6. 1
BONE PATHOLOGIES
BY
Dr. Bhuvan Nagpal
B.D.S. (Hons.), M.D.S. (Oral Pathology)
(Gold Medalist)
Consulting Oral & Maxillofacial Pathologist
Ex. Post Graduate Resident,
Dept. of Oral Pathology & Microbiology,
JSS Dental College & Hospital,
JSS University,
Mysuru, Karnataka, India
Dr. Archana S.
B.D.S., M.D.S. (Oral Pathology)
Consulting Oral & Maxillofacial Pathologist
Ex. Post Graduate Resident,
Dept. of Oral Pathology & Microbiology,
JSS Dental College & Hospital,
JSS University,
Mysuru, Karnataka, India
Dr. Anuradha Nagpal
M.B.B.S. (Hons.)
House Surgeon
Teerthanker Mahaveer Medical College & Research Centre,
Teerthanker Mahaveer University,
Moradabad, Uttar Pradesh, India
7. 2
S.No CONTENTS Page No.
1. INTRODUCTION 3
2. CLASSIFICATION OF BONE DISEASES 4-19
3. SKELETAL DYSPLASIAS 20-76
4. METABOLIC BONE DISEASES 76-100
5. ENDOCRINE BONE DISEASES 101-112
6. INFECTIOUS BONE DISEASES 113-133
7. 134-147
8. FIBRO-OSSEOUS LESIONS 148-180
9. BONE FRACTURES 181-185
10. BONE CYSTS 186-194
11. BONE TUMORS 195-305
12. SYNDROMES AFFECTING BONES 306-353
13. BONE NECROSIS 354-355
14. PSEUDO-DISEASES OF BONE 356-362
15. REFERENCES 363-373
8. 3
INTRODUCTION
Maintaining a strong and healthy skeleton is a complicated process
that requires having the right amount of bone with the right structure and
composition in the right place. Bone is a dense calcified tissue which is
specially affected by a variety of diseases that often cause it to react in a
dynamic fashion.4
Bone diseases are conditions that result in the impairment of normal
bone function and can make bones weak.Some of these diseases involve
the entire bony skeleton, while others effct only single bone. It is
characteristic for certain of these conditions to follow strict mendelian
patterns of heredity, although a specific disease will be inherited in one
case and apparently not in another.These diseases of bone, as a group, may
arise at all ages; some characteristically are congenital and present at birth,
while others develop in early childhood, young adulthood or even later in
life. In addition to conditions that affect bone directly, there are many other
disorders that indirectly affect bone by interfering with mineral
metabolism. Genetic abnormalities can produce weak, thin bones, or bones
that are too dense and also affect the size and shape of the skeleton and can
cause deformities or abnormal growth.29
The maxilla and mandible, like other bones, suffer from both the
generalized and localized forms of skeletal diseases. Although the basic
reactions are the same,the peculiar anatomic arrangement of teeth
embedded partially in bone, through which the bone may be subjected to
an unusal variety of stresses, strains and infections, often produces a
modified response of bone to the primary injury.4,2
9. 4
CLASSIFICATION OF BONE DISEASES:
textbook of general pathology:30
I. Diseases associated with defects in Extracellular structural proteins:
Type1 collagen diseases (Osteogenesis Imperfecta )
Type 2 collagen diseases ( Achondrogenesis II,Stickler syndrome)
Type 9 collagen diseases ( Multiple epiphyseal dysplasia)
Type 10 collagen diseases (Schmid metaphyseal chondroplasia)
II.Diseases associated with defects in folding and degradation of
macromolecules:
Mucopolysaccharidoses
III. Diseases associated with defects in metabolic pathways (enzymes,
ion channels and transporters)
Osteopetrosis
IV. Diseases associated with decreased bone mass
Osteoporosis
V. Diseases caused by osteoclast dysfunction:
VI. Diseases associated with abnormal mineral homeostasis:
Rickets and Osteomalacia
Hyperparathyroidism
Renal Osteodystrophy
VII.Fractures
VIII Osteonecrosis (Avascular Necrosis)
IX. Bone infections
12. 7
Fibrogenic
Desmoplastic fibroma
Fibrosarcoma
Notochordal
Chordoma
Vascular
Hemangioendothelioma
Hemangiopericytoma
Lipogenic
Liposarcoma
2) Osteoclast diseases and dental abnormalities31
Diseases of reduced osteoclast activity
Mutation/disease Gene
defect
Osteoclast defect Tooth eruption
Recessive
osteopetrosis
TCIRG1 Normal formation,
no functional proton
pump no ruffled border
Abnormal in
human
Recessive
osteopetrosis
CLCN7 Normal formation,
no functional chloride
channel, no ruffled
border
Abnormal in
human
Recessive
osteopetrosis
CAII Normal formation,
reduced activity of CAII
enzyme
Deficient,
frequent
infections
13. 8
Recessive
osteopetrosis
OSTM1 Unknown, disease
associated with perinatal
death
Unknown
ADO II CLCN7 Reduced activity of
chloride channel
Normal,
frequent
infections
Pycnodysostosis CTSK Osteoclast activity
reduced, intracellular
collagen fibrils
Supernumerary
teet
Diseases of increased osteoclast activity
Mutation/disease Gene defect Osteoclast defect Tooth eruption
SQSTM1 Osteoclasts
enlarged, more
nuclei, more active
Eruption normal,
loosening due to
increased jaw
remodeling
diseas
TNFRSF11B Osteoclasts
numerous
Formation
normal, reports
of early tooth
loss, cause
unknown
Early onset PDB TNFRSF11A bone similar to PDB Early tooth loss,
possibly due to
osteoclast
overactivity
Expansile TNFRSF11A Increased formation, Early tooth loss,
14. 9
skeletal hyper-
phosphatasia
increased size likely due to
Osteoclast
overactivity
Familiar
expansile
osteolysis
TNFRSF11A Osteoclast enlarged,
more nuclei, more
active
Very early tooth
loss, due to root
resorption of
permanent teeth
ORTHOPAEDICS32
Primary bone diseases
Bone Cysts
Aneurysmal Bone Cyst
Giant Cell Tumour
Simple Bone Cysts
Bone Developmental Diseases
Basal Cell Nevus
Bone Deficiencies
Coxa Vara
Dwarfism
Dysostoses
Ectodermal Dysplasia
Femoral Anteversion
Genu Valgum
15. 10
Gigantism
Leg Length Inequality
Marfan Syndrome
Osteochondrodysplasia
Pectus Excavatum
Bone Malalignment
Bone Resorption
Endocrine Bone Diseases
Acromegaly
Congenital Hypothyroidism
Hyperparathyroidism
Osteitis Fibrosa Cystica
Eosinophilic Granuloma
Hyperostosis
Congenital Cortical Hyperostosis
Diffuse Idiopathic Skeletal Hyperostosis
Exostosis
Hyperostosis Frontalis Interna
Sternocostoclavicular Hyperostosis
Infectious Bone Diseases
Osteitis
Osteomyelitis
Spondylitis
Tuberculosis, Osteoarticula
Metabolic Bone Diseases
16. 11
Mucolipidoses
Osteomalacia
Osteoporosis
Pagets
Pathologic Bone Demineralization
Pseudohypoparathyroidism
Renal Osteodystrophy
Rickets
Orthopaedic Oncology
Osteitis Deformans
Osteochondritis
Osteonecrosis
Primary Hypertrophic Osteoarthropathy
Secondary Hypertrophic Osteoarthropathy
Slipped Epiphysis
Spinal Diseases
4. Skeletal dysplasias can be broadly classified into two main groups:
osteochondrodysplasias and dysostoses.33
The Osteochondrodysplasias, in which there is, generalized abnormality in
bone or cartilage. This group is subdivided into three main categories:
Defects of the growth of tubular bones and or spine
(chondrodysplasias).
Abnormalities of density or cortical diaphyseal structure and or
metaphyseal modeling.
Disorganized development of cartilage and fibrous components of
the skeleton.
17. 12
Dysostoses: This group refers to malformations or absence of individual
bones singly or in combination. They are mostly static and their
malformations occur during blastogenesis (1st 8 weeks of embryonic life).
This is in contrast to osteochondrodysplasias, which often present after this
stage, has a more general skeletal involvement and continue to evolve as a
result of active gene involvement throughout life. The dysostoses group
can be sub-classified into three main categories:
Those primarily concerned with craniofacial involvement and
includes in various craniosynostosis.
Those with predominant axial involvement including the various
segmentation defect disorders.
Those affecting only the limbs.
5. WHO CLASSIFICATION OF BONE TUMOURS (1995)34
CARTILAGE TUMOURS
Osteochondroma 9210/0
Chondroma 9220/0
Enchondroma 9220/0
Periosteal chondroma 9221/0
Multiple chondromatosis 9220/1
Chondroblastoma 9230/0
Chondromyxoid fibroma 9241/0
Chondrosarcoma 9220/3
Central, primary, and secondary 9220/3
Peripheral 9221/3
Dedifferentiated 9243/3
Mesenchymal 9240/3
20. 15
MISCELLANEOUS LESIONS
Aneurysmal bone cyst
Simple cyst
Fibrous dysplasia
Osteofibrous dysplasia
Langerhans cell histiocytosis 9751/1
Erdheim-Chester disease
Chest wall hamartoma
6. FIBRO-OSSEOUS LESIONS35,36,37,38,39,40
Classification by Charles.A.Waldron-1993
Fibrous Dysplasia
Reactive (dysplastic) lesions arising in the tooth-bearing area
(presumably of periodontal origin).
*periapical cemento-osseous dysplasia
*focal cemento-osseous dysplasia
*florid cemento-osseous dysplasia
Fibro-osseous neoplasms (widely designated as cementifying
fibroma, ossifying fibroma or cemento-ossifying fibroma)
Working Classification of FOLs by Miro.S.Makek-1987
I DEVELOPMENTAL DISORDER
1. Fibrous cortical defect.
2. Fibrous dysplasia.
II REACTIVE-REPARATIVE LESION
1. Traumatic periostitis.
2. Periostitis ossificans.
3. Osseous keloid.
21. 16
4. Periapical cemental-dysplasia and florid cementoosseous
dysplasia
5. Sclerosing osteomylitis.
6. Osteitis deformans (Paget).
III FIBROMATOSIS
1. Desmoplastic fibroma.
IV NEOPLASMS
A. TOOTH BEARING AREAS
ONLY
1. Cementoblastoma.
2. Periodontoma.
a) central
b) peripheral
B. ALL CRANIO-FACIAL BONES
1. Osteoma.
a) trabecular
b) compact
2. Osteoid osteoma.
3. Psammous desmo-osteoblastoma.
4. Trabecular desmo- osteoblastoma.
Classification by WHO (1992)
Non Neoplastic Bone Lesions
2.1:Fibrous Dysplasia Of Jaws
2.2:Cemento Osseous Dysplasias
2.2.1:Periapical Cemental Dysplasia
2.2.2:Florid Cemento Osseous Dysplasia
2.2.3:Other Cemento Osseous Dysplasia
22. 17
2.3 Cherubism
2.4.Central Giant Cell Granuloma
2.5.Aneurysmal Bone Cyst
2.6.Solitary Bone Cyst
Classification by Burket
DEPENDING ON ORIGIN
Periodontal ligament
A) Cementifying fibroma.
