Healthy kidneys turn vitamin D into an active hormone (calcitriol), which
helps increase calcium absorption from the intestines into the blood.
• DIETARY REQUIREMENT –
− 2000 mg/day for lactating women
− 1500 mg/day for pregnant women,
postmenopausal 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 –

1. Hypocalcaemia –
- Serum ionized calcium falls below 1.16 mmol/L (true
hypocalcaemia).
- The hallmark of acute hypocalcaemia is neuromuscular irritability -
perioral numbness and carpopedal spasms of the hands and feet.
-Seizures may be the only presenting symptom of hypocalcaemia.
Patients may also present with lethargy and altered mental status.
- Tetany usually only occurs when the total serum calcium level falls
below 7.0 mg/dL which corresponds to an ionized calcium of 1.1
mmol/L.
2. Hypercalcaemia –
- Serum level of ionized (free), not total, calcium increases.
- When the total serum calcium level is >10.5 mg/dL or the ionized
calcium level is > 5.6 mg/dL (1.4 mmol/L).
- Elevations can lead to diffuse precipitation of calcium phosphate in
tissues, leading to widespread organ dysfunction and damage.
-The two most common causes of hypercalcaemia are primary
hyperparathyroidism and malignancy.
Studied the importance of cAMP and Ca ++ in mandibular condylar
growth and adaptation and concluded that calcium is necessary for
maturation of cell. Both calcium and cAMP play a major role in bone
formation
 PHOSPHATE :-

• LOCATION –

− In bone, combined with Calcium (86%)

− In blood and extracellular fluid (0.08%)
− In soft tissues, intracellular phosphate (14%) is
organic (phospholipids, phosphoproteins, etc)
− Normal Serum Phosphate level is “2.5-4.5 mg/dl”
• FUNCTION –

◦- key component of bone mineral

- important in enzyme systems and molecular interactions

- maintains pH of body fluid

• FORMS OF PHOSPHATE –

- bone
majority is hydroxyapatite
- serum
mostly inorganic phosphate (H2PO4-)
• REGULATION –

- plasma phosphate is mostly unbound and reabsorbed by the kidney

- may be excreted in urine

- calcium and phosphate have a reciprocal relationship

- elevated serum phosphate can lead to increased release of PTH and

bone resorption

• DIETARY INTAKE –

◦1000 - 1500 mg/day

 2. PARATHYROID
HORMONE :-

• STRUCTURE –
84 amino acid peptide
• ORIGIN –
synthesized and secreted from chief cells in the four parathyroid glands
• NET EFFECT –
- increases serum calcium
- decreases serum phosphate

• MECHANISM –

I. On bone,

- PTH stimulates osteoblasts to secrete IL-1, IL-6 and other cytokines

to activate osteoclasts and increase resorption of bone
- Increases osteoblast production of M-CSF (macrophage colony-
stimulating factor) and RANKL, which increases number of osteoclasts.
- Inhibits production of OPG, thus also increasing osteoclast number.
- In the bone marrow, two molecules that induce differentiation and
proliferation of more osteoclasts: M-CSF (macrophage colony-stimulating
factor) and RANKL.

- M-CSF and RANKL encounter precursor cells which express RANK

(receptor-activator of NFκB), a transmembrane protein.

- RANK functions as receptor for RANKL. As precursor cell RANK is

trimerized by osteoblast-emitted RANKL, the precursor cells differentiate
first to osteoclast precursors and then to mature osteoclasts.
-Osteoblasts secrete a further protein, osteoprotegerin (OPG). This
is called a decoy receptor to neutralize RANKL acting as its
inhibitor.

- Thus, the formation rate of osteoclasts depends on the relative

amounts of RANKL and OPG produced by osteoblasts. While PTH
induces expression of M-CSF and RANKL, it inhibits production of
OPG, cranking up the generation of osteoclasts.
II. On kidney,
- Stimulates enzymatic conversion of vitamin D3 into its active
hormone form which:
a) increases reabsorption of Ca in kidney (increasing serum Ca)
b) increases excretion of PO4- from kidney (decreasing serum
phosphate)
- Stimulates release of calcitriol (VD3) which in turn causes intestines
to absorb more calcium
 III. On intestine,
◦- No direct action

◦- Indirectly increase Ca absorption by activating 1,25-(OH)2-vitamin D3

• DYSFUNCTION –

1. Hypoparathyroidism -
Rare and almost always by excessive surgical removal of parathyroid
tissue during thyroid or parathyroid surgery.

