13 - Endocrine and metabolic bone disorders

Question 1

What is stored in bones?

Answer 1

calcium (over 95% of the body’s Ca2+)

Question 2

What are the roles of osteoclasts and osteoblasts and what impact does this have on the amount of calcium in bone?

Answer 2

osteoblasts - synthesise bone (make and mineralise osteoid)
—–> assist with deposition of calcium
osteoclasts - consume bone thought release lysosomal enzymes
—–> liberates calcium from the bone

Question 3

What are the 2 components of bone?

Answer 3

• osteoid
  this is the organic component of bone - unmineralised bone made up of type 1 collagen
• calcium hydroxyapatite crystals
  inorganic compound of bone - fills the space between the collagen fibrils

Question 4

What is the mechanism of action of PTH on the bone?

Answer 4

(indirectly activates osteoclasts) works on osteoblasts and inhibits various activities
Stimulates osteoblasts to produce OAF (osteoclast activating factors)

Question 5

What is the action of OAF (osteoclast activating factors)

Answer 5

(produced by osteoblasts) move to osteoclasts and stimulate the breakdown of bone matrix to release Ca2+

Question 6

Give an example of an OAF

Answer 6

RANKL

Question 7

Describe the process of osteoclast differentiation, by which osteoclasts require the action of ostoblasts

Answer 7

• osteoblasts express RANK
• osteoclasts have a receptor for RANK
• on binding, the osteoclasts precursor becomes activated
• osteoclast formation and activity

Question 8

What 2 substances regulate the balance between bone formation and resorption
and what are the corresponding receptors for these located?

Answer 8

PTH and calcitriol regulate the balance

their receptors are located on osteoblasts

Question 9

Describe the structure of regular bone

How is the strength maintained?

Answer 9

• hard cortical bone around the outside
• spongy, trabecular bone on the inside

bone is formed in a lamellar pattern - collagen fibrils are laid down in altering orientations - this gives the maximum mechanical strength

Question 10

Name and describe the type of bone with much less mechanical strength

Answer 10

woven bone

collagen fibrils are organised randomly

Question 11

What is the effect of vitamin D deficiency on bone?

Answer 11

inadequate mineralisation of newly formed bone matrix (osteoid)

Question 12

Describe the presentation of vitamin D deficiency in children

Answer 12

RICKETS

• affects cartilage of epiphyseal growth plates and bone
• skeletal abnormalities (tibia bowing) and pain, growth retardation. increased fracture risk (‘bendy bones’)
• particularly problematic in legs (weight bearing)

Question 13

Describe the presentation of vitamin D deficiency in adults

Answer 13

OSTEOMALACIA
- occurs after epiphyseal closure
- skeletal pain, increased risk fracture, proxoimal myopathy
(- not the same bone deformities that are seen in rickets - epiphyseal growth closure)

Question 14

What are the effects of vitamin D deficiency on bone?What are the typical fracture sites?

Answer 14

stress fractures - due to normal stresses i.e. bearing weight
typical fracture sites are in areas of high bone load
abnormal pelvic fractures - patients walk with a ‘waddling gait’

Question 15

Describe what happens in primary hyperparathyroidism

Answer 15

• the problem is with one of the parathyroid glands
• autonomous secretion of PTH (e.g. parathyroid adenoma)
• patients have high serum calcium and high PTH

Question 16

Describe what happens in secondary hyperparathyroidism

Answer 16

• normal physiological response to low calcium
• —-> this is due to either renal failure or Via D deficiency
• high PTH secondary to low Ca2+

Question 17

Describe what happens in tertiary hyperparathyroidism

Answer 17

• (seen in chronic renal failure)
• chronically low calcium because calcitriol cannot be made
• PTH increases in response to low calcium

Question 18

What is the treatment for tertiary hyperparathyroidism

Answer 18

need to have a parathyroidectomy

Question 19

What are the 2 main effects of kidney failure on calcium serum levels?

Answer 19

• calcitriol cannot be made, so calcium is not absorbed well from the gut
• (reduced excretion of phosphate =) increased serum phosphate —–> decreases bioavailable serum calcium (phosphate binds to calcium)

inadequate bone mineralisation and increased PTH release (-> increased bone reabsorption)
leads to osteitis fibrosa cystica (rare)

Question 20

In what way do patients with chronic kidney failure need to manage their diet?

Answer 20

try to reduce serum phosphate

Question 21

What can result because of high serum phosphate?

Answer 21

vascular calcification

Question 22

When is osteitis fibrosa cystica seen?

Answer 22

in people with very high PTH e.g. in renal failure

Question 23

What is osteitis fibrosa cystica?

What causes it?

Answer 23

hyperparathyroid bone disease

high PTH —> osteoclast stimulation —> increased bone resorption

Question 24

What is the treatment for osteitis fibrosa cystica?

Answer 24

• hyperphosphataemia - low phosphate diet and phosphate binders
• alfacalcidol - active vitamin D/calcitriol analogues
• parathryoidectomy (when tertiary hyperparathyroidism)

Question 25

Define osteoporosis.

