Lecture 4.2: Disorders of Bone

Question 1

Osteogenesis Imperfecta

Answer 1

Aka Brittle Bone disease

Part of a group of genetic disorders of connective tissue

Types I-IV arising from mutations in one of the genes encoding type I collagen

Affects the skeleton, joints, ears, ligaments, teeth, sclerae and skin

Question 2

Osteogenesis Imperfecta: Type I

Answer 2

Mild
Autosomal Dominant/ New Mutation

Blue Sclerae
Mild bone fragility
Fractures after walking
Minimal deformity

Question 3

Osteogenesis Imperfecta: Type II

Answer 3

Lethal
Autosomal Recessive/ New Mutation

Blue Sclerae
Multiple intrauterine fractures
Servere deformity
Still birth/ early neonatal death

Question 4

Osteogenesis Imperfecta: Type III

Answer 4

Severe deforming
Autosomal Recessive/ New Mutation

Normal sclerae
Dentinogenesis imperfecta
Frequent fractures
Deformity of long bones
Short stature
Scoliosis

Question 5

Osteogenesis Imperfecta: Type IV

Answer 5

Intermediate
Autosomal Dominant/ New Mutation

Normal sclerae
Moderate deformity
Short stature
Dentinogenesis imperfecta (possible)

Question 6

Growth Hormone (GH)

Answer 6

GH (somatotropin) is synthesised and stored in the anterior pituitary, and promotes growth of epiphyseal cartilage

Question 7

Growth Hormone (GH): what is it? where is it made?

Answer 7

GH (somatotropin) is synthesised and stored in the anterior pituitary, and promotes growth of epiphyseal cartilage

Question 8

Pituitary Gigantism

Answer 8

Before puberty, excessive GH can cause gigantism through promotion of epiphyseal growth plate activity

Question 9

Pituitary Dwarfism

Answer 9

Before puberty, insufficient GH can affect epiphyseal cartilage and cause pituitary dwarfism (the most common form of proportionate dwarfism)

Question 10

Acromegaly

Answer 10

In adults, excessive GH cannot cause gigantism because the epiphyseal plates have closed

It may, however, cause an increase in bone width by promoting periosteal growth

Hands and feet are broadened, soft tissue is thickened, forehead bulges and chin is enlarged

Question 11

Sex Hormones and Ossification

Answer 11

Androgens and oestrogens induce secondary sexual characteristics in each sex, and give rise to the pubertal growth spurt

Precocious sexual maturity retards bone growth because of premature fusion of epiphyseal growth plates

Deficient sex hormones may lead to epiphyseal plates persisting later into life, leading to prolonged bone growth and tall stature

Question 12

Effect of Thyroid Hormones on Bone

Answer 12

In addition to increasing metabolic rate, thyroxine is involved in neural maturation and bone growth

Question 13

Neonatal Hypothyroidism: symptoms? testing?

Answer 13

Intellectual impairment
Short stature
Heel prick screening test

Question 14

Osteoporosis

Answer 14

Bone resorption exceeds bone formation

In particular, loss of cancellous bone (trabeculae damaged) is associated with reduced mechanical strength and increased susceptibility to fracture

Common sites of fractures include are wrists, hips and spine

Question 15

When does bone mass peak?

Answer 15

25-35 years

Begins to decline from around the age of 40

Question 16

Osteoporosis: Treatment

Answer 16

Bisphosphonates, which adhere to bone and suppress osteoclast activity

Question 17

Primary Osteoporosis

Answer 17

Most common form of osteoporosis

Type 1 occurs in postmenopausal women. This is due to an increase in osteoclast number resulting from oestrogen withdrawal

Type 2 occurs in both sexes, particularly from the age of 70 (senile osteoporosis), and reflects reduced osteoblast function

Question 18

Non-modifiable risk factors for Osteoporosis

Answer 18

• Genetics: family history, ethnicity (black populations
  have a higher peak bone density)
• Age
• Sex
• Slim build
• Previous fractures
• Other disorders (e.g. rheumatoid arthritis)

Question 19

Modifiable risk factors for Osteoporosis

Answer 19

• Increase Calcium and Vitamin D intake
• Increase exercise (immobilisation of bone leads to
  accelerated bone loss)
• Excessive alcohol intake
• No smoking

Question 20

Achondroplasia: Pathophysiology

Answer 20

The most common form of short-limbed dwarfism

Autosomal dominant point mutations in the fibroblast growth factor receptor-3 gene (FGFR3) impacts endochondral ossification and promotes early growth plate closure

The mutation leads to a reduction in:
• Proliferation of chondrocytes in growth plate cartilage
• Cartilage matrix production
• Cellular hypertrophy

Question 21

Genetics of Achondroplasia

Answer 21

If two parents with achondroplasia have a child there is:
• A 25% chance that the child will die soon after birth (the homozygous condition is lethal)
• A 50% chance that the child will be heterozygous and have
achondroplasia
• A 25% chance that the child will have a normal phenotype

Question 22

Achondroplasia: Characteristics/ Symptoms

Answer 22

Normal intelligence
Large head – frontal bossing
Small midface
Proximal long bone shortening
Short fingers / toes
Trident hand
Lumbar lordosis
Spinal stenosis

Question 23

Vitamin D metabolism and Bone

Answer 23

Some vitamin D is dietary but most is synthesized in the skin from 7-
dehydrocholesterol by the action of UV light

Vitamin D is hydroxylated in the liver and then the kidney to form
active calcitriol, which acts primarily to increases calcium absorption by
the small bowel, but also promotes bone mineralisation directly

Question 24

Rickets

Answer 24

Childhood disease in which osteoid fails to calcify due to prolonged deficiency in Vitamin D

Insufficient calcium deposition leads to bones becoming soft and malformed

In the UK, rickets is now most common in Asian immigrant families

Question 25

Rickets: Characteristics/ Symptoms

Answer 25

Prominence of frontal bones of skull (bossing)

Enlargement of the costochondral junctions of the ribs (rachitic or rickety rosary)

Bowed tibia & fibia

Question 26

Osteomalacia

Answer 26

Adult counterpart of rickets

Caused by significant calcium deficiency, or lack of vitamin D as a result of poor diet, lack of sunshine, liver or kidney disease

Question 27

Osteomalacia: Characteristics/ Symptoms

Answer 27

Bone pain
Back ache
Muscle weakness
Increased risk of fracture