Non-neoplastic diseases of the bone

(Pathology 2)

Presenter:
Shifaa’ Al Qa’qa’, MD
Assistant professor of pathology
Renal and genitourinary pathologist
Faculty of Medicine, Al-Balqa Applied University
Fifth floor, room 505
Al-salt, Jordan
Email: shqaqa@bau.edu.jo
Objectives:

1. Describe Paget’s disease of bone.

2. Describe the pathogenesis and pathologic features of osteomyelitis.
3. Describe Osteoporosis, osteomalacia and rickets
The functions of bone include:

- Mechanical support
- Transmission of forces generated by muscles
- Protection of viscera
- Mineral homeostasis
- Providing a niche for the production of blood cells.

Long bone:
- Dense outer cortex (compact bone)
- Central medulla (bony trabeculae separated by
marrow (cancellous bone).
The constituents of bone include:

(A) An extracellular matrix (bone matrix):

1. organic component---osteoid/ (35%): type I collagen with smaller
amounts of glycosaminoglycans and other proteins.
2. inorganic component---mineral component (65%): hydroxyapatite ----
hardness of bone

(B) Bone contains three major cell types; that maintain bone homeostasis:
Osteoblasts
Osteocytes
Osteoclasts
 The bone matrix is synthesized in one of two histologic forms:

Woven bone: Lamellar bone:

- Rapidly produced (e.g. fracture repair, during - slowly produced
fetal development ) - parallel collagen fibers.
- more cellular
- disorganized collagen fibers
- less structural integrity

Always indicates bone abnormality/disease in

adults
Active osteoblasts synthesizing bone Two osteoclasts resorbing
matrix. bone.
Homeostasis and Remodeling

WNT proteins produced by

various cells bind to the RANK signaling activates the
LRP5 and LRP6 receptors transcription factor NF-κB,
on osteoblasts and trigger
which is essential for the
the production of OPG
generation and survival of
Osteoprotegerin (OPG), a osteoclasts.
secreted “decoy” receptor
made by osteoblasts that
can block RANK interaction - parathyroid hormone (PTH)
with RANKL. - IL-1
- glucocorticoids
- bone morphogenetic
factors
- sex hormones (estrogen,
testosterone)

OPG-RANK ratio
Non-neoplastic disorders of bone:

- Congenital disorders of bone and cartilage

- Metabolic disorders of bone

- Paget disease of bone (osteitis deformans)

- Fractures

- Osteonecrosis (avascular necrosis)

- Osteomyelitis
Metabolic disorders of bone:

1. Osteopenia and Osteoporosis

2. Rickets and Osteomalacia
3. Hyperparathyroidism
1. Osteopenia and Osteoporosis:

Osteopenia: decreased bone mass.

Osteoporosis: severe decrease in bone mass---- increases the risk of

fracture.

- localized or generalized (involving the entire skeleton).

Pathogenesis:

Peak bone mass is achieved during young adulthood, influenced by:

- hereditary/genetic factors: polymorphisms/mutation in the genes that influence
bone metabolism (e.g. polymorphisms in the vitamin D /LRP5/6 receptors, genes
in the Wnt signaling pathway)
- Physical activity
- muscle strength
- diet/nutrition (dietary calcium intake)
- the hormonal state

Beginning in the fourth decade----decline in skeletal mass---

average loss of 0.7% of bone mass per year.
Primary osteoporosis:

1. senile osteoporosis (age-related change): low-turnover osteoporosis

- Osteoblasts from older individuals have reduced proliferative and biosynthetic potential and reduced response to growth factors.
- Reduced physical activity
- Calcium nutritional state (Calcium deficiency, increased PTH concentrations, and reduced levels of vitamin D)

2. Postmenopausal osteoporosis: high-turnover osteoporosis

- Estrogen deficiency---- increase inflammatory cytokines----- increase RNAKL/decrease OPG----osteoclast activation
- about 40% of postmenopausal women are affected by osteoporosis.

Secondary osteoporosis (less common):

- Endocrine disorders (e.g., hyperthyroidism, Hyperparathyroidism)
- Gastrointestinal disorders (e.g., malnutrition).
- Drugs (e.g., corticosteroids)
Clinical Course:

Vertebral fractures:
- pain
- loss of height
- deformities (lumbar lordosis, kyphoscoliosis).

Immobility (fractures of the femoral neck, pelvis, or spine):

- pulmonary embolism
- pneumonia.

Diagnosis:
measurement of blood levels of calcium, phosphorus, and alkaline phosphatase are not
diagnostic.
specialized radiographic imaging techniques, such as dual-energy x-ray absorptiometry and
quantitative computed tomography, both of which measure bone density.
Osteopenia: 1-2.5 standard deviation below mean peak bone mass.
Osteoporosis: at least 2.5 standard deviations below mean peak bone mass.
Treatment and prevention:

- exercise,
- appropriate calcium and vitamin D intake.
- Bisphosphonates---reduce osteoclast activity.
- Denosumab---an anti-RANKL antibody that blocks osteoclast
activation.
- menopausal hormone therapy (HRT).
2. Rickets and Osteomalacia:

an impairment of mineralization and a resultant accumulation of

unmineralized matrix.

Due to vitamin D deficiency or its abnormal metabolism.

Rickets----children
Osteomalacia----- adult counterpart----fractures.
3. Hyperparathyroidism
Excess production and activity of PTH

primary hyperparathyroidism
secondary hyperparathyroidism

increased osteoclast activity, bone resorption----osteopenia----

osteoporosis.
Paget disease:
Increased, but disordered and structurally unsound bone.

