Zamala 5-2015

Prof.
DR/Heba Farag
Bone diseases
CLASSIFICATION
It is not easy to classify bone diseases since some of them are of unknown
aetiology or their nature is imperfectly understood. Nevertheless, a classification
is necessary, and the one that follows may serve as a broad framework
I. Hereditary
Affecting all or any bones:
Osteogenesis imperfecta.
Osteopetrosis (marble bone disease; Albers Schonberg disease).
Cherubism (familial fibrous dysplasia).
Affecting mainly membrane-formed bones:
Cleido-Cranial Dysplasia (dysostosis).
Affecting bones formed in cartilage:
Achondroplasia
II. Acquired
Developmental:
Fibrous dysplasia.
Dystrophic:
Osteitis Deformans (Pagets disease of bone).
Leonteasis Ossea.
Inflammatory:
Acute and chronic suppurative osteomyelitis.
Chronic focal sclerosing osteomyelitis.
Chronic diffuse sclerosing osteomyelitis.
Chronic non-suppurative sclerosing osteomyelitis; Garres osteomyelitis.
Osteoradionecrosis.
Hormonal:
Hyperparathyroidism (Von Recklinghausens disease of bone).
Osteoporosis.
Acromegaly (and Gigantism).
Nutritional:
Rickets.
Osteomalacia.
Reparative, representing failure in the normal reparative process:
Traumatic (solitary) Bone Cyst.
Aneurysmal Bone Cyst.
Central Giant Cell Lesion.
Cystic:
Odontogenic Cysts.
Fissural Cysts.
Pseudocysts.
Skeletal Reticuloendothelioses:
Langerhan's cell histiocytosis.
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Unifocal Unisystem: Eosinophilic Granuloma.

Multifocal Unisystem: Hand-Schuller-Christian disease.
Multifocal Multisystem: Leterrer Siwes disease.
Lysosomal storage diseases.
Gauchers Disease.
Niemann-Pick Disease.
Neoplastic:
Benign:
Non-Ossifying Fibroma.
Ossifying Fibroma (Calcifying Fibroma).
Fibro-Osteoma.
Cancellous Osteoma.
Compact Osteoma.
Chondroma.
Giant Cell Tumour (sometimes malignant).
Malignant:
Fibrosarcoma.
Chondrosarcoma.
Osteogenic sarcoma (osteolytic, osteoblastic, telangiectatic).
Myelogenic:
Ewings Sarcoma (Tumour).
Reticulum Cell Sarcoma.
Plasma Cell Myeloma (multiple myeloma).
Metastatic:
Carcinoma of the Breast.
Bronchogenic (lung) Carcinoma.
Carcinoma of the Prostate.
Carcinoma of the Kidney (hypernephroma).
Carcinoma of the Thyroid Gland.
Carcinoma of the Stomach.
Carcinoma of the Colon.
HEREDITARY DISEASES OF BONE

Diseases transmitted from one generation to another through genetic influences
OSTEOGENESIS IMPERFECTA
This is a rare hereditary disease transmitted by an autosomal dominant gene that
may or may not show complete penetrance or expressivity
Aetiology
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The disease is most commonly caused by mutation to the COL1A1 and COL1A2
genes.
It may be transmitted as a dominant or a recessive disorder.
Between 85 and 90 percent of osteogenesis imperfecta cases are dominant.
People with osteogenesis imperfecta are born with defective connective
tissue, usually because of a quantitative or qualitative deficiency of Type-I
collagen.
This deficiency arises from an amino acid substitution of glycine by bulkier
amino acids in the collagen triple helix structure.
The larger amino acid side-chains create a "bulge" in the collagen complex,
which in turn influences the molecular mechanics and interaction between
molecules, which are compromised.
Because of this, the body may respond by hydrolyzing the improperly formed
collagen structure.
If the body does not remove the improper collagen, the relationship between
the collagen fibrils and hydroxyapatite crystals is altered, causing bone
brittleness.
Failure of reticulin fibrils in the corium of the skin to become transformed into
mature collagen fibres has been demonstrated.
Presumably, a comparable defect may also be present in other connective
tissue structures affected by the disease such as ligaments and bone.
Nature
The essential change in the skeleton predisposing to delicate, bent or
otherwise deformed bones that are prone to fracture is deficient or defective
bone formation by osteoblasts. This is observed in both:
Bones formed in membrane at periosteal surfaces.
At sites of endochondral ossification.
Osteoclastic activity is normal.
There are eight different types of OI, Type I being the most common.
The symptoms may vary from one person to another.
Type I osteogenesis imperfecta is mainly characterised by:
Autosomal dominant trait.
Age at presentation: 2-6 years.
Collagen is of normal quality but is produced in insufficient quantities:
Bones fracture easily.
Slight spinal curvature.
Loose joints.
Poor muscle tone.
Discolouration of the sclera, usually giving them a bluish colour.
The blue-gray colour of the sclera is due to the underlying choroidal veins,
which show through the thin sclera.
Early loss of hearing in some children.
Slight protrusion of the eyes.
Types "IA" and "IB" are distinguished by the absence or presence of
dentinogenesis imperfecta.
Genetic Factors
Most cases of osteogenesis imperfecta are caused by a dominant genetic
defect.
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Some children with osteogenesis imperfecta inherit the disorder from a

parent.
Other children are born with osteogenesis imperfecta even though there is
no family history of the disorder.
In these children, the genetic defect occurred as a spontaneous mutation.
Because the defect - whether inherited or due to a spontaneous mutation
(prezygotic) - is usually dominant, a person with osteogenesis imperfecta has
a 50% chance of passing on the disorder to each of his or her children.
Clinical Features
The affected child may be born dead with multiple fractures sustained in utero.
It may be born alive but die shortly afterwards from the many fractures
sustained during delivery.
It may be born in an apparently healthy condition and only show evidence of
bone weakness (tendency to fracture with mild trauma) during childhood and
adolescence.
There is a tendency for the condition to become gradually milder and
disappear as the affected person advances in age.
A remarkable feature of the condition is for the patients to have blue or bluish
sclera (patients are sometimes referred to as blue sclerotics).
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The colour is due to partial visibility of the choroid through the abnormally thin
sclera.
Otosclerosis may develop after the age of 20 years.
The patients suffer from many fractures sustained after relatively mild trauma
during their childhood and adolescence.
The fractures heal readily and exuberantly.
There may be bony swellings especially in the temporal region, and
sometimes in the frontal and occipital regions.
Ossification of the skull may be incomplete with the presence of many
wormian bones.
There may be looseness of the joints due to laxity of the ligaments supporting
them, with consequent easy dislocations.
The skin may be thin.
The parathyroid glands may be enlarged, but the serum calcium and
phosphorus levels are normal.
There may be associated dentinogenesis imperfecta.
Microscopically
The bone trabeculae are narrow and widely separated.
Few osteoblasts are visible.
Osteoclastic activity is normal.
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Osteogenesis imperfecta: Left: Many wormian bones between the

occipital and parietal bones; Right: Blue sclera.
OSTEOPETROSIS
A rare hereditary bone disease of heterogeneous pathogenesis in which failure of
osteoclastic bone resorption leads to increased bone mass. A German
radiologist, Albers-Schon berg, first described the disease in 1904
Nature of the Disease
Normal bone growth and remodelling is achieved by a balance between bone
formation by osteoblasts and bone resorption by osteoclasts.
In osteopetrosis, the number of osteoclasts may be reduced or normal.
The most notable feature mediating the pathogenesis of the disease,
however, is osteoclast dysfunction.
The exact mechanism is only beginning to be understood.
There are at least two types of osteopetrosis.
In one type, deficiency of carbonic anhydrase II enzyme in osteoclasts is
noted.
The absence of this enzyme causes defective hydrogen ion pumping by
osteoclasts.
This causes defective bone resorption, as a highly acidic environment is
needed for dissociation of calcium hydroxyapatite from bone matrix.
The site for the other type has been identified to a locus on chromosome 1
known as 1p21.
The product of this gene belongs to the chloride channel family of proteins
(CLCN7). This gene encodes chloride channel 7.
Chloride channels play important roles in the plasma membrane and in
intracellular organelles.
Defects in this gene are one of the causes of osteopetrosis.
This causes bone resorption to fail while its formation persists normally;
excessive bone is thus formed
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This results in thickened sclerotic bones that have poor mechanical properties
because of failure in remodelling to adjust to functional demands.

Increased bone fragility results from:
Failure of the collagen fibres to connect osteons properly.
Defective or absent remodelling of woven bone to lamellar bone.
The severity of the condition may vary within rather wide limits between different
affected individuals.
Milder forms are not incompatible with normal life expectancy.
In the severest forms, on the other hand, death may occur in utero.
There are at least nine types of osteopetrosis.
Clinical Features
Children with marked involvement who survive may show thickening and
increased density of the base of the skull, and sometimes of the facial bones.
This may lead to optic atrophy, facial palsy and occasionally other
neurological manifestations due to narrowing of the foramina that transmit the
nerves out of the cranial cavity.
There is an accompanying aplastic anaemia due to narrowing of the marrow
spaces and encroachment of bone on the myeloid tissue.
There will be an accompanying hepato-splenomegally due to compensatory
extramedullary haematopoiesis.
Symptoms and Complications
Osteopetrosis tends to comprise a very wide variety of symptoms and
complications and a broad spectrum of severity of symptoms, including:
Pain.
Frequent fractures, especially of the long bones, which often do not heal.
Nerve compression, leading to headache, blindness, deafness or facial
palsy.
Haematological complications, including anaemia, thrombocytopenia,
leucopoenia (pancytopaenia).
Hepato-splenomegally.
Osteomyelitis.
Frontal bossing of the skull.
Unusual dentition, including malformed and unerupted teeth.
Infection, mainly due to the accompanying leucopoenia.
Bleeding, mainly due to the accompanying thrombocytopenia.
Radiographic Features
There is widespread striking radiopacity of the affected bones.
There is no distinction between bone cortex and trabeculae.
Transverse bands of varying density producing a zebra-like effect may be seen.
Histopathologic Features
The affected bones may show the presence of persistent cores of cartilage
within spongy trabeculae.
Bone deposition is normal.
There may be a deficiency in osteoclasts, bone resorption and remodelling.
The number of osteoclasts, however, may be normal, but there is defective
function and lack of adhesion of osteoclasts to bony surfaces.
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CLEIDO-CRANIAL DYSPLASIA (Dysostosis)

