Session 4: Ossification and Disorders of Bone

Question 1

What disorder of bone results from genetic abnormalities in type I collagen synthesis?

Answer 1

Osteogenesis Imperfecta

Question 2

Name the principle collagen type found in bone?

Answer 2

Collagen type I

Question 3

From what progenitor are osteoblasts derived?

Answer 3

Osteoprogenitors

Question 4

What is the osteoid?

Answer 4

The organic part of the matrix of bone secreted by osteoblasts

Question 5

By what mechanism does the parietal bone develop in the foetus?

Answer 5

Intramembranous ossification

Question 6

By what mechanism does the long bones develop in the foetus?

Answer 6

Endochondral ossification

Question 7

What is the highlighted part of the hyaline cartilage referring to?

Answer 7

Growth plates

Question 8

Describe endochondral ossification process

Answer 8

1) Fetal hyaline cartilage model develops

2) Periosteal bone collar forms around diaphysis with degeneration of underlying cartilage

3) Invasion of capillaries and osteoprogenitors create primary ossification centre in diaphysis. Osteoid undergoes calcification to form woven bone.

4) Secondary ossification centres appear in epiphyses around time of birth

5) In childhood - primary and secondary ossification centres are separated by epiphyseal growth plates that allow elongation

6) Growth plates close at end of puberty (no more elongation can occur). But osteoblast reservoir in periosteum allows for thickening (appositional growth)

Question 9

At what stage in growth do the growth plates close?

Answer 9

At the end of puberty

Question 10

How do flat bones develop?

Answer 10

Intramembranous ossification

Question 11

What mutation causes osteogenesis imperfecta (OI)?

Answer 11

Types I-IV arising from mutations in one of the genes encoding type I collagen (COL1A1 or COL1A2).

Question 12

What structures does osteogenesis imperfecta affect?

Answer 12

Skeleton (tibial fractures; deformity of long bones), joints, ears, ligaments, teeth, sclerae (blue sclerae) and skin

Question 13

What is the name of the growth hormone (GH) stored in the anterior pituitary?

Answer 13

Somatotropin

Question 14

What is the role of somatotropin (growth hormone; GH)?

Answer 14

Promote the growth of epiphyseal cartilage

Question 15

How do you distinguish adult and child x-ray?

Answer 15

Presence of growth plates

Question 16

How can disorders of the growth plate arise from excessive somatotropin (growth hormone; GH) BEFORE puberty?

Answer 16

Before puberty - excess GH can cause gigantism through promotion of epiphyseal growth plate activity. Insufficient GH can affect epiphyseal cartilage and lead to pituitary dwarfism.

Question 17

What is acromegaly? When does it occur?

Answer 17

Rare condition resulting from excess secretion of growth hormone (GH). Acromegaly is the condition that results when there is excess GH AFTER puberty (when the epiphyseal growth plates close).

Question 18

What are the symptoms of acromegaly?

Answer 18

Hands and feet are broadened, soft tissues are thickened.

Question 19

What does the Fibroblast Growth Factor Receptor 3 (FGFR3) mutation lead to?

(Achondroplasia)

Answer 19

The mutation leads to a REDUCTION in:
1) Reduced proliferation of chondrocytes in growth plate cartilage
2) Reduced cartilage matrix production
3) Reduced chondrocyte hypertrophy

Question 20

What are the signs/symptoms of Achondroplasia?

Answer 20

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

Question 21

What is osteoporosis?

Answer 21

The loss of cancellous (spongy) bone associated with reduced mechanical strength and increased susceptibility to fractures (common in wrists, hips and spine).

Question 22

Which sex hormones can influence the growth plate?

Answer 22

Androgens and oestrogens

Question 23

Give an example of a condition arising from deficient thyroid hormones in neonates resulting in short stature and intellectual impairment.

Answer 23

Neonatal hypothyroidism results in intellectual impairment and short stature.

It can be diagnosed with the heel prick screening test.

Question 24

At what age does bone mass peak?

Answer 24

Bone mass peaks between age 25-35 years

Question 25

At what age does bone mass begin to decline?

Answer 25

Bone mass begins to decline from around age of 40

Question 26

What is the standard pharmacological treatment for osteoporosis?

Answer 26

Bisphosphonates - these adhere to bone and suppress osteoclast activity

Question 27

What are the two types of primary osteoporosis? When do they occur?

Answer 27

Primary osteoporosis is the most common form of osteoporosis **Type 1: Post-menopausal women** = **increase in osteoclasts** number due to oestrogen withdrawal **Type 2: Both sexes** - from** age of >70** (senile osteoporosis) = **reduced osteoblast** function

Question 28

What are some non-modifiable risk factors for osteoporosis?

Answer 28

1. Genetics: family history, ethnicity (black populations have higher bone density) 2. Age/gender 3. Small frame 4. Previous fractures 5. Other disorders e.g., rheumatoid arthritis, hyperthyroidism

Question 29

What causes rickets?

