Lecture 11: Non-Neoplastic Bone Diseases

Achondroplasia

Autosomal Dominant (AD)- Gain-of-function mutation in FGFR3 gene

↑ FGF effect → ↓↓ enchondral growth → long bones are short

Intramembranous bone formation is not affected – flat bones not affected

Disproportionate short-stature dwarf

Short arms & legs but Trunk of relatively normal length

Normal size/relatively enlarged head with bulging forehead

Depression of the root of the nose/flat nasal bridge

Mildly delayed motor milestones

High risk for osteoarthritis

Thanatophoric dysplasia

Lethal form of dwarfism- Incompatible with life beyond infancy

Gain-in-function mutation in FGFR3 gene

Micromelic shortening of limbs- extremely short limbs

Frontal bossing

Relative macrocephaly

Small chest (pulm. hypoplasia)→ respiratory insufficiency → death

Bell shaped abdomen

Usually die at birth or soon after birth

Osteogenesis imperfecta Type-1

Mutations in alpha1 & alpha 2 chains of type-I collagen (COL1A1 & COL1A2)

Decreased synthesis of type-I collagen (osteopenia)

AD: Qualitatively normal type-1 collagen in ↓ amounts → mild skeletal defects

↓ bone mass → extreme bone fragility

Frequent fractures (often with little or no trauma) since birth & bone deformities

Blue sclera due to visualization of underlying choroid vessels through thinned sclera → Vision problems

Hearing loss; conductive and/or sensorineural

Small misshapen blue yellow, opalescent teeth due to deficiency in dent

Osteopetrosis

AKA Marble bone disease, Albers-Schonberg disease

Hereditary

Impaired osteoclasts b/c impaired acidification of resorption pits → ↓ osteoclast bone resorption → diffuse symmetric skeletal sclerosis → stone-like bones/ abnormally radio-dense

↑ abnormal bone mass, brittle bones which break like chalk

Sclerotic/marble like thick, heavy but brittle bones → Fracture easily

Ends of bones are bulbous → Ehrlenmeyer flask deformity

Bones lack medullary canal (Primary spongiosa persists) → ↓ hematopoiesis → Leukopenia, anemia, thrombocytopenia (pancytopenia)

Extensive extramedullary hematopoiesis → hepatosplenomegaly

Small neural foramina → compression of nerves → blindness, deafness, facial paralysis

Roots of teeth are difficult to visualize

Dx: radiographs showing abnormally dense bones/diffuse symmetric sclerosis

Osteoporosis

Decreased bone mass/density

Primary generalized osteoporosis:

Postmenopausal (cancellous compartment of vertebral bodies)

Senile osteoporosis (cortex is thinned)

Senile osteoporosis

Osteoclasts are working at their normal rate, but osteoblasts are not forming enough bone → ↓ bone mass

Age-related changes in bone

Postmenopausal Osteoporosis

↑ bone loss due to ↓ estrogen

↓ in Estrogen → ↑ tumor necrosis factor (TNF), interlukin-1, & interlukin-6 release from monocytes → ↑ levels of RANK-L & RANK & ↓OPG → ↑ osteoclast recruitment & activity

↓ estrogen ↑ bone resorption & formation but more resorption

Osteoporosis Morphology

Normally mineralized bone that is ↓ in quantity

Entire skeleton is affected

Postmenopausal osteoporosis:

Vertebrae more affected because have greater surface area

Micro-fractures lead to vertebral collapse

Senile osteoporosis: Cortex is thinned by sub-periosteal resorption

Osteoporotic vertebral body (right)

Advanced osteoporosis

Diminished quantity of normal bone

Cortical bone + Trabecular bone thinned

Osteoporosis

Paget’s disease of bone (Osteitis Deformans)

Chronic disorder of increased , but disordered bone mass due to disordered remodeling (rapid breakdown & faulty rebuilding) due to osteoclast dysfunction

Elderly white

SQSTM1 mutations → ↑ NF-kb activity → ↑ osteoclast activity

Infection of osteoclast precursors with viruses

Paramyxovirus such as Measles, RSV

Diseased osteoclasts are hyper-responsive to: Vitamin D & IL-6 → ↑ osteoclast recruitment & bone resorption

Paget’s disease of bone Stages

Osteolytic: ↑ osteoclast activity – abnormally large osteoclasts with many nuclei

Numerous resorption pits

Mixed osteoblastic-osteoclastic stage: Prominent osteoblasts → new bone woven or lamellar which is eventually remodeled to lamellar bone

Osteosclerotic stage: Osteoblastic & osteoclastic activity cease → thickened trabeculae which lack structural stability → fractures easily

Paget’s disease of bone Morphology

Mosaic pattern of dense lamellar bone in sclerotic phase

Prominent irregular cement lines & haphazard orientation of lamellar bone

Sclerotic phase: bones are thicker than normal but structurally unstable & fracture easily