This is a rare hereditary and congenital bone disease. Mutations involving the
transcription core-binding factor a1-subunit gene (CBFA1) cause the disease
Genetic Features
The disease is usually inherited as an autosomal dominant trait.
It is due to a defective gene affecting osteoblast / osteoclast differentiation.
The gene is located on chromosome 6p21.
Mutation or loss of this gene result in Cleido-Cranial dysplasia.
Clinical Features
Cleido-Cranial dysplasia is a rare disease which can occur either spontaneously
or through dominant autosomal inheritance.
There is no sex or racial predilection.
It is characterized by a generalized skeletal dysplasia:
Absence of the clavicles, which occurs in about 10% of cases, or the
presence of hypoplastic clavicles that allow the patient to approximate the
shoulders together in the midline of the body without any discomfort.
These individuals are usually of short stature.
They have relatively long necks with drooping shoulders.
They have persistent or late closure of the fontanels.
The sutures can also remain opened, and the sagittal suture is depressed,
giving the cranium a flat appearance.
In the typical case, the skull is larger than normal and the face is small.
The mandible is relatively large and prognathic, but the maxilla is poorly
developed with a V-shaped high arched palate.
There is imperfect ossification of membrane cranial bones, with the
presence of many wormian bones.
The frontal, parietal and occipital bones are prominent.
The paranasal sinuses are underdeveloped and many other cranial
abnormalities may also be present.
A number of dental anomalies are also frequently associated.
The pelvic bones also show poor development with non-fusion of the
symphysis pubis and poor development of the sacrum.
There are also a number of associated dental anomalies including:
Delayed or failure of shedding of many deciduous teeth.
Failure of eruption of many permanent teeth.
Presence of unerupted supernumerary and/or supplemental teeth.
The unerupted teeth have hooked roots.
The unerupted teeth show different degrees of enamel hypoplasia.
Many conically shaped teeth.
Multiple dentigerous cysts.
Absence of cellular cementum.
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ACHONDROPLASIA
Achondroplasia is a genetic condition that results in abnormally short stature
Nature
Achondroplasia is a genetic (inherited) bone disorder that occurs in about one
in 25,000 live births.
Achondroplasia is inherited by an autosomal dominant gene that causes
abnormal cartilage formation and maturation.
It is the most common type of dwarfism, in which the patient's arms and legs
are disproportionately short in relation to body length.
The head is often large and the trunk is of normal size.
The average height of adult males with the condition is about 130 centimetres.
The average height of affected adult females is about 122 centimetres.
In some cases, the child inherits the condition from an affected parent.
The majority of cases, however, are the result of a new mutation in the family:
The parents are of average height and do not have the abnormal gene.
Mode of Inheritance
Achondroplasia is inherited as an autosomal dominant trait whereby only a
single copy of the abnormal gene is required to cause the condition.
The gene for achondroplasia is fully penetrant, meaning that everyone who
possesses it has achondroplasia. No one with the gene escapes the condition.
However, there is some variation in expression of the gene.
Patient with cleidocranial dysplasia, Left: Relatively long neck and drooping
shoulders; Centre: Absent clavicles; Right: Deep and narrow high arched palate.
This means that children with achondroplasia are not carbon copies of each
other, although they may look alike to the untrained eye.

It is caused by a mutation in the gene for fibroblast growth factor receptor 3
which causes an abnormality of cartilage formation.
More then 97% of achondroplastics have a Gly380Arg mutation in the
transmembrane domain of the fibroblast growth factor receptor 3 gene.
The mutation causes the receptor to send an inhibitory signal to developing
growth plate cartilage cells even in the absence of the ligand.
In only about an eighth of cases is the gene inherited from a parent who has
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achondroplasia.
Conversely, about seven-eighths of cases are due to new mutations.
This means that most cases of achondroplasia occur sporadically and are the
result of a new mutation in a sperm or ovum of one of the normal-appearing
parents.
It also means that it is a pre-zygotic mutation in contrast with fibrous dysplasia
where there is a post-zygotic mutation.
The chance of a new mutation rises with the age of the father.
This suggests that de novo mutations are of paternal origin.
As early as 1912, it was noted that sporadic (new) cases were more often lastborn
than first-born children.
This fits with the fact that the chance of an achondroplastic birth has been
shown to increase with the age of the father.
Clinical Features
The following are the most common clinical features of achondroplasia; however,
each child may experience symptoms differently, these may include:
. Shortened arms and legs, with the upper arms and thighs relatively more
shortened than the forearms and lower legs.
. Large head with prominent forehead and a flattened nasal bridge.
. Crowded teeth with malocclusion.
. Curved lower spine - a condition called lordosis, which may lead to kyphosis,
or the development of a small hump near the shoulders that usually
disappears after the child begins walking.
. Bowed lower legs.
. Flat feet that are short and broad.
. The baby's fingers appear short and the ring and middle fingers diverge
giving the hand a trident (three-pronged) appearance.
. Poor muscle tone and loose joints.
.Frequent middle ear infections which may lead to hearing loss.
. Delayed developmental milestones such as walking (which may occur
between 18 to 24 months instead of around one year of age).
The head is typically large with:
.Prominence of the forehead (frontal bossing),
. Underdevelopment of the midface with lack of prominence of cheek bones.
. A low depressed nasal bridge with narrow nasal passages.
.This is due to the short base of the skull because of deficient growth at
sphenoidal synchondroses, especially the spheno-occipital synchondrosis.
. Most joints can extend more than normal.
For example, the knees can be hyperextended beyond the normal stopping
point.
. Not all joints are lax in this way.
. On the contrary, extension and rotation of the elbow are abnormally limited;
hip extension also tends to be limited.
.Normal intelligence.
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Prof. DR/Heba Farag
Achondroplasia, Left: Short stature, short arms and legs, bowed legs;
Centre: Lordosis; Right: Flat face, depressed bridge of the nose.
ACQUIRED DISEASES OF BONE

Diseases of different aetiologies arising from causes acquired after fertilization of
the ovum, either in utero or after birth
DEVELOPMENTAL
Diseases due to faulty development arising from genetic errors occurring postfertilization
FIBROUS DYSPLASIA OF BONE

Fibrous dysplasia is a skeletal developmental anomaly of the bone-forming
mesenchyme that manifests as a defect in osteoblastic differentiation and
maturation
Fibrous dysplasia of bone is a genetic non-hereditary disease due to a postzygotic
somatic mutation in which abnormal fibro-osseous tissue develops in

place of normal bone during the normal process of bone remodelling.
It has been shown that fibroblast-like cells in fibrotic areas of fibrous dysplasia,
like committed osteogenic precursors and unlike soft tissue fibroblasts, exhibit
high levels of cell surface-associated alkaline phosphatase activity, indicating
that it belongs to the preosteoblast lineage that expresses the early
osteogenic markers.
Pathophysiology
Cancellous bone maintenance is disturbed, and bone undergoing physiologic
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remodelling is replaced by an abnormal proliferation of fibro-osseous tissue.

Trabeculae of woven bone are embedded largely in a collagenous fibrous
matrix.
Reticulin fibrils run directly from the fibrous tissue stroma into the woven bone
matrix at nearly right angles to the bone surface.
Dysplastic lesions are thought to consist of an excess of pre-osteogenic cells
producing a disorganized collagenous matrix.
This matrix is rich in anti-adhesion molecules and poor in pro-adhesion
molecules, in direct contrast to normal lamellar bone.
Though there may be repeated cycles of bone resorption and redeposition, the
woven bone trabeculae do not undergo lamellar remodelling.
Instead, resorption of woven bone trabeculae, due to a several fold increase in
the rate of IL-6 production (also a consequence of raised levels of cAMP), is
followed by deposition of new woven bone trabeculae.
The bone trabeculae arise directly from fibroblast-like pre-osteoblast cells.
The trabeculae are not rimmed by osteoblasts.
They may be rimmed by fibroblast-like cells or they may not be rimmed at all.
The mechanical quality of the affected bones is thus decreased.
As a result of this bone fragility, there is an increased risk of pathological fracture.
The incidence of fracture is around 50% of cases, especially in long bones
and in the mandible.

The extent and pattern of the disease depend upon the stage of development
and the location in the developing embryo at which the mutation occurred.
Thus germ cell mutation is lethal.
Early mutation produces widespread disease.
While late mutation produces few or isolated lesions.
Osteoblast Differentiation Process.

Mutation-bearing cells occur in a mosaic pattern.
Endocrine and skin involvements, when present, also follow embryologic lines
of development.
Incidence
Age:
The initial manifestations of fibrous dysplasia are most commonly observed
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in persons aged 3-15 years.

Sex:
There is no sex predilection in the monostotic form.
There is a definite female preponderance in the polyostotic form.
Site:
The maxilla is affected more often than the mandible at a ratio of about 2:1.
Disease Patterns
Three disease patterns are recognized:
Monostotic form
Cranio-facial form (when one cranial or facial bone is affected).
Polyostotic form restricted to bone lesions.
Polyostotic form with extra-skeletal manifestations.
Approximately 70-80% of fibrous dysplasias are monostotic.
The monostotic form most frequently occurs in the following bones in
decreasing order of frequency:
Cranio-Facial Form
This pattern of the disease occurs in 10-25% of patients with the monostotic
form and in 50% of cases with the polyostotic form.
If lesional tissue reaches the suture between two bones, it pushes and displaces
the suture line distorting it, but it does not destroy or cross it.
Clinical Features
The disease usually first becomes manifest in childhood, and some cases
may be congenital.
Solitary jaw lesions (monostotic) are the commonest form of the disease.
The lesion is usually slowly growing.
Growth usually decreases after puberty (early adulthood, 18-20 yrs) when the
disease process becomes quiescent.

The facial affection produces facial deformity or disfigurement.
It is painless, though pain may sometimes be the presenting feature.
The affected bone is structurally weak and may undergo pathological fracture.
Fibrous dysplasia may be associated with endocrinopathies in 2-3% of cases.
These may include:
Precocious puberty in girls.
Precocious skeletal growth and early skeletal maturity in males.
Hyperthyroidism.
Hyperparathyroidism.
Acromegaly.
Diabetes mellitus.
Cushing syndrome.
Involvement of orbital and periorbital bones may also give rise to:
Visual impairment.
Exophthalmos.
Blindness.
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Involvement of the sphenoid wing and temporal bones may result in
Vestibular dysfunction.
Tinnitus.
Hearing loss.
Distribution of the Lesions

In cases where only one bone is involved, it is most often a femur, tibia, rib or
a facial bone.
When a number of bones are involved, these are quite likely to be bones of
one limb, especially a lower limb (segmental distribution).
When bones of an upper limb are involved, one or more skull bones are
usually also involved.
In a few cases, a limited number of trunk bones, e.g. several ribs, alone or
together with several vertebrae (in a segmental manner) are involved.
Cases in which a limited number of bones are affected merge without any sharp
distinction with cases in which skeletal involvement is relatively widespread.
There are cases in which, though lesions are located predominantly in bones
of one limb on one side (mostly but not exclusively unilateral), there may also
be some lesions in limb bones of the contralateral side, along with lesions in
some skull bones, ribs and pelvis, especially on the side in which the limb
bones are most severely affected.
Altogether, segmental and predominantly unilateral distribution of lesions in
polyostotic cases is an important clinical and radiographic characteristic.
Depending on the amount of bone present in the lesion, the radiographic
picture may be:
An indistinct radiolucent lesion.
Radiolucency mottled with radiopacities.
Completely radiopaque.
.
The radiographic picture of jaw lesions on periapical or occlusal views,
especially those in the maxilla, is sometimes described as having:
- An orange peel appearance.

