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Clinical Pathology > Disease of bone and application of new markers > Flashcards

Disease of bone and application of new markers Flashcards

1
Q

What is cortical bone?

A

Hard, outer layer.

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2
Q

What is trabecular bone?

A

Spongy, inner layer that houses bone marrow.

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3
Q

What is the bone extracellular matrix made from?

A

Mainly collagen. Also hydroxyapatite and minerals (calcium, phosphate)

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4
Q

What is the main function of osteoblasts?

A

Constantly producing and secreting matrix and helping with mineralisation.

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5
Q

What is the main function of osteoclasts?

A

Bone resorption

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6
Q

What is the lineage of osteoblasts?

A

Terminally differentiated products of mesenchymal stem cells.

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7
Q

What is osteoid?

A

Non-mineralised organic matrix, consists of mainly type 1 collagen.

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8
Q

What are the specific functions of osteoblasts?

A
  • Make osteoid
  • Communicate with other bone cells
  • Make hormones (e.g. osteocalcin), matrix proteins and alk. phosphatase
  • Prerequisite for mineralisation
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9
Q

What name is given to osteoblasts that are buried/trapped within the matrix?

A

Osteocytes

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10
Q

What are the morphological features of osteoclasts?

A
  • Large
  • Multi-nucleated
  • Ruffled-resorption border
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11
Q

What are the specific functions of osteoclasts?

A
  • Break down bone, critical for repair and maintenance of bone
  • Produce enzymes such as tartrate resistant acid phosphatase (TRAP) and Cathepsin K - secreted breakdown extracellular matrix
  • Help enhance blood calcium levels
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12
Q

Where are osteoclasts found?

A

In bone pits (resorption bays).

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13
Q

Which hormones regulate osteoclasts?

A

PTH, calcitonin, IL-6

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14
Q

What help with osteoclastic maturation and activity.

A

RANK ligand and osteoprotegrin

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15
Q

What are the morphological features of osteocytes?

A

Star shaped

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16
Q

How do osteocytes communicate with each other?

A

Via cytoplasmic extensions.

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17
Q

What are the functions of osteocytes?

A
  • Mechanosensory properties (i.e. so we know where the bone is where it’s being moved)
  • Involved with regulating bone matrix turnover
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18
Q

How often is an adult skeleton replaced?

A

10

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19
Q

What tests are used in the investigation of bone disease?

A

Gross structure
- X-ray

Bone mass (Calcium)
- DEXA

Cellular function/turnover
- biochemistry

Microstructure/cellular function
- Biopsy, qCT

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20
Q

What are the biochemical markers of bone formation?

A
  • Alkaline phophatase (TAP, BAP)
  • Osteocalcin (OC)
  • Procollagen type 1 propeptides (P1NP)
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21
Q

What are the biochemical markers of bone resorption?

A

Degradation products of bone collagen:

  • Hydroxyproline
  • Pyridinium crosslinks
  • Crosslinked telopeptides of type 1 collagen (NTX, CTX)

Osteoclast enzymes:

  • Tartrate-resistant acid phosphatase (TRACP 5b)
  • Cathepsin K
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22
Q

What is alkaline phosphatase?

A
  • Measured in LFTs and bone profiles
  • In health approx 50% liver/50% bone
  • Specific isoenzymes can be measured where there is diagnostic doubt
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23
Q

What is the function of alkaline phosphatase in bone?

A

Involved in mineralisation.

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24
Q

Which cells release alkaline phophatase?

A

Osteoblasts

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25
Q

What stimulates the release of alkaline phophatase?

A

Release stimulated by increased bone remodelling.

  • Childhood
  • Fractures
  • Hyperparathyroidism (primary or secondary)
  • Paget’s disease
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26
Q

What is P1NP?

A
  • Procollagen type 1N propeptide
  • precursor molecule of type 1 collagen
  • has low diurnal and intraindividual variation
  • serum concentrations not affected by food intake
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27
Q

Which cells synthesise P1NP?