B) Ossifying fibroma.
C) Cementifying ossifying fibroma.
D) Fibroma.
MEDULLARY BONE.
A. Fibro osteoma.
B. Active Juvenile Ossifying fibroma.
C. Cherubism.
D. Fibrous dysplasia.
E. Giant cell tumor.
F. Aneurysmal bone cyst.
G. Hyper parathyroidism jaw lesion (Browns tumor)
H. Paget
23. 18
Proposed classification by Slootweg PJ & Muller H based on clinical,
radiographic & histopathology.
1. Group I: Fibrous dysplasia.
2. Group II: Juvenile ossifying fibroma.
3. Group III: Ossifying fibroma.
4. Group IV: Cemento-osseous dysplasias.
1.Fibrous dysplasia.
2.Reactive/Dysplastic lesions (periodontal origin)
a. Periapical cemento-osseous dysplasia.
b. Focal cemento-osseous dysplasia.
c. Florid cemento-osseous dysplasia.
Neoplastic lesions.
a. Cementifying/Ossifying/Cemento-ossifying fibroma.
b. Juvenile/active/aggressive ossifying fibroma.
i. Trabecular.
ii. Psammomatoid.
Classification by NEVILLE-2002
Fibrous dysplasia
Cemento-osseous dysplasia
a. Periapical cemento-osseous dysplasia.
b. Focal cemento-osseous dysplasia.
c. Florid cemento-osseous dysplasia.
Ossifying fibroma.
7. BONE NECROSIS41,42
Infract
Aseptic (avascular) bone necrosis
Osteochondritis dissecans
25. 20
SKELETAL DYSPLASIA43,44
growthSkeletal dysplasias are a heterogenous group of dysplasias that
include more than 200 recognized conditions. They are disorders of growth
and remodeling of bone and cartilage. Most disorders result in short
stature, which is defined as height more than 2 standard deviations below
the mean for the population at a given age.
Achondroplasia (AP), hypochondroplasia (HP), and thanatophoric
dysplasia (TD) are among the most common skeletal dysplasias.
Epidemiology
Incidence
Achondroplasia 1/15,000-1/20,000 live births
Hypochondroplasia 1/15,000-1/40,000 live births
Thanatophoric dysplasia 1/6,500-20,000 live births
Sex equal distribution
26. 21
Inheritance
Autosomal dominant, mostly de novo mutations in TD, with 100%
penetrance
Cause fibroblast growth factor receptor 3 (FGFR3) gene mutations
AP
99% of cases result from substitution of A or C nucleotide for
G at 1138 in the FGFR3 gene
HP
70% of cases result from substitution of A or G nucleotide for
C at 1620 in the FGFR3 gene
TD
Eleven FGFR3 mutations (6 missense and 5 read-throughs of
the native stop codon) cause 99% of TDI
A single FGFR3 mutation, K650E, is responsible for TD
Recurrence risk in offspring for phenotypically normal
parents with a previously affected pregnancy, the recurrence
risk is not increased over the general population
Classification
Superti-Furga from the International Working Group on
Constitutional Diseases of Bone classified the gene and protein
identified skeletal dysplasias based on only theirmolecular-
pathogenetics.
Gene and protein Clinical phenotype
1. Defects in structural proteins
Collagen:
COL1 Osteogenesis imperfect
27. 22
COL2 Achondrogenesis type
II
Hypochondrogenesis
Spondyloepiphyseal dysplasia
(SED) congenita
Spondyloepimetaphyseal
dysplasia
Kniest dysplasia
Stickler syndrome I
COL9 Multiple epiphyseal dysplasia
(MED) type 2
COL10 Metaphyseal dysplasia
(Schmid type)
COL11 Stickler syndrome II
Otospondylomegaepiphyseal
dysplasia
COMP Pseudoachondroplasia
Multiple epiphyseal dysplasia
type 1
Matrillin-3 (MATN-3) Multiple epiphyseal dysplasia
type 3
Perlecan Schwartz-Jampel type-1,2
28. 23
2. Defects in metabolic pathways:
Diastrophic dysplasia sulfate transporter (DTDST) Achondrogenesis 1B
Athelosteogenesis II
Diastrophic dysplasia
Recessive MED
Arylsulfatase E X-linked chondrodysplasia
punctata
ANKH (Pyrophosphate transporter) Craniometaphyseal dysplasia
CIC7 Severe osteopetrosis
Carboanhydrase II Osteopetrosis with renal
tubular acidosis
3. Defects in degradation of macromolecules:
Lysosomal enzymes Mucopolysaccharidoses
Mucolipidosis
Cathepsin K Pyknodysostosis
Sedlin X-linked SED tarda
.
4. Defects in growth factors and receptors
Fibroblast growth factor receptor 1, 2 Craniosynostosis
Fibroblast growth factor receptor 3 Achondroplasia
Hypochondroplasia
30. 25
Clinical Presentation
Anthropometric parameters should be compared with the gestational
age for the newborn or the chronologic age of the patient,
considering appropriate racial, ethnic, socioeconomic, and perinatal
factors. To detect disproportionately short stature, anthropometric
measurements should include the upper and lower segment ratio and
arm span.
Diagnosis of short-limb skeletal dysplasia is based on the segment of
the long bone affected most severely.
Rhizomelic shortening (short proximal segments, eg,
humerus, femur) is present in patients with achondroplasia,
hypochondroplasia, rhizomelic type of chondrodysplasia
punctata, Jansen type of metaphyseal dysplasia,
spondyloepiphyseal dysplasia (SED) congenita, thanatophoric
dysplasia, atelosteogenesis, diastrophic dysplasia, and
congenital short femur.
Mesomelic shortening (short middle segments, eg, radius,
ulna, tibia, fibula) includes the Langer and Nievergelt types of
mesomelic dysplasias, Robinow syndrome, and Reinhardt
syndrome.
Acromelic shortening (short distal segments, eg, metacarpals,
phalanges) is present in patients with acrodysostosis and
peripheral dysostosis.
31. 26
Acromesomelic shortening (short middle and distal segments,
eg, forearms, hands) is present in patients with acromesomelic
dysplasia.
Micromelia (shortening of extremities involving entire limb)
is present in achondrogenesis, fibrochondrogenesis, Kniest
dysplasia, dys-segmental dysplasia, and Roberts syndrome.
Diagnosis of the short trunk variety includes Morquio
syndrome, Kniest syndrome, Dyggve-Melchior-Clausen
disease, metatrophic dysplasia, SED and
spondyloepimetaphyseal dysplasia (SEMD).
Mental retardation: Skeletal dysplasias associated with mental
retardation can be broadly categorized in the following terms
according to etiology or pathogenesis:
CNS developmental anomalies - Orofaciodigital
syndrome type 1 (hydrocephaly, porencephaly,
hydranencephaly, agenesis of corpus callosum) and
Rubinstein-Taybi syndrome (microcephaly, agenesis of
corpus callosum)
Intracranial pathologic processes - Craniostenosis
syndromes (pressure) and thrombocytopenia-radial
aplasia syndrome (bleeding)
Neurologic impairment - Dysosteosclerosis
(progressive cranial nerve involvement) and
mandibulofacial dysostosis (deafness)
Chromosome aberrations - Autosomal trisomies
32. 27
Primary metabolic abnormalities - Lysosomal storage
diseases
Other disorders - Chondrodysplasia punctata, warfarin
embryopathy (teratogen), and cerebrocostomandibular
syndrome (hypoxia)
Skull
Disproportionately large head - Achondroplasia,
achondrogenesis, and thanatophoric dysplasia
Cloverleaf skull - Thanatophoric dysplasia, Apert
syndrome, Carpenter syndrome, Crouzon syndrome,
and Pfeiffer syndrome
Caput membranaceum - Hypophosphatasia and
osteogenesis imperfecta congenita
Multiple wormian bones - Cleidocranial dysplasia and
osteogenesis imperfecta
Craniosynostosis - Apert syndrome, Crouzon
syndrome, Carpenter syndrome, other craniosynostosis
syndromes, and hypophosphatasia
Eyes
Congenital cataract - Chondrodysplasia punctata
Myopia - Kniest dysplasia and SED congenita
Mouth - Bifid uvula and high arched or cleft palate, as in
Kniest dysplasia, SED congenita, diastrophic dysplasia,
metatrophic dysplasia, and camptomelic dysplasia
33. 28
Ears - Acute swelling of the pinnae, as in diastrophic
dysplasia
Polydactyly
Preaxial - Chondroectodermal dysplasia and short-rib
polydactyly syndromes (frequently in Majewski
syndrome, rarely in Saldino-Noonan syndrome)
Postaxial - Chondroectodermal dysplasia, lethal short-
rib polydactyly syndromes, and Jeune syndrome
Hands and feet
Hitchhiker thumb - Diastrophic dysplasia
Clubfoot - Diastrophic dysplasia, Kniest dysplasia, and
osteogenesis imperfecta
Nails
Hypoplastic nails - Chondroectodermal dysplasia
Short and broad nails - McKusick metaphyseal
dysplasia
Joints - Multiple joint dislocations, as in Larsen syndrome and
otopalatodigital syndrome
Bones - Long bone fractures, as in osteogenesis imperfecta
syndromes, hypophosphatasia, osteopetrosis, and
achondrogenesis type I
Thorax
34. 29
Long or narrow thorax - Asphyxiating thoracic
dysplasia, chondroectodermal dysplasia, and
metatrophic dysplasia
Pear-shaped chest - Thanatophoric dysplasia, short-rib
polydactyly syndromes, and homozygous
achondroplasia
Heart
Atrial septal defect or single atrium -
Chondroectodermal dysplasia
Patent ductus arteriosus - Lethal short-limbed skeletal
dysplasias
Transposition of the great vessels - Majewski syndrome
Diagnosis
First trimester ultrasound showing increased nuchal
translucency, reverse flow in ductus venosus, long-bone
shortening
Second/third trimester ultrasound examination revealing limb
shortening below 5th percentile, recognizable by 20 weeks
gestation; platyspondyly, ventriculomegaly, narrow chest cavity
with short ribs, polyhydramnios, bowed femurs (type 1),
cloverleaf skull (in type II), well-ossified spine and skull
Postnatal clinical exam
Based on clinical examination or prenatal ultrasound
Genetic testing for FGFR3 mutation panel is diagnostic when
combined with clinical examination or prenatal ultrasound
35. 30
Treatment
Supportive
Bowing of the lower limbs may merit surgical straightening
Ultrasound of brain, especially if large fontanel, to rule out mild
hydrocephaly relating to small foramen magnum
Diagnose obstructed sleep apnea
Orthopedic neurologic evaluation of spinal stenosis and kyphosis
Be aware that short eustachian tubes may lead to frequent middle ear
infections and conductive hearing loss
Avoid obesity
CLEIDOCRANIAL DYSPLASIA29
- MARIE
(cleido = collar bone, + cranial = head, + dysplasia = abnormal forming)
,
Cleidocranial dysplasia is a condition characterized by defective
development of the cranial bones and by the complete or partial absence of
the collar bones (clavicles).
Etiology
Several chromosome abnormalities have been linked with this syndrome,
including chromosome 6p21.