-A ground glass pattern On extra-oral films, especially in early lesions with little bone
formation
The radiographic picture with more bone formation is often described as having a smokescreen appearance.
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Fibrous dysplasia of the right maxilla in a 12 year old boy.
The histologic picture is characterized by the replacement of normal bony
trabeculae by a cellular fibro-osseous tissue.
Lesional fibroblast-like cells (pre-osteoblasts) show a definite proclivity
(tendency) to directly form new bone trabeculae.
The newly formed bone trabeculae are characteristically thin, irregularly shaped
and irregularly oriented, and remain mostly discreet (separate from each other),
though much resorption and redeposition might have taken place.
The bone trabeculae are of the coarse fibred or woven bone type.
They are not rimmed by osteoblasts; sometimes they may be rimmed by
fibroblast-like spindle-shaped cells, or they may not be rimmed at all.
Silver staining for reticulin reveals that reticulin fibrils extend directly from the
fibrous tissue into the newly formed woven bone, almost at right angles.
Though bone trabeculae may undergo much resorption and redeposition, they
do not undergo lamellar remodelling.
Rather, the newly formed bone trabeculae are also of the woven bone type.
The histologic picture is closely similar to that of ossifying fibroma and
cementifying fibroma, but in cases of fibrous dysplasia, the lesional bone is
continuous with the cortex with no zone of fibrous tissue or a capsule
separating them.
As the lesion ages, it may become either:
More fibrous, with thick collagen fibres.
Its content of bony trabeculae may become more numerous.
On aging, more numerous bone trabeculae develop in less-collagenized
rather than in well-collagenized lesions.
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Left: The diffuse ground glass appearance of the maxillary bone is striking.
Note also, the absence of lamina dura around the teeth. Right: Ill defined, somewhat
radiopaque lesion associated mainly with the second mola. Notice that the lamina dura
of the second molar is involved and is inconspicuous.
Areas of haemorrhage and degeneration may occur, leading to accumulation
of lipid-filled macrophages.
Biochemical Values
Both serum calcium and serum phosphate are within normal limits.
Alkaline phosphatase enzyme level may be normal or may be only slightly
elevated in monostotic form and in mild polyostotic cases.
Serum alkaline phosphatase enzyme levels may be elevated in the polyostotic
form, more so if many bones are affected.
Complications
Malignant change occurs in 0.4% of cases, but the incidence increases in cases
that have been subjected to irradiation.
Osteosarcoma may develop, this is evidenced by:
- Rapid growth.
- Pain.
The affected bone may be weakened and may undergo pathological fracture,
especially if a limb bone or the mandible is affected.
Facial disfigurement follows lesions affecting facial bones.
Left: Metaplastic woven bone trabeculae developing directly from fibroblasts;

Right: Cellular fibrous tissue containing irregular, partially calcified bone trabeculae with no
osteoblastic rimming.
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Fig. 132: Left: Reticulin fibrils extending directly into metaplastic woven bone;
Right: Trabeculae of lesional bone continuous with bone cortex.
Differences between fibrous dysplasia and ossifying fibroma

Fibrous Dysplasia Ossifying Fibroma
Age at onset: < 25 years > 25 years
Gender Female predilection No sex difference
Size 60% > 4 cm 85% < 4 cm
Location About 25% in the head and neck 90% in mandible
ALBRIGHT SYNDROME
Also known as the McCune-Albright Syndrome
The condition was first described in 1937 by Donovan James McCune and Fuller
Albright.
Evidence of the sporadic nature of the syndrome has included its occurrence
in only one of monozygotic twins.
In Albright Syndrome, the somatic mutation of Gs occurs during early
embryonic development with mosaicism resulting from mixture of daughter cells
of one mutated stem cell among daughter cells of normal stem cells.
The same GNASl arginine 201 mutation seen in fibrous dysplasia has been
found in 49 patients with Albright Syndrome, with a net preponderance of the
substitution by histidine (n = 34) as opposed to cysteine (n = 15).
No difference in severity of manifestations of the disease was noted between
the two types of mutations.
The proportion and distribution of affected cells in a tissue is determined by
the exact stage in development at which the mutation occurred.
Thus, mutations that occur later in embryogenesis give rise to fewer mutant
cells, milder phenotype, and fewer affected organs than mutations that occur
earlier during embryonic development.
Albright Syndrome consists of polyostotic fibrous dysplasia associated with:
Sexual precocity in females.
Precocious skeletal growth and early skeletal maturity in males, with
ultimate below average height.
Caf au lait cutaneous pigmentation.
This is the most common extraskeletal manifestation.
It occurs in more than 50% of cases.
The pigmentation in polyostotic fibrous dysplasia is ipsilateral to the
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side of bony lesions, a feature that differentiates this disease from

pigmentation in von Recklinghausen's neurofibromatosis.
The pigmented areas tend to be arranged in a linear or segmental
pattern near the midline of the body, usually overlying the lower
lumbar spine, sacrum, buttocks, upper back, neck, and shoulders.
Often the spots are limited to one side of the body, which usually
corresponds to the side with more severe bone involvement and they do
not cross the midline.
They are often arranged in a segmental pattern, which follows the
developmental lines of Blaschko (lines of ectodermal migration during
early embryogenesis).
Consistent with this pattern is the tendency of the macules to stop at
and do not cross the midline.
Similar lesions may occur on the lips and oral mucosa.
Pigmentation may occur at birth and may occasionally precede the
development of skeletal and endocrine abnormalities.
The caf-au-lait spots in the syndrome are single or multiple tan-brown
hyperpigmented flat macules with irregular borders.
They become more obvious with advancing age or with sun or
ultraviolet light exposure.
The lesions have irregular borders that have been described as
resembling the "coast of Maine", in contrast to those of
neurofibromatosis in which the margins tend to be smoother, likened
to the "coast of California".
However, the fact that the melanotic macules in Albright Syndrome
sometimes do not have the characteristic serrated or irregular borders
has been noted and was emphasized by Albright himself.
Albright Syndrome: Left: Precocious sexual development in a 5-yearold

female patient; Right: Caf au lait pigmentation.
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Prof. DR/Heba Farag
FAMILIAL FIBROUS DYSPLASIA (Cherubism)

This special variant of fibrous dysplasia is an autosomal-dominant disorder of
variable penetrance. It occurs in children and is more severe in boys
Aetiology
The lesion is an autosomal dominant hereditary condition.
The mutated gene is called SH3BP2 and is located on chromosome 4p16.3.
The gene shows variable expressivity according to the sex of the patient,
usually being more severe in males.
Some non-familial cases have been reported.
The onset of the lesion is related to signals triggered by eruption of permanent
teeth.
Incidence
Age:
Cherubism usually becomes manifest in young children. More severely
affected persons manifest the disease at an earlier age.
Sex:
There is no sex predilection, but males are usually more severely affected.
Site:
The mandibular rami are always affected bilaterally and symmetrically.
The maxillary tuberosities are the next most common site.
The disease may affect any area of the jaws; bilaterally and symmetrically.
The only parts of the jaws that have never been reported to be affected are
the mandibular condyles and coronoid processes.
Classification
Grade 1:
Affecting the mandible without showing root resorption.
Grade 2:
Affecting mandible and maxillary tuberosities without root resorption.
Grade 3:
Affecting both mandible and maxilla except mandibular condyle and
coronoid process; may show root resorption.
Grade 4:
Affecting both mandible and maxilla except mandibular condyle and coronoid
process, as well as the floor of the orbit; may show root resorption.
Grade 5:
Rare aggressive form affecting both mandible and maxillae.
Clinical Features
This varies depending upon:
The area of the mandible or maxilla affected.
The severity of the involvement.
The age of the patient.
There is no typical picture that will fit every case or even the majority of cases.
Cases exhibiting varying degrees of severity merge together with no clear
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dividing line.
Both mandibular rami are invariably affected, with no case being reported
lacking their involvement.
Any other part of the jaws, with the exception of the mandibular condyles and
coronoid processes, may be additionally affected, again symmetrically.
The fact that both halves of the mandible and both halves of the maxilla are
affected in the same areas and approximately to the same extent is an
outstanding feature of the condition.
There has never been any evidence of underdevelopment of either jaw.
No case has been reported in which other facial bones than the mandible and
the maxilla have been involved.
In minimally affected patients, the facial appearance is within the normal range.
In slightly more severely affected patients, the angles of the jaw are definitely
enlarged and the face is broad with marked fullness of the rami.
In more severely affected patients, with involvement of the body of the
mandible as well as the rami, patients present a broad face and a heavylooking
jaw, and the mandible is thickened in every plane.
Intra-orally, the alveolar process is broad and bossellated.
On palpation, the surface feels as though it is covered by, hard, raised domes.
Where the bone on the surface of the domes has been resorbed, a round
mass of a firm fibrous nature can be felt.
The maxillae may also be involved.
This usually occurs in cases where the mandible is grossly affected.
The extent of maxillary involvement varies from involvement of the tuberosities
only, to cases with gross maxillary involvement.
Maxillary involvement exaggerates the deformity, and when extensive causes
the major part of the disfigurement.
The normal contours of the maxillae are distorted.
The anterior wall is thickened and bulges forwards, and the infra-orbital
margins cannot be palpated as a definite ridge.
The vault of the palate may be obliterated, or only a midline cleft may be left.
Speech may be indistinct.
Absence or premature loss of teeth has been reported when the tooth bearing
part of the jaw is involved.
In severe cases, a rim of sclera is exposed between the iris and the lower
eyelid (thus the cherubic look).
This has been observed only in cases of involvement of the maxillae in the region
of the infra-orbital ridge and the maxillary antrum raising the orbital floor.
The non-involved parts of the jaws have a normal contour.
Course of the Disease
Following early onset, rapid development takes place in the next 2 3 years.
The dysplasia makes its appearance in all involved areas simultaneously
producing the above described clinical features.
There follows a period during which no marked changes occur.
At puberty or early adolescence, gradual improvement of the facial contour
commences.
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Fig. 134: Familial Fibrous Dysplasia: A 10

year-old patient displaying marked fullness
of the face over both the maxilla and
mandible.
Between 20 to 30 years of age, definite bone remodelling takes place and a
more normal contour develops.

There is always some residual enlargement.
In young patients, there are well-defined multilocular radiolucencies of
irregular shape.
These are equal and identical on both sides.
The lesions are always found in both mandibular rami.
This causes expansion and widening of the rami, with thinning of the cortical
plates. The cortex is reduced to a mere expanded shell of irregular contour.
The inferior alveolar canal may be displaced.
There is also displacement of unerupted teeth when the tooth-bearing area is
involved.
The coronoid process is often blunt, and the mandibular notch shallow.
Dental Abnormalities
There may be missing, unerupted or displaced teeth.
There may be early shedding of the deciduous dentition.
This is often followed by early loss of permanent teeth, especially the
mandibular second and third molars.
The dental abnormalities vary in severity depending upon the degree of
involvement of the tooth-bearing area of the jaws.
In a reported case, calcification was normally advanced only in those
permanent teeth whose calcification had commenced before clinical onset of
the disease at 2 years.
In those teeth commencing calcification after this time, i.e., second premolars
and second molars which would normally begin to calcify at 2 to 3 years, there
was no evidence of their presence at the age of 5 years.
The dental abnormalities are not related to nor are they part of the condition.
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Fig. 135: Familial Fibrous Dysplasia: Note radiolucent lesions involving

the mandibular rami with marked broadening of the rami.
Fibrous tissue consisting mainly of spindle-shaped fibroblasts replaces the
bone in affected areas.
There are large numbers of multinucleated giant cells distributed throughout
the fibrous tissue.
Mature collagen fibres may also be found.
Giant cells tend to be grouped in foci, mainly around vascular areas and areas
of extravasated red blood cells.
New bone formation is rare within the fibrous tissue, and bone within the
lesion is only conspicuous by its absence.
In some cases, there may be perivascular cuffing of eosinophilic material, in
which a few cells may be peripherally embedded.
In the adult, the maxillae are normal and the multilocular rarefactions of the
mandible have become replaced by a moderate irregular sclerosis.
Fig. 136: Familial Fibrous Dysplasia: Left: Multilocular radiolucency involving the
posterior part of the body of the mandible and the ramus; Right: Missing and displaced
teeth, broadening of the alveolar process
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Fig. 137: Left: Giant cells in cellular connective tissue. Note absence of bone trabeculae;
Right: Perivascular acidophilic material around small blood vessel and giant cell in
fibrous connective tissue.
.
DYSTROPHIC BONE DISEASES

