Metabolic Bone

Diseases

Constitution of bone

 It is a specialized dense
connective tissue
Where the matrix is impregnated
by calcium salts making it hard
and rigid
Matrix is made up of organic and
inorganic intercellular substances
and surround osteocytes

 Bone has organized canalicular

mechanism and is highly vascular
It consists of cells and
intercellular substances
It is covered by periosteum
Bone grows by surface deposition

Cells of bone
Osteogenic cells they are
precursors of other cells
They are found in the inner layer of
periosteum

Osteoblasts they are found

where active bone is being
formed
They lay down fibers and matrix

 Osteocytes they are resting cells in

the bony matrix
They lie in spaces called lacunae
Lacunae are surrounded by canaliculi
Canaliculi anastomose with neighboring
lacunae canaliculi
Processes of osteocytes occupy these
canaliculi

Osteoclasts they are large giant cells

They have 5-15 nuclei
They remove the bone or resorption of
bone

All bone cells work in harmony

Intercellular substance
Two types
Inorganic matter is made up of
calcium
It provides rigidity
Strong acids dissolve salts
Organic matter is made of
collagen fibers
All the elements are secreted by
osteoblasts
Organic matter is destroyed by
burning

Histological classification
Two types
Compact or dense
Bone is hard
Present in the shaft of long
bones

Cancellous or spongy
Bone has larger marrow
spaces
Bone is less hard
Present in the ends of long
bones

Microscopic structure of compact bone

Bone is covered by periosteum
It consists of two layers
Outer fibrous layer
Inner osteogenic and vascular
layer
Periosteum is firmly bound to
bone by Sharpeys fibers
Compact bone is characteristic by
the presence of Haversian system

Histology of bone
Centrally situated Haversian
canal
Containing vessels and nerves

Canal is surrounded by 6-12

concentric lamellae
Lamellae are composed of
collagen fibers with calcium
deposits
Collagen fibers run spirally

Histology of bone
Between the lamellae or on the
lamellae are lacunae present
They imprison osteocytes
Canaliculi are occupied by
processes of osteocyte
The processes are responsible
for nourishment of osteocytes

Histology of bone
Haversian canals are connected with
one another and communicate with
marrow cavity through Volkmanns
canals
Interstitial lamellae lie in the angles
between the adjoining the haversian
lamellae
They belong to older bone
Near periosteum outer circumferential
lamellae are present
Near endosteum inner circumferential
lamellae are present

 Centrally situated Haversian

canal
Containing vessels and nerves

Canal is surrounded by 6-12

concentric lamellae
Lamellae are composed of
collagen fibers with calcium
deposits
Collagen fibers run spirally

 Between the lamellae or on the

lamellae are lacunae present
They imprison osteocytes
Canaliculi are occupied by
processes of osteocyte
The processes are responsible
for nourishment of osteocytes

 Haversian canals are connected with

one another and communicate with
marrow cavity through Volkmanns
canals
Interstitial lamellae lie in the angles
between the adjoining the haversian
lamellae
They belong to older bone
Near periosteum outer circumferential
lamellae are present
Near endosteum inner circumferential
lamellae are present

Definition & Types

Most of the diseases are associated with depletion
of bone tissue.
I. Osteoporosis- Bone mass is abnoarmally low
II. Osteomalacia- Osseous connective tissue(osteoid)
is present but insufficiently mineralized
III. Osteitis Fibrosa- PTH over-production leads to bone
resorption and replacement by fibrous tissue

OSTEOPOROSIS

OSTEOPOROSIS
porous bone
skeletal disorder characterised by compromised
bone
strength
predisposing a person to an increased risk of
fracture.
Bone strength
Bone density (g/cm2 or g/cm3) - peak bone mass
and amount of bone loss.
Bone quality - architecture, turnover, damage
accumulation, and mineralisation of the bone
18

OSTEOPOROSIS

Normal Bone Osteoporotic Bone

19

OSTEOPOROSIS DEFINITION
Osteoporosis occurs when the holes between bone
become bigger, making it fragile and liable to break
easily

A progressive systematic skeletal disease

characterized by low bone mass and microarchitectural deterioration of bone tissue, with a
consequent increase in bone fragility and
susceptibility to fracture

CLASSIFICATION OF OSTEOPOROSIS
Primary osteoporosis in the elderly can be classified as type I
or II:
Type I (menopausal) osteoporosis occurs mainly in persons
aged 51 to 75, is six times more common in women, and is
associated with vertebral and Colles' (distal radius)
fractures.
Type II (senescent) osteoporosis occurs in persons > 60, is
two times more common in women, and is associated with
vertebral and hip fractures.
Overlap between types I and II is substantial, so this
classification is of limited clinical use.
Primary osteoporosis is thought to result from the hormonal
changes that occur with age, particularly decreasing levels
of sex hormones (estrogen in women, testosterone in men).
Several other risk factors are usually contributory.

