Endocrine and Metabolic Bone Disorders Flashcards Preview

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Flashcards in Endocrine and Metabolic Bone Disorders Deck (39)
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1
Q

Identify and describe the 2 components of bone

A
  1. Osteoid - organic component - unmineralised bone made up of type 1 collagen
  2. Calcium hydroxyapatite crystals - inorganic component - fill the space between collagen fibrils
2
Q

What 2 types of cells are involved in bone turnover and outline their function in bone turnover

A
  1. Osteoblasts - synthesise bone (osteoid component)
  2. Osteoclasts - enzymatic bone resorption
3
Q

What happens if there is imbalances in bone turnover

A
  • There is constant remodelling of bone by bone turnover
  • If there is imbalance with too much bone resorption and inadeqaute bone synthesis then this can lead to weakened bone structure and make the bone prone to fracture
4
Q

Describe how PTH has its actions on osteoblasts and osteoclasts

A
  • PTH directly binds osteoblasts bu acting on PTH receptors on osteoblasts
  • It has indirect effects on osteoclasts as osteoblasts release OAFs (osteoclast activating factors)
5
Q

Give an example of an OAF (osteoclast activating factor)

A
  • RANKL
6
Q

Describe osteoblast-osteoclast interaction leading to osteoclast differentiation and thus bone resorption and what modulates the interaction between osteoblasts and osteoclasts

A
  • Calcitiriol and PTH bind osteoblasts to promote OAF release by osteoblasts
  • Osteoblasts express RANKL (an OAF)
  • Osteoclast precursors have RANK receptors which bind the RANKL (RANK-ligand) and become activated
  • Thus osteoclast differentiation and fusion occurs to form the activated osteoclast and thus bone resorption
7
Q

Describe the layers and then the arrangement of bone

A
  • Cortical bone on outside - very hard
  • Trabecular bone on inside - spongy
  • Lamellar arrangement of collagen fibrils to give the maximum mechanical strength
8
Q

What is the type of bone which is weaker and why is it weaker than normal bone?

A

Woven bone - due to irregular thus weak arrangement of collagen fibrils - not in the lamellar arrangement as occurs in normal bone which otherwise give the bone high mechanical strength

9
Q

How does vitamin D deficiency manifest bone problems in the child - what is the name of the condition, what is the pathophysiology including where it affects it and what are the clinical signs and symptoms?

A
  • Rickets
  • Inadequate mineralisation of newly formed osteoid bone matrix
  • Affects cartilage of epiphyseal plates and bone
  • Skeletal abnormalities (tibia bowing), pain, growth retardation, increased fracture risk
10
Q

How does vitamin D deficiency manifest bone problems in the adult - including the name of the condition, the pathophysiology and the clinical signs?

A
  • Osteomalacia
  • Inadequate bone mineralisation of newly formed osteoid bone matrix
  • After epiphyseal closure, affects bone
  • Skeletal pain, increased fracture risk, proximal myopathy
  • No bone deformities as in rickets in children
11
Q

What are the differences in the manifestation of inadequate vitamin D in the child and in the adult?

A
  • Child - rickets vs Adult - osteomalacia
  • In children it affects them prior to epiphyseal closure and in adults it affects them after epiphyseal closure
  • Thus you have skeletal deformities in rickets in children whereas there are no skeletal deformities in osteomalacia in adults as development has already occured
12
Q

1) Why does vitamin D deficiency lead to increased risk of bone fracture, what type of fracture is this and where does it manifest?
2) How do patients change their gait in response and why?

A

1)

  • Vitamin D promotes calcium maintenance within the bone and also osteoblast activation
  • Insufficiency fractures at sites of high bone loading and stress

2)

  • Waddling gait due to pain from abnormal bone fractures
13
Q

What happens pathophysiologically in primary hyperparathyroidism?

A
  • Autonomous PTH secretion which does not respond to negative feedback by serum calcium
  • So high PTH and high serum calcium (hypercalcaemia)
14
Q

What happens pathophysiologically in secondary hyperparathyroidism?

A
  • Low plasma [Ca2+] due to renal failure or vitamin D deficiency
  • This leads to increased PTH due to less negative feedback
15
Q

What happens pathophysiologically in tertiary hyperparathyroidism?

