66. Hereditary, inflammatory and metabolic bone diseases

Bone is comprised of?

An organic osteoid matrix which is mineralized by calcium-phosphate-salt called hydroxyapatite

- Proteins like type 1 collagen

- Noncollagenous proteins

What type of bone does osteoblasts produce?

Woven bone:

- Result of rapid bone formation

- Randomly ordered

- Weak

- Characteristic for bone growth during childhood

- If present in adults: sign of pathology - too rapid bone formation

Lamellar bone:

- More orderly layered, therefore stronger

- Takes longer time to form

What is a tool used to diagnose bone abnormalities?

X-rays

Radiolucent? (x-ray)

Tissues that are easily penetrated by x-ray

- Appear black/dark

Soft tissue like skin & muscle are radiolucent, as well as clear lungs

Radiopaque? (x-ray)

Tissues that are not easily penetrated by x-rays

- Visible as white/light grey

- Bone is radiopaque

Pathological fracture?

A fracture which occurs after a force that would NOT fracture a healthy bone

- Examples include experiencing a fracture after lifting something or even a sneeze

Congenital disorders of bone?

- Achondroplasia

- Thanatophoric dwarfism

- Osteogenesis imperfecta

- Osteopetrosis

Achondroplasia?

Cartilage proliferation in the epiphyseal growth plate

- Gain-of-function mutation in Fibroblasts Growth Factor Receptor 3

- Autosomal dominant inherited

What does the mutation in achondroplasia lead to?

Mutation impairs endochondral ossification, but not intramembranous ossification

= Therefore affects growth of long bones, but not flat bones

Patient will have short extremities with normal-size head and chest.

- Mental function is not affected

Thanatophoric dwarfism?

More severe form of achondroplasia

- Also due to gain-of-function of FGFR3, but a different mutation

- Affected babies develop such a small chest that they die soon after birth due to respiratory insufficiency

Osteogenesis imperfecta?

Congenital defect of bone formation resulting in weak bone

- Most frequently due to an autosomal dominant defect in the synthesis of type 1 collagen

Clinical features of osteogenesis imperfecta?

- Multiple fractures

- Blue sclera

- Hearing loss

• Type 1 collagen is also found in sclera -> if collagen is decreased, the veins underneath will be more exposed

• Hearing loss is due to fracture of bone within the ear

Osteopetrosis?

Petra = "rock" in greek

Congenital defect in the resorption function of osteoclasts

- Resulting in abnormally thick & heavy bones

- Bone marrow is replaced by bone

- Bones easily fracture, despite their thickness

How does Osteopetrosis show on X-ray?

Bone including the bone marrow is completely radiopaque

Cause of Osteopetrosis?

Carbonic anhydrase II deficiency --> osteoclast dysfunction --> failure of normal bone resorption

What can carbonic anhydrase in osteopetrosis also lead to?

- Renal tubular acidosis

What are the consequences of bone marrow deprivation in Osteopetrosis?

Myelophthisis - occurs due to ossification of the bone marrow, causing anemia, thrombocytopaenia & leukopaenia

= Extramedullary haematopoiesis occurs

Treatment osteopetrosis?

Bone marrow transplant

Acquired disorders of bone?

- Osteoporosis

- Paget disease of bone

- Rickets and osteomalacia

- Generalized osteitis fibrosa cystica

- Osteomyelitis

- Avascular necrosis

Osteoporosis?

Occurs when bone mass is decreased

- Resulting in a porous bone with increased risk for fracture

Who develops osteoporosis?

Elderly and postmenopausal women (as they have decreased estrogen levels)

When does bone mass peak?

At age 30

Approx. 1% of bone is lost per year after the peak

What does the rate of bone loss depend on?

- Diet

- Exercise

- Estrogen levels (it decreases rate of bone loss)

Consequences of osteoporosis?

- Fracture (often occur in the neck of femur)

- Kyphosis (shortening of the spine)

Treatment osteoporosis?

- Exercise

- Vitamin D

- Calcium supplements

Paget disease of bone?

Imbalance between osteoclast and osteoblast function

- Usually seen in late adulthood (<55y/o)

- Etiology is unknown, but may be viral

- Affects one or more bones, but never the whole skeleton.

How are the bones morphology in Paget disease?

Bones are thickened, but weak and fragile

What bones are commonly affected by Paget disease?

- Spine

- Pelvic bones

- Skull

Three phases of Paget disease?

1. Lytic phase: Osteoclasts are highly active, resorbing too much bone

2. Mixed lytic & blastic phase:

Osteoblasts start producing bone to compensate for the excessive bone resorption

3. Sclerotic phase:

Osteoclasts and osteoblasts calm down & stop remodelling the bone

Clinical features of Paget disease?

- Bone pain (microfractures)

- Bone deformities

- Increased hat size (skull is thickened)

- Hearing loss (compressed cranial nerve)

Complications Paget disease?

- High-output cardiac failure (AV shunts form in the remodelled bone)

- Osteosarcoma - malignant tumor of osteoblasts, as they are highly active and proliferative in Paget disease

Rickets and osteomalacia?

Due to vitamin D hypovitaminosis

- Lack of vitamin D impairs the mineralization of osteoid

Hypovitaminosis D in children?

Leads to rickets

- As their growth plate has not closed yet

- Pigeon breast deformity

- Bowing of the legs

Hypovitaminosis D in adults?

Osteomalacia

- Their growth plates are closed

Bones become weak and the risk for fracture increases

Generalized osteitis fibrosa cystica?

"Von Recklinghausen disease of bone"

- Complication of hyperparathyroidism -> parathyroid adenoma

- PTH increases the osteoclast activity & bone resorption => causing loss of bone mass

- Brown cystic masses form within the bones (can be mistaken for primary bone tumors)

Osteomyelitis?

Inflammation of the bone and bone marrow

- Most frequently affect children

- Infection often spread haematogenously into the bone marrow

- Can also occur after fracture

Pathogen that often cause osteomyelitis?

- Most common: Staphylococcus aureus

- TB can also cause it

Symptoms of osteomyelitis?

Fever, night sweats, malaise, constant bone pain, and swelling, warmth and restricted movement at the infection site

- Leukocytosis

Avascular necrosis?

"Osteonecrosis"

- Ischemic necrosis of bone and bone marrow

- Often occur due to trauma or fracture