22

RISK FACTORS
Female
Thin or small frame
Low body weight
Smoker

23

RISK FACTORS
Advanced age
History of fragility
fracture
Family historyprimary relative with
Osteoporosis or
fragility fracture
24

RISK FACTORS
Post Menopausal
Hormonal imbalances can result in rapid
bone loss
Women can lose up to 20% of their bone
mass in 5-7 years

25

Risk Factors
Amenorrhea, Anorexia & Bulimia
Diet low in calcium
Certain medications
Low testosterone in men

26

ETHNICITY &
OSTEOPOROSIS

Caucasian & Asian-American Women

High Risk

27

MEN & OSTEOPOROSIS

Underdiagnosed
Unrecognized
Underreported
Inadequately researched
28

SYMPTOMS AND WARNING SIGNS

29

PATHOPHYSIOLOGY

 Hallmark of osteoporosis is a reduction in skeletal mass

caused by an imbalance between bone resorption and
bone formation.
Under physiologic condition, bone formation and
resorption are in fair balance.
A change in either , that is, increased bone resorption or
decreased bone formation may result in osteoporosis
Osteoporosis can be caused both by a failure to build
bone and reach peak bone mass as a young adult and
by bone loss later in life

PATHOLOGY
Inadequate peak mass
Excessive bone resorption:
Deficiency of estrogen
Calcium metabolism, Vitamin D metabolism
Hyperparathyroidism
Inadequate bone formation during remodelling

INVESTIGATIONS
Radiological evidence of decreased bone mass is more reliable.
Following features may be noticed on X-rays:
Loss of vertical height of a vertebra due to collapse
Cod fish appearance. The disc bulges into the adjacent vertebral bodies
so that the disc becomes biconvex
Ground glass appearance of the bones, conspicuous in bones like the
pelvis
Singhs index: Singh et al. graded osteoporosis into 6 grades based on
the trabecular pattern of the femoral neck trabeculae.
Metacarpal index and vertebral index are other methods of quantification

 BIOCHEMISTRY:
Serum calcium, phosphates and alkaline phosphatase are within
normal limits
Total plasma proteins and plasma albumin may be low
Markers of bone resorption: deoxy-pyridinoline, N-telopeptide
DENSITOMETRY:
Method to quantify osteoporosis
In this method absorption of photons (emitted from gamma
emitting isotopes) by the bone calcium is measured
2 types of bone densitometry: ultrasound based and X-ray based
Dual energy X-ray absorptiometry (DEXA) scan is an X-ray based
bone densitometry, and is the gold standard in the quantification
of bone mass

 NEUTRON ACTIVATION ANALYSIS

Calcium in the bone is activated by neutron bombing,
and its activity measured
BONE BIOPSY

TREATMENT
Principle objectives of treatment are alleviation of pain
and prevention of fractures
Divided into medical and orthopeadic

MEDICAL TREATMENT
High protein diet: Increasing protein intake may increase the formation of
organic matrix of the bone
Calcium supplementation: Helpful in cases with deficiency of calcium in
their diet
Androgens: These hormones have an anabolic effect on the protein matrix
of bone, and in some instances ameliorate symptoms
Estrogens (HRT): Halt the progressive loss of bone mass in postmenopausal
osteoporosis
Vitamin D: This is given, in addition to the above, to increase calcium
absorption from the gut
Alandronate: Used in once a day dose, empty stomach. Oesophagitis is a
troubling complication
Calcitonin: Helps in building up the bone mass and also acts as an analgesic

