Hereditary and Acquired Disorders of Bone and Bone Repair

What are Dysostoses?

malformations of individual bones or a group of bones. caused by localized problems in migration and condensation of mesenchyme and its differentiation into the cartilage anlage

Genetic alterations affecting which genes are often associated with Dysostoses?

Homeobox genes

What are 4 common types of Dysostoses?

1. Congenital absence of individual bones (aplasia)

2. Formation of extra bones (supernumerary ribs, digits)

3. Fusion of adjacent digits (syndactylism)

4. Hypoplasias of bone (mandible, maxilla)

T/F: Dysostoses frequently occur alongside other anomalies, like cleft lip, coloboma of the optic discs, and hernias.

True

What is Coloboma of the optic nerve?

a congenital anomaly of the optic disc in which there is a defect of the inferior aspect of the optic nerve. The issue stems from incomplete closure of the embryonic fissure while in utero

What are the 3 (arbitrary) categories of Dysostoses?

1. Predominantly craniofacial involvement

2. Predominantly vertebral involvement

3. Affecting only the extremities

Craniofacial dysostoses occur as a result of the abnormal development of which pharengeal arches during embryogenesis?

first and second arches

T/F: Craniofacial dysostoses are typically heterogeneous.

True

What are some potential issues faced by patients with craniofacial dysostoses?

feeding or breathing problems

What are dysplasias?

a group of more than 450 disorders that result from global disorganization of bone and/or cartilage.

What is the most common skeletal dysplasia?

Achondroplasia

Achondroplasia is the result of an autosomal dominant gain-of-function mutation in which gene?

FGFR3

Which type of bone formation is affected by Achondroplasia?

endochondral

Bone (width/length) is affected by Achondroplasia.

length

T/F: Appositional growth is not affected by Achondroplasia, resulting in normal bone width.

True

T/F: Most instances of Achondroplasia are familial mutations.

False

T/F: Most instances of Achondroplasia are acquired mutations.

True

Why do homozygotes for Achondroplasia die soon after birth?

due to a constricted thoracic cage

What is Vosoritide?

Analogue of C-Type Natriuretic peptide that is potent stimulator of endochondral ossification and inhibits FGFR3 pathway

T/F: Patients with Achondroplasia have a normal lifespan and intelligence.

True

What is the most common inherited disorder of connective tissue?

Osteogenesis imperfecta

Osteogenesis imperfecta related to a defect in the synthesis of which type of collagen?

Type I

What are the 2 most common inheritance patterns for osteogenesis imperfecta?

1. AD

2. sporadic

What is the fundamental abnormality of osteogenesis imperfecta?

there is "too little bone"

Which subtype of OI is the severe form that results in fetal demise?

Type II

Which subtype of OI is associated with a normal lifespan and increased childhood fractures?

Type I

What are 3 key clinical presentations of OI, not including bone fragility?

1. Blue sclera

2. Small blue-yellow teeth (dentin deficiency)

3. hearing loss

What is osteopetrosis?

Increased density of atypically soft/brittle bone due to decreased bone resorption.

Osteopetrosis is often due to a hereditary deficiency in (osteoblast/osteoclast) activity.

osteoclast

Most mutations relating to osteopetrosis interfere with what part of bone resorption?

the process of acidification of the osteoclast resorption pit

Which two osteoclast enzymes are responsible for the acidification of the resorption pit?

1. Carbonic anhydrase II

2. H+-ATPase (proton pump)

T/F: Due to their increased bone density, osteopetrosis patients are at a decreased risk of fracture.

False

Why are osteopetrosis patients at an increased risk of fracture?

the deposited bone is not remodeled and tends to be woven, which is weaker than remodeled bone.

Why are osteopetrosis patients at an increased risk of anemia and infections?

they have decreased medullary space for hematopoiesis.

Why are osteopetrosis patients at an increased risk of facial paralysis or deafness?

their skeletal malformations can result in small neural foramina--> nerve compression

T/F: Osteopetrosis is the first genetic disease to be treated with hematopoietic stem cell transplantation.

