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Y2 Clinical Pathology > Diseases of the Bone > Flashcards

Diseases of the Bone Flashcards

1
Q

What are the purposes of bone?

A
  1. to support the body structurally
  2. protection of vital organs
  3. allows movement
  4. provides an environment for bone marrow, where blood cells are produced
  5. acts as a storage area for minerals, particularly calcium
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2
Q

What are the 2 different forms of bone and where are they found?

A

cortical bone:

  • this is the hard outer layer

trabecular bone:

  • this is the spongy inner layer
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3
Q

What are the 3 different types of cells found within bone?

A
  • bone forming cells
  • bone resorbing cells
  • bone co-ordinating cells
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4
Q

What is the extracellular composition of bone like?

A

organic matrix (30%):

  • mainly collagen (osteoid)
  • ground substance

inorganic components (70%):

  • hydroxyapatite (calcium and phosphate)
  • minerals (magnesium, sodium and potassium)
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5
Q

What is the extracellular matrix made up from?

A

the extracellular matrix (osteoid) is mainly collagen

this provides tensile strength

it is produced by osteoblasts

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6
Q

What is involved in mineralisation of bone?

A

hydroxyapatite

this is a calcium-phosphate hydroxide salt

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7
Q

WHat is involved in bone remodelling?

A

bone is vascular and metabollically active

this is a cellular process

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8
Q

What is the role of the osteoblast?

A

it creates and repairs new bone

  • the osteoblast becomes an osteocyte
  • it makes osteoid
  • it mineralises the organic matrix
  • it communicates with other bone cells
  • it makes hormones
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9
Q

What is the role of the osteoclast?

A

it breaks down old bone

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10
Q

What component are involved in the osteoclasts breaking down old bone?

A

RANKL and osteoprotegrin

RANKL is an apoptosis regulator gene

osteoprotegrin binds and opposes RANKL and controls cell proliferation levels

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11
Q

What hormones influence the osteoclasts to breakdown old bone?

A
  • PTH
  • calcitonin
  • IL-6
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12
Q

How do osteoclasts break down bone?

A

they remove bone by dissolving the mineral and breaking down the matrix in a process called bone resorption

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13
Q

Where do osteocytes originate from?

A

the osteoprogenitor cell becomes an osteoblast

the osteoblast then becomes an osteocyte

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14
Q

Where are osteocytes found in bone?

A

the osteocytes are found closer towards the centre than the osteoblasts, which are found on the outside

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15
Q

How often is the human skeleton replaced?

How does remodelling occur in normal bone?

A

normal bone is in a constant state of turnover caused by resorption by osteoclasts, and formation by osteoblasts

the adult skeleton is replaced every 10 years

osteoporosis occurs when bone destruction is greater than formation

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16
Q

What are the 3 stages involved in the bone remodelling cycle?

A

1 - resorption:

  • osteoclasts break down the old bone

2 - reversal:

  • mononuclear cells appear on the bone surface

3 - formation:

  • osteoblasts lay down new bone until the resorbed bone is completely replaced
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17
Q

What components are involved in osteoclast stimulation and inhibition?

A

osteoclast stimulation:

  • RANK
  • RANKL (ligand)

osteoclast inhibition:

  • ​OPG
  • denosumab
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18
Q

What are the systemic regulators of the bone remodelling cycle?

A
  • parathyroid hormone
  • calcitrol
  • other hormones including thyroid hormones, sex hormones, glucocorticoid
  • insulin-like growth factors, prostaglandins, tumour growth factor-beta and cytokines
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19
Q

What is the role of RANK in the bone remodelling cycle?

A

RANK receptor activation of RANKL/osteoprotegrin (OPG) system

allows the processes of bone resorption and formation to be tightly coupled

this allows a wave of bone formation to follow each cycle of bone resorption to maintain skeletal integrity

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20
Q

How does ageing affect bone?

A

there is decreasing bone mass with age

peak bone mass is around 30-40 years of age

females experience bone loss due to menopause

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21
Q

How does bone resorption and formation change with age?