A
  • Chronic low plasma [Ca2+]
  • So there is autonomous secretion of PTH to try and compensate to increase plasma [Ca2+] again
16
Q

Give 2 ways in which renal failure can lead to hypocalcaemia

A
  • Decreased formation of calcitriol (1,25-(OH)2-D3) because there is decreased conversion of 25-OH-D3 using renal 1α-hydroxylase. This causes reduced Ca2+ absorption at the gut, leading to hypocalcaemia
  • Decreased PO43- excretion so there is increased serum phosphate and this phosphate binds calcium so it further decreases bioavailable serum calcium so leads to hypocalcaemia
17
Q

Why would impaired renal function lead to osteitis fibrosis cystica - outline the pathophysiology of it

A
  • Less calcitriol formation so less Ca2+ absorption at the gut so there is hypocalcaemia and also decreased phosphate excretion and increased plasma phosphate which binds calcium so further decreases serum calcium levels
  • SO hypocalcaemia
  • This leads to decreased bone mineralisation
  • Also the lower serum calcium levels leads to PTH increase due to less negative feedback
  • This leads to increased bone resorption
  • SO hypocalcaemia → decreased bone mineralisation AND high PTH → increased bone resorption BOTH lead to osteitis fibrosis cystica
18
Q

1) Why does renal failure lead to vascular calcification and increased risk of macrovascular disease?
2) So how is hyperphosphataemia managed in patients with renal failure?

A

1)

  • Renal failure leads to decreased PO43- so there is increased serum phosphate level causing hyperphosphataemia
  • Hyperphosphataemia contributes to vascular calcification
  • Vascular calcification leads to increased risk of macrovascular disease

2)

  • Diet mamagement - low phosphate diet
  • Phosphate binders - collate phosphate at the gut to reduce absorption at the gut
19
Q

What signs might we see that indicate osteitis fibrosis cystica on an X-ray?

A
  • Radioluscency at points of high bone resorption at where hyperparathyroidism has resulted in high osteoclast activity
  • ‘Pepper pott skull’
20
Q

3 things you can do to treat osteitis fibrosis cystica?

A
  1. Alphacalcidol - active vitamin D drug (1,25-(OH)2-D3 to combat hypocalcaemia
  2. Parathyroidectomy - in tertiary hyperparathyroidism
  3. Hyperphosphataemia - low phosphate diets or phosphate binders
21
Q

1) What is the pathophysiology of osteoporosis?
2) In what kind of people would you see osteoporosis?

A

1)

  • Reduction in bone mineral density resultin in increased risk of bone fracture and increased risk of fracture after minimal trauma
  • Trabecular meshwork loss - weaker bone

2)

  • Older women (post-menopausal) - oestrogen loss which normally preserves normal bone turnover
  • Everyone as they age due to loss of bone mineral density
22
Q

1) How do we measure bone mineral density?
2) How can we use it to diagnose osteoporosis - at what level?

A

1)

  • DEXA scans measure bone mineral density
  • T-scores are given - normal range is 1.0 - 0.0
  • The femoral neck and lumbar spine are scanned

2)

  • T-scores >2.5 standard deviations below the average range - usually -2.5 or lower are indicative of osteoporosis
23
Q

In what ways is the serum biochemistry abnormal in osteomalacia?

A
  • Low 25-OH-Vit D3
  • Low Ca2+
  • High PTH - secondary hyperparathyroidism
24
Q

Give 5 types of predisposing conditions, including examples where they are subcategories, or explanations where necessary

A
  1. Postmenopausal oestrogen deficiency - leads to loss of bone matrix
  2. Age-related deficiency in bone haemostasis - e.g. osteoblast senescense
  3. Hypogonadism
  4. Endocrine conditions - Cushing’s syndrome, Hyperthyroidism, Primary hyperparathyroidism
  5. Iatrogenic - prolonged use of glucocorticoids, heparin
25
Q

List 5 different treatment options for osteoporosis

A
  1. Oestrogen / selective oestrogen receptor modulators
  2. Teriparatide
  3. Bisphosphonates
  4. Denosumab
26
Q

1) Why is oestrogen given as treatment for osteoporosis, and to whom?
2) What should be co-administered with it and why?
3) 2 possible side-effects of oestrogen therapy

A

1)

  • Anti-resorptive effects on the skeleton preventing bone loss in post-menopausal women

2)

  • Progestogen to prevent uncontrolled endometrial hyperplasia in women with an intact uterus

3)