Inheritance
When inherited, it appears as a dominant mendelian characteristic and may
be transmitted by either sex. In those cases which appear to have
developed sporadically, it has been suggested that they represent a
recessively inherited disease or more likely, either an incomplete
36. 31
penetrance in a genetic trait with variable gene expression or a true new
dominant mutation.
Clinical features
The disease affects men and women in equal frequency.
Skull
Fontanels often remain open or atleast exhibit delayed closing
and for this reason tend to be rather large.
The sutures also may remain open and wormain bones are
common.
Sagittal suture is characteristically sunken, giving the skull a
flat appearance.
Frontal,parietal and occipital bones are prominent and
paranasal sinuses are underdeveloped and narrow.
Head is brachycephalic9wide and short)
Shoulder girdle
Either complete absence of clavicles or partial absence or
even thinning of one or both clavicles.
Unusal mobility of shoulders
37. 32
Defects in the vertebral column, pelvis and long bones as well as in
the digits are also relatively more common.
Dental abnormalities
High, narrow, arched palate and actual cleft palate.
Maxilla is underdeveloped and smaller than normal in
relationto maxilla.
The lacrimal and zygomatic bones are also reported to be
underdeveloped.
38. 33
Proloned retention of deciduous teeth and subsequent delay in
eruption of the succedaneous teeth.
The roots are often somewhat short and thinner than usual and
may be deformed.
There may be paucity or absence of cellular cementum on the
roots of the permanent teeth.
Treatment and prognosis:
Care of the oral conditions.
The retained deciduous teeth should be restored if they become
carious, since their extraction doe not necessarily induce eruption of
the permanent teeth.
Mulltidisciplinary approach utilizing the pedodontist, the
orthodontist and the oral surgeon should be followed.
39. 34
Correct timing of surgical procedures for uncovering teeth and
orthodontic repositioning can give excellent functional results.
OSTEOGENESIS IMPERFECTA 29,39,45,46
Synonyms: BRITTLE BONE SYNDROME, ADAIR-DIGHTON
SYNDROME, VAN DER HOEVE SYNDROME, EKMAN-
LOBSTEIN SYNDROME, FRAGILITAS OSSIUM,
OSTEOPSATHYROSIS
Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly
affect the bones. The term "osteogenesis imperfecta" means imperfect
bone formation.
Frequency
This condition affects an estimated 6 to 7 per 100,000 people
worldwide. Types I and IV are the most common forms of
osteogenesis imperfecta, affecting 4 to 5 per 100,000 people. Types
II and III are rarer, with an estimated incidence of 1 to 2 per 100,000
people:
No known differences based on sex exist.
Age os onset of symptoms varies depending on the type as follows:
Type I Infancy
Type II In utero
Type III Half of cases in utero, other half neonatal period
Type IV- usually in infancy
Causes:
Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes
cause osteogenesis imperfecta.
40. 35
Mutations in the COL1A1 and COL1A2 genes are responsible for
about 90 percent of all cases of osteogenesis imperfecta. These genes
provide instructions for making proteins that are used to assemble type I
collagen, which is the most abundant protein in bone, skin, and other
connective tissues that provide structure and strength to the body.
Most of the mutations that cause osteogenesis imperfecta type I
occur in the COL1A1 gene. These mutations reduce the amount of type I
collagen produced in the body, which causes bones to be brittle and
fracture easily. The mutations responsible for osteogenesis imperfecta
types II, III, and IV can occur in the COL1A1 or COL1A2 gene. These
mutations typically alter the structure of type I collagen molecules. A
defect in the structure of type I collagen weakens connective tissues,
particularly bone, resulting in the characteristic features of osteogenesis
imperfecta.
Mutations in the CRTAP and LEPRE1 genes are responsible for
rare, often severe cases of osteogenesis imperfecta. The proteins produced
from these genes work together to process collagen into its mature form.
Mutations in either gene disrupt the normal folding, assembly, and
secretion of collagen molecules. These defects weaken connective tissues,
leading to severe bone abnormalities and problems with growth.
In cases of osteogenesis imperfecta without identified mutations in
the COL1A1, COL1A2, CRTAP, or LEPRE1 gene, the cause of the
disorder is unknown. Researchers are working to identify additional genes
that are associated with this condition.
Inheritance:
Most cases of osteogenesis imperfecta have an autosomal dominant
pattern of inheritance, which means one copy of the altered gene in each
cell is sufficient to cause the condition. Many people with type I or type IV
41. 36
osteogenesis imperfecta inherit a mutation from a parent who has the
disorder. Almost all infants with more severe forms of osteogenesis
imperfecta (type II and type III) have no history of the condition in their
family. In these infants, the condition is caused by new (sporadic)
mutations in the COL1A1 or COL1A2 gene. The disorder is not passed on
to the next generation because most affected individuals do not live long
enough to have children.
Less commonly, osteogenesis imperfecta has an autosomal recessive
pattern of inheritance. Autosomal recessive inheritance means two copies
of the gene in each cell are altered. The parents of a child with an
autosomal recessive disorder typically are not affected, but each carry one
copy of the altered gene. Some cases of osteogenesis imperfecta type III
are autosomal recessive; these cases usually result from mutations in genes
other than COL1A1 and COL1A2. Rare cases of osteogenesis imperfecta
caused by mutations in the CRTAP or LEPRE1 gene also have an
autosomal recessive pattern of inheritance.
Syndrome resembling osteogenesis imperfect
Congenital brittle bones with craniosynostosis and ocular
proptosis:
Patients develop craniosynostosis, hydrocephalus, ocular proptosis,
facial dysmorphism, and several metaphyseal fractures associated
with generalized low bone density few years after birth.
Congenital brittle bones with congenital joint contractures:
Patients are born with brittle bones, leading to multiple fractures and
joint contractures and pterygia (arthrogryposis multiplex congenita)
due to dislocation of the radial head.Wormian bones are present, and
inheritance appears to be recessive
42. 37
The basic defect is mapped to locus 17p12 (18-cM interval), where a
bone telopeptidyl hydroxylase is located.
Osteoporosis-pseudoglioma syndrome:
Inheritance is autosomal recessive. Individuals with Osteoporosis-
pseudoglioma syndrome have mild to moderate OI with blindness
due to hyperplasia of the vitreous, corneal opacity and secondary
glaucoma. The ocular pathology may be secondary to failed
regression of the primary vitreal vasculature during fetal growth
.The genetic defect has been mapped to chromosome region 11q12-
13 The defect is specifically in the LRP5 gene that encodes for the
low-density lipoprotein receptor-related protein
Congenital brittle bones with optic atrophy, retinopathy and
severe psychomotor retardation:
Congenital brittle bones with microcephaly
Congenital brittle bones with redundant callus:
Patients with this SROI develop hyperplastic calluses in long
bones after having a fracture or orthopedic surgery involving
osteotomies. Mutations in the type I procollagen genes have not
been found in these patients. Inheritance appears to be autosomal
dominant. Their initial presentation often resembles that of OI with
bone fragility and deformity, but these patients develop hard,
painful, and warm swellings over long bones that may initially
suggest inflammation or osteosarcoma. Patients with this SROI have
white sclera and normal teeth. On radiographs, a redundant callus
43. 38
can be observed around some fractures. The size and shape of the
callus may remain stable for many years after a rapid growth period.
Histomorphometric studies show that the bone lamella are arranged
in meshlike fashion, as opposed to the typical parallel arrangement
in patients with OI. A variant of this SROI is called aspirin-
responsible expansile bone disease.
Congenital brittle bones with mineralization defect:
This rare form of SROI is clinically indistinguishable from
moderate-to-severe OI. Diagnosis is possible only by means of bone
biopsy, in which a mineralization defect affecting the bone matrix
and sparing growth cartilage is evident. Patients have normal teeth,
and they do not have wormian bones. They have no radiologic signs
of growth-plate involvement despite the mineralization defect
evident on bone biopsy. This form of SROI shares several
characteristics with fibrogenesis imperfecta ossium, and a mild form
of this SROI may exist. The pattern of inheritance suggest gonadal
mosaicism or a somatic recessive trait. The structure of the collagen
molecule appears to be normal, and no mutations of COL1A1 and
COL1A2 genes have been found.
Congenital brittle bones with rhizomelia:
This particular form of SROI with short humerus and femora
and recessive inheritance was only described in a First Nations
community of Quebec. The severity in terms of fractures and
disability is moderate to severe. Fractures may be present at birth. In
44. 39
linkage studies, the genetic defect has been mapped to the short arm
of chromosome 3, where no genes codify type I procollagen
Clinical presentation:
Classification b y Sillence et al (1979)
Osteogenesis imperfecta, type I
Osteogenesis imperfecta Tarda
Osteogenesis imperfect with blue sclera
Gene map locus 17q21.31-q22,7q22.1
Osteogenesis imperfect congenital: type II
Osteogenesis imperfecta congenital, neonatal lethal
Vrolik type of Osteogenesis imperfect
Gene map locus 17q21.31-q22,7q22.1
Osteogenesis imperfecta, progressively deforming, with normal
sclera: type III
Gene map locus 17q21.31-q22,7q22.1
Osteogenesis imperfect, type IV
Osteogenesis imperfect with normal sclera
Gene map locus 17q21.31-q22
45. 40
Researches have defined three more types of osteogenesis imperfect
Type V
Type VII
Type VIII
Type I - Mild forms
Patients have no long-bone deformity.
The sclera can be blue or white. Blue sclera also may occur in
other disorders, such as progeria, cleidocranial dysplasia,
Menkes syndrome, cutis laxa, Cheney syndrome, and
pyknodysostosis.
Dentinogenesis imperfecta may be present.
Over a lifetime, numbers of fractures can range from 1 or 2 to
60.
Height is usually normal in individuals with mild forms of OI.
People with OI have a high tolerance for pain. Old fractures
can be discovered in infants only after radiographs obtained
for other reasons other than an assessment of OI, and they can
occur without any signs of pain.
Exercise tolerance and muscle strength are significantly
reduced in patients with OI, even in the mild forms.
Fractures are most common during infancy, but they may
occur at any age.
46. 41
Other possible findings include kyphoscoliosis, hearing loss,
premature arcus senilis, and easy bruising.
Type II - Extremely severe
Type II is often lethal.
Blue sclera may be present.
Patients may have a small nose and/or micrognathia.
All patients have in utero fractures, which may involved the
skull, long bones, and/or vertebrae.
The ribs are beaded, and long bones are severely deformed.
Causes of death include extreme fragility of the ribs,
pulmonary hypoplasia, and malformations or hemorrhages of
the CNS.
Type III - Severe
Patients may have joint hyperlaxity, muscle weakness,
chronic unremitting bone pain, and skull deformities (eg,
posterior flattening) due to bone fragility during infancy.
Deformities of upper limbs may compromise function and
mobility.
47. 42
The presence of dentinogenesis imperfecta is independent of
the severity of the OI.
The sclera have variable hues.
In utero fractures are common.
Limb shortening and progressive deformities can occur.
Patients may have a triangular face with frontal bossing.
Basilar invagination is an uncommon but potentially fatal
occurrence in OI.
Vertigo is common in patients with severe OI.
The incidence of congenital malformations of the heart in
children with OI is probably similar to that of the healthy
population.