Answer 29

Failure of osteoid to calcify in children due to lack of calcium.

Question 30

What is the effect of rickets?

Answer 30

**Long bones become soft and deformed** (bowing of legs) Frontal bone bossing, enlargement of costochondral junctions of the ribs (rachitic or rickety rosary)

Question 31

What does the photomicrograph show?

Answer 31

Surfaces of the bone trabeculae covered by thicker than normal layer of non-mineralised osteoid (red stain) leading to weakening.

Question 32

What is osteomalacia?

Answer 32

Adult counterpart of rickets - caused by significant calcium deficiency or lack of vitamin D (poor diet, lack of sunshine, cultural, liver or kidney disease)

Question 33

What are common symptoms of osteomalacia?

Answer 33

Bone pain, back ache, muscle weakness, increased risk of fracture

Question 34

What is the most common form of short-limbed dwarfism?

Answer 34

Achondroplasia

Question 35

What is the name of the autosomal dominant point mutation leading to Achondroplasia?

Answer 35

Fibroblast growth factor receptor-3 gene (FGFR3) impacts endochondral ossification and leads to short-limbed dwarfism.

Question 36

What is exostoses and when do they form?

Answer 36

Exostoses is an extra growth of bone that extends outward from existing bone. These can form when there are abnormalities in heparan sulphate (HS) synthesis which affect chondrogenesis signalling pathways.

Question 37

What gene mutation leads to abnormalities in the heparan sulphate (HS) synthesis?

Answer 37

Autosomal dominant mutations in the exostosin-1 and exostosin-2 (Ext-1 and Ext-2) genes.

Question 38

How is vitamin D obtained?

Answer 38

Some vitamin D is dietary (e.g. from fish). Most vitamin D is produced in the skin from 7-dehydrocholesterol by the action of UV light (sun).

Question 39

Where is vitamin D hydroxylated?

Answer 39

Vitamin D is hydroxylated in the liver and then the kidney to form the ACTIVE 1,25 dihydroxy vitamin D (calcitriol).

Question 40

What is the role of calcitriol?

Answer 40

Increase calcium absorption in the small bowel Promote bone mineralisation (promotes bone production)

Question 41

What are the signs of rickets?

Answer 41

Long bones become soft and deformed, frontal bone bossing, enlargement of the costochondral junctions of the ribs (rachitic or rickety rosary).

Question 42

What is the pathogenesis of osteomalacia in trabecular bone?

Answer 42

In osteomalacia - surfaces of the bony trabeculae are covered by a thicker than normal layer of non-mineralised osteoid (red stain) leading to weakening.

Question 43

What are the most common fracture sites in osteomalacia?

Answer 43

Femoral neck, pubic ramus, spine and ribs

Question 44

What disorder of bone is this: Short-limbed dwarfism resulting from an activating mutation in the FGFR-3 gene leading to reduced chondrocyte activity at the epiphyseal growth plate, and early closure?

Answer 44

Achondroplasia

Question 45

What disorder of bone is this: Loss of bone density due to overactive osteoclasts following menopause?

Answer 45

Type I osteoporosis

Question 46

What disorder of bone is this: Increased stature as a consequence of enhanced activity at epiphyseal growth plates stimulated by an over-active pituitary gland before puberty?

Answer 46

Gigantism

Question 47

What disorder of bone is this: Brittle bones form due to defects in type I collagen production?

Answer 47

Osteogenesis imperfecta types I-IV

Question 48

What disorder of bone is this: Diminished stature as a consequence of reduced activity at epiphyseal growth plates resulting from an under-active pituitary gland before puberty?

Answer 48

Pituitary dwarfism

Question 49

What disorder of bone is this: Reduced mineralisation of osteoid leading to bone pain and muscle weakness in adults with a vitamin D deficiency?

Answer 49

Osteomalacia

Question 50

What disorder of bone is this: Increase in appositional growth in adults resulting from an over-active pituitary gland?

Answer 50

Acromegaly

Question 51

What disorder of bone is this: Loss of bone density due to diminished osteoblast function with age?

Answer 51

Type II osteoporosis

Question 52

What disorder of bone is this: Bone softening in childhood as a consequence of a vitamin D deficiency?

Answer 52

Rickets (failure of osteoids to calcify in children)

Question 53

Intramembranous ossification is the method by which most ___ bones are formed.

Answer 53

Intramembranous ossification is the method by which most flat bones are formed. It takes place within condensations of embryonic mesenchymal cells at ossification centres. These cells differentiate into osteoprogenitor cells, which in turn proliferate to form a layer of osteoblasts. These cells secrete the osteoid that calcifies to form woven bone. Neighbouring ossification centres fuse and undergo remodelling to form mature bone.

Question 54

Endochondral ossification is the method by which most bones, particularly ___ bones are formed.

Answer 54

Endochondral ossification is the method by which most bones, particularly long bones are formed.

Question 54

Late in the first trimester, a periosteal bone ___ surrounds the cartilaginous template, causing the cartilage to become ischaemic.