True

T/F: Donor stem cells may reverse many of the skeletal abnormalities in an osteopetrosis patient.

True

What is Paget's disease?

Increased but disordered structurally unsound bone due to chaotic bone remodeling and increased osteoblastic+osteoclastic activity

What are some risk factors for Paget's disease?

1. Genetic variations in the pathways that regulate osteoclast activity, like NFKB

2. Potential role of RNA virus infection of osteoclasts, like measles

What are the 3 stages of Paget's disease?

1. Osteolytic stage

2. Mixed osteolytic-osteoblastic stage

3. Quiescent osteosclerotic stage

What does the new bone look like during the mixed osteolytic-osteoblastic stage of Paget's disease?

it is disorganized and poorly mineralized

Remodeling of the new bone during the sclerotic phase of Paget's disease results in what appearance of lamellar bone?

a mosaic pattern of lamellar bone with prominent cement lines between random lamellar bone units

80% of Paget's disease cases involve what two skeletal structures?

1. axial skeleton

2. proximal femur

T/F: Most cases of Paget's disease are asymptomatic and are discovered incidentally by radiographs.

True

What are some sign/symptoms of Paget's disease? (5)

1. Pain

2. chalkstick fractures

3. osteoarthritis from femoral head distortion

4. Tibia bowing

5. irregularly thick cortical and cancellous bone.

What is the treatment for Paget's disease?

Calcitonin and bisphosphonates

What type of cancer may develop in 5-10% of Paget's disease patients with severe polyostotic disease (affecting multiple bones)?

sarcoma

What blood test result may indicate Paget's disease?

elevated Alk. Phosphatase

What is osteoporosis?

Reduction in bone mass owing to small incremental losses incurred in constant turnover of bone

How does osteoporosis differ from OI?

osteogenesis results in a reduction in bone with normal proportions of protein matrix and minerals. OI has a higher proportion of minerals to the protein matrix.

What are some clinical presentations of osteoporosis?

1. vertebral instability

2. back pain

3. increased hip, wrist, and vertebral body fracture.

What is the localized presentation of osteoporosis?

diffuse atrophy of limb

What is the generalized presentation of osteoporosis?

Postmenopausal, senile, hyperthyroidism, malnutrition

At what point in life do most people reach their peak bone mass?

young adulthood

At what point in life does bone resorption outpace bone formation?

after age 40

Which 3 physiologic changes with menopause lead to osteoporosis?

1. decreased estrogen

2. increased IL-1, IL-6 levels

3. increased osteoclast activity

What 2 types of bone loss are associated with senile osteoporosis?

1. trabecular

2. cortical bone loss

What is secondary osteoporosis?

Low bone mass leading to fragility fractures in presence of underlying disease/medication

What are 2 possible complications of bone fractures?

1. pulmonary embolism

2. pneumonia

How is osteoporosis diagnosed?

DEXA scan (bone density scan)

What are 3 treatments for osteoporosis?

1. Exercise

2. appropriate calcium and vitamin D intake

3. bisphosphonates

What are the 5 steps of fracture repair?

1. Hematoma formation fills in the fracture gap, and fibrin mesh provides the framework for repair

2. Fibroblasts and osteogenic cells stimulated by cytokines. This activated osteoblasts and osteoclasts.

3. Procallus (End of week one): some bone forms in the gap, but this cannot be weight bearing.

4. Bony Callus (Week 2): endochondral ossification and mineralization allows for controlled weight bearing.

5. Excess fibrous tissue, cartilage, and bone resorbed at non-stressed sites; fortification of the weight bearing sites

What are some possible complications of fracture repair? (3)

1. Delayed union or nonunion.

2. Infection in open fractures

3. systemic issues like vit. D deficiency.

What are some potential reasons for delayed fracture union? (3)

1. Inadequate immobilization

2. normal callus unable to form

3. Pseudoarthrosis