A
  • Osteoblasts
  • Serum concentration increased with increased osteoblast activity
  • Decreased by reduced osteoblast activity
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28
Q

What are NTX and CTX?

A
  • Cross-linking molecules which are released with bone resorption, correlate highly with bone resorption
  • Increased in periods of high bone turnover
  • Have diurnal variation
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29
Q

Do NTX and CTX predict bone mineral density?

A

No

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30
Q

What type of collagen are collagen-related markers based primary on?

A

Type 1 collagen

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31
Q

Are changes in bone markers disease-specific?

A

No - reflect alterations in skeletal metabolism. Some markers vary a lot by individual.

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32
Q

What are the possible uses of bone markers?

A

Evaluation of bone turnover and loss

Evaluation of treatment effect
- CTX used to monitor response to anti-responsive treatment

Evaluation of compliance with medication

  • P1NP used to monitor compliance with teriparatide
  • CTX used to monitor compliance/response to anti-resorptive therapy
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33
Q

What do DEXA scores mean?

A
  • 1 and above: bone density is considered normal

Between -1 and -2.5: osteopenia

  • 2.5 and below: osteoporosis
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34
Q

What is osteoporosis?

A

Generalised loss of bone with propensity to fractures - spine, hip.

decreased bone mass + deranged bone micro-architecture = failure of structural integrity

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35
Q

What does diagnosis rely on?

A
  • DEXA/X-ray

- No abnormalities are seen in routine biochemical tests, perhaps because they are too insensitive

36
Q

What is a fragility fracture?

A

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

37
Q

What should be your suspicion in a person with a history of fragility fractures?

A

Low bone mass

38
Q

What Hx should prompt investigation for vertebral fractures?

A
  • Unexplained loss of height
  • Kyphosis
  • Severe back pain
39
Q

What are the endocrine causes of secondary osteoporosis?

A
  • Early menopause
  • Amenorrhoea
  • Hypogonadism
  • Hormone ablation for breast/prostate cancer
  • hyperparathyroidism
  • hyperthyroidism
  • Cushing’s
  • hyperprolactinaemia
  • diabetes
40
Q

What are the haematological causes of secondary osteoporosis?

A
  • Myeloma
  • Haemoglobinopathies
  • Systemic mastocytosis
41
Q

What are the gastrointestinal causes of secondary osteoporosis?

A
  • Coeliac disease
  • IBD
  • Chronic liver disease
  • Any cause of malabsorption
42
Q

What are the rheumatological causes of secondary osteoporosis?

A
  • RA

- Inflammatory arthropathies

43
Q

What are the respiratory causes of secondary osteoporosis?

A
  • COPD

- Cystic fibrosis

44
Q

What are the metabolic causes of secondary osteoporosis?

A
  • Homocystinuria
45
Q

Which drugs may cause secondary osteoporosis?

A
  • Steroids (prenisolone >7.5mgs daily for >3m)
  • Heparin
  • Ciclosporin
  • Anticonvulsants
46
Q

What investigations might one use for the secondary causes

A
  • Ca and bone profile
  • U&Es
  • TFTs
  • FBC
  • Vit D
  • PTH
  • Plasma viscosity (+/- myeloma screen)
  • Coeliac screen
  • In men: 9am testosterone, SHBG, LH, FSH and LFTs
  • In young amenorrhoeic women: LH, FSH, estradiol prolactin
  • Loss of height, back pain or kyphosis consider lateral X-ray T5-L5 spine
47
Q

What antiresorptive treatments are available to treat osteoporosis?

A
  • Bisphosphonates - alendronic/zolendronic acid, oral/IV
  • Denosumab - monoclonal Ab to RANKL
  • Raloxifene
48
Q

What anabolic treatments are available?

A
  • Terparatide SC

- Synthetic PTH

49
Q

What element can be used as treatment for osteoporosis?

A

Strontium

50
Q

What is the mechanism of action for bisphophonates?