A

with increasing age there is decreased bone formation and increased bone resorption

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22
Q

What is involved in the investigation of bone disease?

A

gross structure:

  • X-ray
  • MRI
  • CT

bone mass (calcium):

  • DEXA

cellular function / turnover:

  • biochemistry

microstructure / cellular function:

  • biopsy
  • qCT
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23
Q

What are the biochemical markers of bone formation?

A

products of active osteoblasts:

  • alkaline phosphatase (TAP, BAP)
  • osteocalcin (OC)
  • procollagen type I propeptides (P1NP)
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24
Q

What are the biochemical markers of bone resorption?

A

degradation products of bone collagen:

  • hydroxyproline
  • pyridinium crosslinks
  • crosslinked telopeptides of type I collagen (NTX, CTX)

osteoclast enzymes:

  • tartrate-resistant acid phosphatase (TRACP 5b)
  • cathepsin K
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25
Q

How is alkaline phosphatase measured?

A

it is measured in LFTs and bone profiles

specific isoenzymes can be measured where there is diagnostic doubt

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26
Q

What is the purpose of bone alkaline phosphatase?

What is its release stimulated by?

A

it is released by osteoblasts and is involved in mineralisation

release is stimulated by increased bone remodelling

  • childhood / pubertal growth spurt
  • fractures
  • hyperparathyroidism - primary or secondary
  • pagets disease of the bone
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27
Q

What is P1NP?

How does it vary?

What will increase and decrease it?

A

procollagen type 1N propeptide is a precursor molecule of type I collagen that is synthesised by osteoblasts

it has low diurnal and intraindividual variation

serum concentrations are not affected by food intake

it is increased with increased osteoblast activity and decreased with reduced osteoblast activity

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28
Q

What are collagen cross-links (NTX, CTX)?

How do they vary?

A

cross-linking molecules which are released with bone resorption

they correlate highly with bone resorption

they have diurnal variation

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29
Q

When would collagen cross-links (NTX, CTX) be increased and decreased?

What can they not be used to predict?

A

they are increased in periods of high bone turnover

e.g. hyperthyroidism, adolescents, menopause

they decrease with anti-resorptive therapy

they do not predict bone mineral density

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30
Q

What are most bone markers based on?

How do changes in bone markers relate to diseases?

A

collagen-related markers are based primarily on type I collagen, which is widely distributed in several tissues

changes in bone markers are not disease specifc, but reflect alterations in skeletal metabolism

some markers are characterised by significant intraindividual variability

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31
Q

What are the uses of new bone markers?

A

evaluation of bone turnover and bone loss

evaluation of treatment effect:

  • CTX is used to monitor response to anti-resorptive therapy

evaluation of adherence with medication:

  • P1NP is used to monitor compliance with teriparatide
  • CTX is used to monitor compliance / response to anti-resorptive therapy
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32
Q

What is a DEXA scan?

A

a DEXA scan is also called a bone density scan

it is a common technique used to measure bone density

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33
Q

What is a T score?

How is it interpreted?

A

- 1.0 and above:

  • bone density is considered normal

between -1 and -2.5:

  • osteopenia (low bone mass)

-2.5 and below:

  • presence of osteoporosis
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34
Q

What are the 5 main bone disorders?

A
  1. metastatic disease
  2. hyperparathyroidism
  3. osteomalacia / rickets
  4. osteoporosis
  5. paget’s disease
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35
Q

What is the definition of osteoporosis?

How can this be summarised?

A

a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture

decreased bone mass + deranged bone microarchitecture = failure of structural integrity

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36
Q
A
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37
Q

In general, what is osteoporosis?

What are the common risk factors?

A

generalised loss of bone with propensity to fractures (particularly spine and hip)

there are several common risk factors for bone loss

mainly ageing and glucocorticoids

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38
Q

How is osteoporosis diagnosed?

A

no abnormalities are seen in routine biochemical tests

diagnosis relies on DEXA / X-ray

increasing use of bone markers in management

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39
Q

How can osteoporosis change someone’s life?

A

it can lead to loss of mobility, independence, increased social isolation and depression

40
Q

What is a fragility fracture?