Diseases due to faulty bone metabolism and turnover
PAGETS DISEASE OF BONE (Osteitis Deformans)
This is a condition of older individuals characterized by progressive skeletal
deformation due to regional breakdown in the process of remodeling
General Features
Pagets disease of bone is the second most common bone disease after
osteoporosis, affecting up to 23% of adults over the age of 55.
It is a chronic bone disease characterized by focal regions of increased bone
resorption accompanied by increased formation of new, highly disorganized
bone.
The aetiology of PDB has been difficult to determine, as it likely involves both
genetic and environmental factors.
Genetic factors play an important role in PDB and mutations or polymorphisms
have been identified in four genes that cause classical Paget's disease.
The mutations predispose to PDB by disrupting normal signalling, leading to
osteoclast activation.
Although Paget's has traditionally been considered a disease of the osteoclast,
there is evidence that stromal cell and osteoblast function are also abnormal.
The primary cellular defect in PDB is generally thought to reside in the OCL,
since the bone lesions are characterized by large numbers of hypermultinucleated
osteoclasts, and inhibition of osteoclast activity in PDB patients
results in prolonged clinical and histological remissions.
Although osteoblasts and other cells in the bone microenvironment also
participate in the disease, the increased bone formation has been thought to
represent a secondary response of osteoblasts to the elevated bone resorption.
Environmental factors also contribute to Paget's disease.
Most research has focused on paramyxovirus infection as a possible
environmental trigger but evidence in favour of the involvement of viruses in
the disease remains inconclusive.
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Recent evidence indicates that the disease is triggered by infection of
osteoclasts by a slow virus as the measles or respiratory syncytial virus (RSV)

in patients with a genetic susceptibility for the disease.
A striking feature of pagetic osteoclasts is the characteristic nuclear inclusions
that are similar to nucleocapsids of paramyxoviruses.
These nuclear inclusions are not present in other bone marrow cells in the
Pagetic lesion or in non-pagetic bone in patients with Paget's disease.
Incidence
Age:
Pagets disease is recognized most commonly after age 40 years and is
rarely diagnosed in persons younger than 20 years.
By the ninth decade of life, prevalence reaches nearly 10%.
Sex:
The male-to-female ratio is approximately 1:1.
Site:
The axial skeleton, the skull and leg bones are most frequently affected.
Pathophysiology
The osteoclast is the primarily affected cell in Paget's disease.
Osteoclasts in Pagetic lesions are increased in both number and size.
In cross-section they are seen to contain up to 100 nuclei, in contrast to
normal osteoclasts, which contain 420 nuclei
The process of normal bone remodelling is disturbed.
In the early years, osteoclastic resorption of normal bone is accelerated.
Later, as bone is resorbed, new and abnormal bone is formed by increased
osteoblastic activity.
This osteoblastic activity is triggered by stimulatory cytokines secreted by the
hyperactive osteoclasts that recruit and activate osteoblasts.
In the late phase, osteoclastic resorption slows down and osteoblastic
apposition predominates.
The disease may burn-out leaving enlarged dense sclerotic bone comprised
of atypical trabeculae of Pagetic bone with many reversal lines giving a mosaic
appearance.
The disease may affect a single bone (monostotic) or multiple bones
(polyostotic form).
General Considerations
Many individuals with Pagets disease are asymptomatic.
The diagnosis is most commonly made incidentally during an unrelated
radiological or biochemical investigation.
On occasion, the disease manifests with severe musculoskeletal impairment
with neurological and cardiovascular complications.
Pagets disease has a predilection for the axial skeleton and may be
widespread at the time of diagnosis.
The condition commonly affects the pelvis and spine, particularly the lumbar
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spine with a frequency of 30-75%.

The sacrum is involved in 30-60% of cases and the skull in up to 65% of
cases.
The proximal long bones, especially the femur, are also frequently affected (in
25-35% of cases).
Though any bone may be affected, the fibula, ribs, and bones in the hands
and feet are only infrequently involved.
Pagets disease may affect one bone and then remain limited in its course, or
it may progress from a few localized areas to the rest of the skeleton.
Monostotic Pagets disease occurs in 10-35% of cases.
The most common presenting complaint is pain.
Other typical findings and complaints of patients with Pagets disease may
include the following:
Pathologic fractures commonly result from weakened pagetic bone.
Nonspecific headaches, impaired hearing, and tinnitus are common
symptoms of Pagets disease with skull involvement.
The patient's head dress size may increase or change due to skeletal
deformity and enlargement, especially of the skull and lower limbs.
The most common cranial symptom is hearing loss, occurring in 30-50%
of patients with skull involvement. Vertigo or tinnitus may also occur with
a frequency of 25% of patients with cranial involvement.
Nausea, dizziness, syncope, ataxia, incontinence, gait disturbances, and
dementia can be observed with cerebellar or brainstem compressive
syndromes.
Involvement of the jaw and facial bones is uncommon in Pagets disease,
but it does occur.
Facial disfigurement and malocclusion may occur following enlargement
of either jaw.
Tooth loss may occur with progressive root resorption.
Absent periodontal membrane space and lamina dura are associated with
excessive cementum formation.
Increased bone pain with an enlarging soft tissue mass and a lytic lesion
is suggestive of a neoplastic transformation (osteosarcoma), especially if
a pathologic fracture is present.
Clinical Features
Clinical features are extremely variable and depend on which bones are affected.
Typically, patients with Pagets disease present without any signs or symptoms.
Visual inspection may reveal bone deformities, such as an enlarged skull,
spinal kyphosis, and bowing of the long bones of the lower extremities.
Localized pain and tenderness may be elicited with manual palpation.
Superficial palpation reveals increased warmth of the skin over the affected
bones.
Skin temperature may be correlated with both increased metabolic activity of
bone and bone pain.
The legs are usually the first to be affected; but in many other cases, the
earliest observable change may be in the skull.
Persistent bone pains in the legs may be the first sign.
Deformities of the bones of the legs (sabre tibia).and enlargement of the
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cranium are the next noticeable changes.

The face may escape from the bony deformity.
Occasionally, however, the bones of the face may become greatly thickened,
especially the maxillae.
The patient may need frequent remakes of his dentures, which become too
small for the increased size of the jaws.
The vault of the palate is flattened and obliterated.
The increase in the size of the jaws may either be a part of a generalized
condition or may occur alone (Leonteasis Ossea).
The advanced stage of the disease is highly characteristic:
The main feature is an enlarged head.
Kyphosis.
Bent shoulders.
Sunken chest.
Bowed legs, the femurs bowed outwards and the tibia bowed forwards.
Out-turned toes.
The above-mentioned features provide a living justification of the name Osteitis
Deformans which Sir James Paget coined when he first described the condition.
Radiographic features are diagnostic with an initial osteolytic phase, commonly in
the skull and tubular bones, followed by an osteoblastic and then an
osteosclerotic phase that is most notable in the axial skeleton and pelvis.
Osteolysis of the cranial vault is most frequent in the frontal or occipital
regions giving rise to the typical appearance of scattered circumscribed
radiolucencies known as osteoporosis circumscripta.
Lytic lesions may be the only finding in the early osteolytic stage.
Later, as the osteoblastic stage supervenes, the irregular radiodensities of the
skull vault give rise to what is known as a Cocks Comb or a hair on end
appearance due to intermingling bone resorption and bone formation.
Still later, in the mixed osteoblastic-osteosclerotic stage, focal radiodensities
give rise to what is known as a cotton-wool appearance.
Areas of lysis and radiodensities may be separate or superimposed.
An enlarged bone with increased radiodensity and trabeculations is
characteristic.
Fig. 138: Pagets disease affecting the

maxillae, marked expansion of the
maxilla and separation of teeth, flattened palatal vault.
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Osteolytic stage, radiolucent areas with root resorption.
Course of the Disease

In generalized Pagets disease, the blood flow to the bones is greatly
increased, sometimes up to 20 times the normal.
The first change is softening of the bones.
This is brought about by both the excessive vascularity of the bones and, even
more so, by intense osteoclastic activity.
The resorbed bone is replaced by fibrous tissue in which new bone is laid
down by proliferating osteoblasts.
This new bone in turn undergoes resorption and redeposition, and the cycle
goes on and on until eventually the bone presents a peculiar complex pattern
described by Schmorl as a mosaic pattern.
The bones are very hard and dense.
The new bone is disordered, poorly mineralized, and lacks structural integrity.
The initial osteolytic phase is marked by disordered areas of resorption by an
increased number of noticeably large osteoclasts.
These abnormal osteoclasts may contain as many as 100 nuclei each.
Fig. 140: Sclerotic stage with extreme radiodensity and

pronounced hypercementosis of roots.
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Fig. 141: Pagets disease; Left: Cock's comb appearance, multiple radiopacities
radiating from the vault of the skull; Middle: Cotton wool appearance of the base of the
skull and the maxilla; Right: Involved maxilla showing cotton wool appearance.
The subsequent osteoblastic phase follows with haphazard production of new
bone matrix and formation of woven bone.

Repeated episodes of bone resorption and bone formation result in the
appearance of many small irregularly shaped bone fragments that appear to
be joined as if in a jigsaw or mosaic pattern.
This pattern is the characteristic histologic feature of Pagets disease.
As the disease progresses, the osteoblastic phase predominates.
Excessive abnormal bone formation occurs, causing more compact and
dense, though still finely porous bone.
Marrow spaces are filled with loose highly vascularised connective tissue.
The hypervascularity consists of an increased number of patent capillaries
and dilated arterioles, as well as larger venous sinuses and numerous patent
arterio-venous shunts.
The normal trabecular appearance is distorted with a mosaic pattern of
prominent, irregularly scalloped and deeply staining cement lines (reversal
lines) joining areas of lamellar bone.
Pagetic bone shows no tendency to form haversian systems.
Biochemical Findings
The following indices are increased in different phases of Pagets disease:
Indices of Bone Resorption:
Urinary hydroxyproline.
Urinary collagen cross-links.
Urinary calcium/creatinine (fasting).
Indices of Bone Formation:
Serum total or bone-specific alkaline phosphatase.
Serum osteocalcin.
General Complications
Skeletal pain.
Skeletal deformities.
Pathological fractures.
Secondary osteoarthritis.
Hearing deficit or loss.
Other cranial nerve deficits.
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Congestive heart failure as a result of greatly increased cardiac output.
Sarcomas:
Osteogenic sarcoma.
Chondrosarcoma.
Fibrosarcoma.
188
Metastatic carcinomas.
Haematologic malignancies.
Giant cell tumours.
Dental Complications
In the osteolytic stage, there is root resorption, often pronounced.
In the osteoblastic stage, the teeth show hypercementosis.
Patchy osteosclerosis may affect the jawbones.
Difficulty of tooth extraction mainly due to hypercementosis.
Excessive haemorrhage following dental extractions due to the many patent
arteriovenous shunts.
Delayed healing of extraction sockets due to defective nourishment of the
bone because the arteriovenous shunts divert blood from the capillary beds
around the extraction socket (dry sockets).
Need for frequent remaking of dentures due to continued enlargement of
affected alveolar processes.
Fig. 142: Upper left: Early osteolyticstage, multinucleated osteoclasts ontrabecular surfaces immediately
adjacent to rows of plump osteoblasts.-Upper right: Mixed phase,simultaneous bone resorption and
bone deposition-Lower: Sclerotic phasefollowing continued resorption anddeposition, resulting in many
irregular
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reversal lines.
LEONTEASIS OSSEA (Localized Pagets Disease)

In some instances of Pagets disease of bone, the skull, facial bones or the
maxillae alone may be affected. Such instances are referred to by some authors
as Leonteasis Ossea
Leonteasis Ossea, greatlyenlarged maxillary alveolar process.