Hypercalciuria may be present in about 36% of patients with
OI, but it does not appear to affect renal function.
Respiratory complications secondary to kyphoscoliosis are
common in individuals with severe OI.
Constipation and hernias are also common in people with OI.
Type IV - Undefined
This type of OI is not clearly defined.
Whether patient have normal height or whether scleral hue
defines the type has not been established in consensus.
Dentinogenesis imperfecta may be present. Some have
suggested that this sign can be used to divide type IV OI into
subtypes a and b.
Fractures usually begin in infancy, but in utero fractures may
occur. The long bones are usually bowed.
Type V-
48. 43
Is a mild to moderately severe autosomal dominant
osteogenesis imperfecta (OI), which does not appear to be
associated with collagen type I mutations.
There are normal coloured sclerae and ligament laxity. There
is no dentinogenesis imperfecta.
Typically patients have ossification of interosseous membrane
of the forearm with radial head dislocation, hyperplastic callus
formation and an abnormal histopathological pattern
Type VI.
This is a moderate to severe form of brittle bone disease with
accumulation of osteoid due to a mineralisation defect, in the
absence of a disturbance of mineral metabolism.
Patients with OI type VI sustain more frequent fractures than
patients with OI type IV. Fractures are first documented
between 4 and 18 months of age.
Sclerae are white or faintly blue and dentinogenesis
imperfecta is uniformly absent. All patients have vertebral
compression fractures. The underlying genetic defect is not
yet known
Type VII.
This is a moderate to severe autosomal recessive form,
characterised by fractures at birth, bluish sclerae, early
deformity of the lower extremities, coxa vara, and osteopaenia
Rhizomelia (proximal limb shortening) is a prominent
clinical feature.
The disease has been localised to chromosome 3p22-24.1,
which is outside the loci for type I collagen genes.
Diagnosis:
49. 44
Diagnosis is made based on clinical and physical findings, accompanied by
relevant tests.
These include;
Taking a skin sample to assess the collagen production in the body.
X-rays may show thining of bones and past or current fractures.
An ultrasound may be used during pregnancy to detect limb
abnormalities at 15-18 weeks gestation. However these may not be
always accurate.
Management
Type III requires lifelong and specialised care.
Patients are of normal intelligence and prolonged admission to
hospital should not affect their education.
Multidisciplinary care including physiotherapy, rehabilitation,
bracing and splinting is good practice.
50. 45
Intramedullary rodding and osteoclasis needs to be used very
selectively.
A specialised course of rehabilitation may be needed.
Recent advances have shown the use of growth hormone and
bisphosphonate to be beneficial
Bisphosphonate therapy is used under specialist centre guidance and
is particularly useful for pain and recurrent fractures in type 3.
(Bisphosphoantes bind to, and stabilise bone by inhibiting osteoclast
activity, whilst stimulating osteoblast activity.)
Cyclical intravenous pamidronate administration can reduce bone
pain and fracture incidence, and increase bone density and level of
mobility, with minimal side effect
Effects on bone include increase in size of vertebral bodies and
thickening of cortical bone. This also allows for better corrective
surgery, e.g. intramedullary rodding of the long bones.
However, substantial variability in individuals response to treatment
has been noted.
Research continues into use of transplanted normal stromal cells
from bone marrow.
Prevention
In families with known collagen mutations, fetal DNA analysis from
chorionic villus biopsy, in the first trimester, may be possible.
It can be difficult to give genetic advice:
In type I and type IV, there is a 50% probability of affected child,
where one parent is affected.
However, where neither parent is affected with the lethal and
progressively deforming type II and III, it may be impossible to give
51. 46
chance of further offspring being affected, because of germline and
somatic-cell mosaicism.
However, general guidelines are, in child with type I or IV with
clinically unaffected parents, likely to be new dominant mutation
and risk of further affected offspring is probably no greater than
normal (50% of any offspring of child will be affected). Following
diagnosis of type II infant, general advice is that there is a 7%
chance of further offspring being affected.
The design of potential gene therapy is complicated by the genetic
heterogeneity of the disease and by the fact that most of the
osteogenesis imperfecta mutations are dominant negative, where the
mutant allele product interferes with the function of the normal
allele
DENTINOGENESIS IMPERFECTA (HEREDIATARY
OPALESCENT DENTIN)29,39
Dentinogenesis imperfecta represents a group of hereditary
conditions that are characterized by abnormal dentin formation. These
conditions are genetically and clinically heterogenous and can affect only
the teeth or can be associated with the condition osteogenesis imperfecta.
Frequency:
1 in 6000-8000 children
Background:
52. 47
Among the earliest reported cases were those of Wilson and
Steinbrecher, who traced this condition through four generations of one
family. Excellent studies of the chemical, physical, histologic
roentgenographic, and clinical aspects of Dentinogenesis imperfect were
made by Finn in 1938 and br Hodge and his coworkers in 1939 and 1940.
Heys and her co-workers have described the clinical and genetic factors in
18 families affected with dentinogenesis imperfecta occurring in
association with osteogenesis imperfect.
Classification:
Shields classification;
Type I: Dentinogenesis imperfecta that always occurs in families
with osteogenesis imperfecta, although latter may occur with out
dentinogenesis imperfect. Type I segregates as an autosomal dominant
traitwith variable expressivity.but can be recessiveif the accompanying
osteogenesis imperfceta is recessive(usually the severe OI congenital type)
Type II: Dentinogenesis imperfecta that never occurs with osteogenesis
imperfceta unless by chance.This is mostly reffered as Herediatary
opalescent dentin.It is inherited as autosomal dominant trait.
isolate in Maryland.It is inherited as autosomal dominant trait.
Revised classification:
Dentinogenesis imperfect I: Dentinogenesis imperfect without
osteogenesis imperfecta(opalescent dentin).
Dentinogenesis imperfect II:Brandywine type dentinogenesis
imperfect
53. 48
Etiology:
Mutations in the DSPP gene cause dentinogenesis imperfecta.
Mutations in the DSPP gene have been identified in people with
type II and type III dentinogenesis imperfecta. DI type II and type III are
autosomal dominant conditions that have been linked to chromosome
4q12-21, suggesting these may be allelic mutations of the DSPP gene. In
several different families the gene responsible for DI type II has been
identified as the DSPP gene that codes for the dentin sialophosphoprotein,
the most abundant noncollagenous protein in dentin Dentinogenesis
imperfecta type I occurs as part of osteogenesis imperfecta, which is
caused by mutations in one of several other genes.
The DSPP gene provides instructions for making three proteins that
are essential for normal tooth development. These proteins are involved in
the formation of dentin, which is a bone-like substance that makes up the
protective middle layer of each tooth. DSPP mutations alter the proteins
made from the gene, leading to the production of abnormally soft dentin.
Teeth with defective dentin are discolored, weak, and more likely to decay
and break
Inheritance:
This condition is inherited in an autosomal dominant pattern, which
means one copy of the altered gene in each cell is sufficient to cause the
disorder.In most cases, an affected person has one parent with the
condition.
Clinical presentation:
In all three DI types the teeth have a variable blue-gray to yellow
brown discoloration that appears opalescent due to the defective,
54. 49
abnormally colored dentin shining through the translucent enamel. Due to
the lack of support of the poorly mineralized underlying dentin, the enamel
frequently fractures from the teeth leading to rapid wear and attrition of the
teeth. The severity of discoloration and enamel fracturing in all DI types is
highly variable even within the same family. If left untreated it is not
uncommon to see the entire DI affected dentition worn off to the gingiva.
Radiographic features:
Teeth have bulbous crowns, roots that are narrower than normal, and pulp
chambers and root canals that are smaller than normal or completely
obliterated.The pulp chambers are large in DI type III.
Histologic features:
The appearance of enamel is essentially normal except for its peculiar
shade. The dentin, on the other hand, is composed of irrgular tubules,often
with large areas of uncalcified matrix . The tubules tend to be larger in
diameter and thus less numerous than normal in a given volume of dentin
.In some areas there may be complete absence of tubules Cellular
inclusions, probably odontoblasts in the dentin are not uncommon,, the
pulp chamber is usually almost obliterated by the continued deposition of
55. 50
dentin. . The odontoblasts have only limited ability to form well-organized
dentinal matrix, andthey appear to degenerate readily, becoming
entrapped in this matrix.
Chemical and Physical Features.
Chemical analysis explains many of the abnormal features of the
teeth of dentinogenesis imperfecta 1. Their water content is greatly
increased, as much as 60 per cent above normal, while the inorganic con-
tent is less than that of normal dentin. As might be expected, the density, x-
ray absorption, and hardness of the dentin are also low. In fact, the micro-
hardness of the dentin closely approximates that of cementum, thus
explaining the rapid attrition of affected teeth. There is no significant
information available on teeth in type III.
Treatment.
The treatment of patients with dentinogenesis imperfecta is directed
primarily toward preventing the loss of enamel and subsequent loss of
dentin through attrition. Cast metal crowns on the posterior teeth and
jacket crowns on the anterior teeth have been used with considerable
success, although care must be taken in the preparation of the teeth for
such restorations. Caution must also be exercised in the use of partial
appliances which exert stress on the teeth, because the roots are easily
fractured. Experience has further shown that fillings are not usually
permanent because of the softness of the dentin.
OSTEOPOROSIS 29.39,47,48
Osteoporosis is a disease characterized by low bone mass and
deterioration of bone structure that causes bone fragility and increases the
56. 51
risk of fracture. There are a variety ofdifferent types of osteoporosis. The
that is, osteoporosis that is not caused by some other specific disorder.
Bone loss caused by specific diseases or medications is referred to as
secondary osteoporosis
Primary Osteoporosis
Primary osteoporosis is mainly a disease of the elderly, the result of
the cumulative impact of bone loss and deterioration of bone structure that
occurs as people age. Thisform of osteoporosis is sometimes referred to as
age-related osteoporosis. Since postmenopausal women are at greater risk,
(including children and young adults) rarely get primary osteoporosis,
although it can occur on occasion. This rare form of the disease is
exact causes of the disease are not known, or idiopathic. Since the exact
mechanisms by which aging produces bone loss are not all understood
(that is, it is not always clear why some postmenopausal women develop
osteoporosis while others do not), age-related osteoporosis is also partially
idiopathic
Idiopathic Primary Osteoporosis
There are several different forms of idiopathic osteoporosis that can
affect both children and adolescents, although these conditions are quite
rare .Juvenile osteoporosis affects previously healthy children between the
ages of 8 and 14. Over a period of several years, bone growth is impaired.
The condition may be relatively mild, causing only one or two collapsed
bones in the spine (vertebrae), or it may be severe, affecting virtually the
entire spine. The disease almost always goes into remission
57. 52
(spontaneously) around the time of puberty with a resumption of normal
bone growth at that time. Patients with mild or moderate forms of the
disease may be left with a curvature of the spine (kyphosis) andshort
stature, but those with a more severe form of the disease may be
incapacitated for life Primary osteoporosis is quite rare in young adults. In
this age-group, the disease is usually caused by some other condition or
factor, such as anorexia nervosa or glucocorticoid use (Khosla et al. 1994).