Biphosphanates:
Sodium alendronate ( 10mg/day or 70mg/week)
Risedronate (5mg/day or 35mg/week)
Ibandronate: once a month
Selective estrogen receptive modulator-SERM- Raloxifene
Teriparatide(recombinant PTH hormone): daily injection
Used in established osteoporosis, very low BMD, cannot tolerate
Biphosphonates
CI:Young, Pagets disease, radiation therapy

ORTHOPAEDIC TREATMENT
Exercises: Weight bearing is a major stimulus to bone
formation. Increased guarded activity would therefore
be of benefit to the patient
Bracing: Prophylactic bracing of the spine by using an
ASH brace or Taylor brace maybe useful in prevention of
pathological fractures in a severely osteoporotic spine

PREVENTION
Adequate intake of dietary calcium
Decreased alcohol consumption and caffeine use
Regular exercise
Smoking cessation

OSTEOPETROSIS

Definition
Osteopetrosis is a bone disease that makes bones abnormally
dense and prone to breakage (fracture).
Osteopetrosis, literally "stone bone", also known asmarble
bone diseaseandAlbers-Schnberg disease, is an extremely
rare inheriteddisorderwhereby thebonesharden,
becomingdenser.
A clinical syndrome characterized by the failure of osteoclasts to
resorb bone. As a consequence, bone modeling and remodeling are
impaired.
In contrast to more prevalent conditions likeosteoporosis, in which
the bones become less dense and more brittle, orosteomalacia, in
which the bones soften.

Aetiology
1. Failure of Bone cells and bone modeling and
remodeling

Osteoblasts synthesize bone matrix, which are composed

predominantly of type I collagen and are found at the boneforming surface.
Extracellular matrix surrounds some osteoblasts, which become
osteocytes.
Osteoclasts can tightly attach to the bone matrix by integrin
receptorsto form a sealing zone, within which is a sequestered,
acidified compartment.
Acidification promotes solubilization of the bone mineral in the
sealing zone, and various proteases, notably cathepsin K, catalyze
degradation of the matrix proteins.
Bone modeling and remodeling differ in that modeling implies a
change in the shape of the overall bone and is prominent during
childhood and adolescence.
Modeling is the process by which the marrow cavity expands as
the bone grows in diameter.

2. Failure of Osteoclast development and

maturation
For precursor cells to mature, functional osteoclasts
require the action of 2 distinct signals. The first is
monocyte-macrophagecolony-stimulating factor
(M-CSF), which is mediated by a specific membrane
receptor and its signaling cascade.
The second is the receptor activating NF-kappa B
ligand (RANKL), acting through its cognate receptor,
RANK.
A soluble decoy receptor, osteoprotegerin, can bind
RANKL, limiting its ability to stimulate
osteoclastogenesis.

3. Genetic and molecular defects in

The primary underlying defect in all types of
osteopetrosis

osteopetrosis is failure of the osteoclasts to

reabsorb bone.
A number of heterogeneous molecular or genetic
defects
can
resultgenetic
in impaired
I. The
specific
defectosteoclastic
in humans is known
only in osteopetrosis caused by carbonic anhydrase
function:
II deficiency
II. Based on its inheritance pattern, infantile
osteopetrosis seems to be transmitted in an
autosomal recessive manner
III. Viruslike inclusions have been reported in
osteoclasts of some patients with benign
osteopetrosis

Carbonic anhydrase isoenzyme II

deficiency
This enzyme catalyzes the formation of carbonic
acid from water and carbon dioxide.
Carbonic acid dissociates spontaneously to
release protons, which are essential for creating
an acidic environment required for dissolution of
bone mineral in the resorption lacunae.
Lack of this enzyme results in impaired bone
resorption.

Clinical Features
Infantile osteopetrosis

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life.

Failure to thrive and growth retardation are symptoms.
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 may 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 suffer from anemia, easy bruising and bleeding (due to thrombocytopenia), and
recurrent infections (due to inherent defects in the immune system)
Extramedullary hematopoiesis may occur, with resultant hepatosplenomegaly,
hypersplenism, and hemolysis
Other manifestations include sleep apnea and blindness due to retinal degeneration

 They are often transverse fractures with multiple areas of callus

formation and normal healing.
Additionally, there is crowding of the marrow, so bone marrow
function is affected resulting in myelophthisic anaemia
andextramedullary haematopoiesiswith splenomegaly. This may
terminate inacute leukaemia.

