Endocrine and Metabolic Bone Disorders

Question 1

What percentage of the body’s calcium is stored in the bone?

Answer 1

>95% of body’s Ca2+

Question 2

What are the two main components of bone and what proportion of its mass is made up by these?

Answer 2

Organic component/osteoid(unmineralised bone) - makes up 35% bone mass; mostly made of type 1 collagen fibres (95%)

Inorganic mineral component - makes up 65% of bone mass; calcium hydroxyapatite crystals fill the space between collagen fibrils

Question 3

What are the two main cells involved in bone remodelling? Describe their functions.

Answer 3

Osteoblasts - synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)

Osteoclasts - release lysosomal enzymes whihc break down bone (bone resporption)

Question 4

What is required for the formation of an osteoclast?

Answer 4

RANKL found on onsteoblasts

Question 5

Describe the process of osteoclast differentiation.

Answer 5

RANKL expressed on osteoblast surface

RANKL binds to RANK-R (on the osteoclast precursor) to stimulate osteoclast formation and activity

Activated osteoclast is invovled in bone resorption

Question 6

How do osteoblasts help regulate bone formation and resorption?

Answer 6

Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) – regulate balance between bone formation & resorption

Question 7

What is the RANK ligand?

Answer 7

• An osteoclast-activating factor – it increases the activation of osteoclasts
• It stimulates the maturation of osteoclasts from osteoclast precursors
• If there are more mature osteoclasts, you get more bone resorption

Question 8

What are the two types of bone? What are the two ways in which collagen fibrils are laid down?

Answer 8

Cortical - hard bone

Trabecular - spongy bone

Both formed in lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong.

Woven bone =disorganised collagen fibrils, wekaer.

Question 9

What are the effects of Vit D deficiency on bone, in adults and children?

Answer 9

Inadequate mineralisation of newly formed bone matrix/osteoid:

Children –> rickets

• Epiphyseal growth plates + bone affected
• Skeletal abnormalities, pain
• Growth retardation and increased fractures

Adults –> osteomalacia

• After epiphyseal closure but affects bone
• Skeletal pain
• Increased fracture risk
• Proximal myopathy

Question 10

What are the zones where insufficiency fractures are common?

Answer 10

Looser zones

Question 11

What type of gait is typical in a pelvic fracture caused by Vit D deficiency?

Answer 11

Waddling gait

Question 12

Summarise the three types of hyperparathyroidism.

Answer 12

Question 13

Name a hyperparathyroid bone disease.

Answer 13

Osteitis fibrosa cystica

Question 14

How can renal disease cause osteitif fibrosa cystica? Name another consequence.

Answer 14

Vascular calcification

NB: in patients with renal failure you need to monitor clacium deficiency and monitor the parathyroid and ensure that they do not develop tertiary hyperparathyroidism.

Question 15

What is the cellular cause of osteoitis fibrosa cystica?

Answer 15

Excess osteoclastic bone resorption secondary to high PTH

Question 16

What are Brown tumours?

Answer 16

Radiolucent bone lesions

Question 17

What is the treatment of hyperparathyroid bone disease?

Answer 17

1. Low phosphate diet + Phosphate binders (reduce GI phosphate absorption) - to treat the hyperphosphataemia
2. Alphacalcidol – ie calcitriol analogues
3. Parathyroidectomy in 3^o hyperparathyroidism - Indicated for hypercalcaemia &/or hyperparathyroid bone disease

Question 18

What are the bone features in osteoporosis?

Answer 18

• Fewer trabeculae
• Reduced bone mass
• Bone mineral density >2.5 SDs below the average value for young healthy adults (a T score of -2.5 or lower)

–> weaker bone predisposed to fractures after minimal trauma

Question 19

What is measured to predict future fracture risk in osteoporosis? How?

Answer 19

Bone mineral density

DEXA - Dual Energy X-ray Absorptiometry of femoral neck and lumbar spine

Ca content of bone is measured - the more mineral the greater the bone density.

Question 20

Compare and contrast osteomalacia and osteoporosis.

Answer 20

• Osteomalacia is Vid D deficiency –> inadequately mineralised bone. In osteoporosis the cause is bone reabsorption exceeding formation.
• In osteomalacia the serum biochemistry is ABNORMAL (low 25(OH)D, low Ca and high PTH i.e. secondary hyperparathyroidism) whereas in osteoporosis the serum biochemistry in normal.

BOTH predispose to fracture.

Question 21

What are the predisposing factors for osteoporosis?

Answer 21

• Postmenopausal oestrogen deficiency –> loss of bone matrix + risk of fracture
• Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence
• Hypogonadism in young women and in men
• Endocrine conditions e.g. Cushing’s syndrome, Hyperthyroidism, Primary hyperparathyroidism
• Iatrogenic - Prolonged use of glucocorticoids, Heparin

Question 22

How debilitating are hip fractures one year later?

Answer 22

• 20% die within a year
• 80% are unable to carry out at least one independent activity of daily living

Question 23

List the treatment options for osteoporosis.

