Endocrine and metabolic bone disorders

Question 1

What does bone contain a large store of?

Answer 1

calcium (more than 95

% of body’s store)

Question 2

What are the 2 components of bone?

Answer 2

1. Osteoid (organic component – unmineralised bone made up of type 1 collagen). 35%
2. Calcium hydroxyapatite crystals (inorganic component, fill the space between collagen fibrils). 65%

Question 3

What are osteoblasts?

Answer 3

They synthesise bone (osteoid)

Question 4

What are osteoclasts?

Answer 4

They release lysosomal enzymes which break down bone

Question 5

How does PTH activate osteoclasts?

Answer 5

PTH stimulates osteoblasts to produce osteoclasts activating factors. One of these is called RANKL - it binds to the RANK receptor on the osteoclast to stimulate bone resorption.

Question 6

How does PTH affect osteoblasts (direct or indirect)?

Answer 6

Direct effect by binding to osteoblasts

Question 7

Describe the interaction between osteoblasts and osteoclasts during osteoclast differentiation

Answer 7

Osteoblasts express RANKL which binds to a receptor on the osteoclast precursor. Once it binds this stimulates osteoclast activity.

Question 8

Which receptors can be found on osteoblasts?

Answer 8

Receptors for PTH & calcitriol (1,25 (OH)2 vitamin D)

THEY REGULATE BALANCE BETWEEN BONE FORMATION AND RESORPTION

Question 9

What are the different types of bone?

Answer 9

lamellar:
hard, cortical bone
spongy, trabecular bone

woven bone

Question 10

How is bone organised?

Answer 10

• Bone is formed in a lamellar pattern
• This means that collagen fibrils are laid down in altering orientations
• This gives the most mechanical strength possible

Question 11

What is woven bone?

Answer 11

• It is weak bone

- This is because it doesn’t have the same organisation of collagen fibrils (fibrils laid quite randomly)

Question 12

What does vitamin D deficiency lead to?

Answer 12

Inadequate mineralisation of newly formed bone matrix (osteoid)

Question 13

What is rickets?

Answer 13

• Affects children
• Affects the cartilage of epiphysial growth plates and bones
• Skeletal abnormalities causes e.g. tibia bows, pain, growth retardation, increased fracture risk

Question 14

What is osteomalacia?

Answer 14

• Affects adults
• After epiphysial closure so affects bones
• Skeletal pain, increased fracture risk, proximal myopathy
• No bony deformities as in rickets

Question 15

What is the effect of vitamin D deficiency on bone?

Answer 15

• There are typical fracture sites for severe vitamin D deficiency
• Normally in places where there is a lot of bone loading
• Normal stresses (e.g. weight bearing) on abnormal bone cause insufficiency fractures at looser zones e.g. the pelvis
• Patients may walk with a ‘waddling gait’ due to pain from abnormal pelvis fractures

Question 16

What is primary hyperparathyroidism?

Answer 16

Adenoma which secretes too much PTH. Because of the autonomous secretion of PTH here, patients have a high serum calcium and high PTH

Question 17

What is secondary hyperparathyroidism?

Answer 17

There is a normal physiological response to low calcium because of either renal failure or vitamin D deficiency -> increased release of PTH

Question 18

What is tertiary hyperparathyroidism?

Answer 18

Seen in chronic renal failure, there is chronically low calcium because calcitriol cannot be made. PTH increases to try and drive calcium increase.

Question 19

What happens if the kidneys fail?

Answer 19

• Calcitriol cannot be made, so calcium isn’t absorbed from the gut very well -> hypocalcaemia
• The kidneys excrete phosphate, so less excretion results in increased serum phosphate. Phosphate binds to calcium, further decreasing bioavailable serum calcium
• This results in inadequate bone mineralisation (-> osteitis fibrosa cystica), and increased PTH release
• Increased PTH increases bone resorption, which also leads to osteitis fibrosa cystica

Question 20

What do patients with renal failure have to ensure?

Answer 20

• Need to manage their diet very strictly to reduce phosphate intake

Question 21

What is a problem with having high phosphate?

Answer 21

Vascular calcification

Question 22

What is osteitis fibrosa cystica?

Answer 22

• Rare, hyperparathyroid bone disease
• Seen in people with very high PTH
• Seen in renal failure

Question 23

What is the mechanism behind osteitis fibrosa cystica?

Answer 23

• In renal failure there is not enough calcium hence

High PTH -> osteoclast stimulation -> increased bone resorption

Question 24

What is seen in radiography in osteitis fibrosa cystica?

Answer 24

The areas of radiolucency on the x-rays show where bones are so thin because of the over-activity of osteoclasts. We see a pepper-pot skull. ‘Brown tumours’ – radiolucent bone lesions where bone has been broken down.

Question 25

What is the treatment of osteitis fibrosa cystica?

Answer 25

Hyperphosphataemia: Low phosphate diet (can be hard) Phosphate binders – reduce GI phosphate absorption by collating phosphate in the gut Alphacalcidol – i.e. calcitriol analogues – you have to give patients active vitamin D (can’t convert into active form as their kidneys are failing) Parathyroidectomy in tertiary hyperparathyroidism Indicated for hypercalcaemia &or hyperparathyroid bone disease

Question 26

What is osteoporosis and who does it affect?

Answer 26

- Increased risk of fracture - reduction in bone mass - particularly a problem in post menopausal women, but everyone loses bone mass with age

Question 27

What is a measure of osteoporosis?

Answer 27

- Bone mineral density – it predicts fracture risk - Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower) - A DEXA scan can give a T-score

Question 28

How is bone mineral density measured? | What is scanned?