 Adult osteopetrosis
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.
Approximately one half of patients are asymptomatic, and
the diagnosis is made incidentally.
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 may
fracture easily. Approximately 40% of patients have
recurrent fractures. Osteomyelitis of the mandible occurs in
10% of patients.
Other manifestations include visual impairment due to
retinal degeneration and psychomotor retardation.

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
metaphysis

Absent

May or may not be present

Risk of fracture

Low

High

Serum acid phosphatase

Normal

Very high

Investigation
Laboratory findings in infantile osteopetrosis

1. Serum calcium - Generally reflects oral intake;

hypocalcemia can occur and cause rickets if it is
severe enough
2. Parathyroid hormone (PTH) - Often is elevated
(secondary hyperparathyroidism)
3. Acid phosphatase - Increased due to increased
release from defective osteoclasts
4. Creatinine kinase isoform BB (CK-BB) - levels are
increased due to increased release from
defective osteoclasts

 Laboratory findings in adult

osteopetrosis
1. Acid phosphatase and CK-BB - Concentrations are
often increased in type II disease
2. Serum bone-specific alkaline phosphatase - Values
may also be increased in various types of the disease

Genetic screening
Mutation screening of appropriate candidate
genes should be undertaken in patients whose
presentation corresponds to any of the known
genetic lesions.

Histologic findings
Failure of osteoclasts to resorb skeletal tissue is
the pathognomonic feature of true osteopetrosis.
Remnants of mineralized primary spongiosa are
seen as islands of calcified cartilage within mature
bone.
Woven bone is commonly seen.
Osteoclasts can be increased, normal, or
decreased in number.

Radiography
i.
ii.

Patients usually have generalized osteosclerosis.

Bones may be uniformly sclerotic, but alternating
sclerotic and lucent bands may be noted in iliac
wings and near the ends of long bones.
iii. The bones may be clublike or may have the
appearance of a bone within bone (endobone).
iv. Radiographs may also show evidence of fractures
or osteomyelitis.
v. The entire skull is thickened and dense, especially
at the base.
vi. Sinuses are small and underpneumatized.
vii. Vertebrae are extremely radiodense.
viii. They may show alternating bands, known as the

Differentiating type 1 from type 2 adult

osteopetrosis

Type I disease - Sclerosis of the skull mainly affects the

vault with marked thickening; the spine does not show
much sclerosis.
Type II disease - Sclerosis is found mainly in the base of
the skull; the spine always has the rugger-jersey
appearance, and the pelvis always shows subcristal
sclerosis; transverse banding of metaphysis is common in
patients with type II disease but not in patients with type
I disease (this finding confirms type II disease, but its
absence does not necessarily indicate type I disease)

Treatment
1. Vitamin D analogs
These supplements increase serum calcium levels by
increasing calcium absorption from the
gastrointestinal tract.
Calcitriol(Rocaltrol, Calcijex,Vectical) in large
doses, with restricted calcium intake, sometimes
improves osteopetrosis dramatically.
It can be used to treat infantile osteopetrosis and
appears to help by stimulating dormant osteoclasts
and, thus, bone resorption.
Markers of bone turnover (eg, serum osteocalcin,
bone-specific alkaline phosphatase, urine
hydroxyproline levels) increase during therapy.

2. Corticosteroids
These agents have anti-inflammatory properties
and cause profound and varied metabolic effects.
Corticosteroids modify the body's immune
response to diverse stimuli.
Prednisone is an immunosuppressant used for
the treatment of autoimmune disorders.
It may decrease inflammation by reversing
increased capillary permeability and suppressing
polymorphonuclear leukocyte activity.
The drug stabilizes lysosomal membranes and
suppresses lymphocytes and antibody production.

3. Hematopoietic Growth Factors

Epoetin alfa is a purified glycoprotein produced
from mammalian cells modified with gene coding for
human erythropoietin (EPO). Biological activity
mimics human urinary EPO, which stimulates division
and differentiation of committed erythroid progenitor
cells and induces the release of reticulocytes from
bone marrow into the blood stream.
Darbepoetin is an erythropoiesis-stimulating
protein closely related to erythropoietin, a primary
growth factor produced in kidney that stimulates
development of erythroid progenitor cells.
Its mechanism of action is similar to that of
endogenous erythropoietin, which interacts with
stem cells to increase red cell production.