A

a fracture caused by injury that would be insufficient to fracture a normal bone

it occurs as a result of minimal trauma

41
Q

What are the common sites for a fragility fracture?

A
  1. spine
  2. neck of femur
  3. wrist
42
Q

What does osteoporotic fracture incidence correlate with?

A

osteoporotic fracture incidence correlates with progressive trabecular and cortical bone loss over time

43
Q

When is vertebral fracture and hip fracture incidence high and why?

A

vertebral fracture incidence is high early after menopause when trabecular bone is rapidly lost

incidence of hip fracture increases after the age of 70 corresponding to the predominant loss of cortical bone

44
Q

what are the 6 main risk factors for fracture?

A
  1. age
  2. sex
  3. recent fragility fracture
  4. vertebral fractures - number and severity
  5. smoking
  6. alcohol
45
Q

What are 7 less prominent risk factors for fracture?

A
  1. falls
  2. drugs
  3. inflammatory conditions
  4. malabsorption
  5. type 1 diabetes mellitus
  6. family history
  7. BMI
46
Q

What is the FRAX calculation tool used for?

A

the ten year probability of fracture with BMD (bone mineral density)

47
Q

What are endocrine secondary causes of osteoporosis?

A
  • early menopause
  • amenorrhoea in pre-menopausal women
  • hypogonadism
  • hormone ablation for breast/prostate cancer
  • hyperparathyroidism
  • hyperthyroidism
  • cushings disease
  • hyperprolcatinaemia
  • diabetes
48
Q

What are gastrointestinal secondary causes of osteoporosis?

A
  • coeliac disease
  • IBD
  • chronic liver disease
  • any cause of malabsorption
49
Q

What are rheumatological secondary causes of osteoporosis?

A

rheumatoid arthritis and other inflammatory arthropathies

50
Q

What are haematological secondary causes of osteoporosis?

A
  • myeloma
  • haemoglobinopathies
  • systemic mastocytosis
51
Q

What are respiratory, metabolic and other secondary causes of osteoporosis?

A

respiratory:

  • COPD
  • cystic fibrosis

metabolic:

  • homocystinuria

others:

  • immobility
  • CKD
52
Q
A
53
Q

What drugs can be secondary causes of osteoporosis?

A
  • glucocorticoids
  • heparin
  • ciclosporin
  • anti-convulsants
  • aromatase inhibitors
  • androgen deprivator
54
Q

What are the investigations for secondary causes of osteoporosis in all patients?

A
  • calcium and bone profile
  • U&Es
  • TFTs
  • FBC
  • vitamin D
  • parathyroid hormone
  • plasma viscosity (+/- myeloma screen)
  • coeliac screen
55
Q

What investigations for secondary causes of osteoporosis are only performed in men?

A
  • 9am fasting testosterone
  • SHBG
  • LH, FSH
  • LFTs
56
Q

Which investigations for secondary causes of osteoporosis are only performed in young amenorrhoeic women?

A
  • LH
  • FSH
  • oestradiol
  • prolactin
57
Q

What significant feature must be present to consider an X-ray to determine a secondary cause of osteoporosis?

A

loss of height, back pain or kyphosis

a lateral X-ray of T5-L5 spine is considered

58
Q

What are the 2 categories of treatments to prevent osteoporotic fractures?

A
  1. antiresorptive treatments
  2. anabolic treatments
59
Q

What are examples of anabolic treatments for prevention of osteoporotic fractures?

A

parathyroid hormone / PTHrP analogues

these are teriparatide and abaloparatide

60
Q

What are the 3 categories of antiresorptive treatments for the prevention of osteoporotic fractures?

A

SERMS:

  • selective oestrogen receptor modulators
  • raloxifene

Bisphosphonates:

  • for oral therapy - alendronate, risedronate, ibandronate
  • for IV therapy - zoledronate, ibandronate

RANK-L inhibitor:

  • denosumab
61
Q

What is the mechanism of action of bisphosphonates?