Answer 25

(reduction in bone mass) Having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults

Question 26

Describe the features of bone in someone who has osteoporosis

Answer 26

loss of bony trabeculae weaker bone predisposed to fracture after minimal trauma

Question 27

Who is most likely to have problems caused by osteoporosis?

Answer 27

post-menopausal women | elderly

Question 28

How is bone mineral density measured? Name the key areas that are looked at during this test

Answer 28

using Dual Energy X-ray Absorptiometry (DEXA) the scan looks at the mineral (calcium) content of the bone the femoral neck and lumbar spine are scanned

Question 29

What are the similarities between osteomalacia and osteoporosis?

Answer 29

both predispose to fractures

Question 30

How can you differentiate between osteomalacia and osteoporosis?

Answer 30

BIOCHEMISTRY IS COMPLETELY NORMAL IN OSTEOPOROSIS osteomalacia - diagnosed using serum biochemistry osteoporosis - diagnosed using DEXA scan osteomalacia - caused by Vitamin D deficiency causing inadequately mineralised bones osteoporosis - when bone reabsorption exceeds formation

Question 31

List predisposing conditions for osteoporosis

Answer 31

- post menopausal oestrogen deficiency - age-related deficiency in bone homeostasis - hypogonadism - endocrine conditions - ----> Cushings - ----> hyperthyroidism - ----> primary hyperparathyroidism - iatrogenic - ----> prolonged use of glucocorticoids - ----> heparin

Question 32

What are the 1st, 2nd and 3rd line treatments for osteoporosis?

Answer 32

Bisphosphonates Denusomab Teriparatide NOTE: with oestrogen replacement, there is risk of breast cancer and VTE

Question 33

What are the benefits of oestrogen replacement to prevent osteoporosis in post-menopausal women?

Answer 33

It has an anti-resorptive effect in bone and, hence, prevents bone loss

Question 34

What are some cautions and risks of oestrogen replacement?

Answer 34

In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma Risks: • Breast cancer • Venous thromboembolism

Question 35

What are the 2 types of SERMs? | Give an example of each

Answer 35

``` Selective Oestrogen Receptor Modulators 1- Tissue selective ER antagonists/anti-oestrogens e.g. tamoxifen 2- Tissue selector ER agonists e.g. raloxifene ```

Question 36

Describe the effects of tissue selective ER antagonists/anti-oestrogens

Answer 36

* Antagonises ERs in breast but has oestrogenic activity in bone * Oestrogenic effects on endometrium limit its use in osteoporosis management

Question 37

Describe the effects of tissue selector ER agonists

Answer 37

* Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus * Reduces breast cancer risk (anti-oestrogen) but increases risk of venous thromboembolism

Question 38

What is the action of bisphosphonates in treatment of osteoporosis?

Answer 38

* 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 39

What conditions are bisphosphonates used to treat?

Answer 39

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

Question 40

Describe the pharmacokinetics of bisphosphonates

Answer 40

* 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, years

Question 41

Give some of the unwanted actions of bisphosphonates

Answer 41

• Oesophagitis (heart burn): may require switch from oral to IV • 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 ---> hence, patients are given a bisphosphonate holiday so bones can recover from treatment

Question 42

What is the action of Denosumab in treatment of osteoporosis?

Answer 42

• Human monoclonal antibody • binds RANKL, inhibiting osteoclast formation and activity -----> Hence inhibits osteoclast-mediated bone resorption

Question 43

Describe the pharmacokinetics of Denosumab

Answer 43

Subcutaneous injection every 6 months

Question 44

What is teriparatide? | What is its action in treatment of osteoporosis?

Answer 44

• Recombinant PTH fragment • Increases bone formation and bone resorption, but formation outweighs resorption (3rd line treatment for osteoporosis - very expensive)

Question 45

Describe the pharmacokinetics of teriparatide

Answer 45

Daily subcutaneous injection

Question 46

What is Paget’s disease?

Answer 46

Active/accelerated, localised but disorganised bone metabolism – usually slowly progressive. There is increased bone breakdown and bone formation.

Question 47

What happens in the bone in Paget's disease?

Answer 47

- excessive bone resorption (over activity of osteoclasts) - followed by compensatory increase in bone formation (osteoblasts) BUT the new bone formed is woven bone

Question 48

What is Paget’s disease characterised by histologically?

Answer 48

Abnormal, large osteoclasts - that are excessive in number

Question 49

State some clinical features of Paget's disease

Answer 49

(most patients are asymptomatic) - Fracture - Pain - Bone deformity - Increased vascularity (warmth over affected bone) - Most commonly affected bones are: pelvis, femur, tibia, skull, and spine - ^arthritis - deafness: cochlear involvement - radiculopathy - due to nerve compression

Question 50

Describe how you would diagnose Paget’s disease.

Answer 50

Biochemical Findings: - Plasma calcium = NORMAL - Plasma ALP (alkaline phosphatase) = HIGH Radiological findings: - x-rays: -----> (early) lytic lesions -----> (later) thickened, early, deformed bones - Radioisotope scanning can be performed to indicate areas of involvement

Question 51

What is the treatment for Paget's?

Answer 51

- bisphosphonates | - simple analgesia