2. Hyperparathyroidism -

a) Primary hyperparathyroidism → parathyroid adenoma or cancer.

- High PTH and high calcium level.
a) Secondary hyperparathyroidism →chronic renal failure , low calcium
and high phosphate.
◦ - Parathyroid glands persistently produce PTH to maintain calcium
level

c)Tertiary hyperparathyroidism → bypass the compensatory

mechanism.
◦- Develops a high PTH level, leads to hypercalcemia.

◦- High PTH and high calcium levels.

 3. CALCITONIN :-

• STRUCTURE –
- 32 amino-acid peptide hormone

• ORIGIN –
- produced by clear cells in the Para follicles of the thyroid gland
(C cells)
-stimulated by increase in the serum calcium concentration
- also stimulated by gastrointestinal hormones such as gastrin.
• NET EFFECT –

- opposes the action of the parathyroid hormone

- limited help in regulating blood calcium and phosphate levels

- inhibit number and activity of osteoclasts

• FUNCTION –

- primary role of calcitonin is skeletal conservation

I. In bone,
- it inhibits osteoclastic bone resorption by decreasing number
and activity of osteoclasts as they have receptors for calcitonin
- Incresed serum Ca > secretion of calcitonin > inhibition of
osteoclasts > decrease Ca (transiently)
II. On intestines, inhibits Vitamin D induced resorption of calcium.

III. On kidney, increases resorption of phosphate and inhibits calcium

reabsorption
Effects of Vitamins on Bone
◦Growth and maintenance of bone depends on adequate dietary intake of
minerals and vitamins

VITAMIN D :-

• STRUCTURE –
◦- fat soluble secosteroid (steroid with a 'broken ring’)

• ORIGIN –

◦- produced by skin when exposed to sunlight (UV B-generated Vitamin D)

- dietary intake (lipid-soluble vitamin D3)

- enters the circulation bound to

vitamin D–binding protein

- active metabolite 1,25-(OH)2-vitamin D3

formed by two hydroxylation in the liver

and kidney, respectively which then enters

the target cell, and binds to the vitamin D

receptor (VDR)
• NET EFFECT –

- Vitamin D allows body to absorb calcium

- maintains normal serum calcium levels by activating osteoclasts for
bone resorption and increasing intestinal absorption of
calcium (increase serum Ca++)
- promotes the mineralization of osteoid matrix
 ACTION OF CALCITRIOL ON VARIOUS ORGANS:

On bone:

stimulates calcium uptake for deposition as calcium phosphates in

osteoblasts of bone.

Calcitriol along with parathyroid hormone increases the mobilization of

calcium and phosphate from the bone.

On kidney:

Minimizes the excretion of calcium and phosphate by decreasing their

excretion and enhancing absorption.(from DCT)
On intestine:
- increases the intestinal absorption of calcium.

Calcitriol binds
with a cytosolic
receptor

calcitriol-
receptor
• DIETARY REQUIREMENTS –

- Vitamin D under age 50 — 400 to 800 IU

- Vitamin D over age 50 — 800 to 1,000 IU
• DYSFUNCTION –

1. Vitamin D deficiency –
a)In children → Rickets
- Rickets is a rare disease that causes
the bones to become soft and bend.
- Presents as bowing of the legs.
- Occurs in children between 6 months
to 2 years of age.
- Affects long bones.
- Lack of calcium causes failure of
mineralization
- Resulting into formation of
cartilaginous form of bone.
b) In adults → osteomalacia.
- Causes weak bones, bone pain,
and muscle weakness.
- Only the flat bones and
diaphysis of long bones are
affected
- Seen in patients with low dietary
intake and little exposure to
sunlight or due to malabsorption
- Prone for fractures of bones.
- Severe periodontitis
c) In the elderly → osteopenia, osteoporosis and falls risk

d) Vitamin D deficiency may even contribute to obesity, diabetes,

hypertension, depression, fibromyalgia, chronic fatigue
syndrome, neuro-degenerative diseases including Alzheimer’s
disease and cancers.
2. Vitamin D toxicity –
- nausea, vomiting, poor appetite, constipation, weakness, and
weight loss.
- Excess vitamin D can also damage the kidneys.
- Too much vitamin D also raises the level of calcium in your
blood.
- High levels of blood calcium (hypercalcaemia) can cause
confusion, disorientation, and problems with heart rhythm.
3. Phenytoin (dilantin) -the anticonvulsant drug causes impaired
metabolism of vitamin D.