4. Immunomodulator
Gamma-1b interferon is synthesized by
eukaryotic cells in response to viruses and a
variety of natural and synthetic stimuli.
It possesses antiviral, immunomodulatory, and
antiproliferative activity.
Gamma interferon has potent phagocyteactivating effects not seen with other interferon
preparations.
It works by stimulating osteoclast activity.

Infantile osteopetrosis
Vitamin D (calcitriol) appears to help by stimulating dormant
osteoclasts, thus stimulating bone resorption.
Large doses of calcitriol, along with restricted calcium intake,
sometimes improve osteopetrosis dramatically.
However, calcitriol usually produces only modest clinical
improvement, which is not sustained after therapy is discontinued
Treatment with gamma interferon improves white blood cell
function, greatly decreasing the incidence of new infections. With
treatment, trabecular bone volume substantially decreases and
bone-marrow volume increases. This results in increases in
hemoglobin, platelet counts, and survival rates. Combination
therapy with calcitriol is clearly superior to calcitriol alone.
Erythropoietin can be used to correct anemia. Corticosteroids have
also been used to treat anemia, as well as to stimulate bone
resorption.

Adult osteopetrosis
Adult osteopetrosis requires no treatment by itself,
although complications of the disease may require
intervention.
No specific medical treatment exists for the adult
type.

Surgical treatment
In pediatric 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) or for functional reasons (eg, in
patients with multiple fractures, deformity, and loss of
function).
Severe, related degenerative joint disease may warrant
surgical intervention as well.

Disease of mineralization :
Osteomalacia / Rickets

Definition
diseases where organic matrix of the bone fails to calcify
properly, leaving large osteoid seams / inadequate
mineralization of bone
* osteoid throughout the skeleton is incompletely calcified
in growing bones of children-> Rickets
in bones of adult-> Osteomalacia

Rickets
Define :
inadequate mineralization of growing bones in children,
affecting physeal growth and ossification, resulting in
deformities of endochondral skeleton

Etiology :
Type 1
1. due to deficiency of vitamin D
- diminished intake eg malnutrition
- diminished absorption eg gastric abnormalities, biliary diseases
- lack of exposure to sunlight
2. due to disturbance of vit D metabolism
- hepatic factor eg lack of 25 hydroxylation of vit D
- renal factor eg lack of 1hydroxylation
- unresponsive of target cells to 1-25 dihydroxy vit D

Type 2
1. defective absorption of phosphates through
renal tubules
- hypophosphataemia rickets (X- linked dominant)
- Fanconi syndrome
- renal tubular acidosis
- oncogenic rickets
2. diminished intake or absorption of phosphates

Clinical features :
- may present with tetany or convulsions
- failure to thrive, listlessness and muscular faccidity
- craniotabes (pressure over the soft membranous
bones of the skull gives the feeling of a ping pong
ball being compressed and released)
- bossing of the skull (evident after age of 6 month)
- broadening of ends of long bones, commonly
wrists and knees
- delayed teeth eruption
- Harrison's sulcus (horizontal depression along
lower part of chest)
- Rachitic rosary (costochomdral junctions on
anterior chest wall become prominent giving rise
to appearance of a rosary)
- muscular hypotonia (child's abdomen becomes
protuberant / pot belly because of marked
muscular hypotonia)
- deformities- knock knees, bow legs

Investigation :
- X-ray -> delayed appearance of epiphysis
-> widening of epiphyseal plates
(normal : 2-4mm) due to excessive
accumulation of uncalcified osteoid at
growth plate
-> cupping of metaphysis
-> splaying of the metaphysis
-> bone deformities eg knock
knees, bow legs, coxa vara

Widening and cupping of the

metaphyseal regions (see the
image below) Anteroposterior and
lateral radiographs of the wrist

- serum calcium and phosphates decreases,

alkaline phosphatase increases
- urine calcium decreases
- calcium phosphate product (calcium x
phosphorus level mmol/L)
normal : 3
diagnostic : < 2.4

Treatment :
Medical treatment
- Vit D 600 000 units single oral dose induces rapid
healing
If line of sclerosis(healing) on metaphyseal side of growth
plate is not seen on X-ray within 3-4 weeks of therapy,
same dose is repeated
Unresponsive to Vit D therapy, then maintenance dose of
400 IU of Vit D is given per day