Three phases:
(1) An initial osteolytic stage,
(2) a mixed osteoclastic–osteoblastic stage---ends with a
predominance of osteoblastic activity
(3) quiescent osteosclerotic stage.

- begins in late adulthood (about 1% of the U.S. population older than age 40
is affected)
- Relatively common in whites in England, France, Austria, regions of Germany, Australia, New Zealand, and
the United States.
Pathogenesis:

1. Genetic causes:
SQSTM1 gene mutations:
- 50% of familial Paget disease and 10% of sporadic cases.
- The mutations increase the activity of NF-κB---increases osteoclast
activity.

- Activating mutations in RANK

- inactivating mutations in OPG juvenile Paget disease

2. Environmental causes:
- The geographic distribution
- infection of osteoclast precursors with viruses (measles/ RNA viruses)
alters vitamin D sensitivity and IL-6 secretion---increased bone resorption.
Morphology:

The hallmark, seen in the sclerotic phase; Mosaic

pattern of lamellar bone pathognomonic of Paget
disease.

The bone is thickened but lacks structural stability,

making it vulnerable to deformation and fracture
Clinical Course:

monostotic in about 15% of cases

polyostotic in 85% of cases.

The axial skeleton or proximal femur is involved in up to 80% of cases.

Most cases are asymptomatic and are discovered as an incidental radiographic finding or elevated serum alkaline phosphatase.

Pain (fractures or by bone overgrowth that compresses spinal and cranial nerve roots).

Bone deformity/overgrowth----osteoarthritis

Enlargement of the craniofacial skeleton may produce leontiasis ossea (lion face)

Secondary osteosarcoma
- Occurs in less than 1% of all individuals with Paget disease.
- appears in 5% to 10% of those with severe polyostotic disease.
Prognosis:

In the absence of malignant transformation, Paget disease is usually

not a serious or life-threatening disease.

Most affected individuals have mild symptoms that are readily

suppressed by treatment with calcitonin and bisphosphonates.
Osteomyelitis:

Infection of bone and marrow.

All types of organisms (viruses, parasites, fungi, and bacteria) can

produce osteomyelitis,

Pyogenic (bacterial) Osteomyelitis Most common

Mycobacterial Osteomyelitis
Pyogenic (bacterial) osteomyelitis

Organisms may reach the bone by:

(1) hematogenous spread---children/long bone

(2) extension from a contiguous site (diabetic foot)---adults

(3) direct implantation after compound fractures or orthopedic
procedures----adults
Staphylococcus aureus:
80% to 90% of the cases

Escherichia coli, Pseudomonas, and Klebsiella

genitourinary tract infections
intravenous drug abusers

Mixed bacterial infections

direct spread, inoculation of organisms during surgery, or into open fractures.

Haemophilus influenzae and group B streptococci

In the neonatal period.

Salmonella infection
sickle cell disease.

In almost 50% of suspected cases, no organisms can be isolated.

Morphology:

In the acute phase:

Neutrophilic inflammatory reaction
Necrosis of bone cells and marrow
subperiosteal abscess-----soft tissue abscess---draining sinus (skin).

The dead bone is known as a sequestrum.

suppurative arthritis
In infants (uncommonly in adults).
the epiphyseal infection may spread into a joint.
can cause destruction of the articular cartilage and permanent disability.
Subacute and chronic phase:
After the first week,
chronic inflammatory cells
fibrous tissue
deposition of reactive bone at the periphery
involucrum
Clinical Course:
acute systemic illness with malaise, fever, chills, leukocytosis, and marked throbbing
pain over the affected region--- Hematogenous osteomyelitis

unexplained fever----most often in infants.

localized pain----most often in adults.

The diagnosis:

Radiographic findings: a lytic focus of bone destruction surrounded by a zone of

sclerosis.

Biopsy and bone cultures are required to identify the pathogen in most instances.

Treatment:
The combination of antibiotics and surgical drainage is usually curative.
Chronic osteomyelitis:

Occurs in 5% to 25% of cases

- delay in diagnosis
- extensive bone necrosis
- inadequate antibiotic therapy or surgical debridement
- weakened host defenses.

Complications of chronic osteomyelitis:

- acute flare-ups
- pathologic fracture
- secondary amyloidosis
- endocarditis
- sepsis
- squamous cell carcinoma in the draining sinus tracts.
- sarcoma in the infected bone.
Mycobacterial osteomyelitis:

developing countries
developed world (immigration and immunocompromised patients)

1% to 3% of individuals with pulmonary or extrapulmonary tuberculosis exhibit osseous infection.

- The organisms are usually blood borne and originate from a focus of active visceral disease
- Direct extension (e.g., from a pulmonary focus into a rib) also may occur.

Typically, affected individuals present with localized pain, low-grade fevers, chills, and weight loss.

Infection is usually solitary except in immunocompromised individuals.

The histologic findings??.

Mycobacterial osteomyelitis tends to be more destructive and resistant to control than pyogenic
osteomyelitis.
Pott disease :

Tuberculous spondylitis (is a destructive infection of vertebrae).

The spine is involved in 40% of cases of mycobacterial
osteomyelitis.

- Destruction of discs and vertebrae

- compression fractures
- scoliosis or kyphosis
- neurologic deficits secondary to spinal cord and nerve
compression.
Thank you