- Resulting vitamin D deficiency leads to hypocalcaemia,

hypophosphatemia, secondary hyperparathyroidism all of which
contribute to increased bone loss.

- It directly decreases calcium absorption leading to hypocalcaemia.

- Also causes vitamin K deficiency

Vitamin A

◦Hypervitaminosis:

Chronic loss of appetite, itching and painful swellings over the limbs,

hyper-ostosis of the shafts of long bones

◦ Hypovitaminosis

 Affects primarily the epithelial structures.

In general, over- all bone growth is retarded and that in the later stages
of the disease, endochondral bone growth ceases entirely
Vitamin C

◦ Hypovitaminosis

 The pathologic findings in bone can be traced to the failure of collagen

production

A decreased activity of fibroblasts, osteoblasts and odontoblasts, which

ultimately affects collagen production
5. FIBROBLAST GROWTH FACTOR-23 (FGF23)
:-
-FGF23 is a bone-derived phosphate and vitamin D-regulating hormone.
- Produced by osteocytes and osteoblasts in response to 1,25-
dihydroxyvitamin D and dietary phosphate loading.
- The main function of FGF23 seems to be regulation of phosphate
concentration in plasma.
- Increases renal phosphate excretion by reducing the number of
Na/phosphate cotransporters in the apical membrane of the proximal
tubule.

- It counters PTH by inhibiting 1α-hydroxylation of vitamin D. It thus

lowers active vitamin D, which in turn reduces uptake of Ca via the
intestines.

- FGF-23 acts as a counter-regulatory hormone to mitigate vitamin D

toxicity
Effect of hormones:
◦During childhood the most important hormone that stimulates bone
growth are the insulin like growth factor which is produced by
bone tissue it is in turn stimulated by human growth hormone

◦At puberty the hormones known as sex steroids i.e.. Estrogen and
androgens secreted by adrenal glands. They are responsible for
the sudden growth spurt that occurs during the teenage years
◦Parathyroid hormone : Has a direct action on adult bone. It is
responsible for maintenance of blood calcium level (10-12mg%)

It has 4 main sites of action

1)Kidney : Tubular resorption of calcium from the glomerular filtrate

and decrease in resorption of phosphate

2)Bone : Stimulates osteoclastic activity and increases resorption of

bone leading to increased liberation of calcium and phosphate

3)Intestine: It increase absorption of calcium from diet

4)Lactating Mammary Glands : It acts to decrease calcium secretion

◦The removal of osseous tissue during progressive tooth movement
is directly relayed to-

1)Bone porosity

2)Remodeling rate

3)Resorption rate

4)Osteoclast recruitment

◦The osteoclast resorption rate is largely controlled by metabolic

factors mainly the PARATHYROID HORMONE
GROWTH HORMONE :

• STRUCTURE –
It is a 191 amino acid protein produced by somatotrophs in the anterior
pituitary under control of the hypothalamus
• ORIGIN –
GH secretion is stimulated by GH releasing hormone (GHRH), inhibited by
somatostatin. GH is secreted in short bursts of pulses only during sleep or
during exercise
• NET EFFECT –
Growth hormone (GH) is essential for longitudinal bone growth.
• FUNCTION –

- increases serum calcium by increased

absorption in intestine and decreasing
urinary excretion
- GH stimulates hepatocytes to secrete
insulin-like growth factor-1 (IGF-1) into the
blood.
◦In bone, part of it is embedded by mineralization, together
with other growth factors like TGFβ and PDGF (transforming
growth factor β and platelet-derived growth factor) creating a
reservoir of growth factors that is only activated in case of
bone resorption .
 THYROID HORMONE :

-Thyroid hormones are required

for skeletal development and
establishment of peak bone
mass.
- Hypothyroidism in children
results in growth retardation
with delayed skeletal
development, whereas
thyrotoxicosis accelerates bone
- In adults, T(3) regulates bone turnover and bone mineral
density, and normal euthyroid status is essential to maintain
optimal bone strength.

- But thyrotoxicosis is an important and established cause of

secondary osteoporosis, and an increased risk of fracture
SEX HORMONES

- In hypogonadism, lack of these hormones results in

osteoporosis.
- Overproduction of androgens or oestrogens during
childhood initially accelerates growth but results in early
epiphyseal closure with reduced final height.
1. ESTROGEN-

- Estrogens reduce the number and activity of osteoclasts.