When idiopathic forms of primary osteoporosis do occur in young adults,
they appear in men as often as they do in women (this is in contrast to age-
related primary osteoporosis, which occurs more often in women). The
characteristics of the disease can vary broadly and may involve more than
one disorder. Some young adults with idiopathic primary osteoporosis may
have a primary defect in the regulation of bone cell function, resulting in
depressed bone formation, increased bone resorption, or both Others with
a mild form of the disease may simply have failed to achieve an adequate
amount of skeletal mass during growth. In some patients, the disease runs a
mild course, even without treatment, and the clinical manifestations are
limited to asymptomatic spinal compression fractures. More typically,
however, multiple spine fractures occur over a 5 10 year period leading to
a height loss of up to 6 inches.
Age-Related Osteoporosis
Age-related osteoporosis is by far the most common form of the
disease There are many different causes of the ailment, but the bone loss
that leads to the disease typically begins relatively early in life, at a time
when corrective action (such as changes in diet and physical activity) could
potentially slow down its course. While it occurs in both sexes, the disease
is two to three times more common in women This is partly due to the fact
58. 53
that women have two phases of age-related bone loss a rapid phase that
begins at menopause and far the most common form of the disease There
are many different causes of the ailment, but the bone loss that leads to the
disease typically begins relatively early in life, at a time when corrective
action (such as changes in diet and physical activity) could potentially slow
down its course. While it occurs in both sexes, the disease is two to three
times more common in women. This is partly due to the fact that women
have two phases of age-related bone loss a rapid phase that begins at
menopause and lasts 4 8 years, followed by a slower continuous phase that
lasts throughout the rest of life . By contrast, men go through only the
slow, continuous phase. As a result, women typically lose more bone than
do men. The rapid phase of bone loss alone in women results in losses of
5 10 percent of cortical bone (which makes up the hard outer shell of the
skeleton) and 20 30 percent of trabecular bone (which fills the ends of the
limb bones and the vertebral bodies in the spine, the sites of most
osteoporotic fractures). The slow phase of bone loss results in losses of 20
25 percent of cortical and trabecular bone in both men and women, but
over a longer period of time. Although other factors such as genetics and
nutrition contribute, both the rapid phase of bone loss in postmenopausal
women and the slow phase of bone loss in aging women and men appear to
be largely the result of estrogen deficiency. For women, the rapid phase of
bone loss is initiated by a dramatic decline in estrogen production by the
ovaries at menopause. The loss of estrogen action on estrogen receptors in
bone results in large increases in bone resorption combined with reduced
bone formation. The end result is thinning of the cortical outer shell of
bone and damage to the trabecular bone structure. There may be some
countervailing forces on this process, as the outside diameter of the bone
can increase with age, thus helping to maintain bone strength. By contrast,
59. 54
the slower phase of bone loss is thought to be caused by a combination of
factors including age-related impairment of bone formation, decreased
calcium and vitamin D intake, decreased physical activity, and the loss of
e
kidney as well as its effects on bone . This leads to further impairment of
absorption of calcium by the intestine and reduced ability of the kidney to
conserve calcium. If the amount of calcium absorbed from the diet is
insufficient to make up for the obligatory calcium losses in the stool and
urine, serum calcium begins to fall. Parathyroid hormone levels will then
increase, removing calcium from bone to make up for the loss. The net
result of this process is an increase in bone resorption. It is important to
realize that these mineral losses need not be great to result in osteoporosis.
A negative balance of only 50 100 mg of calcium per day over a long
period of time is sufficient to produce the disease. For aging men, sex
steroid deficiency also appears to be a major factor in age-related
osteoporosis. Although testosterone is the major sex steroid in men, some
of it is converted by the aromatase enzyme into estrogen. In men, however,
the deficiency is mainly due to an increase in sex hormone binding
globulin, a substance that holds both testosterone and estrogen in a form
that is not available for use by the body. Between 30 50 percent of elderly
men are deficient in biologically active sex steroids . In fact, except for the
lack of the early postmenopausal phase, the process of bone loss in older
men is similar to that for older women. As with women, the loss of sex
steroid activity in men has an effect on calcium absorption and
conservation, leading to progressive secondary increases in parathyroid
hormone levels. As in older women, the resulting imbalance between bone
resorption and formation results in slow bone loss that continues over life.
Sinc testosterone may stimulate bone formation more than estrogen does,
60. 55
however, decreased bone formation plays a relatively greater role in the
bone loss experienced by elderly men.
Secondary Osteoporosis
Young adults and even older individuals who get osteoporosis often
do so as a byproduct of another condition or medication use. In fact, there
are a wide variety of diseases along with certain medications and toxic
agents that can cause or contribute to the development of osteoporosis.
causes are said to
bone loss than would be expected for a normal individual of the same age,
gender, and race. Secondary causes of the disease are common in many
premenopausal women and men with osteoporosis in fact, by some
estimates the majority of men with osteoporosis exhibit secondary causes
of the disease. In addition up to a third of postmenopausal women with
61. 56
osteoporosis also have other conditions that may contribute to their bone
loss. This section briefly describes some of the more common diseases,
disorders, and medications that can cause or contribute to the development
of osteoporosis
Diseases and Disorders That Can Cause Osteoporosis
Several genetic diseases have been linked to secondary osteoporosis.
Idiopathic hypercalciuria and cystic fibrosis are the most common. Patients
with cystic fibrosis have markedly decreased bone density and increased
fracture rates due to a variety of factors, including calcium and vitamin D
malabsorption, reduced sex steroid production and delayed puberty, and
increased inflammatory cytokines .Some patients with idiopathic
hypercalciuria have a renal defect in the ability of the kidney to conserve
calcium. This condition may be aggravated if they are advised to lower
their dietary calcium intake to prevent kidney stones. Several studies have
documented low bone density in these individuals, and they may respond
to drugs that decrease calcium excretion in the urine. Other genetic
disorders although rare, should be considered in patients with osteoporosis
after more common causes have been excluded. Estrogen or testosterone
syndrome, anorexia nervosa, athletic amenorrhea, cancer, or any chronic
illness that interferes with the onset of puberty) leads to low peak bone
mass . Estrogen deficiency that develops after peak bone mass is achieved
but before normal menopause (due to premature ovarian failure for
example) is associated with rapid bone loss. Low sex steroid levels may
also be responsible for reduced bone density in patients with androgen
insensitivity or acromegaly. By contrast, excess thyroid hormone
(thyrotoxicosis), whether spontaneous or caused by overtreatment with
62. 57
thyroid hormone, may be associated with substantial bone loss; while bone
turnover is increased in these patients, bone resorption is increased more
than bone formation. Likewise, excess production of glucocorticoids
drome)
can lead to rapidly progressive and severe osteoporosis, as can treatment
with glucocorticoids The relationship between diabetes and osteoporosis is
more controversial .
In general, patients with type 1 (insulin-dependent) diabetes,
particularly those with poor control of their blood sugar are at greater risk
of osteoporosis than are those with type 2 (non-insulin dependent)
diabetes. Primary hyperparathyroidism is a relatively common condition in
older individuals, especially postmenopausal women, that is caused by
excessive secretion of parathyroid hormone. Most often, the cause is a
benign tumor (adenoma) in one or more parathyroid glands; very rarely
(less than 0.5 percent of the time) the cause is parathyroid cancer .
Diseases that reduce intestinal absorption of calcium and
phosphorus, or impair the availability of vitamin D, can also cause bone
disease. Moderate malabsorption results in osteoporosis, but severe
malabsorption may cause osteomalacia .Celiac disease, due to
inflammation of the small intestine by ingestion of gluten, is an important
and commonly overlooked cause of secondary osteoporosis. Likewise,
osteoporosis and fractures have been found in patients following surgery to
remove part of the stomach (gastrectomy), especially in women. Bone loss
is seen after gastric bypass surgery even in morbidly obese women who do
not have low bone mass initially. Increased osteoporosis and fractures are
Glucocorticoids, commonly used to treat both disorders, probably
contribute to the bone loss.Similarly, diseases that impair liver function
63. 58
(primary biliary cirrhosis, chronic active hepatitis, cirrhosis due to hepatitis
B and C, and alcoholic cirrhosis) may result in disturbances in vitamin D
metabolism and may also cause bone loss by other mechanisms. Primary
biliary cirrhosis is associated with particularly severe osteoporosis.
Fractures are more frequent in patients with alcoholic cirrhosis than any
other types of liver disease, although this may be related to the increased
risk of falling among heavy drinkers Human immunodeficiency virus
(HIV) infected patients also have a higher prevalence of osteopenia or
osteoporosis. This may involve multiple endocrine, nutritional, and
metabolic factors and may also be affected by the antiviral therapy that
HIV patients receive. Autoimmune and allergic disorders are associated
with bone loss and increased fracture risk. This is due not only to the effect
of immobilization and the damage to bone by the products of inflammation
from the disorders themselves, but also from the glucocorticoids that are
used to treat these conditions. Rheumatic diseases like lupus and
rheumatoid arthritis have both been associated with lower bone mass and
an increased risk of fractures. Many neurologic disorders are associated
with impaired bone health and an increased risk of fracture. This may be
due in part to the effects of these disorders on mobility and balance or to
the effects of drugs used in treating these disorders on bone and mineral
metabolism. Unfortunately, however, health care providers often fail to
assess the bone health of patients who have these disorders or to provide
appropriate preventive and therapeutic measures. There are many disabling
conditions that can lead to bone loss, and thus it is important to pay
attention to bone health in patients with ndevelopmental disabilities, such
as cerebral palsy, as well as diseases affecting nerve and muscle, such as
poliomyelitis and multiple sclerosis. Children and adolescents with these
disorders are unlikely to achieve optimal peak bone mass, due both to an
64. 59
increase in bone resorption and a decrease in bone formation. In some
cases very rapid bone loss can produce a large enough increase in blood
calcium levels to produce symptoms . Fractures are common in these
individuals not only because of bone loss, but also because of muscular
weakness and neurologic impairment that increases the likelihood of falls.
Bone loss can be slowed but not completelyprevented by antiresorptive
therapy. Epilepsy is another neurologic disorder that increases the risk of
bone disease, primarily because of the adverse effects of anti-epileptic
drugs. Many of the drugs used in epilepsy can impair vitamin D
metabolism, probably by acting on the liver enzyme which converts
vitamin D to 25 hydroxy vitamin D. In addition, there may be a direct
effect of these agentson bone cells. Due to the negative bone-health effects
of drugs, most epilepsy patients are at riskof developing osteoporosis. In
those who have low vitamin D intakes, intestinal malabsorption, or low
sun exposure, the additional effect of antiepileptic drugs can lead to
osteomalacia. Supplemental vitamin D may be effective in slowing bone
loss, although patients who develop osteoporosis may require additional
therapy such as bisphosphonates. Psychiatric disorders can also have a
negative impact on bone health. While anorexia nervosa is the psychiatric
disorder that is most regularly associated with osteoporosis, major
depression, a much more common disorder, is also associated with low
bone mass and an increased risk of fracture. One factor that may cause
bone loss in severely depressed individuals is increased production of
cortisol, the adrenal stress hormone. While the response of individuals with
major depression to calcium, vitamin D, or antiresorptive therapy has not
been specifically documented, it would seem reasonable toprovide these
preventive measures to patients at high risk. Finally, several diseases that
are associated with osteoporosis are not easily categorized. Aseptic
65. 60
necrosis (also called osteonecrosis or avascular necrosis) is a well-known
skeletal disorder that may be a complication of injury, treatment with
glucocorticoids, or alcohol abuse .This condition commonly affects the
ends of the femur and the humerus. The precise cause is unknown, but at
least two theories have been suggested. One is that blood supply to the
bone is blocked by collapsing bone. The other is that microscopic fat
particles block blood flow and result in bone cell death. Chronic
obstructive pulmonary disease (emphysema and chronic bronchitis) is also
now recognized as being associated with osteoporosis and fractures even in
the absence of glucocorticoid therapy. Immobilization is clearly associated
with rapid bone loss; patients with spinal cord lesions are at particularly
high risk for fragility fractures. However, even modest reductions in
physical activity can lead to bone loss .Hematological disorders,
particularly malignancies, are commonly associated with osteoporosis and
fractures as well.