Leonteasis Ossea is no longer considered to represent an independent
pathological entity.
It appears rather to represent a miscellaneous category of which some
components are not well understood.
Some cases appear to result from spreading, sclerosing osteoperiostitis.
Others are associated with polyposis of the colon (Gardners syndrome).
Some cases may represent a localised monostotic form of Paget's disease.
Some have a familial pattern pointing to some ill-understood developmental
disorder.
In some instances, the thickened bones are rarefied rather than sclerotic.
INFLAMMATORY DISEASES OF BONE
Acute and chronic bone diseases due to specific or nonspecific infections
Healing of Extraction Sockets
The healing of a socket after an extraction is by essentially the same process as
the healing of a bone fracture and takes place in the following stages:
Formation of a blood clot filling the socket.
Organisation of the blood clot.
Epithelialisation of the surface of the wound.
Formation of woven bone in the connective tissue filling the socket.
Replacement of the woven bone by lamellar bone and remodelling of the
alveolus.
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Immediately after extraction, there is free bleeding which helps to wash debris
out of the socket.

Torn vessels retract and, after a few minutes, the blood clots.
Tissue damage provokes a mild, subclinical inflammatory reaction.
Blood vessels of the bone surrounding the socket dilate and leucocytes and
macrophages invade the clot from its periphery.
Macrophages and platelets present in a hypoxic state in the clot release
angiogenic and growth factors such as acidic FGF (FGF-1) and basic FGF
(FGF-2) which are important factors in wound healing, as well as vascular
endothelial growth factor released by platelets.
Endothelial cells of neighbouring capillary vessels are stimulated by angiogenic
factors released by macrophages and platelets when present in a low-oxygen
environment in the clot, and are chemotactically attracted to the wound area
by fibronectin found on the fibrin network.
These growth factors stimulate the proliferation of fibroblasts and endothelial
cells that give rise to angiogenesis and developing granulation tissue.
Capillaries in the surrounding tissue are stimulated to proliferate and send
solid sprouts into the clot.
Stem endothelial cells from uninjured blood vessels in the surrounding bone
develop pseudopodia and push through the extracellular matrix into the clot to
establish new blood vessels.
To migrate, endothelial cells need collagenases and plasminogen activator to
degrade the clot and part of the extracellular matrix.
Zinc-dependent metalloproteinases digest the basement membrane and
extracellular matrix to allow cell migration, proliferation and angiogenesis.
The sprouts later undergo canalization producing new capillary vessels within
the clot.
They are accompanied by proliferating fibroblasts from the surrounding marrow.
Organisation is accompanied by gradual digestion of the clot by fibrinolysin
enzyme released by leucocytes.
Because the migration and proliferation of fibroblasts requires oxygen and
nutrients, angiogenesis is necessary for later stages in wound healing, like
fibroblast and epidermal migration.
Fibroblasts and capillary buds continue to grow in from the surrounding
connective tissue until the clot is completely replaced by granulation tissue.
When macrophages and other growth factor-producing cells are no longer in a
hypoxic environment, they stop producing angiogenic factors.
Thus, when the granulation tissue is adequately perfused, migration and
proliferation of endothelial cells is reduced and ultimately ceases.
Initially fibroblasts utilize the fibrin cross-linking fibres to migrate across the
wound, subsequently adhering to fibronectin.
Fibroblasts then deposit ground substance into the wound bed, and later
collagen, which they can adhere to for migration.
Epithelium begins to proliferate over the surface during the second week and
eventually forms a complete, protective covering.
The increased blood supply to the socket is accompanied by resorption of the
surrounding dense lamina dura by osteoclasts.
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Small fragments of bone, which have been injured during extraction and have
lost their blood supply are separated by osteoclasts and are eventually shed.
In the connective tissue filling the socket, coarse, woven bone is laid down.
In an adult, this starts about a month after the extraction and may be complete
in another month.
During the following months woven bone is, in turn, resorbed and replaced by
trabeculae of lamellar bone until the normal bone pattern is restored.
A layer of compact bone forms over the surface and the alveolus is
remodelled.
The alveolus becomes narrower and its surface sinks below the adjacent parts
of the ridge where teeth are still standing.
If all the teeth are lost, resorption goes on relatively rapidly at first then more
slowly for some years until the alveolar bone is entirely resorbed.
Delayed Healing of Extraction Wounds
For normal healing to take place, the socket must fill with blood clot, and the
clot must persist until it becomes organised.
It is uncommon for the clot to fail to form unless the local blood supply is very
poor or an excessive amount of vasoconstrictor is injected near the socket.
The functions of the clot are that it prevents infected debris from entering the
socket.
It protects the underlying bone from oral bacteria and acts as a support for
subsequent organisation to occur and granulation tissue to grow.
Delayed healing of extraction wounds may be due to:
Infection is the most common cause of delayed healing and the usual
result is a painful, localised osteitis of the bone around the socket.
This is called a "dry" socket because it is empty and does not contain a
blood clot.
DRY SOCKET
Localised osteitis of the lamina dura lining an extracted tooth socket
It is a socket in which the blood clot disintegrates or fails to form, it produces a
foul odour, with no pus formation and is accompanied by severe pain.
Normally, a blood clot forms at the site of a tooth extraction.
This blood clot serves as a protective layer over the underlying bone and
nerve endings in the empty tooth socket.
The clot provides the foundation for the growth of new tissue and bone.
In some cases, the clot does not form properly or is physically dislodged
before undergoing organisation.
With the blood clot gone, bone and nerves in the socket are exposed to air, food
and fluids.
This can cause severe pain, not only in the socket, but is also referred along
the nerves radiating to the ear and eye on the same side of the face.
Severe pain following an extraction is usually due to this cause.
Pain commonly begins the day after the extraction, but sometimes may be
delayed for up to a week.
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The pain is deep-seated, severe and throbbing in character.
The cause is unknown but many possible causes have been blamed:
Bacterial contamination of the socket.

Difficult or traumatic tooth extraction surgery.
Excessive use of vasoconstrictor in the anaesthetic drug used.
Dry socket occurs in about 3% to 5% of all tooth extractions; it is much more
common in the mandibular molar-premolar area.
Nature of the Condition
For this condition to be diagnosed there must be:
Failure to form a blood clot in an extraction socket, or breakdown of the
clot after its formation.
Presence of bare bone of the socket.
Presence of severe pain.
Clinical Features
Dry sockets tend to be more common in the mandible than in the maxilla and
are more common in posterior teeth than in anterior teeth.
This is because the cortical bone in the posterior mandibular area is thick.
The vascularity of the mandible is not as good as that of the maxilla.
The condition follows extractions done under local analgesia rather than those
performed under general anaesthesia.
It has been demonstrated that the more difficult the extraction, the higher the
chance of a dry socket.
The condition occurs twice as often after single extractions as it does after
multiple extractions completed during the same sitting.
Bacteria, especially anaerobic bacteria, have been linked to its formation.
Several investigators have found strains of streptococci, fusospirochaets,
Treponema denticola, and bacteroides within extraction sites.
During the first few days after extraction, there are no radiographic differences
between a dry socket and a normally healing socket.
Ten to fourteen days following extraction, certain differences are observed:
In the normally healing socket, the lamina dura is mostly resorbed about
two weeks after extraction in preparation for new bone formation to
invade the organising blood clot.
In cases of dry socket, however, the lamina dura remains radiographically
distinct two weeks following extraction.
Later, resorption of normal living bone neighbouring and surrounding the
lamina dura leads to its separation and eventual exfoliation.
During that period of time, small bony spicules representing parts of the
lamina dura may be seen in the socket.
This is followed by loss of these spicules through their exfoliation.
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Dry socket, alveolar osteitis, Left: Clinical picture; Right: Radiographic picture
demonstrating sharply defined sclerotic lamina dura two weeks following extraction.
ACUTE SUPPURATIVE OSTEOMYELITIS

An acute inflammatory destructive process of bone, bone marrow and periosteum
secondary to infection with pyogenic organisms
Predisposing Factors
Age
Acute haematogenous osteomyelitis is primarily a disease of children.

Direct trauma and contiguous focus osteomyelitis are more common
among adults and adolescents than in children.
Sex
The disease is much more common in boys than in girls.
Male-to-female ratio is approximately 2:1.
Trauma
A history of trauma is common.
Jawbones, however, have a peculiar and unique position because of the
presence of teeth.
In jawbones, the trauma may take the form of an extraction of a septic
tooth.
Pathogenesis
Haematogenous osteomyelitis is an infection caused by bacterial seeding
from the blood.
Acute haematogenous osteomyelitis is characterised by an acute infection
of the bone and bone marrow caused by the seeding of bacteria within
the bone from a remote source.
This condition occurs primarily in children.
The most common site is the rapidly growing and highly vascular
metaphysis of growing long bones.
Direct or contiguous inoculation osteomyelitis is caused by direct contact of
bacteria and the tissue during trauma or surgery.
Direct inoculation (contiguous-focus) osteomyelitis is an infection in the
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bone secondary to the inoculation of organisms from direct trauma, such

as cases of fracture of the mandible.
Spread from a contiguous focus of infection such as a periapical infection,
or sepsis after a surgical procedure such as extraction of a septic tooth or
spread from a dry socket.
Bacteriology
Acute haematogenous osteomyelitis:
Newborns (younger than 4 months): Staphylococcus aureus, Enterobacter
species, and group A and B Streptococcus species.
Children (aged 4 m to 4 yrs): Staph aureus, group A Streptococcus
species, Haemophilus influenzae, and Enterobacter species.
Children, adolescents (aged 4 yrs to adult): Staph aureus (80%), group A
Streptococcus species, H influenzae, and Enterobacter species.
Adult: Staph aureus and often Enterobacter or Streptococcus species.
Direct contact osteomyelitis:
Generally: Staph aureus, Enterobacter and Pseudomonas species.
Puncture wound: Staph aureus and Pseudomonas species.
Clinical manifestations of direct inoculation osteomyelitis are more localized
than those of haematogenous osteomyelitis.
Infection of bone is accompanied by occlusion of blood vessels, which causes
localised bone necrosis and local spread of infection.
Infection may spread through the bone cortex and spread under the periosteum,
with formation of subcutaneous abscesses that may drain through the skin.
Haematogenous osteomyelitis usually presents with a slow insidious
progression of symptoms.
Direct osteomyelitis generally is more localized, with prominent signs and
symptoms.
General symptoms of osteomyelitis include the following:
Abrupt onset of high fever.
Fatigue.
Irritability.
Malaise.
Restriction of movement of the affected part.
Local oedema, erythema, and tenderness.
Patients with acute osteomyelitis of the jaws or peripheral bones usually are:
Febrile.
Show weight loss.
Fatigue.
Localized warmth.
Swelling.
Erythema.
Tenderness.
196
If treatment of acute osteomyelitis is only partially successful, low-grade
chronic osteomyelitis develops with:
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Intermittent bone pain lasting several months to many years.