- Part of this effect is mediated via the RANK system.

- The result is a decrease in the rate of osteoclast generation.

- By the same and other mechanisms, activity levels and

lifespan of existing osteoclasts are reduced.

- Estrogens reduce bone resorption.

- Postmenopausal osteoporosis starts with a decrease in

estrogen concentrations.
2. PROGESTERONE –

- act directly on bone by engaging an osteoblast receptor or indirectly

through competition for a glucocorticoid osteoblast receptor.
- Progesterone seems to promote bone formation and/or increase bone
turnover.
- Peaks during pregnancy to release Calcium from the mother's bones to
help calcify the bones of the foetus.
3. FOLLICLE STIMULATING HORMONE (FSH) –

- The hormone stimulating oestrogen production, has a direct effect on

bone
- Stimulates osteoclast activity, an effect that would counter that of
thyrotropin.
4. ANDROGEN –

- In males, androgen levels come down only at a later age.

- Male osteoporosis manifests itself at least ten years later then

in females.

- Also in males, androgens are being converted to oestrogens

by the enzyme aromatase, expressed in fatty tissue.

- bone-protective effect of androgens might in fact be due to

estrogens.
CORTISOL & RELATED GLUCOCORTICOIDS:

- Glucocorticoids affect bone formation as

well as bone resorption.
- Inhibits osteoblast function but also
reduces the life span of osteoblasts.
- Glucocorticoids simultaneously induce
RANKL and inhibit OPG production in
osteoblasts which increases the number and
activity of osteoclasts.
- Effects on both sides of the coin therefore
strongly promote osteoporosis.
BIOMARKERS
DISORDERS OF BONE
METABOLISM :
1. Osteoporosis
a) Primary osteoporosis
b) Secondary osteoporosis
2. Rickets and osteomalacia
3. Bone resorption in the context of inflammatory
disease
4. Paget's disease of bone (osteitis deformans)
5. Bone metastasis
 OSTEOPOROSIS :

Primary or idiopathic osteoporosis –

- Most common form of the disease

- Main symptoms of osteoporosis are bone fractures
- In women, net resorption accelerates with menopause due to the
fall in oestrogens.
- Factors that contribute to the negative net effect:

a) Decrease in oestrogen and androgen concentrations

b) Reduced physical activity

c) Insufficient vitamin D and calcium intake

d) Reduced UV exposure, resulting in decreased vitamin D

e) Reduced renal function secondary to other causes

 ORTHODONTIC
CONSIDERATIONS :
Role of calcium metabolism in orthodontic tooth
movement –
- Orthodontic tooth movement is a unique
process in which a solid object (tooth) is made to
move through a solid medium (bone)
- Whenever force is applied over a tooth surface,
it results in formation of :
a) Area of pressure (same direction)
b) Area of tension (opposite direction)
Parathyroid hormone:
- Acts through osteoclasts for increasing the plasma calcium level.
- Causes bone resorption and so tooth movement is favoured

Calcitriol:
- Calcitriol along with PTH increases the plasma calcium level.
- But as opposed to PTH, it has its action both on bone deposition and
resorption but mainly on bone deposition.
- As a result, it does not favour tooth movement in orthodontics.
◦Calcitonin:

◦- Increases the deposition of calcium into the bone through osteoblast.

◦- It also suppresses the activity of osteoclasts

◦- As a result it increases the bone mass and doesn’t favour

orthodontic treatment.
◦Orthodontics is contraindicated in patients with active metabolic bone
disease because of excessive resorption and poor bone formation

◦If the metabolic problems are resolved medically, these patients can be
treated orthodontically assuming sufficient skeletal structure remains
◦Is it easier to move teeth in younger patients?

- The alveolar bone in young persons who comprise the majority of

our patients is not very dense. It contains large marrow spaces.
Since tooth movement is facilitated by the formation of resorptive
cells, whose number again increases according to the number of
marrow spaces, the anatomic condition can hardly be more
favorable than in the supporting structures of majority of the young
orthodontic patients.
◦Clinical considerations is it easier to move teeth in younger
patients
◦Why does cortical bone offer good anchorage?

- The marrow space contains a large surface area for cellular activity
which is indispensable for tooth movement on the other hand if bone
involved in tooth movement is of a compact character the surface area
where the cellular reaction can take place is greatly reduced

- When one is planning orthodontic treatment, the tooth should remain in

spongy bone during movement on the other hand when teeth are pitted
against cortical bone they can be used to our advantage to provide more
anchorage
◦How soon after extraction can we start treatment?