Medications and Therapies That Can Cause Osteoporosis
Osteoporosis can also be a side effect of particular medical therapies.
Glucocorticoid-Induced Osteoporosis (GIO).
GIO is by far the most common form of osteoporosis produced by drug
treatment. While it has been known for many years that excessive
production of the adrenal hormone cortisol can cause thinning of the bone
uncommon. With the increased use of prednisone and other drugs that act
like cortisol for the treatment of many inflammatory and autoimmune
diseases, this form of bone loss has become a major clinical concern. The
concern is greatest for those diseases in which the inflammation itself and/
or the immobilization caused by the illness also caused increased bone loss
66. 61
and fracture risk. Glucocorticoids, which are used to treat a wide variety of
inflammatory conditions (e.g.,rheumatoid arthritis, asthma, emphysema,
chronic lung disease), can cause profound reductions in bone formation
and may, to a lesser extent, increase bone resorption leading to loss of
trabecular bone at the spine and hip, especially in postmenopausal women
and older men. The most rapid bone loss occurs early in the course of
treatment, and even small doses (equivalent to 2.5 7.5 mg prednisone per
day) are associated with an increase in fractures. The risk of fractures
increases rapidly in patients treated with glucocortocoids, even before
much bone has been lost. This rapid increase in fracture risk is attributed to
damage to the bone cells, which results in less healthy bone tissue. To
avoid this problem, health care providers are urged to use the lowest
possible dose of glucocorticoids for as short a time as possible. For some
diseases, providers should also consider giving glucocorticoids locally
(e.g., asthma patients can inhale them), which results in much less damage
to the bone.
Other Medications That Can Cause Osteoporosis.
Cyclosporine A and tacrolimus are widely used in conjunction with
glucocorticoids to prevent rejection after organ transplantation, and high
doses of these drugs are associated with a particularly severe form of
osteoporosis. Bone disease has also been reported with several frequently
prescribed anticonvulsants, including diphenylhydantoin, phenobarbital,
sodium valproate, and carbamazepine. Patients who are most at risk of
developing this type of bone disease include those on long-term therapy,
high medication doses, multiple anticonvulsants, and/or simultaneous
therapy with medications that raise liver enzyme levels. Low vitamin D
intake, restricted sun exposure, and the presence of other chronic illnesses
67. 62
increase the risk, particularly among elderly and institutionalized
individuals. In contrast, high intakes of vitamin A (retinal) may increase
fracture risk. Methotrexate, a folate antagonist used to treat malignancies
and (in lower doses) inflammatory diseases such as rheumatoid arthritis,
may also cause bone loss, although research findings are not consistent. In
addition, gonadotropin-releasing hormone (GnRH) agonists, which are
used to treat endometriosis in women and prostate cancer in men, reduce
both estrogen and testosterone levels, which may cause significant, bone
loss and fragility fractures.
Diagnosis
Diagnosis of osteoporosis is made by three methods:
Radiographic measurement of bone density
Laboratory biochemical markers
Bone biopsy with pathologic assessment
Of these three the best is radiographic bone density measurement. A
variety of techniques are available, including single-photon
absorptiometry, dual-photon absorptiometry, quantitative computed
tomography, dual x-ray absorptiometry, and ultrasonography. Most often,
site specific measurements are performed. The most common sites
analyzed are those with greatest risk for fracture: hip, wrist, and vertebrae.
The forearm and heel that are easily measured using single-photon
absorptiometry, quantitative computed tomography, and ultrasonography
can be inexpensive, but these sites are typically unresponsive to therapy
and give less information about response to therapy. Increased risk for
fracture correlates with decreasing bone density. Serial measurements over
time can also give an indication of the rate of bone loss and prognosis.
68. 63
The two main biochemical markers for bone formation are serum
alkaline phosphatase and serum osteocalcin. Markers for bone resorption
include urinary calcium and urinary hydroxyproline:
Alkaline phosphatase, which reflects osteoclast activity in bone, is
measured in serum, but it lacks sensitivity and specificity for
osteoporosis, because it can be elevated or decreased with many
diseases. It is increased with aging. Fractionating alkaline
phosphatase for the fraction more specific to bone doesn't increase
usefulness that much.
Osteocalcin, also known as bone gamma-carboxyglutamate. It is
synthesized by osteoblasts and incorporated into the extracellular
matrix of bone, but a small amount is released into the circulation,
where it can be measured in serum. The levels of circulating
osteocalcin correlate with bone mineralization, but are influenced by
age, sex, and seasonal variation. Laboratory methods also vary.
Urinary calcium can give some estimate of resorbtion (loss of) bone,
but there are many variables that affect this measurement. Thus, it is more
specific for osteoporosis when measured following overnight fasting.
Urinary hydroxyproline is derived from degradation of collagen, which
forms extracellular bone matrix. However, hydroxyproline measurement is
not specific for bone, because half of the body's collagen is outside the
bony skeleton. It is also influenced by many diseases, as well as diet.
Bone biopsy is not often utilized for assessment of bone density. This
test has limited availability, and is best utilized as a research technique for
analysis of treatment regimens for bone diseases. The best clinical use of
bone biopsy combines double tetracycline labelling to determine
69. 64
appositional bone growth and rule out osteomalacia. Doses of tetracycline
are given weeks apart, and the bone biopsy is embedded in a plastic
compound, sliced thinly, and examined under fluorescent light, where the
lines of tetracycline (which autofluoresce) will appear and appositional
growth assessed.
Consequences of Osteoporosis
Osteoporotic bone is histologically normal in its composition--there is
just less bone. This results in weakened bones that are more prone to
fractures with trauma, even minor trauma. The areas most affected are:
Hip (femoral head and neck)
Wrist
Vertebrae
Hip fractures that occur, even with minor falls, can be disabling and
confine an elderly person to a wheelchair. It is also possible to surgically
put in a prosthetic hip joint. Wrist fractures are common with falls forward
with arms extended to break the fall, but the wrist bones break too.
Vertebral fractures are of the compressed variety and may be more subtle.
Vertebral fractures may result in back pain. Another consequence is
shortening or kyphosis (bending over) of the spine. This can lead to the
appearance of a "hunched over" appearance that, if severe enough, can
even compromise respiratory function because the thorax is reduced in
size. Persons suffering fractures are at greater risk for death, not directly
from the fracture, but from the complications that come from
hospitalization with immobilization, such as pulmonary thromboembolism
and pneumonia. Men start out with a greater bone mass to begin with, so
they have a greater reserve against loss. The best long-term approach to
70. 65
osteoporosis is prevention. If children and young adults, particularly
women, have a good diet (with enough calcium and vitamin D) and get
plenty of exercise, then they will build up and maintain bone mass. This
will provide a good reserve against bone loss later in life. Exercise places
stress on bones that builds up bone mass, particularly skeletal loading from
muscle contraction with weight training exercises. However, any exercise
of any type is better than none at all, and exercise also provides benefits for
prevention of cardiovascular diseases that are more common in the elderly.
Athletes tend to have greater bone mass than non-athletes. Exercise in later
life will help to retard the rate of bone loss.
Treatment
Persons with osteoporosis may benefit from an improved diet,
including supplementation with vitamin D and calcium, and moderate
exercise to help slow further bone loss.
Most drug therapies work by decreasing bone resorbtion. At any
given time, there is bone that has been resorbed but not replaced, and this
accounts for about 5 to 10% of bone mass. By decreasing resorbtion of
bone, a gain in bone density of 5 to 10% is possible, taking about 2 to 3
years. However, no drug therapy will restore bone mass to normal. Women
past menopause with accelerated bone loss may benefit from hormonal
therapy using estrogen with progesterone. The estrogen retards bone
resorption and thus diminishes bone loss. This effect is most prominent in
the first years after menopause.
One of the more common non-estrogen therapies is the use of
alendronate, a biphosphonate that acts an an inhibitor of osteoclastic
activity. Alendronate may be beneficial, particularly in women who cannot
71. 66
tolerate estrogen therapy. Alendronate is effective in inhibiting bone loss
after menopause.
Raloxifene is a selective estrogen receptor modulator that may also
replace estrogen therapy. Raloxifene can act in concert with estrogen in
bone to inhibit resorbtion and decrease the risk for fractures. Though
raloxifene inhibits bone resorbtion, it does not have an anabolic effect.
Additional potential benefits from raloxifene therapy include decreased
risk for breast cancer, because raloxifene acts antagonistically to estrogen
on the uterus. Conversely, raloxifene acts in concert with estrogen to
protect against and reduce atherogenesis.
Other drug therapies are less commonly employed. Calcitonin, a
hormone that decreases bone resorbtion, may be taken by injection or by
nasal spray. Sodium fluoride can increase the measured bone density in
vertebra, but seems to have no overall effectiveness in reducing vertebral
fracture. Fluoride helps reduce tooth decay.
OSTEOPETROSIS (MARBLE BONE DISEASE,
OSTEOSCLEROSIS) 29,39,49,50
A Osteopetrosis is a clinical syndrome characterized by the failure
of osteoclasts to resorb bone. As a consequence, bone modeling and
remodeling are impaired. The defect in bone turnover characteristically
results in skeletal fragility despite increased bone mass, and it may also
cause hematopoietic insufficiency, disturbed tooth eruption, nerve
entrapment syndromes, and growth impairment. Human osteopetrosis is a
heterogeneous disorder encompassing different molecular lesions and a
range of clinical features. However, all forms share a single pathogenic
72. 67
nexus in the osteoclast. German radiologist, Albers-Schönberg, first
described osteopetrosis in 1904.
Frequency:
The condition is quite rare; incidences have been reported at 1 in
20,000-500,000 for the dominant form and 1 in 200,000 for the
recessive form.
Three variants of the disease are diagnosed in infancy, childhood
(intermediate), or adulthood.
Etiology:
The primary underlying defect in all types of osteopetrosis is failure of
the osteoclasts to reabsorb bone. A number of heterogeneous molecular or
genetic defects can result in impaired osteoclastic function. The exact
molecular defects or sites of these mutations largely are unknown. The
defect might lie in the osteoclast lineage itself or in the mesenchymal cells
that form and maintain the microenvironment required for proper
osteoclast function. The following is a review of some of the evidence
suggesting disease etiology and heterogeneity of these causes:
The specific genetic defect in humans is known only in osteopetrosis
caused by carbonic anhydrase II deficiency.