A
  • Mimic pyrophosphate structure
  • Taken up by skeleton
  • Ingested by osteoclasts
  • Inhibit osteoclast formation, migration and osteolytic activity, promote apoptosis
  • Concentrated in newly mineralising bone and under osteoclasts
  • Modulate signalling from osteoblasts to osteoclasts
51
Q

What are the drawbacks of bisphosphonates?

A
  • Poor absorption
  • Difficult to take
  • Can cause oeophageal/upper GI problems
  • Flu-like side effects
  • Osteonecrosis of the jaw
  • Atypical femur fractures
52
Q

What are lytic bone metastases and which cancers are they commonly associated with?

A

Destruction of normal bone (osteoclasts).

  • Breast
  • Lung
  • Kidney
  • Thyroid
53
Q

Which haematological malignancy is associated with lytic bone lesions?

A

Multiple myeloma

54
Q

What are sclerotic bone metastases and which cancers are they commonly associated with?

A

Deposition of new bone

  • Prostate
  • Lymphoma
  • Breast/lung (15-25%)
55
Q

What are the usual sites of metastatic spread in the skeleton?

A
  • Spine
  • Pelvis
  • Femur
  • Humerus
  • Skull
56
Q

What are the presenting symptoms of bone mets?

A

Pain

  • Often worse at night and gets better with movement initially
  • Usually becomes constant

Broken bones
- Pathological fractures

Numbness, paralysis, trouble urinating
- Spinal cord compression from bone mets

Loss of appetite, nausea, thirst, confusion, fatigue
- Symptoms of hypercalcaemia

Anaemia
- Disruption of bone marrow

57
Q

What are the symptoms of hypercalcaemia?

A

Mild

  • Polyuria
  • Polydipsia
  • Mood disturbance
  • Anorexia
  • Nausea
  • Fatgue
  • Constipation

Severe

  • Abdo pain
  • Vomiting
  • Coma
  • Pancreatitis
  • Dehydration
  • Cardiac arrhythmias
58
Q

What are the non-PTH mediated causes of hypercalcaemia?

A
  • Malignancy
  • Vit D intoxication
  • Chronic granulomatous disorders e.g. sarcoidosis
  • Medications
  • Immobilisation
  • Hyperthyroidism
  • Acromegaly
  • Phaeochromocytoma
  • Adrenal insufficiency
59
Q

Which drugs can cause hypercalcaemia?

A
  • Thiazide diuretics
  • Lithium
  • Teriparatide
  • Theophylline toxicity
60
Q

What are the PTH-mediated causes of hypercalcaemia?

A
  • Sporadic primary hyperparathyroidism
  • MEN1 and 2A genes
  • Familial isolated hyperparathyroidism
61
Q

Which cells secrete parathyroid hormone?

A

Chief cells of parathyroid glands

62
Q

What stimulates the release of PTH?

A
  • Low Ca and Mg

- Increased Vit D

63
Q

What inhibits the release of PTH?

A
  • Increased levels of blood Ca
64
Q

What are the actions of PTH?

A
  • Increased decomposition of bone, releasing Ca
  • Increased absorption of Ca from food by intestines
  • Reabsorption of Ca from urine by kidneys
65
Q

What are the test results in primary hyperparathyroidism and the main causes?

A
  • Ca: usually high
  • PTH: inappropriately high
  • Low phosphate and high alk phos common
  • Causes: sporadic or famillial
66
Q

What are the test results in secondary hyperparathyroidism and the main causes?

A
  • Ca: Normal or low
  • PTH: Appropriately high
  • Phosphate high if due to CKD
  • Causes: mainly CKD or Vit D deficiency
67
Q

What are the test results in tertiary hyperparathyroidism and the main causes?

A
  • Ca: usually high
  • PTH: inappropriately high
  • Phosphate can be high or low
  • Causes - After prolonged secondary HPT, usually in CKD
68
Q

What is the presentation of primary hyperparathyroidism (PHPT)?

A
  • Previously used to present with severe hypercalcaemia and/or symptomatic renal and skeletal disease
  • Now presentation much earlier so usually asymptomatic
  • > 45 years
  • 2:1 F:M
  • Inappropriately elevated PTH in the presence of high calcium suggests PHPT
69
Q

What is the cause of 85% of PHPT?