- Extraction spaces contain tissue undergoing reconstruction which is rich

in cells and vascular supply, such an area is ideally suitable for tooth
movement and due advantage should be taken of this by commencing
treatment as soon as possible following extraction. Thereby one avoids
atrophy and narrowing of the alveolar process, resulting in bone loss and
cortical bone formation at the extraction site
◦Why do teeth move faster in the upper arch?

- A common example is space closure in a class I four premolar extraction

case. It is often necessary to use headgear on the maxillary 1st molars to
maintain the class I relationship the relative resistance of the mandibular
molars to mesial movements is well known.
◦Why do teeth move faster in the upper arch? Why are mandibular
molars more difficult to move mesially than maxillary molars?

- 2 physiologic factors:

A)Thin cortices and trabecular bone of the maxilla offer less resistance to
resorption than thick cortices and more coarse trabeculae of the
mandible

B)The leading root of mandibular molars being translated mesially forms

bone that is far more dense than the bone formed by translating
maxillary molars mesially, why this occurs is not known
◦Why do I have to be careful with cases suffering from
periodontitis?

- Moving teeth when progressive periodontal disease is present invites

disaster

- Osteoclasts thrive in the diseased tissue environment

- When teeth are moved in the presence of active periodontal disease

resorption is normal or even enhanced and bone formation inhibited this
may exacerbate the disease process resulting in a rapid loss of
supporting bone
- We need healthy bone for adequate retention

- Teeth that have been moved recently are surrounded by lightly calcified
woven bone.

- Thus the teeth are not adequately stabilized and have a tendency to
move to their original position

- During retention phase the bone matures

 CONCLUSION
◦It is necessary to apply optimal forces to particular type of bone to
produce desired results and check for the stability of the bone once
the treatment is complete.

◦Bone metabolism is a continual cycle of bone growth and resorption

that is carefully orchestrated by the dynamic relationship between
osteoclasts, osteoblasts and an array of hormonal and regulatory
influences. The complete process is still to be understood and the
practical applications to be further discovered.
REFERENCES
◦ Tencate’s- Oral Histology. Antonio Nanci, Elevier, seventh edition
◦ Orban’s – Oral Histology and Embryology. GS Kumar, Elsevier, Twelfth edition
◦ A colour atlas and textbook of oral antomy histology and embryology. B.K.B.
Berkvitz, G.R.Holland, B.J.Moxham, Wolfe, second edition
◦ Theory and practice of histological techniques. John D Bankroft, Marilyn Gamble,
Churchill Livingstone, Fifth edition
◦ Oral Histology: Development, structure and function : Ten Kates ; 10 th Edition
◦ Orthodontics- Principles and practice Graber Vanarsdall 3rd edition
◦ Fundamentals of anatomy and physiology: Tortora; 10th Edition
◦ Orthodontics – Current Principles and Techniques – First South Asian Edition
REFERENCES
◦ Principles and practice of Orthodontics by T M Graber- 3rd edition
◦ Contemporary Orthodontics by Profitt
◦ Human Physiology- Tortora
◦ Guyton and Hall – Human Physiology
◦ Textbook of biochemistry – Satyanarayan
◦ Essentials of biochemistry - Harold
◦ BONE METABOLISM - Version 1.6 e ©Arno Helmberg 2009-2019, Medical University
of Innsbruck
◦ Textbook of physiology – A.K.Jain
REFERENCES
◦ Effect of altered bone metabolism on orthodontic tooth movement - Dr. Midgett et
al( AJODO vol 80 sept 1981)
◦ Normal Bone Metabolism - Evan Watts, Orthobullets
◦ VIVO Pathophysiology – Endocrine Control of Calcium and Phosphate Homeostasis -
Richard Bowen
◦ Mohamed AM. An overview of bone cells and their regulating factors of
differentiation. Malays J Med Sci. 2008;15(1):4–12.
◦ David, Valentin et al. “Calcium regulates FGF-23 expression in
bone.” Endocrinology vol. 154,12 (2013): 4469-82. doi:10.1210/en.2013-1627
◦ Shaker JL, Deftos L. Calcium and Phosphate Homeostasis. [Updated 2018 Jan 19].
In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South
Dartmouth (MA): MDText.com, Inc.; 2000
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