Infantile osteopetrosis seems to be transmitted as an autosomal
recessive manner based on its inheritance pattern.
Viruslike inclusions have been reported in osteoclasts of some
patients with benign osteopetrosis, but the clinical significance
remains uncertain.
73. 68
Absence of biologically active colony-stimulating factor (CSF-1)
due to a mutation in its coding gene causes impairment of
osteoclastic function in the osteopetrotic (Op/Op) mouse. Altered
CSF-1 production also has been shown in toothless (tl) osteopetrotic
rats. Knockout mice of some proto-oncogenes have been shown to
have osteopetrosis.
Clinical Classification of Human Osteopetrosis
Characteristic Adult onset Infantile Intermediate
Inheritance Autosomal
dominant
Autosomal
recessive
Autosomal
recessive
Bone marrow
failure
None Severe None
Prognosis Good Poor Poor
Diagnosis Often dignosed
incidentally
Usually diagnosed
before age 1 y
Not applicable
74. 69
CLINICAL
Infantile osteopetrosis (also called malignant osteopetrosis) is
diagnosed early in life. Its clinical manifestations are described
below.
Failure to thrive and growth retardation are symptoms.
Bony defects occur. Nasal stuffiness due to mastoid and
paranasal sinus malformation is often the presenting feature of
infantile osteopetrosis. Neuropathies related to cranial nerve
entrapment occur due to failure of the foramina in the skull to
widen completely. Manifestations include deafness, proptosis,
and hydrocephalus. Dentition might be delayed. Osteomyelitis
of the mandible is common due to an abnormal blood supply.
Bones are fragile and can fracture easily.
Defective osseous tissue tends to replace bone marrow, which
can cause bone marrow failure with resultant pancytopenia.
Patients might have anemia, easy bruising and bleeding (due
to thrombocytopenia), and recurrent infections (due to
inherent defects in the immune system). Extramedullary
hematopoiesis might occur with resultant
hepatosplenomegaly, hypersplenism, and hemolysis.
Other manifestations include sleep apnea and blindness due to
retinal degeneration.
Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in
late adolescence or adulthood.
Two distinct types have been described, type I and type II, on
the basis of radiographic, biochemical, and clinical features.
75. 70
Types of Adult Osteopetrosis
Characteristic Type I Type II
Skull sclerosis
Marked sclerosis
mainly of the vault
Sclerosis mainly of
the base
Spine
Does not show much
sclerosis
Shows the rugger-
jersey appearance
Pelvis No endobones
Shows endobones in
the pelvis
Transverse banding of
metaphysic
Absent
May or may not be
present
Risk of fracture Low High
Serum acid phosphatase Normal Very high
Recent work has demonstrated that the clinical syndrome of adult
type I osteopetrosis is not true osteopetrosis, but rather, increased
bone mass due to activating mutations of LRP5. These mutations
cause increased bone mass but no associated defect of osteoclast
function. Instead, some have hypothesized that the set point of bone
responsiveness to mechanical loading is altered, resulting in an
altered balance between bone resorption and deposition in response
to weight bearing and muscle contraction.
Some cases of type II osteopetrosis result from mutations of CLCN7,
the type 7 chloride channel. However, in other families with the
76. 71
clinical syndrome of type II adult osteopetrosis, linkage to other
distinct genomic regions have been demonstrated. Therefore, the
clinical syndrome is genetically heterogeneous.
Approximately one half of patients are asymptomatic, and the
diagnosis is made incidentally, often in late adolescence because
radiologic abnormalities start appearing only in childhood. In other
patients, the diagnosis is based on family history. Still other patients
might present with osteomyelitis or fractures.
Many patients have bone pains. Bony defects are common and
include neuropathies due to cranial nerve entrapment (eg, with
deafness, with facial palsy), carpal tunnel syndrome, and
osteoarthritis. Bones are fragile and might fracture easily.
Approximately 40% of patients have recurrent fractures.
Osteomyelitis of the mandible occurs in 10% of patients.
Bone marrow function is not compromised.
Other manifestations include visual impairment due to retinal
degeneration and psychomotor retardation.
Physical findings are related to bony defects and include short
stature, frontal bossing, a large head, nystagmus,
hepatosplenomegaly, and genu valgum in infantile osteopetrosis.
Investigations
Diagnosis is made by x-rays which are usually diagnostic. CT scans
may occasionally be required and the use of MRI tends to be limited to
imaging of the marrow in the severe recessive disease, which is usually
fatal without marrow transplantation.
77. 72
Generalized osteosclerosis; bones may be uniformly sclerotic, but
alternating sclerotic and lucent bands may be noted in iliac wings
and near ends of long bones.
Bones may be club-like or appear like a bone within bone.
The entire skull is thickened and dense, especially at the base.
Sinuses are small.
Vertebrae are very radiodense and may show alternating bands
(rugger-jersey sign).
There may be evidence of fractures or osteomyelitis.
Severe osteopetrosis
Characteristic changes (Erlenmeyer-Flask deformity of the
metaphyses) on X-ray.
Plasma calcium reduced, acid phosphatase raised, calcitriol
raised.
Mild osteopetrosis
X-ray show generalised increase in bone density and clubbing
of metaphyses.
In vertebral bodies, alternating lucent and dense bands cause a
sandwich-like appearance.
Associated Diseases
Deficiency of carbonic anhydrase can cause petrosis associated with
renal tubular acidosis, cerebral calcification, growth failure and mental
retardation.
Management
Vitamin D appears to help by stimulating dormant osteoclasts and
therefore stimulate bone resorption. Large doses of calcitriol, along
78. 73
with restricted calcium intake, sometimes improve osteopetrosis
dramatically but it usually produces only modest clinical
improvement, which is not sustained after therapy is discontinued.
Gamma interferon has produced long-term benefits. It improves
white blood cell function and so decreases infections. Trabecular
bone volume substantially decreases, and bone-marrow volume
increases. This leads to an increase in haemoglobin, platelet counts
and survival rates. Combination therapy with calcitriol is superior to
calcitriol alone.
Erythropoietin can be used to correct anemia.
Corticosteroids have been used to stimulate bone resorption and
treat anemia but may be used for months or years and are not the
preferred treatment option.
Bone marrow transplant improves some cases of infantile
osteopetrosis. It can cure both bone marrow failure and metabolic
abnormalities in patients whose disease arises from an intrinsic
defect of the osteoclast lineage. Bone marrow transplant is the only
curative treatment but it may be limited to those patients whose
defects are extrinsic to the osteoclast lineage and whose condition is
unlikely to respond.
Surgery:
In infantile osteopetrosis, surgical treatment is sometimes
necessary because of fractures.
In adult osteopetrosis, surgical treatment may be needed for
aesthetic reasons (eg, in patients with notable facial
deformity), functional reasons (eg, in patients with multiple
fractures, deformity, and loss of function) or for severe related
degenerative joint disease.
79. 74
Adult osteopetrosis requires no treatment by itself, though complications
of the disease might require intervention. No specific medical treatment
exists for the adult type.
Complications
Bone marrow failure, with severe anaemia bleeding and infections.
Growth retardation and failure to thrive.
Hereditary Multiple Exotosis (Osteochondromatosis) 32,41
This is an hereditary developmental disorder of the skeleton in
which multiple cartilage-capped bony outgrowths
(exostoses/osteochondromas) protrude from the bone cortex in the
metaphyseal region of bones Preformed in cartilage, such as the long bones
of the extremities particularly in the region of the knee, ankle, or shoulder
The exostoses tend to have a bilateral and symmetrical distribution. The
scapulae, ribs, inominate bones, vertebrae, and metacarpal and metatarsal
bones may also be involved. Although not common, hereditary multiple
exostosis is the most frequently seen systemic disorder of skeletal
development. It is apparently inherited as an autosomal dominant, but there
is an unexplained 3:1 preponderance of affected males compared to
females. The precise origin of the cartilage-capped lesions is uncertain.
The usual explanation is that the exostoses arise from foci of
misplaced or misdirected epiphyseal cartilage which grows outwardly
rather than longitudinally, abetted by a lack of normal restraint from the
covering perichondrium. The exostoses grow by endochondral ossification
80. 75
of the cartilage cap, and growth of the exostoses ceases at or prior to the
skeletal maturation of the individual.
Pathology
Pathologically and radiographically, the exostoses are seen as sessile
or stalked bony protuberances, with various shapes (knobby,
hemispherical, conical) and sizes (1-10 cm. in diameter), protruding from
the metaphyseal region of the involved bones The exostoses of long bones
characteristically point away from the joint because the epiphyseal site of
origin of the exostoses lags behind the advancing epiphyseal growth plate
as the long bones increase in length. Grossly, the exostoses are covered
with periosteum and capped with a thin layer of cartilage In some (3-5%)
cases of hereditary multiple exostosis, the cartilage cap or remnants of it
undergoes malignant transformation to a sarcoma, most often a peripheral
chondrosarcoma. Malignant transformation is less often seen in solitary
exostosis which, although microscopically similar and much more
common than multiple exostosis, does not have an hereditary basis and is
not a systemic disorder of skeletal development.
81. 76
METABOLIC BONE DISEASES29 ,32,39,51,52
Mature bone consists of: an organic matrix (osteoid) composed
mainly of type 1 collagen formed by osteoblasts; a mineral phase which
contains the bulk of the body's reserve of calcium and phosphorus in
crystalline form (hydroxyapatite) and deposited in close relation to the
collagen fibers; bone cells; and a blood supply with sufficient levels of
calcium and phosphate to mineralize the osteoid matrix. Bone turnover and
remodeling occurs throughout life and involves the two coupled processes
of bone formation by osteoblasts and bone resorption by osteoclasts and
perhaps osteolytic osteocytes. The metabolic bone diseases may reflect
disturbances in the organic matrix, the mineral phase, the cellular
processes of remodeling, and the endocrine, nutritional, and other factors
which regulate skeletal and mineral homeostasis These disorders may be
hereditary or acquired and usually affect the entire bony skeleton The
acquired metabolic bone diseases are the more common and include:
osteoporosis, osteomalacia, the skeletal changes of hyperparathyroidism
and chronic renal failure (renal osteodystrophy), and osteitis deformans
(Paget's disease of bone). The diagnosis of metabolic bone diseases
requires a careful history and physical examination, specific radiographic
examination, and appropriate laboratory tests. Bone biopsy may be
indicated in some cases. The ilium is the standard biopsy site for the
evaluation of metabolic bone diseases. The preparation of undecalcified
bone sections permits a distinction to be made between osteoid and
mineralized bone and thus the histological identification of disorders of
bone mineralization.
82. 77
Rickets and Osteomalacia
The diseases resulting from vitamin D deficiency are rickets in
infants and growing children and osteomalacia in adult life.The bone
changes in both conditions are characterized by inadequate mineralization,
resulting in a deficient amount of the mineral phase of bone and an excess
of unmineralized osteoid. The osteoid excess is caused by a failure of the
process of mineralization to keep up with the new formation of osteoid
during bone formation and remodeling. In rickets, which mainly affects
children between the ages of 6-30 months, inadequate mineralization
occurs not only in bone but also in epiphysial cartilage at sites of
endochondral ossification, resulting in growth disturbances, skeletal
deformities, and susceptibility to fractures. Presenting symptoms of
osteomalacia ("softness of bone") include diffuse skeletal pain, bone
tenderness, and muscular weakness.