Answer 28

- BMD is measured using a DEXA scan (dual energy x-ray absorptiometry) - The femoral neck and lumbar spine are scanned - The scan looks at the mineral (calcium) content of bone - The more mineral, the greater the bone density (bone mass)

Question 29

What is the difference between osteomalacia and osteoporosis?

Answer 29

Both predispose to fractures but osteomalacia is caused by insufficiency of mineralised bone due to vitamin D deficiency whilst osteoporosis is decreased bone mass

Question 30

What happens in osteomalacia?

Answer 30

- Vitamin D deficiency (adults) causing inadequately mineralised bone - Serum biochemistry is abnormal (low 25(OH) vitamin D, low Ca2+, high PTH (secondary hyperparathyroidism)

Question 31

What happens in osteoporosis?

Answer 31

- Bone reabsorption exceeds formation - Decreased bone mass - Serum biochemistry normal - Diagnosis via DEXA scan

Question 32

What are some predisposing conditions for osteoporosis?

Answer 32

Postmenopausal oestrogen deficiency - Oestrogen deficiency leads to a loss of bone matrix, subsequent increased risk of fracture Age-related deficiency in bone homeostasis (men and women) e.g. osteoblast senescence Hypogonadism in young women and in men Endocrine conditions - Cushing’s syndrome - Hyperthyroidism - Primary hyperparathyroidism Iatrogenic Prolonged use of glucocorticoids o Heparin

Question 33

What are the treatment options for osteoporosis?

Answer 33

- Oestrogen/Selective Oestrogen Receptor Modulators - Bisphosphonates - Denosumab - Teriparatide

Question 34

How does oestrogen therapy work?

Answer 34

- Treatment of post-menopausal women with pharmacological doses of oestrogen - Anti-resorptive effects on the skeleton - Prevents bone loss

Question 35

What are some precautions that must be taken when giving oestrogen HRT?

Answer 35

- Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer - Use limited largely due to concerns with increased risk of breast cancer and venous thromboembolism

Question 36

What are selective oestrogen receptor modulators (SERMS)? | raloxifen and tamoxifen and describe their effects on bone, endometrium and breast

Answer 36

1. Tissue selective ER antagonists/anti-estrogens e.g. tamoxifen - Antagonises ERs in breast but has oestrogenic activity in bone - Oestrogenic effects on endometrium limit its use in osteoporosis management 2. Tissue selective ER agonist raloxifene has been further developed for its selectivity on bone - Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus - Reduces breast cancer risk (anti-oestrogen) but increases risk of venous thromboembolism

Question 37

What are bisphosphonates - how do they work?

Answer 37

- Bind to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone - Decrease osteoclast progenitor development and recruitment - Promote osteoclast apoptosis - Net result = reduced bone turnover

Question 38

When are bisphosphonates used?

Answer 38

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

Question 39

Describe the pharmacokinetics of bisphosphonates

Answer 39

- Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally) – so these tablets are a pain to take - Accumulates at site of bone mineralisation and remains part of bone until it is resorbed – months, year

Question 40

What are some unwanted actions of bisphosphonates?

Answer 40

- Oesophagitis (heart burn): may require switch from an oral to an intravenous preparation - Osteonecrosis of the jaw: greatest risk in cancer patients receiving intravenous bisphosphonates - Atypical fractures: may reflect over-suppression of bone remodelling in prolonged bisphosphonate use * Patients are given bisphosphonate holiday so that bones can recover from this treatment

Question 41

What is denosumab?

Answer 41

- Human monoclonal antibody - Denosumab binds RANKL, inhibiting osteoclast formation and activity - Hence inhibits osteoclast-mediated bone resorption -> helpful treatment for osteoporosis

Question 42

How is denosumab administered? | Is it the 1st line of treatment for osteoporosis and why?

Answer 42

* Subcutaneous injection every 6 months | - 2nd line to bisphosphonates (largely because of price

Question 43

What is teriparatide?

Answer 43

- Recombinant parathyroid hormone fragment – amino-terminal 34 amino acids of native PTH - Increases bone formation and bone resorption, but formation outweighs resorption

Question 44

How is teriparatide administered? | Is it the 1st line of treatment for osteoporosis and why?

Answer 44

- 3rd line treatment for osteoporosis - Daily subcutaneous injection - Very expensive

Question 45

What is paget's disease?

Answer 45

- Accelerated, localised but disorganised bone remodelling - Excessive bone resorption (osteoclastic over activity) followed by a compensatory increase in bone formation (osteoblasts), but the new bone formed is woven bone - This bone is structurally disorganised, mechanically weaker than normal adult lamellar bone, frail, bone deformity and hypertrophy - Most patients are asymptomatic - Characterised by abnormal, large osteoclasts – excessive in number

Question 46

Describe the familial link of paget's disease, its prevalence, epidemiology

Answer 46

- Often positive family history (possible genetic cause) - There is evidence for viral origin (e.g. measles virus) - Highest in UK, N America, Australia and NZ - Lowest in Asian and Scandinavia - Men and women affected equally - Disease usually not apparent in people younger than 50 years

Question 47

What are the clinical features of paget's disease?

Answer 47

- Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected - Arthritis - Fracture - Pain - Bone deformity - Increased vascularity (warmth over affected bone) - Deafness – if cochlear involvement - Radiculopathy – pinched nerve in spinal column due to nerve compression - Bowing of tibia

Question 48

How is paget's disease diagnosed?

Answer 48

- Plasma [Ca2+] is normal - Plasma alkaline phosphatase is usually increased - Plain x rays = Lytic lesions (early), thickened, enlarged, deformed bones (later) - Radionuclide bone scan demonstrates extent of skeletal involvement

Question 49

How is paget's disease treated?

Answer 49

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