Local tenderness and sinus drainage.
Chronic osteomyelitis is often polymicrobial.
Radiographic changes are not evident for 14-21 days and initially manifest as
periosteal elevation followed by cortical or medullary radiolucencies.
Approximately 40-50% of focal bone loss is necessary to cause detectable
radiolucency on plain films.
There are irregular radiolucencies described as moth-eaten appearance,
intermingled with irregular radiopacities indicating unresorbed sequestra.
There is peripheral new bone formation, which, in the mandible, is restricted to
the lower border.
This is characterized by irregular masses of necrotic bone lying in a vast area
of acute, and later chronic, inflammatory cells.
The necrotic bone is characterized by absence, due to death, of osteocytes,
leaving empty lacunae.
The dead bone is separated from the neighbouring living bone by osteoclastic
resorption at the expense of the neighbouring living bone.
Dead bone does not undergo resorption because osteoclasts need an
available blood supply to live and function.
There is subperiosteal new bone formation forming what is known as the
involucrum in long bones. In the mandible, this new bone formation is mainly
restricted to the lower border.
: Acute osteomyelitis of the mandible, moth-eaten appearance.
Complications
Complications of acute osteomyelitis of the jaws include:
Unilateral numbness of the lower lip.
Pathological fracture.
Ankylosis of the TMJ if infection spreads to the joint.
In the maxilla, infection may spread to the maxillary sinus.
Pyaemia is very rare in oral osteomyelitis.
Necrosis and exfoliation of developing tooth germs in children.
Root resorption, loosening or exfoliation of erupted teeth.
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CHRONIC OSTEOMYELITIS
This is a persistent inflammation of bone characterized by a complex of
inflammatory processes including necrosis of bone and marrow tissue,
suppuration, resorption, and sclerosis. It is a milder form than acute osteomyelitis
Types
There are several types of chronic osteomyelitis:
Chronic suppurative osteomyelitis (CSO).
Chronic focal sclerosing osteomyelitis.
Chronic diffuse sclerosing osteomyelitis. Also known as chronic sclerosing
or diffuse sclerosing osteomyelitis (DSOM).
Chronic non-suppurative sclerosing osteomyelitis, also known as Garres
osteomyelitis.
Osteoradionecrosis.
CHRONIC SUPPURATIVE OSTEOMYELITIS
Cases of osteomyelitis where the clinical manifestations are milder than in acute
osteomyelitis, but where the interaction between the virulence of the infecting
organisms and the patients resistance results in a protracted suppurative process
Pathogenesis
This may frequently develop as a sequel of untreated or inadequately treated
acute osteomyelitis resulting from Staphylococcal or Streptococcal infection.
Occasionally, it may develop from dental infections as a low-grade
inflammatory reaction without a preceding acute stage such as in cases of:
Periapical infection secondary to pulpitis.
After tooth extraction, especially lower third molars.
Infections secondary to fractures of the jaws.
Clinical Features
The mandibular molar area is the most frequently affected area of the jaws.
The symptoms are usually of long duration.
There is swelling of the affected area of the jaw.
There is also looseness of related teeth.
There is discomfort during mastication.
Sinus tracts draining pus may be present.
There is usually pain of varying intensity.
There is mild fever.
There is leukocytosis.
There may be paraesthesia of the mental nerve (lower lip).
Radiolucent lesion mottled with irregular areas of radiopacity.
The appearance has been described as a "moth-eaten" appearance.
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Chronic inflammatory cells are seen infiltrating a fibrous bone marrow.
Irregular bone trabeculae, with empty lacunae, are seen in the fibrous tissue.
Both osteoblastic and osteoclastic activities may be seen in the surrounding
bone frequently with many reversal lines.
Chronic suppurative osteomyelitis of the right side of the

mandible; Left: Clinical picture; Right: Radiographic picture.
CHRONIC FOCAL SCLEROSING OSTEOMYELITIS

An uncommon form of localized proliferative reaction of bone with high tissue
resistance to mild prolonged bacterial infection
Clinical Features
Usually affects young patients in the second or third decades of life.
The mandible is usually involved where there may be a carious or heavily
filled lower molar or premolar.
There may be no signs or symptoms other than mild pain associated with the
carious tooth.
Typically, a well-circumscribed radiopaque area of sclerotic bone surrounding
the apex or apices of a carious or heavily filled tooth.

The border of the sclerotic area may be clearly distinguishable from the normal
surrounding bone.
The radiopacity, however, may merge imperceptibly with the normal
surrounding bone.
The lesion is clearly distinguishable from benign cementoblastoma by:
Absence of radiolucent margin surrounding the lesion.
The outline of the root is well demarcated with no root resorption.
The lesion consists of a dense mass of bony trabeculae with little intervening
marrow.
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The marrow tissue present is fibrotic.
The marrow tissue is infiltrated by a small number of chronic inflammatory
cells, mainly lymphocytes.
Chronic focal sclerosing osteomyelitis, radiopacity at the apex of the distal root of heavily filled
mandibular permanent first molar.
CHRONIC DIFFUSE SCLEROSING OSTEOMYELITIS

Similar to chronic focal sclerosing osteomyelitis except that the infection reaches
the bone through a wide area of entry
Clinical Features
The condition may be met with at any age, but is more common in older
individuals.
It may be observed in edentulous areas, especially in the mandible.
There may be some vague pain.
There may also be a foul taste.
Otherwise, the condition may remain symptomless for many years.
It may undergo acute exacerbation with suppuration and draining sinuses.
The radiographic picture of chronic diffuse sclerosing osteomyelitis appears as:
An area of diffuse bone sclerosis appearing as a diffuse radiopacity.
The lesion may be extensive and is often bilateral.
The border between lesional and normal bone is often indistinct.
It may involve both the mandible and the maxilla.
The histopathologic picture of chronic condensing osteomyelitis appears as:
Dense, irregular bony trabeculae.
Some trabeculae show active osteoblastic activity.
There may be focal areas of osteoclastic activity.
The alternation of osteoblastic and osteoclastic activities may result in a
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mosaic appearance, which, however, is not as extensive as that of Pagets

disease of bone.
The marrow is distinctly fibrous with focal areas of lymphocytic and
plasma cell infiltration.
Chronic diffuse sclerosingosteomyelitis, diffuse radiopacity in the

mandible caused by periapical inflammation that spread (osteomyelitis).
The inflammation caused bone production rather than bone destruction suggesting
chronic rather than acute osteomyelitis.
CHRONIC NON-SUPPURATIVE SCLEROSING OSTEOMYELITIS

(Garres Osteomyelitis)
Chronic osteomyelitis with proliferative periostitis. A focal thickening of the
periosteum with peripheral subperiosteal reactive bone formation resulting from
mild chronic infection
Clinical Features
The disease occurs in children and young adults having high tissue vitality.
It shows a definite predilection for the mandible.
The presenting features are pain in the jaw and toothache.
These are associated with a bony hard swelling of the outer surface of the jaw
of at least several weeks duration.
Lateral jaw radiographs fail to show the proliferative periosteal reaction.
An occlusal radiograph, however, will show focal subperiosteal overgrowth of
bone on the outer surface of the cortex opposite the offending tooth.
The mass of new bone is generally smooth and well calcified.
It may show a thin cortical layer.
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The new mass of bone is composed of reactive bone with bordering osteoid.
Many bony trabeculae are rimmed by active osteoblasts.
The bone marrow is fibrous.
There may be patchy diffuse areas of lymphocytic and plasma cell infiltration
in the intervening marrow.
Chronic osteomyelitis (Garres type) of the right side of the mandible, clinical
and occlusal radiographic pictures.
OSTEORADIONECROSIS
Osteoradionecrosis is generally recognised as the presence of exposed bone in a
previously irradiated field, which fails to heal within a three-month period
Osteoradionecrosis is bone necrosis in previously irradiated tissues.
In 90% of cases, osteoradionecrosis is induced by secondary trauma; in the
other 10%, it occurs spontaneously.
The most prominent aetiological factor is the effect of radiation on the
endothelial linings and fibrous coats of blood vessels resulting in
hypocellularity and vasculitis followed by endarteritis obliterans (obliteration of
small arteries and arterioles), ischemia, fistula formation, and pathological
fracture of the bone.
There is an increased risk of developing the condition for those who receive a
combination of both radiation therapy and chemotherapy.
There is also mucositis with spontaneous breakdown of the oral mucosal lining
from eating, tooth brushing, ingestion of hot food, or poor oral hygiene.
The mucosa in the irradiated area tends to be thinner and telangiectatic.
This makes it more susceptible to mechanical injury.
Post-radiation tooth extraction results in poor healing due to compromised
vasculature and consequently poor blood supply of the tissues.
The degree of damage is related to the severity of the surgical trauma.
Bone injury can occur through direct trauma e.g. tooth extraction (84%),
related cancer surgery or biopsy (12%), denture irritation (1%) or by exposure of
the irradiated bone to the hostile environment of the oral cavity secondary to
overlying soft tissue necrosis.
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The irradiated mandible, periosteum, and overlying soft tissue undergo
hyperaemia, inflammation, and endarteritis.

These conditions ultimately lead to thrombosis, cellular death, progressive
hypovascularity, and fibrosis.
The radiated bed is hypocellular and is devoid of fibroblasts, osteoblasts, and
undifferentiated osteoprogenitor cells.
Ninety-five percent of osteoradionecrosis cases in the head and neck region
involve the mandible.
The most vulnerable areas are the buccal cortices of the premolar and molar
area and the retromolar triangle supplied by the inferior alveolar artery.
Predisposing factors for mandibular osteoradionecrosis include:
Doses of < 65 Gray delivered in more than 6 weeks resulted in no cases of
osteoradionecrosis as compared to a 50% incidence when higher doses were
delivered in less than 6 weeks.
Radiation damage in the oral soft tissues and jawbones makes the tissue
environment favourable for anaerobic microorganisms especially actinomyces.
Higher tissue density in the radiated area predisposes to osteoradionecrosis.
Bone has a density 1.6 to 1.8 times greater than soft tissues and therefore is
more susceptible to the effects of radiation.
The mandible has a higher density compared to the maxilla, which may
explain the higher incidence of mandibular involvement.
Severity of surgical trauma; technique of tooth extraction also contribute.
Precautions
Preventive measures should be taken to help reduce the risk and/or severity
of osteoradionecrosis.
The maxilla and mandible are unique in that they are the only bones directly in
contact with the external environment through the gingival attachment of the
teeth, which poses greater potential for disease and infection.
The bacterial load of the mouth is greater than any other site of the body and
consequently, any changes to that environment can result in infection.
During treatment, a patient is likely to develop mucositis and xerostomia that
can change the oral environment and tissue resilience, which causes an
increased risk of dental caries and periodontal disease.
Prior to radiation treatment, a patient should have a full dental examination by
a dentist trained in dealing with the requirements of oral cancer patients.
Each tooth should be carefully evaluated, charted and an individual treatment
plan should be developed for each tooth to ensure its long-term fitness so as
not to require extraction afterwards.
Any teeth that are unsuitable for proper restoration should be extracted not less
than 2-3 weeks before the start of radiation to allow sufficient time for healing.
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Left: The patient developed osteoradionecrosis following radiotherapy.