Surgical treatment (established long bone deformities)

- conservative methods eg. splints (mermaid splints),
orthopaedic shoes
-> mild deformities correct spontanously
- operative methods eg. corrective osteomies
-> moderate or severe deformities often require surgery,
after 6 months of starting medical treatment

Prevention :
- balanced diet that contains of calcium (sources : daily
products, soya beans, nuts) and Vit D (sources : oily
fish, eggs)
- pregnant and breastfeeding women should take daily
supplement of 10ug of Vit D
- Vit drops for all babies and young children aged 6
months -5 yrs old

Osteomalacia
Define :
inadequate mineralization of
bones in adult, results of
failure to replace turnover of
calcium and phosphorus in the
organic matrix of bone
Hence, bone content is
demineralised and bone
substance is replaced by soft
osteoid tissue

Etiology :
- malabsorption
- lack of exposure to sunlight
- under-nutrition during pregnancy
- after partial gastrectomy

Clinical features :
- bone pains (backache to
diffuse bone pains may
occur)
- muscular tenderness
(difficulty in climbing stairs)
- spontaneous fractures occur
usually in spine and may
result in kyphosis

Investigation :
- X-ray-> diffuse rarefaction of bones
-> Looser's zone (pseudo-fractures)
radiolucent zones occur at sites of stress, commonly at pubic
rami, axillary border of scapula, ribs, medial cortex of the neck of
femur
-> triradiate pelvis (female)
-> acetabulum protruding into pelvis
- low serum calcium and phosphates, high alkaline phosphatase
- bone biopsy-> excessive uncalcified osteoid

Treatment :
- maintenance dose of 400 IU of Vit D daily
- calcium supplementation should be given
- treat underlying causes

Metabolic Disease Disorder

High bone turnover
Pagets Disease
and Hyperparathyroidism

Pagets disease(Osteitis
deformans)

Paget disease is a localized disorder of bone remodeling that typically begins

with excessive bone resorption followed by an increase in bone formation.
This osteoclastic overactivity followed by compensatory osteoblastic activity
leads to a structurally disorganized mosaic of bone (woven bone), which is
mechanically
-weaker, larger, less compact, more vascular, and more susceptible to fracture
than normal adult lamellar bone.
It is the second most common bone disorder (after osteoporosis) in
elderly persons.
Paget disease may involve a single bone but is more frequently multifocal.
It has a predilection for the axial skeleton (ie, spine, pelvis, femur, sacrum, and
skull, in descending order of frequency), but any bone may be affected.
After onset, Paget disease does not spread from bone to bone, but it may
become progressively worse at preexisting sites.

Etiology
The cause of Paget disease is unknown. Both genetic and environmental
factors have been implicated.
Studies of potential genetic markers for Paget disease have found an
association between human leukocyte antigenA (HLA-A), HLA-B, and HLA-C
(class I) and clinical evidence of disease.
Alterations in cytokine expression have been found in persons with Paget
disease: elevated interleukin-6 (IL-6) levels are found in bone marrow plasma
and peripheral blood in patients with Paget disease but not in healthy controls.
Macrophage-colony stimulating factor (M-CSF) may play a role in Paget
disease. M-CSF is a growth factor produced by many cells, including
osteoblasts and marrow fibroblasts. Significantly high levels of M-CSF have
been found in patients with untreated Paget disease.
Environmental factors
- Viral infection(i.e paramyxoviruses)

Symptoms
Most persons with Paget disease are asymptomatic.
However, when symptoms do occur, bone pain is the most common
complaint. The bone pain is dull, constant, boring, and deep below the
soft tissues. It may persist or exacerbate during the night.
Hip pain is most common when the acetabulum and proximal femur are
involved, especially in the sclerotic stage.
Bowing of the femur and long bones or protrusion of the acetabulum
causes pain that becomes worse with weightbearing and is relieved with
rest.
Knee and shoulder pain may occur because of altered mechanical forces
across the articular joints from deformed bones.
Nonspecific headaches, impaired hearing, and tinnitus commonly result
from skull involvement.
The most common cranial symptom is hearing loss, occurring in patients
with skull involvement. The most common neurologic complication is
deafness as a result of involvement of the petrous temporal bone.