A
  • Single adenoma
  • Additional 5% have multiple
  • Most adenomas encapsulated and consist of parathyroid chief cells
70
Q

What percentage of PHPT is caused by malignancy?

A

1-2% (carcinoma)

71
Q

What are the features of parathyroid carcinoma?

A
  • Features of invasion on histology

- Usually aggressive disease, with significant hypercalcaemia and possibility of distant metastases.

72
Q
  • What are the features of glandular hyperplasia?
A
  • Approx 6-10% of cases of PHPT
  • All 4 glands enlarged (lower glands usually larger than upper ones, usually composed of Chief cells)
  • Can occur sporadically or part of genetic syndromes (MEN1, MEN2A or familial hyperparathyroidism)
  • Medical or surgical therapy
  • If surgery: 3-5 glands often removed
73
Q

What is an ectopic adenoma?

A
  • Rarely ectopic adenomas in mediastitinum

- Some parathyroid adenomas found in thymus gland (parathyroid cells which migrated during embryogenesis)

74
Q

What are the clinical manifestations of PHPT?

A
  • Symptoms related to hypercalcaemia (as described)
  • Renal (nephrolithiasis, CKD)
  • Bone disease (osteoporosis, ostoitis, fibrosa cystica)
  • Proximal muscle wasting
75
Q

What are the indications for surgery in PHPT?

A
  • Symptomatic hypercalcaemia
  • In asymptomatic patients with primary
  • Ca > 0.25mmol/L above normal
  • Renal stone disease
  • Calculated creatinine clearance
  • Age
76
Q

What are the calcimimetics e.g. Cinacalcet)?

A
  • Activates CaSR in the parathyroid gland

- Therefore leads to reduced PTH secretion

77
Q

What are calcimimetics used for?

A
  • Use to normalise Ca in symptomatic patients, or those who are not fit or unwilling to have surgery
  • Use limited by GI side effects, particularly nausea
  • Does not seem to alter bone disease
  • No data on renal outcomes or quality of life
78
Q

What is Paget’s disease of the bone?

A
  • Rapid bone turnover and formation leading to abnormal bone remodelling
  • Polyostotic or monostotic
  • Elevated alk. phos. reflecting increased bone turnover
79
Q

What is the epidemiology of Paget’s disease?

A
  • > 50 yo
  • Higher prevalance in men
  • Probable genetic and environmental triggers
  • FH in 10-15%
80
Q

What are the clinical features of Paget’s disease of bone?

A
  • Bone deformity
  • Bone pain
  • Fractures
  • Arthritis
  • Cranial nerve defects if skull affected - hearing and vision loss
  • Risk of osteosarcoma
  • Most commonly affects pelvis, femur and lower lumbar vertebrae
81
Q

What investigations are necessary in Paget’s disease?

A
  • Lab assessment
  • Plain x-rays
  • Nuclear medicine bone scans
82
Q

What is osteomalacia?

A

Lack of mineralisation of bone due to Vit D deficiency or lack of Ca and or phosphate.

83
Q

Describe the adult form of osteomalacia?

A

Widened osteoid seams with lack of mineralisation.

84
Q

Describe the childhood form of osteomalacia (rickets)?

A

Widened epiphyses and poor skeletal growth.

85
Q

What are the main causes of osteomalacia?

A
  • Insufficient Ca absorption from intestine due to lack of dietary Ca or Vit D deficiency or resistance
  • Excessive renal phosphate excretion - rare genetic forms (hereditary hypophosphataemic rickets)
86
Q

What are the clinical features of osteomalacia?

A
  • Diffuse bone pains, usually symmetrical
  • Muscle weakness
  • Bone weakness
  • High alk. phos.
  • Low Vit D
  • Possibly low Ca and high PTH (secondary HPT)
  • Adult population at risk - nursing home/Hijab/Burka wearing/malabsorption

Clinical Pathology (65 decks)

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