Right: Lateral oblique radiograph of case of osteoradionecrosis. Bone necrosis
and pathologic fracture are evident.
HORMONAL BONE DISEASES

The more common hormonal bone diseases include osteoporosis, the skeletal
changes of hyperparathyroidism and renal osteodystrophy
HYPERPARATHYROIDISM
(Osteitis Fibrosa Cystica; Von-Recklinghausens Disease of Bone)
The disease is due to excessive secretion of parathormone.
The parathyroid glands regulate serum calcium and phosphorus levels through
the secretion of parathyroid hormone (PTH).
Parathyroid hormone raises serum calcium levels while lowering the serum
phosphorus concentration.
The regulation of PTH secretion occurs through a negative feedback mechanism
in which calcium-sensing receptors on the membranes of parathyroid cells trigger
decreased PTH production as serum calcium concentration rises and vice versa.
Aetiology
Hyperparathyroidism, leading to increased secretion of parathormone may be:
Primary.
Secondary.
Primary hyperparathyroidism is a metabolic disorder in which parathyroid cells,
either neoplastic or hyperplastic secrete excessive amounts of PTH in the
absence of any known stimulus.
Primary hyperparathyroidism is usually caused by a functioning adenoma
of a single parathyroid gland.
Less commonly, it may be caused by diffuse hyperplasia of all four
parathyroid glands, with no renal pathology.
Rarely primary parathyroid carcinoma or multiple parathyroid adenomas.
The bone changes of primary hyperparathyroidism regress or disappear within a
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few weeks after surgical removal of the causative parathyroid lesion.

The primary retention of phosphate by diseased kidneys results in hyperphosphataemia,
which causes hypocalcaemia, resulting in secondary
hyperparathyroidism.
The hyperparathyroidism increases bone resorption, which may normalize
serum calcium levels by releasing calcium deposited in bones.
Secondary hyperparathyroidism is associated with many conditions that lead
to hypocalcaemia and most often occurs as a consequence of:
The hyperphosphataemia and hypocalcaemia of chronic renal failure.
The complex bone changes in chronic renal failure are called renal
osteodystrophy and include:
Osteomalacia,
Rickets "renal rickets",
Osteitis fibrosa cystica and other bone changes associated with the
disease.
In secondary hyperparathyroidism, elevated PTH levels do not result in
hypercalcaemia.
This has been attributed to excessive urinary excretion of calcium in patients
with chronic renal failure.
Incidence
Primary hyperparathyroidism most frequently occurs in adults, and is rarely
seen in children less than 10 years of age.
It has a peak incidence between the third and fifth decades.
It has a female to male ratio of two or three to one.
Clinical Features
The symptoms of primary hyperparathyroidism may be minimal for many years,
depending upon the extent of the metabolic disorder.
The clinical presentations are divisible into three categories:
Manifestations of hypercalcaemia, such as neuro-muscular weakness,
fatigue, gastro-intestinal symptoms, and, rarely, coma in cases of severe
hypercalcaemic crisis.
Renal stones (often bilateral); calcification of the kidneys (nephrocalcinosis);
and metastatic calcification of other tissues.
Bone resorption and fibrous replacement resulting in diffuse osteopenia
(difficult to distinguish radiologically from osteoporosis).
In some cases, "cystic" or tumour-like lesions of bone (brown tumours of
hyperparathyroidism) may occur.
Although having a high prevalence in primary hyperparathyroidism, brown
tumours are frequently encountered in secondary hyperparathyroidism due to
the greater prevalence of this condition.
Swellings and deformities may arise because of the bone lesions.
Pathological fractures; the fractures heal readily, but other fractures occur.
A complication that is rarely seen today is widespread alterations and deformities
affecting the demineralised and softened bones of the entire skeleton.
The skull and jaws are sometimes affected.
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The teeth are of normal density and radiopacity.
The bone of the jaws, however, shows decreased density and radiopacity with
a radiolucent honeycombed appearance.
The trabecular pattern of bone is finer and exhibits trabecular mottling best
observed in cranial bones.
There is widespread or generalized loss of the lamina dura.
Sometimes there are large radiolucent areas denoting areas of total
destruction of bone corresponding to the sites of fibrous lesions.
The characteristic feature is widespread osteoclastic activity in many bones.
There is exuberant fibroblastic proliferation occupying the widened Haversian
canals and replacing the resorbed bone.
The bone marrow is replaced by fibrous tissue as occurs in fibrous dysplasia
and in the early stage of Pagets disease of bone.
Osteoid tissue may develop within the fibrous tissue with formation of new
bone trabeculae rimmed by a row of osteoblasts.
Bone resorption, however, invariably outstrips new bone formation.
Groups of osteoclasts are seen actively engaged in resorbing bone.
The bone stains weakly with eosin (pale) because of its decreased content of
calcium salts.
There are frequent areas of haemorrhage and extravasated red blood cells,
imparting a dark reddish or brownish colour to the lesion.
Multinucleated foreign body giant cells may also be seen aggregated around
areas of extravasated blood cells.
Fig. 155: Brown tumour of hyperparathyroidism. Increased osteoclastic activity producing

irregular bone resorption with hemorrhage, macrophage, multinucleated giant cells and
fibrous connective tissue proliferation.
Primary hyperparathyroidism, in the absence of renal disease, is
biochemically characterized by:
Hypercalcaemia.
Hypophosphataemia.
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Hypercalciuria.
Elevated serum alkaline phosphatase activity.
Increased levels of PTH measured by radioimmunoassay.
OSTEOPOROSIS
Osteoporosis is defined as a decrease in bone density (bone mass per unit
volume) of normally mineralized bone, and an alteration of bone architecture
resulting in thinning and increased porosity of the bone cortices and trabeculae
with an increased risk of fracture
Incidence
Osteoporosis is a very common bone disease in most parts of the world and is
increasing in prevalence with the increased aging of the population.
Presently, it has been estimated that ten million people, mainly postmenopausal
women, in the U.S. have osteoporosis, and an additional 18
million have low bone mass (osteopenia).
Osteoporosis is also a broadly used clinical term for a generalized loss of
bone density resulting in skeletal fragility, bone pain, and pathological
fractures (of the spine, wrist, hip, and ribs).
This is particularly prevalent in postmenopausal women and in both sexes
with advancing age.
Risk Factors
Of the potential predisposing risk factors in post-menopausal and senile
osteoporosis, the most notable are:
Low bone mass at maturity (early adult life).
Oestrogen (and androgen in males) deficiency.
Negative calcium balance.
Steroid therapy or anticonvulsant medication.
Smoking or frequent exposure to passive smoking.
High alcohol intake.
Lack of physical exercise.
Pathogenesis
Bone turnover and remodelling occurs throughout life and involves the tightly
coupled processes of bone formation by osteoblasts and bone resorption by
osteoclasts.
In the growing person, the total bone mass increases with skeletal growth as
bone formation exceeds bone resorption.
Bone mass then remains constant for several years during skeletal maturity
when bone formation and bone resorption are nearly equal.
Bone mass then begins to decline after the age of 40 to 50 years, at a faster rate
in women than in men, as bone resorption exceeds bone formation.
The progressive bone loss over the ensuing decades may amount to 30-50%,
or more, of the initial skeletal mass.
The detrimental effect of progressive bone loss tends to be greater in those
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who are genetically predisposed to have a smaller bone mass at maturity.

Although not the only consideration in pathogenesis, sex hormone deficiency
is a major factor associated with the development of post-menopausal or
senile osteoporosis.
Postmenopausal osteoporosis is mainly attributable to increased bone
resorbing activity of osteoclasts caused by oestrogen deficiency,
Senile osteoporosis, on the other hand, is attributed to inadequate osteoblastic
function.
Oestrogens normally react with and signal osteoblasts directly stimulating
them to lay down bone through high-affinity oestrogen-receptors.
With a deficiency of oestrogen (or of androgen in men), osteoclastic activity
predominates, resulting in an increased resorption and loss of bone mass.
A large number of experimental studies indicate that, in osteoporotic
conditions, osteoblasts are characterized by lower proliferation and defective
function compared with normal osteoblasts.
Clinical Features
A 'silent' risk factor for bone fracture, osteoporosis is a major cause of the
hundreds of thousands of fractures (of hip ~300,000, spine, and wrist)
occurring annually in the U.S. in women over the age of 45 years.
Estimates are that approximately 10-20% of women die within 1 year following
osteoporotic hip fracture.
Osteopenia ("too little" bone) is a descriptive term for a loss of bone density
observed radiologically.
Osteopenia may be local (as in disuse atrophy of an immobilized limb) or it
may be generalized.
Osteoporosis may be asymptomatic for a time, and may be only recognized
by clinical x-rays taken for some other purpose.
At some critical point, the fracture threshold is reached, the fragile skeleton
fails to meet mechanical demands, and
Bone pain,
Microfractures, and
Overt fractures of the vertebrae and other bones occur.
This condition of symptomatic osteoporosis occurs most frequently in
postmenopausal and aging white females, less commonly in white males, and
rarely in blacks of either sex.
Pathology
The excessive bone loss in postmenopausal and senile osteoporosis
produces thinning and increased porosity of the trabecular bone of the axial
skeleton (vertebrae, ribs, and pelvis).
The cortices of cylindrical bones are also thinned from the inside by endosteal
resorption, resulting in enlargement of the medullary cavity without a
corresponding change in the outer diameter of the bone.
The vertebral bodies, particularly in the thoracolumbar region, may be
weakened by micro fractures and collapse anteriorly, resulting in compression
fractures and wedging of the vertebrae, loss of stature, and kyphotic deformity
of the spine ("dowager's hump").
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213
Histopathology
Histologically, the amount of cortical and cancellous bone in osteoporosis is
decreased compared to the normal for a similar site, sex, and age.
The remaining bone has a lamellar structure and osteoid seams of normal width.
The bone cortices are thinned, and the haversian canals are widened.
The trabeculae of cancellous bone are decreased in size and number.
The trabeculae are thin, discontinuous, and widely separated.
Osteoblasts are not numerous.
Resorptive surfaces of trabecular and endosteal bone may be:
Smooth (graded "inactive") or
Irregular and scalloped (active) by resorption cavities (Howship's lacunae)
corresponding to the actual or previous locations of osteoclasts.
Laboratory Findings
Routine laboratory tests of blood and urine are usually normal in the typical
osteoporotic patient:
Normal serum calcium,
Normal serum phosphate,
Normal serum alkaline phosphatase.
In severe acute fracture, there is an associated increase in serum alkaline
phosphatase activity.
Urinary markers of increased bone resorption after menopause include
measurements of urinary cross-linked peptides derived from breakdown of
type I collagen.
Left: Micro-architecture of normal bone; Right: Micro-architecture of

osteoporotic bone.
NUTRITIONAL BONE DISEASES

RICKETS AND OSTEOMALACIA
Diseases resulting from vitamin "D", calcium or inorganic phosphorus deficiency,
they comprise rickets in infants and osteomalacia in adult life
General Considerations
The bone changes in both conditions are characterized by inadequate
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mineralization, resulting in a deficient amount of the mineral phase and an