  • Increased risk of breast cancer
  • Venous thromboembolism
27
Q

Give 2 types (with one example for each) of selective estrogen receptor modulators (SERMs) and say how they work to treat osteoporosis and 1 possible side effect for each

A
  1. Selective oestrogen antagonists e.g. Tamoxifen
  • Antagonises ER in breast but weirdly has oestrogen effects in bone
  • Side effect: oestrogenic effects on endometrium limits its use in osteoporosis management
  1. Selective oestrogen agonists e.g. Raloxifene
  • Oestrogenic activity in bone, but weirdly anti-oestrogenic effect in breast and uterus
  • Side effect: reduces breast cancer risk but increases risk of venous thromboembolism
28
Q

What is the mechanism by which bisphosphonate works?

A
  • Bind to hydroxyapatite
  • Ingested by osteoclasts, impairing the osteoclast ability to carry out bone resorption
  • Decreases osteoclast progenitor development and recruitment
  • Promote osteoclast apoptosis
  • Net result = decreased bone turnover
29
Q

4 times when bisphophonates are used?

A
  • Osteoporosis - first line treatment
  • Malignancy - associated hypercalcaemia and reduce bone pain from metastases
  • Paget’s disease - reduce bony pain
  • Severe hyperglycaemic emergency - i.v. initially (+++re-hydration first)
30
Q

Describe the pharmacokinetics of bisphophonates

A
  • Orally active but poorly absorbed so taken on an empty stomach
  • Accumulates at sites of bone mineralisation and remains part of bone until it is resorbed - takes a long time
31
Q

3 possible unwanted effects of bisphosphonates and ways to manage these where applicable and one general way to avoid unwanted effects?

A
  1. Oesophagitis (heart burn) - can switch from oral to i.v. administration
  2. Osteonecrosis of the jaw - greatest risk in cancer patients recieving i.v. bisphosphonates
  3. Atypical fractures - due to prolonged suppression of bone remodelling
  • Bisphosphonate holidays so bone can recover from the treatment
32
Q

1) What is the mechanism for how Denusomab works to treat osteoporosis?
2) How is Denosumab administrated?
3) When is it used in treatment?

A

1)

  • Human monoclonal antibodies
  • Binds RANKL, inhibiting osteoclast activity and formation
  • Hence inhibit osteoclast mediated bone resorption

2)

  • Subcutaneous injection

3)

  • 2nd line treatment to bisphosphonates due to price
33
Q

1) What is the mechanism for how Teriparatide works to treat osteoporosis?
2) How is Teriparatide administrated?
3) When is it used in treatment?

A

1)

  • It is a recombinant parathyroid fragment - 34 A.A. part of the amino terminal of PTH
  • It induces both bone formation and resorption, but induces more formation than resorption

2)

  • Daily subcutaneous injection

3)

  • 3rd line treatment for osteoporosis as it is very expensive
34
Q

What is the pathophysiology of Paget’s disease?

A
  • Accelerated, localised but disorganised bone remodelling
  • Excessive bone resorption (XS osteoclast activity) but then compensatory bone formation by osteoblast activity, but the new bone being formed is woven bone
  • Woven bone is structurally disorganised, therefore weaker than normal adult lamellar bone, leading to bone frailty and bone hypertrophy / deformity
35
Q

In terms of the origins of Paget’s disease, how is the FHx and what is the possible evidence of its origin?

A
  • Positive family history
  • Evidence for viral origin (e.g. measles virus)
36
Q

What bones are most commonly affected by Paget’s disease?

A
  • Skull
  • Thoracolumbar spine
  • Pelvis
  • Femur
  • Tibia
37
Q

List 7 clinical signs of Paget’s disease?

A
  1. Arthritis
  2. Fracture
  3. Pain
  4. Bone deformity
  5. Increased vascularity so warmth over affected bone
  6. Deafness (cochlear involvement)
  7. Radiculopathy - due to compressed nerve
38
Q

4 findings for diagnosis of Paget’s?

A
  1. Plasma [Ca2+] is normal
  2. Plasma [alkaline phosphatase] (the bone isoenzymes) is usually increased
  3. Plain x rays = Lytic lesions (early), thickened, enlarged, deformed bones (later)
  4. Radionucleide bone scan demonstrates extent of skeletal involvement
39
Q

2 treatments for Paget’s?

A
  1. Bisphosphonates – very helpful for reducing bony pain and disease activity
  2. Simple analgesia