A

they mimic the structure of pyrophosphate

they are taken up by the skeleton and ingested by osteoclasts

this inhibits osteoclast formation and activity and promotes apoptosis

this slows down the rate of bone resorption

62
Q

How does denosumab work?

A

it is a RANK ligand inhibitor

it inhibits osteoclast formation, function and survival

it is a monoclonal antibody that is given by injection every 6 months

63
Q

What is the main complication of treatment for osteoporosis?

What are the 2 different types and how do they arise?

A

bone metastases that are common in several malignancies

lytic:

  • destruction of normal bone (osteoclasts)
  • breast / lung
  • kidney / thyroid

sclerotic / osteoblastic:

  • deposition of new bone
  • prostate
  • lymphoma
  • breast / lung
64
Q

What are the usual sites of spread for bone metastases?

A
  • spine
  • pelvis
  • femur
  • humerus
  • skull
65
Q

What are the 5 main presenting symptoms of bone metastases?

A

Pain:

  • often worse at night and gets better with movement initially
  • eventually becomes constant

broken bones:

  • pathological fractures
  • commonly femur, humerus, vertebral

numbness, paralysis and trouble urinating:

  • caused by spinal cord compression from bone metastases

loss of appetite, nausea, thirst, confusion, fatigue:

  • symptoms of hypercalcaemia

anaemia:

  • disruption of bone marrow
66
Q

What are the mild symptoms of hypercalcaemia?

A
  • polyuria and polydipsia (excessive thirst)
  • mood disturbance
  • anorexia
  • nausea
  • fatigue
  • constipation
67
Q

What are the severe symptoms of hypercalcaemia?

A
  • abdominal pain
  • vomiting
  • coma
  • pancreatitis
  • dehydration
  • cardiac arrhythmias
68
Q

What are the 2 categories of causes of hypercalcaemia?

A

non-PTH mediated:

  • PTH is low / suppressed

PTH mediated:

  • PTH is high
69
Q

What are the non-PTH mediated causes of hypercalcaemia?

A
  • malignancy
  • vitamin D intoxication
  • chronic granulomatous diseases (e.g. sarcoidosis)
  • medications
  • immobilisation
  • other endocrine conditions:

hyperthyroidism, acromegaly, phaeochromocytoma, adrenal insufficiency

70
Q

What types of medications cause non-PTH mediated hypercalcaemia?

A
  • thiazide diuretics
  • lithium
  • teriparatide
  • theophylline toxicity
71
Q

What are the causes of PTH-mediated hypercalcaemia?

A
  • primary hyperparathyroidism
  • also familial causes:
  • MEN1 and 2A
  • familial hypocalciuric hypercalcaemia
  • familial isolated hyperparathyroidism
72
Q

What is parathyroid hormone?

Where is it secreted from?

A

it is a polypeptide containing 84 amino acids

it is secreted by the chief cells of the parathyroid gland

73
Q

What are the stages involved in the regulation of parathyroid hormone levels ?

A
  • low levels of blood calcium stimulate the parathyroid gland to release PTH
  • PTH increases the levels of blood calcium through several mechanisms
74
Q

By which 3 mechanisms does PTH release increase the levels of blood calcium?

A
  1. increased decomposition of bone releases calcium
  2. increased absorption of calcium from food by intestines
  3. increased reabsorption of calcium from urine by kidneys
75
Q

What are levels of calcium and PTH like in primary hyperparathyroidism?

What are the main causes?

A

calcium levels are usually high

PTH is inappropriately high

low phosphate and high alkaline phosphate

causes are sporadic or familial

76
Q

What are the levels of calcium and PTH like in secondary hyperparathyroidism?

What are the causes?

A

calcium is normal or low

PTH is appropriately high

phosphate is high if it is due to chronic kidney disease

mainly caused by chronic kidney disease or vitamin D deficiency

77
Q

What are the levels of calcium and PTH like in tertiary hyperparathyroidism?

What are the causes?

A

calcium is usually high

PTH is inappropriately high

phosphate can be high or low

it is usually caused by prolonged secondary hyperparathyroidism in CKD

78
Q

What suggests primary hyperparathyroidism?