Answer 54

Late in the first trimester, a periosteal bone collar surrounds the cartilaginous template, causing the cartilage to become ischaemic.

Question 55

When do the growth plates close?

Answer 55

Puberty

Question 56

What type of bone is disproportionately impacted in osteoporosis?

Answer 56

Cancellous (spongy) bone

Question 57

Apart from the wrist, which two bones/ sites are most commonly fractured in osteoporosis?

Answer 57

Vertebrae

Question 58

At what age range does bone mass density reach its peak?

Answer 58

25-35 years

Question 59

What type of osteoporosis: Loss of bone density resulting from disease (e.g., multiple myeloma) or long-term steroid usage?

Answer 59

Secondary osteoporosis

Question 60

What type of osteoporosis: Affects both men and women, and results from an age-related decrease in osteoblast activity?

Answer 60

Primary osteoporosis type 2

Question 61

What type of osteoporosis: Affects post-menopausal women, and results from an increase in osteoclast activity?

Answer 61

Primary osteoporosis, type 1

Question 62

Identify features in the section of ground bone.

Answer 62

A = Osteocytes in lacunae B = Volkmann's (perforating) canal C = Haversian (central) canal D = Canaliculi E = Interstitial lamella

Question 63

In the following diagram of ground bone, which letters indicate a feature that provides channels for osteocyte communication?

Answer 63

A = Canaliculi are small channels which connect lacunae

Question 64

Which hormone is primarily responsible for the release of calcium stored in bone?

Answer 64

Parathyroid hormone

Question 65

How many genes contribute to the development of osteoporosis?

Answer 65

Many genes contribute to the phenotype (i.e., it's polygenic)

Question 66

Bisphosphonates have two phosphate groups that bind ___ ions, allowing the drug to accumulate at bony surfaces.

Answer 66

Bisphosphonates have two phosphate groups that bind calcium ions, allowing the drug to accumulate at bony surfaces. Bisphosphonates are taken up by osteoclasts and reduce bone loss by reducing their action.

Question 67

Describe Types I, II, III and IV of Osteogenesis Imperfecta.

Answer 67

- Severity - Inheritance pattern - Features/Presentation

Question 68

Name the locations of some deformities and fractures/callouses that are typically presented in Osteogenesis Imperfecta (OI)?

Answer 68

Deformities: - Tibia - Carpal bone Fractures and callouses: - Femurs Forearms bones are typically shortened, thinned and bowed as well

Question 69

Achondroplasia is an autosomal dominant disorder, and lethal in the homozygous form. What percentage of offspring will suffer from achondroplasia assuming one affected parent?

Answer 69

There is a 50% chance that the offspring might suffer from achondroplasia (punnett square)

Question 70

A lack of growth hormone prior to puberty will also impact the growth of epiphyseal cartilage. What disorder results from this?

Answer 70

Pituitary dwarfism

Question 71

A) Why would an excess of growth hormone post-puberty not lead to gigantism? B) What would result instead?

Answer 71

A) Because the growth plates close usually near the end of puberty. B) Acromegaly would result instead.

Question 72

The following x-ray shows a child diagnosed with rickets. Identify the three areas where you can see the epiphyseal growth plate.

Answer 72

The femur and the tibia

Question 73

In osteoporosis, bone ___ exceeds bone formation, ___ bone mineral density.

Answer 73

In osteoporosis, bone resorption exceeds bone formation, leading to decreased bone mineral density.

Question 74

What disorder results from the absence of epiphyseal cartilage?

Answer 74

Pituitary dwarfism

Question 75

Why would an excess of growth hormone post-puberty not lead to gigantism?

Answer 75

Because the growth plates close usually near the end of puberty.

Question 76

What would result instead of gigantism due to excess growth hormone post-puberty?

Answer 76

Acromegaly would result instead.

Question 77

Identify the three areas where you can see the epiphyseal growth plate in a child diagnosed with rickets.

Answer 77

The femur and the tibia

Question 78

In osteoporosis, what exceeds bone formation?

Answer 78

Bone resorption exceeds bone formation.

Question 79

What is reduced in osteoporosis?

Answer 79

Bone mineral density.

Question 80

What type of bone loss is associated with reduced mechanical strength and increased susceptibility to fracture?

Answer 80

Loss of cancellous bone.

Question 81

Common sites of fracture in osteoporosis other than the hips include the?

Answer 81

Wrists and spine.

Question 82

Which one of the following statements is TRUE regarding osteoporosis?

Answer 82

Type 1 osteoporosis occurs in postmenopausal women.

Question 83

What occurs in both women and men, particularly from the age of 70, and reflects reduced function?

Answer 83

Type 2 osteoporosis (senile) reflects reduced osteoblast function.

Question 84

Name two non-modifiable risk factors for osteoporosis.

Answer 84

- Family history - Increasing age - Female sex - Post-menopause - History of fractures

Question 85

Rheumatoid arthiritis vs Osteoarthiritis