Paget’s disease of bone

Paget’s disease of bone

Paget’s disease of bone

Paget’s disease of bone Clinical

Monostotic

Mostly Polyostotic

Axial skeleton or proximal femur

Not a serious life-threatening condition & progresses over many years

Onset late adulthood (>50) & more common with increasing age

Asymptomatic + X-ray as thick sclerotic coarse bone

Symptoms are usually mild:

Bone pain at site of affected bone due to micro-fracture or overgrowth causing nerve impingement → hearing loss, numbness

Enlargement of craniofacial skeleton (lion face), Bowing of leg bones, Painful jaw enlargement with separation of teeth

Anterior bowing of the femur → distorts femoral head → secondary osteoarthritis

Paget’s disease of bone

Paget’s disease of bone Complications

Severe secondary osteoarthritis due to abnormal joint alignment

Chalk-stick bone fractures in long bones due to weaker bones of lower extremity

Compression fractures of spine → kyphoscoliosis

Hypervascularity of pagetic bones makes overlying skin warm

↑ blood flow due to ↑ bone remodeling acts as arteriovenous shunt → high- output congestive heart failure → left ventricular hypertrophy

Tumors & tumor-like conditions develop in pagetic bone

Benign: giant cell tumor, extraosseous masses of hematopoiesis

Malignant: osteosarcoma

elevated serum alkaline phosphatase

Paget’s disease of bone

Paget’s disease of bone Xrays

“Burnt out stage” - Pagetic bone typically are enlarged bone with thick, coarsened trabeculae – densely sclerotic bone

Mixed phase – osteosclerotic with osteolytic areas

Hyperparathyroidism

↑ production of parathyroid hormone (PTH) → ↑ osteoclast activity → ↑ bone resorption → osteopenia

Osteoporosis: generalized

More severe in phalanges, vertebrae & proximal femur

Dissecting osteitis: osteoclasts tunneling & dissecting through trabeculae (railroad tracks) → ↓ bone density → fracture

Brown tumor: mass of reactive tissue not a true tumor

Microfractures with secondary hemorrhage, influx of macrophages, ingrowth of fibrous tissue

Brown color is due to vascularity, hemorrhage, hemosiderin deposition

Radiolucent

Brown tumor can undergo cystic degeneration → osteitis-fibrosa-cystica

Brown tumor

Healing of fracture

Inflammatory (hours to 1 week): Hematoma forms immediately after fracture & fills the fracture gap. → inflammatory cells come

Soft callus (2 to 3 weeks): uncalcified, formed by fibroblasts & chondroblasts

Bony callus formation (3 to 12 weeks): formed by osteoblasts (woven bone)

Remodeling (months to years): osteoclasts remodel new bone

Lamellar bone laid down which increases the bone strength

Reduces the size of the callus

Medullary cavity formed

If nonunion fracture persists

malformed callus → cystic degeneration → pseudoarthrosis (false joint)

Osteonecrosis (avascular/aseptic necrosis)

Localized area of infarction/death of bone & marrow cells

Medullary cavity (most common) or in subchondral location

Mostly due to ischemia:

Vascular injury – trauma causing fracture

Corticosteroids

Systemic disease – hemoglobinopathies such as sickle cell disease/crisis; hyper-lipedemia

Radiation

Caisson disease – in divers - nitrogen bubbles can embolize to skeletal system causing bone ischemia

Pregnancy, Infection, Alcohol abuse

Osteonecroses of the jaw

Complication of long-term bisphosphonate therapy & more likely to occur if patient also on chemotherapy

Osteochondroses

Self-limiting, non-inflammatory, non-infectious developmental disorders in growing children & adolescents who are often athletes & is mostly related to repetitive injury

Caused by ischemic necrosis

Near joints/epiphyses

M > F

Pain, swelling & reduced function

Legg-Calve-Perthes disease: osteonecrosis of femoral head in children → osteoarthritis

Osgood-Schlatter disease: osteonecrosis of tibial epiphysis at knee

Osteomyelitis

Inflammation of bone & marrow

Secondary to infection:

Pyogenic bacteria & mycobacteria

Coccidiodomycosis (fungus)

Viruses & parasites

Hematogenous: metaphysis of long

Minor occult injury to skin, GIT

Involve vertebrae in adults & long bones in children

Extension from contiguous site:

sinus infection → orbital bones, cranium

Dental pathology/periapical abscess or procedure → maxilla/mandible

Infection of feet in diabetics

Direct implantation: After traumatic injury or orthopedic procedures

Staph aureus

Osteomyelitis Morphology

Acute phase:

Neutrophilic inflammatory reaction

Necrosis of bone & marrow → subperiosteal abscess

Dead bone is known as sequestrum

Rupture of periosteum → soft tissue abscess → draining sinus

In infants epiphysial infection → spread through articular surface → septic arthritis → destruction of articular cartilage and permanent disability

Chronic phase (after 1 week): cytokines from chronic inflammatory cells stimulate

Osteoclastic bone resorption

Reactive bone formation at the periphery – involucrum (sleeve of living tissue around dead infected bone)

Osteomyelitis

Osteomyelitis