Lecture 4.2: Disorders of Bone Flashcards
Osteogenesis Imperfecta
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
Osteogenesis Imperfecta: Type I
Mild
Autosomal Dominant/ New Mutation
Blue Sclerae
Mild bone fragility
Fractures after walking
Minimal deformity
Osteogenesis Imperfecta: Type II
Lethal
Autosomal Recessive/ New Mutation
Blue Sclerae
Multiple intrauterine fractures
Servere deformity
Still birth/ early neonatal death
Osteogenesis Imperfecta: Type III
Severe deforming
Autosomal Recessive/ New Mutation
Normal sclerae
Dentinogenesis imperfecta
Frequent fractures
Deformity of long bones
Short stature
Scoliosis
Osteogenesis Imperfecta: Type IV
Intermediate
Autosomal Dominant/ New Mutation
Normal sclerae
Moderate deformity
Short stature
Dentinogenesis imperfecta (possible)
Growth Hormone (GH)
GH (somatotropin) is synthesised and stored in the anterior pituitary, and promotes growth of epiphyseal cartilage
Growth Hormone (GH): what is it? where is it made?
GH (somatotropin) is synthesised and stored in the anterior pituitary, and promotes growth of epiphyseal cartilage
Pituitary Gigantism
Before puberty, excessive GH can cause gigantism through promotion of epiphyseal growth plate activity
Pituitary Dwarfism
Before puberty, insufficient GH can affect epiphyseal cartilage and cause pituitary dwarfism (the most common form of proportionate dwarfism)
Acromegaly
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
Sex Hormones and Ossification
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
Effect of Thyroid Hormones on Bone
In addition to increasing metabolic rate, thyroxine is involved in neural maturation and bone growth
Neonatal Hypothyroidism: symptoms? testing?
Intellectual impairment
Short stature
Heel prick screening test
Osteoporosis
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
When does bone mass peak?
25-35 years
Begins to decline from around the age of 40
Osteoporosis: Treatment
Bisphosphonates, which adhere to bone and suppress osteoclast activity
Primary Osteoporosis
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
Non-modifiable risk factors for Osteoporosis
- Genetics: family history, ethnicity (black populations
have a higher peak bone density) - Age
- Sex
- Slim build
- Previous fractures
- Other disorders (e.g. rheumatoid arthritis)
Modifiable risk factors for Osteoporosis
- Increase Calcium and Vitamin D intake
- Increase exercise (immobilisation of bone leads to
accelerated bone loss) - Excessive alcohol intake
- No smoking
Achondroplasia: Pathophysiology
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
Genetics of Achondroplasia
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
Achondroplasia: Characteristics/ Symptoms
Normal intelligence
Large head – frontal bossing
Small midface
Proximal long bone shortening
Short fingers / toes
Trident hand
Lumbar lordosis
Spinal stenosis
Vitamin D metabolism and Bone
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
Rickets
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