 Back and neck pain are common complaints, as Paget

disease frequently affects the spine, especially the lumbar
and sacral regions.
Softened bone at the base of the skull may lead to
platybasia, the descent of the cranium onto the cervical
spine.
Progressive pain, paresthesias, limb paresis, gait
difficulties, or bowel and bladder incontinence may be
caused by compression of the spinal cord or spinal nerve
secondary to platybasia or vertebral fractures.

Investigations
Measurement of serum alkaline phosphatasein some cases, bonespecific alkaline phosphatase (BSAP)can be useful in the diagnosis
of Paget disease.
Elevated levels of urinary markers, including hydroxyproline,
deoxypyridinoline, C-telopeptide,andN-telopeptide, may help
identify patients with Paget disease.
Check for serum uric acid level- Elevated serum uric acid levels have
been found in men with severe Paget disease and have been
associated with gouty arthritis.
Serum total acid phosphatase is an osteoclastic enzyme that may be
elevated in active Paget disease. In males, however, the clinical value
of this finding is compromised, as acid phosphatase levels also may
be elevated in the presence of metastatic prostate carcinoma

 Plain radiographs and bone scanning should be

performed upon initial diagnosis. Repeated radiography
may be helpful in monitoring an osteoarthritis program
or in evaluating for malignant degeneration.
Computed tomography (CT) scanning and magnetic
resonance imaging (MRI) are not needed for the
diagnosis of Paget disease of bone. However, both are
useful in the evaluation of complications of Paget
disease, such as neoplastic degeneration, articular
abnormalities, and spinal involvement with neurologic
compromise.
Bone biopsies may be indicated to evaluate for
malignant transformation.

Treatment
The short-term objective of Paget disease treatment is to control disease
activity. The long-term objectives of treatment are to minimize or prevent
disease progression and to decrease complications from the disease, if
possible.
Indications for drug treatment of Paget disease are as follows:
Metabolic active disease - Bone pain, fatigue fracture, skull/spine fracture,
radiculopathy, osteolytic lesions, bony deformities, weight-bearing bone
involvement, compression of spinal cord and nerve roots, bone compression of
the eighth cranial or optic nerve
Preparation for orthopedic surgery (joint replacement anticipated at involved
sites within 6 months)
Hypercalcemia or hypercalciuria - Recurrent renal calculi due tohypercalciuria,
or fractures; serum alkaline phosphatase or urine hydroxyproline levels greater
than twice the upper limit of the reference range; immobilization

 When Paget disease occurs around a joint, treatment is often administered in

an attempt to prevent development of osteoarthritis.
Drug therapy for Paget disease should include bisphosphonate treatment with
serial monitoring of bone markers.
Response to therapy is indicated by reduction of symptoms and decreases in
levels of BSAP (a bone formation marker) and deoxypyridinoline,Ctelopeptide,orN-telopeptide (bone resorption markers).
Secondary osteoarthritic pain may be reduced by nonsteroidal antiinflammatory drugs or other nonnarcotic analgesics.
Orthotic devices, including canes and walkers, may be useful for patients with
gait abnormalities resulting from Paget disease that involves the lower limbs.
Because of the increased risk of malignancy, patients with Paget disease
should be monitored indefinitely.
Chemotherapy, radiation, or both may be used to treat neoplasms that arise
from pagetic bone.
Amputation may also be necessary in the presence of a malignant
transformation.

Hyperparathyroidism

Parathyroid gland anatomy and physiology

Normally 4 in number
Located behind the thyroid gland one behind each pole of the thyroid
Each 6mm x 3mm x 2mm Dark brown color
Secreted by the chief cells of the parathyroid gland
Controls extracellular Calcium and phosphate
Regulates intestinal reabsorption
Regulates Renal excretion
Regulates exchange of Ca and PO4 ions in ECF
Excess activity of Parathyroid - Rapid absorption of calcium from bones
Hypercalcemia
Removal of half - no major problem, removal of - Hypoparathyroidism Hypofunction of Parathyroid Hypocalcemia - Tetany

Hyperparathyroidism
Classification
Primary : excessive release of PTH and manifests as hypercalcemia (no renal
disease and no malignancy)
Looses sensitivity to circulating calcium : Parathyroid adenoma

Secondary: parathyroid glands become hyperplastic after long-term

hyperstimulation and release of PTH
Elevated PTH levels do not result in hypercalcemia
Resistance to the action of PTH : Chronic renal failure, intrinsic
parathyroid gland abnormalities
Hyperparathyroidism + Renal pathology = Renal osteodystrophy