When do the majority of cases present?

A

inappropriately elevated PTH in the presence of high calcium suggests PHPT

majority of cases present > 45 years of age

women are twice as likely to be affected compared to men

79
Q

What are the four types of adenomas that cause primary hyperparathyroidism?

A
  1. benign adenomas
  2. glandular hyperplasia
  3. ectopic adenomas
  4. parathyroid carcinoma (malignant)
80
Q

What type of adenoma causes the most cases of primary hyperparathyroidism?

A

benign adenomas

single adenoma account for 85% of cases of primary HPT

81
Q

What causes glandular hyperplasia?

How many cases of PHPT does this cause?

A

all 4 parathyroid glands are enlarged

this accounts for 6-10% of cases of primary HPT

it can occur sporadically or part of genetic syndromes

it requires medical or surgical therapy

82
Q

What are ectopic adenomas?

A

there are rarely ectopic adenomas in the mediastinum

some parathyroid adenomas are found in thymus gland

these are parathyroid cells which migrated during embryogenesis

83
Q

What is parathyroid carcinoma?

A

it accounts for 1-2% of all cases of hyperparathyroidism

there are features of invasion on histology

it is usually an aggressive disease, with significant hypercalcaemia and possibility of distant metastases

84
Q

What are the clinical manifesttions of classical primary hyperparathyroidism?

A
  • symptoms related to hypercalcaemia
  • renal disease - nephrolithiasis, chronic kidney disease
  • bone disease - osteoporosis, osteitis, fibrosa cystica
  • proximal muscle wasting
85
Q

When is surgery used as a treatment for hyperparathyroidism?

A

it is used in symptomatic hypercalcaemia

it is used in asymptomatic patients with primary HPT:

  • calcium > 0.25 mmol/L above normal
  • renal stone disease
  • calculated creatinine clearance < 60ml / min
  • age < 50 years
  • osteoporosis at any site or history of fragility fracture
  • 24 hour urine calcium > 10 mmol/day
86
Q

What is the medical treatment for hyperparathyroidism?

A

calcimimetics (Cinacalcet)

this activates CaSR in the parathyroid gland and leads to reduced PTH secretion

87
Q

When are calcimimetics used?

A

they are used to normalise calcium in symptomatic patients or those who are not fit for surgery

it does not seem to alter bone disease

88
Q

What is Paget’s disease of bone caused by?

A

rapid bone turnover and formation leads to abnormal bone remodelling

it can be polyostotic (more than one bone affected) or monostotic

elevated alkaline phosphatase reflects increased bone turnover

89
Q

Which types of patients tend to be affected by Paget’s disease of bone?

A
  • mainly over 50 years old
  • higher prevalence in men
  • probable genetic and environmental triggers
  • family history in 10-15% of cases
90
Q

What are the clinical features of Paget’s disease?

A
  • bone pain
  • bone deformity
  • fractures
  • arthritis
  • cranial nerve defects if the skull is affected - hearing and vision loss
  • risk of osteosarcoma

most commonly afefcts pelvis, femur and lower lumbar vertebrae

91
Q

What is osteomalacia?

How does it present in adult form and in childhood?

A

lack of mineralisation of bone

adult form:

  • widened osteoid seams with lack of mineralisation

childhood:

  • classic childhood rickets
  • widened epiphyses and poor skeletal growth
92
Q

What are the causes of osteomalacia?

A

insufficient calcium absorption from the intestine

due to lack of dietary calcium or vitamin D deficiency / resistance

excessive renal phosphate excretion

rare genetic forms (e.g. hereditary hypophosphataemic rickets)

93
Q
A
94
Q

What are the clinical features of osteomalacia?

A
  • diffuse bone pains (usually symmetrical)
  • muscle weakness
  • bone weakness
  • high alkaline phosphatase, low vit D, possibly low calcium and high PTH (secondary hyperparathyroidism)
95
Q

What is the adult population at risk from osteomalacia?

A
  • nursing home residents / elderly
  • asian population (hijab / burka wearing)
  • malabsorption

Y2 Clinical Pathology (76 decks)

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