Answer 23

Oestrogen

Bisphosphonates

Denosumab

Teriparatide

Question 24

When would you treat osteoporosis with HRT?

Answer 24

Post-menopausal women - osteorgen is given to have anti-resoprtive effects on the skeleton and to prevent bone loss.

Additional progestogen needed if INTACT uterus to prevent endometrial hyperplasia/cancer.

Question 25

Describe the mechanism of action of bisphosphonates.

Answer 25

* Bind avidly to **hydroxyapatite** and ingested by **osteoclasts** – **impair** ability of osteoclasts to reabsorb bone * Decrease osteoclast **progenitor** development and recruitment * Promote osteoclast **apoptosis** (programmed cell death) * Net result = **reduced bone turnover.**

Question 26

Lsit 4 uses of bisphosphonates.

Answer 26

1. Osteoporosis – first line treatment 2. Malignancy - if associated hypercalcaemia or to reduce bone pain from metastases 3. Paget’s disease – reduce bony pain 4. Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)

Question 27

Descirbe the pharmacokinetics of bisphosphonates. Why are they not used much in younger people?

Answer 27

**Orally** active but **poorly absorbed**; take on an **empty stomach** (food, especially milk, reduces drug absorption generally) Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years (unsure about long term effects so not used as much in younger people)

Question 28

List and explain the unwanted actions of bisphosphonates.

Answer 28

* **Oesophagitis** - may require switch from oral to iv preparation * **Osteonecrosis** of the jaw - greatest risk in cancer patients receiving iv bisphosphonates * **Atypical fractures** - may reflect over-suppression of bone remodelling in prolonged bisphosphonate use

Question 29

What is the mechanism of action of Denosumab?

Answer 29

* Human monoclonal antibody * Binds RANKL, inhibiting osteoclast formation and activity * Hence inhibits osteoclast-mediated bone resorption

Question 30

Describe the administration of denosumab.

Answer 30

* SC injection 6/12ly * 2nd line to bisphosphonates

Question 31

What type drug is teripartide? How does it act?

Answer 31

* Recombinant PTH fragment - amino-terminal 34 aa's of native PTH * Increases bone formation and bone resorption, but formation outweighs resorption * 3rd line for osteoporosis

Question 32

How is teripartide administered?

Answer 32

SC injection DAILY

Question 33

Describe Paget's Disease.

Answer 33

Accelerated, localised but disorganised bone remodelling. 1. Excessivee resorption (by osteoclastic overactivity) 2. Then compensatory increase in bone formation (by osteoblasts) 3. New bone = WOVEN so structurally disorganised and mechanically wekaer than adult lamellar bone 4. Causes bone frailty, hypertrophy and deformity.

Question 34

Describe the prevalence of Paget's Disease of bone.

Answer 34

* Highest in UK, N America, Australia and NZ * Lowest in Asian and Scandinavia * Men and women equally * Disease not apparent under 50 - most asymptomatic

Question 35

What is a characteristic cellular feature of Paget's?

Answer 35

Abnormal, large osteoclasts – excessive in number

Question 36

Why would you feel warmth over bone in Paget's ?

Answer 36

Increased vascularity

Question 37

What bones are most commonly affected in Paget's?

Answer 37

Skull, thoracolumbar spine, pelvis, femur and tibia

Question 38

What are the clinical features of Paget's?

Answer 38

* Arthritis * Fracture * Pain * Bone deformity * **Increased vascularity** (warmth over affected bone) * **Deafness** – cochlear involvement * **Radiculopathy** – due to nerve compression

Question 39

How is Paget's Disease diagnosed?

Answer 39

Blood test: * Plasma Ca normal * But plasma ALKALINE PHOSPHATASE increased Plain X ray: * Lytic lesions (early), thickened, enlarged, deformed bones (later) Radionucleotide bone scan * Shows extent of skeletal involvement

Question 40

What are the treatment options for Paget's disease?

Answer 40

* Bisphosphonates – very helpful for reducing bony pain and disease activity * Simple analgesia

Question 41

What are the possible causes of Paget's?

Answer 41

* Could be genetic (often positive family history) * Viral origin - measles ?

Question 42

Vitamin D deficiency: - is relatively common in the elderly - can be associated with renal failure - is called rickets in children - is usually confirmed by the presence of a low circulating 1,25(OH)2D level - can be a cause of proximal myopathy

Answer 42

True True True False True

Question 43

Paget's disease: - is defined as demineralisation of bone - is caused by inadequate levels of calcitriol - may be associated with a localized vasodilatation - is often asymptomatic - may be treated with bisphosphonates

Answer 43

False False True False True Response Feedback: Inadequate levels of calcitriol cause rickets in children or osteomalacia in adult, not Paget’s disease of bone Can be asymptomatic, but often presents with bone pain

Question 44

Parathyroid hormone: - is low in hypercalcaemia of malignancy - inhibits synthesis of calcitriol - stimulates renal excretion of phosphate - is usually low in renal failure - stimulates bone resorption

Answer 44

True False True False True