Types;
Nutritional rickets
There is a disturbed calcium-phosphorus metabolism due to
defective nutrition and calcium absorption, such as occurs in malnutrition,
coeliac disease and various familial genetic defects.
Coeliac or gluten induced rickets
This is a digestive disorder leading to malabsorption of both fat and
vitamin D. The disease starts in early childhood and the stools show
excessive amounts of fat. Diagnosis is confirmed by jejunal biopsy and the
serum calcium levels. Sometimes the phosphate levels are low
Etiology and Pathogenesis
Rickets and osteomalacia may be caused by: a deficiency or
abnormal metabolism of vitamin D; a deficiency or abnormal
83. 78
utilization/excretion of inorganic phosphate (Pi). A deficiency of vitamin
D may be due to:a dietary lack of the vitamin; insufficient ultraviolet
exposure to form endogenous vitamin D; and, most commonly,
malabsorption interfering with the intestinal absorption of fats and fat-
soluble vitamin D. An abnormal metabolism of vitamin D commonly
occurs in chronic renal failure. Vitamin D3 is photosynthesized in the skin
by ultraviolet radiation of 7-dehydrocholesterol. Vitamins D2 and D3, both
of which are biologically inactive, are also absorbed in the intestines from
dietary sources. Vitamins D2 and D3 are enzymatically hydroxylated in the
liver to 25-hydroxyvitamin D, which is transported to the kidney and
converted to 1,25- and 24,25-dihydroxyvitamin D. 1,25-dihydroxyvitamin
D, termed calcitriol or vitamin D hormone, is the most active metabolite of
vitamin D. The main function of vitamin D is to maintain a normal serum
balance of calcium and phosphate (Pi) through action of the active
metabolites on target organs: the intestine, bone, and parathyroid gland.
1,25-dihydroxyvitamin D increases the intestinal absorption of calcium and
Pi, thus bringing the concentration of serum calcium and Pi to a critical
level required for the mineralization of newly formed osteoid. Conversely,
if there is an inadequate amount of 1,25- dihydroxyvitamin D, the
intestinal absorption of calcium decreases, and the serum calcium level
falls, calling forth PTH secretion to support the calcium level .(Serum
calcium has a negative feedback on PTH secretion by parathyroid chief
cells: a low serum calcium level increases PTH secretion, and a high serum
calcium level decreases PTH secretion.) The increased PTH secretion
tends to restore the serum calcium level but also stimulates increased renal
Pi clearance, resulting in lower serum Pi levels. If the concentrations of
serum calcium and Pi fall below a critical level, mineralization of osteoid
cannot take place, resulting in osteomalacia (and rickets). An inadequate
84. 79
dietary intake of vitamin D sufficient to cause rickets or osteomalacia is
rare in developed countries which utilize foods supplemented with vitamin
D. There are exceptions: premature infants; the economically
underprivileged; elderly people; dietary idiosyncrasy. . As to the historical
role of limited exposure to ultraviolet radiation, rickets was described long
ago as a common disease of "smokey cities and cloudy skies". The most
common cause of osteomalacia today is intestinal malabsorption of fats
and fat-soluble vitamin D resulting from: hepatic disease (biliary tract
obstruction, primary biliary cirrhosis, alcoholic liver disease), chronic
pancreatitis, intestinal diseases (regional ileitis, sprue), and surgical
operations (gastrectomy, resection of portions of the small intestine).
Osteomalacia is often a component of renal osteodystrophy, the collection
of bone disorders that occur in varying degrees of severity in almost all
patients with chronic renal failure (CRF). The development of
osteomalacia and rickets ("renal rickets") in CRF is due to the loss of renal
parenchyma accompanied by: a decreased renal enzymatic capacity to
convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, resulting in
impaired intestinal absorption of calcium and hypocalcemia; and a
decreased renal excretion of Pi, resulting in hyperphosphatemia and a
reciprocal decrease in serum calcium to a level below that required for the
mineralization of osteoid. (This stimulates the increased secretion and
synthesis of PTH and secondary hyperplasia of the parathyroid gland,
resulting in the superimposed bone changes of osteitis fibrosa.) Drug-
induced rickets and osteomalacia may occur in association with the use of
the anticonvulsive drug phenytoin and is attributed to phenytoin's
interference with vitamin D metabolism in the liver. Rickets and
osteomalacia are also associated with hyperphosphatemia. An induced
deficiency of serum Pi may occur in peptic ulcer patients receiving long-
85. 80
term treatment with antacids containing aluminum hydroxide, which forms
insoluble complexes with Pi in the intestine and blocks its absorption.
Rickets and osteomalacia may also accompany renal tubular disorders in
which there is an impaired renal resorption of Pi, resulting in
hyperphosphatemia and hyperphosphaturia, or metabolic acidosis which
also affects the metabolism of vitamin D, calcium, and Pi. These
hypophosphatemic disorders include: renal tubular acidosis (RTA) of
which there are several types; the Fanconi syndrome of sporadic or familial
origin; and two hereditary forms of hypophosphatemia, namely, x-linked
hypophosphatemia (also termed vitamin D-resistant rickets), which is the
most common cause of rickets in the U.S. today, and vitamin D-dependent
rickets (autosomal recessive), in which there is a defect in the synthesis or
cellular utilization of 1,25-dihydroxyvitamin D.. Rickets is also seen in
children with hypophosphatasia, a rare heritable enzyme deficiency which
is characterized by extremely low levels of alkaline phosphatase in the
blood and tissues.
Pathology
The morphological characteristics of rickets, in the order of their
development, are as follows:
failure of mineralization of the epiphyseal provisional zone of
mineralization, resulting in disordered endochondral ossification;
failure of mineralization of newly formed osteoid, resulting in an
excess of osteoid (hyperosteoidosis) as shown by wide osteoid
seams; and skeletal deformities caused by interference with
endochondral ossification or by bending of the osteomalacic
(softened) bones. Hyperosteoidosis caused by a failure of
86. 81
mineralization is common to both osteomalacia and rickets. The
widened osteoid seams contain prominent osteoblasts. Osteoclasts
are rare (unmineralised osteoid does not stimulate an osteoclastic
reaction) Hyperosteoidosis also occurs in other skeletal disorders,
such as Paget's disease of bone and osteitis fibrosa caused by
hyperparathyroidism.
In these conditions ,in contrast to osteomalacia and rickets, there is a
high rate of bone turnover and no failure or delay of bone
mineralization. Bone biopsy is the definitive method of establishing
the diagnosis of osteomalacia.
Osteomalacic bone has a smudgy appearance of label uptake (or in
some cases no uptake at all), indicating defective and delayed
mineralization
Grossly, long-standing osteomalacia may produce fractures and
deformities of the softened bones. The main deformities are
kyphosis, bowing of the long bones, and narrowing of the pelvis.
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"); and a depression ("Harrison's grove") at
the lower margin of the rib cage produced by muscle contraction of
the diaphragm.
Investigations
The diagnosis of osteomalacia (and rickets) depends upon a careful
history and physical examination, x-ray studies, appropriate laboratory
87. 82
tests, and bone biopsy if indicated. The usual presenting symptoms are
muscle weakness and diffuse bone pain. The routine laboratory tests
usually show: decreased serum calcium and Pi; increased serum alkaline
phosphatase; and decreased 24-hour urinary calcium. Undecalcified bone
sections stained with the von Kossa technique allow a clear distinction to
be made between osteoid and mineralized bone A biopsy of severe
osteomalacia shows that virtually all (~100%) bone surfaces are covered
by osteoid (whereas in normal bone, surface osteoid is <20%).
Mineralization dynamics can be evaluated if two single 10 day-spaced
doses of tetracycline (which binds to the mineralization front and is
autofluorescent) are given to the patient before the bone biopsy is
performed. A biopsy of normal bone shows two discrete and separated
layers of fluorescent label uptake marking successive mineralization fronts.
The radiographic picture is that of diffuse osteopenia which may be
indistinguishable from that of osteoporosis except for the presence in
osteomalacia of characteristic bands of radiolucency ("pseudofractures/
Looser's zones"). Osteomalacia may coexist with osteoporosis in the aged.
Bone biopsy is the ultimate way to establish the diagnosis of osteomalacia.
BONE CHANGES IN HYPERPARATHYROIDISM
(GENERALIZED OSTEITIS FIBROSA CYSTICA, VON
RECKLINGHAUSEN'S DISEASE OF BONE)
Hyperparathyroidism is a syndrome of hypercalcemia resulting from
excessive release of parathyroid gland.
Epidemiology:
In the United States, about 100,000 people develop the disorder each
year. Women outnumber men two to one, and risk increases with age. In
88. 83
women 60 years and older, two out of 1,000 will develop
hyperparathyroidism each year.
Types:
Primary defect of the parathyroid gland because of hypersecretion of
PTH as seen with adenoma's of the parathyroid gland
Secondaray causes arise from conditions that produces abnormally
low ionic plasma Ca levels and thereby stimulates production of
PTH.
Tertiary conditions in which PTH secretion has become autonomous
after prolonged stimulation of gland owing to secondary
parathyroidis
Pathology
In most cases is due to single parathyroid adenoma (80% of patients)
Malignant tumor: occurs in about 1% of patients with
hyperparathyroidism
Occurs often in association with multiple endocrine neoplasia
syndrome, and rarely to parathyroid carcinoma
Hyperparathyoidism is sometimes seen in renal cell carcinoma and
squamous cell carcinoma;
Clinical presentation:
The skeletal changes in hyperparathyroidism are characterized by
diffuse or focal resorptive loss and fibrous replacement of bone due
to an excess of osteoclastic over osteoblastic activity and caused by
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an over-production of parathormone (PTH) in primary or secondary
hyperparathyroidism.
Primary hyperparathyroidism is a metabolic disorder in which
parathyroid cells, either neoplastic or hyperplastic and in the absence
of any known stimulus, secrete excessive amounts of PTH. Primary
hyperparathyroidism is usually caused by a functioning adenoma of
a single parathyroid gland, less commonly by diffuse hyperplasia of
all four parathyroid glands, and rarely by primary parathyroid
carcinoma or multiple parathyroid adenomas.Primary
hyperparathyroidism most frequently occurs in adults, has a peak
incidence between the third and fifth decades and a female to male
ratio of two or three to one, and is rarely seen in children under 10
years of age. Primary hyperparathyroidism, in the absence of renal
disease, is characterized biochemically by hypercalcemia,
hypophosphatemia, hypercalciuria, elevated serum alkaline
phosphatase activity (in the presence of bone disease), and increased
levels of PTH measured by radioimmunoassays.
Secondary hyperparathyroidism is associated with many conditions
that lead to hypocalcemia and most often occurs as a consequence of
the hyperphosphatemia and hypocalcemia of chronic renal failure.
The complex bone changes in chronic renal failure are called renal
osteodystrophy and include osteomalacia, rickets ("renal rickets"),
osteitis fibrosa and other bone changes of hyperparathyroidism.
Some non-parathyroid carcinomas (arising in lung, kidney, or
elsewhere and without bony metastases) may produce a PTH-like
hormone associated with a syndrome resembling
hyperparathyroidism. This syndrome is called