Tertiary : excessive secretion of parathyroid hormone (PTH) after a long period of

secondary hyperparathyroidism and resulting in hypercalcemia
Long lasting disorders of the calcium feedback control system
Cannot be treated by medication

Symptoms
Asymptomatic hyperparathyroidism
have no signs or symptoms
diagnosis being made on further investigation after a
coincidental finding of hypercalcemia

Symptomatic hyperparathyroidism
associated with the effects of an increased level of calcium symptoms "neurological" in origin
most common symptom is fatigue and tiredness
lack of energy, memory problems, depression, problems
with concentration, sleeping disorders
Other symptoms
kidney - stones, bone pain - osteoporosis
headaches, gastroesophageal reflux, decreased sex drive,
thinning hair, hypertension, and palpitations

Orthopaedic manifestations
Bone pains due to Osteoporosis
Radiological
Subperiosteal bone resorbtion and
acroosteolysis Radial side & tuft of
phalanges
Osteitis fibrosa cystica Brown tumor
of hyperparathyroidism
Pepper Pot appearance - skull

Chondrocalcinosis & pseudogout

Proximal muscle weakness
affecting lower more than upper limbs

Lateral radiograph skull: diffuse lytic

lesions giving classical pepper pot
skull appearance.

 Diagnosis
Gold Standard : PTH immunoassay

PTH Raised
Raised

PTH Raised

Calcium levels

Primary
hyperparathyroidism

Normal

Secondary
hyperparathyroidism

Investigations
Laboratory investigations
PTH level
normal range for the PTH-intact assay - 10-65 pg/ml
elevated PTH levels with hypercalcemia establishes diagnosis
of hyperparathyroidism
in older individuals, hypercalcemia of malignancy - associated
with suppressed PTH levels
immunoradiometric assay for PTH detects fully intact
molecule - more accurate
rapid PTH assay provides an accurate PTH level
used intraoperatively - determine quantitatively the excision of
hyperfunctioning parathyroid tissue
decrease PTH concentration - > 50% from the baseline level 5-10 mts
after excision - absence of residual hyperfunctioning tissue

 Calcium levels: Hypercalcemia or normal calcium depending

on the type of hyperparathyroidism
Urinary calcium excretion : may be elevated
Phosphate levels: decreased serum phosphate level of
< 2.5 mg/dL (0.81 mmol/L) may be seen
Increased bone turnover : elevated alkaline phosphatase
and urinary pyridinoline (bone resorption)

Imaging Studies
Noninvasive imaging modalities
Technetium-99m sestamibi imaging, Ultrasonography CT scanning & MRI
Ultrasonography and 99mTc sestamibi scanning
widely available and relatively inexpensive
Radiology
typical radiography findings
bone-density measurements based on (DEXA) at the hip and spine
brown tumors are seen only in patients who are severely affected
soft tissue calcification in joints, kidneys & lungs
CT scanning
of spine provides estimates of spinal bone density
serial measurements provides an early indication progressive osteopenia
Percutaneous needle biopsy - aspiration cytology & tissue PTH
malignancy suspected

Treatment
Emergency Department Care
Focused on the treatment of hypercalcemia
Goal of treatment is to reduce calcium level to below 11.5 mg/dL
Intravenous administration of isotonic saline
First and vital step in management of severe hypercalcemia
Severe hypercalcemia - nearly always accompanied by severe dehydration

Patients with hypercalcemia with alterations of mental status

loop diuretics
facilitate the urinary excretion of calcium
prevents volume overload - following administration of large volumes of saline
Initiation of loop diuretics should only after rehydration has taken place

Postmenopausal with mild hyperparathyroidism - estrogen therapy

it may inhibit demineralization of the skeleton - reduce blood calcium levels

 directed at hypercalcemia
symptomatic patients adviced surgery removal of
the parathyroid tumor (parathyroid adenoma)
Present belief : almost all patients with
hyperparathyroidism should be evaluated for surgery
will almost always progress as the tumor grows
if surgery is not available - monitor
Calcium level: via urine tests - results inform kidney
function
Bone density: used to assess the risk of osteoporosis
Check for kidney stones: abdominal X-rays

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