excess of unmineralized osteoid.
Osteoid excess is caused by failure of the process of mineralization to keep pace
with new formation of osteoid during bone formation and remodelling.
In rickets, which mainly affects children between the ages of 6-30 months,
inadequate mineralization occurs not only in bone but also in epiphyseal
cartilage at sites of endochondral ossification, resulting in growth disturbances,
skeletal deformities, and susceptibility to fractures.
Presenting symptoms of osteomalacia include diffuse skeletal pain, bone
tenderness, and muscular weakness.
Aetiology
Rickets and osteomalacia may be caused by:
A deficiency or abnormal metabolism of vitamin "D".
Dietary deficiency in calcium.
A deficiency or abnormal utilization/excretion of inorganic phosphate (Pi),
especially if the phosphorus ratio is low.
A deficiency of vitamin "D" may be due to:
Dietary lack of the vitamin.
Insufficient ultraviolet exposure for synthesis of endogenous vitamin "D".
Malabsorption interfering with the intestinal absorption of fats and the fatsoluble
vitamin "D".
Abnormal metabolism of vitamin "D" commonly occurs in chronic renal failure.
The morphological characteristics of rickets, in the order of their development,
Clinical Features (Rickets)
A child with severe rickets may have:
A prominent forehead ("frontal bossing") due to osteoid excess.
Beading of the ribs at the costochondral junctions ("rachitic rosary")
caused by overgrowth of cartilage and osteoid.
Curved limb bones.
Lateral flattening of the rib cage with forward displacement of the sternum
("pigeon breast").
A depression ("Harrison's groove") at the lower margin of the rib cage
(sternum) produced by muscle contraction of the diaphragm.
Associated oral and dental changes may include:
There may be a high palate.
Pushing forward of the premaxilla.
Protrusion of the upper anterior teeth.
The mandible may bend downwards producing an anterior open bite.
The enamel of teeth may be hypoplastic.
There may be delayed eruption of teeth.
Clinical Features (Osteomalacia)
Grossly, long-standing osteomalacia may produce fractures and deformities of
the softened bones.
The main deformities include:
Kyphosis.
Collapse of the vertebrae causing shortening of the stature.
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Bowing of the long bones.

Narrowing of the pelvis.
The skull and jaws are rarely affected.
Rickets, clinical and radiographic views showing bowed legs (bowed outwards).
Histopathology
Bone biopsy is the definitive method of establishing the diagnosis.
Undecalcified bone sections stained with the von Kossa technique allow a
clear distinction to be made between osteoid and mineralized bone.
A bone biopsy of a patient with osteomalacia stained with the von Kossa
technique shows wide seams of osteoid (red) bordering the trabecular and
endosteal bone (black).
A biopsy of severe osteomalacia shows that virtually all bone surfaces are
covered by osteoid (in normal bone, surface osteoid is less than 20%).
The radiographic picture is that of diffuse osteopenia (decreased bone
density), which may be indistinguishable from that of osteoporosis.
The routine laboratory tests usually show:
Decreased serum calcium.
Decreased serum Pi.
Increased serum alkaline phosphatase; and
Decreased 24-hour urinary calcium excretion.
LANGERHANS CELL HISTIOCYTOSES (Histiocytosis X)
This disease spectrum results from accumulation and proliferation of cells
resembling Langerhan's cells. These cells in combination with lymphocytes,
eosinophils, and normal histiocytes form typical LCH lesions
Pathogenesis:
There are two types of histiocytoses: malignant (true histiocytic lymphomas),
and "reactive" (benign histiocytoses) or Langerhans cell histiocytosis
It has been found that IL-17A induces LC fusion into multinucleated giant cells.
These in turn recruit other inflammatory cells and cause local tissue destruction.
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This creates the characteristic lesions of Langerhan's cell histiocytosis.
However, these findings have not yet been independently reproduced.
Unifocal: Eosinophilic Granuloma

This represents the most benign and localized form of the three Langerhans cell
histiocytoses. It is a tumour-like proliferation of Langerhans cells in bone
History
In 1940, Jaffe and Lichtenstein coined the term eosinophilic granuloma.
In 1953, Lichtenstein proposed that eosinophilic granuloma, Hand-SchullerChristian disease and Letterer-Siwes disease should be included under the
term Histiocytosis X.
In 1987, the Histiocyte Society introduced the term Langerhans Cell
Histiocytosis as the new name for Histiocytosis X.
Incidence
Intra-osseous eosinophilic granuloma can be solitary or multifocal lesions.
Eosinophilic granuloma accounts for 60%-70% of cases of Langerhans cell
histiocytosis.
All bones may be affected except the bones of the hands and feet.
Ten to twenty percent of cases occur in the jaws, of which about two thirds
occur in the mandible.
Patients age varies, but the lesion usually occurs during the first three
decades of life.
The ratio of males to females is about 2:1.
The lesion does not have to be granulomatous or contain eosinophils for
diagnosis of eosinophilic granuloma to be reached.
The aetiology of the lesion is unknown, but various hypotheses have been
proposed:
Infection.
Immunological response.
Clinical Features
Eosinophilic granuloma presents as a palpable mass with or without pain.
Other signs and symptoms include:
Persistent oral ulcer.
Gingivitis.
Loose teeth.
Foul breath and taste.
Difficulty with mastication.
Headaches.
Sensory disturbances.
Typically appears as a peripheral radiolucent lytic lesion of bone.
The radiolucency may be well-defined or diffuse.
It may be round or oval in shape.
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The radiolucency is usually peripherally placed in bone so that the related
teeth appear to be floating in space.
Eosinophilic granuloma lesions consist of sheets of Langerhans cells with
eosinophilic granules and distinct cell borders.
Langerhans cells are distinct from histiocytes, but similar to them in that both
originate from monocytes.
Eosinophilic granulocytes are often seen, but their presence is not necessary
to reach a diagnosis.
Sometimes, Langhans type giant cells may be present.
Immunohistochemistry and Ultrastructure
Langerhans cells stain positive for S-100 protein.
They also stain positive for CD1 antigen.
They contain ultrastructural cytoplasmic inclusion bodies that look like tennis
rackets, known as "Birbeck" granules, which are specific to Langerhans cells.
Eosinophilic Granuloma, Left: Radiographic picture showing lesion involving

the mandibular second deciduous molar region; Right: Histologic picture showing
sheets of histiocytes and some eosinophilic granulocytes.
Multifocal Unisystem: Hand-Schuller-Christian Disease

One of the three major diseases of Langerhans cell histiocytosis. It is
characterized by the presence of the triad of bone lesions, exophthalmos and
diabetes insipidus
Aetiology and Pathogenesis
The aetiology of the condition is unclear.
Recent studies indicate that a disorder of the immune system may be an
important factor.
Due to the clonality of CD1a+ histiocytes, current opinion holds that it is a
clonal neoplastic disease with a variety of presentations that differ in severity
and behaviour.
51 | P a g e
Prof. DR/Heba Farag

The lesions are characterized by proliferation of Langerhans type histiocytic cells
producing simultaneous damage in various anatomic locations.
Incidence
There is a wide age range, but it occurs mostly in children under 10 years.
In children, there is a male preponderance (80%), whereas when it occurs in
adults females predominate.
There are multifocal disseminated lesions affecting bones, orbital involvement
and affection of the posterior pituitary stalk or the hypothalamus.
Clinical Features
The oral condition may clinically simulate severe periodontal disease.
There is often a mild dull pain.
There may be tooth mobility and tooth loss.
Lesions of the posterior mandibular area are more common.
There is atrophy of alveolar bone.
There are multifocal disseminated lesions especially in skull bones.
There is diabetes insipidus due to involvement of the posterior pituitary.
This can precede other signs of the disease or appear during the course of its
development.
There is also a possibility of a deficiency of growth hormone and thyroid
stimulating hormone of the anterior lobe of the pituitary gland.
There is exophthalmos due to retro-ocular orbital involvement.
Multiple osteolytic lesions involving the jaws, especially the mandible, and the
vault of the skull.
Mandibular lesions may be sharply-defined or ill-defined, with no cortical border.
The teeth appear to be floating in space.
Hand-Schuller-Christian disease, Left: Clinical picture; Right: Multiple punched out radiolucencies of the
skull.
Hyperplasia and proliferation of reticulo-endothelial cells, typically Langerhans
cells.
52 | P a g e
Prof. DR/Heba Farag

These may be admixed with variable numbers of eosinophils, lymphocytes
and plasma cells.

Occasionally, there may be areas of necrosis surrounded by intense infiltration
of neutrophils.
Areas of foam cells and occasional multinucleated histiocytes may be present.
There is dense infiltration of CD1 positive histiocytes in the upper and middle
dermis.
Ultrastructurally, there are intracytoplasmic inclusion "Birbeck" granules.
Hand-Schuller-Christian disease,: Histiocytes with some admixed
eosinophilic granulocytes; Right: Histiocutes and a Touton-type giant cell.
53 | P a g e

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Prof.

Prof. DR/Heba Farag

Unifocal Unisystem: Eosinophilic Granuloma.

HEREDITARY DISEASES OF BONE

Prof. DR/Heba Farag

Prof. DR/Heba Farag

Some children with osteogenesis imperfecta inherit the disorder from a

Prof. DR/Heba Farag

Osteogenesis imperfecta: Left: Many wormian bones between the

Prof. DR/Heba Farag

because of failure in remodelling to adjust to functional demands.

Prof. DR/Heba Farag

CLEIDO-CRANIAL DYSPLASIA (Dysostosis)

Prof. DR/Heba Farag

other, although they may look alike to the untrained eye.

Prof. DR/Heba Farag

Prof. DR/Heba Farag

ACQUIRED DISEASES OF BONE

FIBROUS DYSPLASIA OF BONE

somatic mutation in which abnormal fibro-osseous tissue develops in

Prof. DR/Heba Farag

remodelling is replaced by an abnormal proliferation of fibro-osseous tissue.

and in the mandible.

Osteoblast Differentiation Process.

Prof. DR/Heba Farag

in persons aged 3-15 years.

disease process becomes quiescent.

Prof. DR/Heba Farag

Distribution of the Lesions

The radiographic picture of jaw lesions on periapical or occlusal views,

especially those in the maxilla, is sometimes described as having:

- An orange peel appearance.

Prof. DR/Heba Farag

Fibrous dysplasia of the right maxilla in a 12 year old boy.

Prof. DR/Heba Farag

Left: Metaplastic woven bone trabeculae developing directly from fibroblasts;

Prof. DR/Heba Farag

Differences between fibrous dysplasia and ossifying fibroma

Prof. DR/Heba Farag

side of bony lesions, a feature that differentiates this disease from

Albright Syndrome: Left: Precocious sexual development in a 5-yearold

Prof. DR/Heba Farag

FAMILIAL FIBROUS DYSPLASIA (Cherubism)

Prof. DR/Heba Farag

Prof. DR/Heba Farag

Fig. 134: Familial Fibrous Dysplasia: A 10

more normal contour develops.

Prof. DR/Heba Farag

Fig. 135: Familial Fibrous Dysplasia: Note radiolucent lesions involving

Prof. DR/Heba Farag

DYSTROPHIC BONE DISEASES

Prof. DR/Heba Farag

osteoclasts by a slow virus as the measles or respiratory syncytial virus (RSV)

Prof. DR/Heba Farag

spine with a frequency of 30-75%.

Prof. DR/Heba Farag

cranium are the next noticeable changes.

Fig. 138: Pagets disease affecting the

Prof. DR/Heba Farag

Osteolytic stage, radiolucent areas with root resorption.

Course of the Disease

Fig. 140: Sclerotic stage with extreme radiodensity and

Prof. DR/Heba Farag

bone matrix and formation of woven bone.