(51) Diseases of the bone and new markers Flashcards
(167 cards)
1
Q
What is the purpose of bone?
A
- structural support for the body
- protection of vital organs
- blood cell production (bone marrow)
- storage bank for minerals (especially calcium)
2
Q
What is cortical bone and trabecular bone?
A
Cortical bone = hard, outer layer
Trabecular bone = spongy, inner layer
3
Q
What 2 types of cells are associated with bone?
A
Bone forming cells and bone reabsorbing cells (osteoblasts and osteoclasts)
4
Q
What is the extracellular component of bone composed of?
A
- organic matrix = mainly collagen
- inorganic components = hydroxyapatite and minerals (calcium and phosphate)
5
Q
What is the name for bone before it has mineralised?
A
Osteoid
6
Q
Bone matrix is mineralised by what? (to form mature bone tissue)
A
Hydroxyapatite (calcium-phosphate-hydroxide salt)
7
Q
Briefly, what do osteoblasts do?
A
Produce and secrete bone matrix and help with mineralisation
8
Q
Briefly, what do osteoclasts do?
A
Absorbs bone tissue during growth and healing
9
Q
Describe some features of bone as a dynamic tissue
A
- extracellular matrix
- protein and mineral
- mainly collagen
- constant remodelling
- highly vascular tissue
- metabolically active
10
Q
What does collagen do?
A
Provides tensile strength
11
Q
What are osteoblasts?
A
Terminally differentiated products of mesenchymal stem cells that make osteoid
12
Q
What is osteoid?
A
Non-mineralised organic matrix, consists of mainly type 1 collagen
- prerequisite for mineralisation
13
Q
What do osteoblasts do?
A
- make osteoid
- communicate with other bone cells
- make hormones eg. osteocalcin, matrix proteins and alkaline phosphatase
14
Q
What is the name for osteoblasts that are buried/trapped within the matrix?
A
Osteocytes
15
Q
Describe the appearance of osteoclasts
A
Large and multi-nucleated with a ruffled-resorption border
16
Q
Where are osteoclasts found?
A
In bone pits (resorption bays)
17
Q
What do osteoclasts do?
A
- break down bone = critical for repair and maintenance of bone
- produce enzymes that are secreted to break down extracellular matrix
- help enhance blood calcium levels
18
Q
Which enzymes do osteoclasts produce? (secreted to break down extracellular matrix)
A
Tartrate resistant acid phosphatase (TRAP) and Cathepsin K
19
Q
Which hormones are osteoclasts regulated by?
A
PTH, calcitonin and IL-6
20
Q
RANK ligand and osteoprotegrin do what?
A
Help with osteoclastic maturation and activity
21
Q
What are osteocytes?
A
Trapped/buried osteoblasts
22
Q
Describe the appearance of osteocytes
A
Star-shaped
23
Q
How do osteocytes communicate with each other?
A
Via cytoplasmic extensions
24
Q
What are the functions of osteocytes?
A
- mechanosensory properties
- involved with regulating bone matrix turnover
25
Describe bone remodelling
Normal bone is in a constant state of turnover caused by resorption by osteoclasts and formation by osteoblasts
26
How often is the adult skeleton completely replaced?
Every 10 years
27
Simply, what is osteoporosis?
When there is more bone destruction than there is formation
28
What are the 4 main stages in the bone cycle?
- resting
- resorption
- osteoid formation
- mineralisation
29
How is bone mass measured?
Total mass of skeletal calcium in grams
30
How does bone mass change with age?
Increases from birth until a peak at around 30-40 where it then starts declining
31
Where is there a steeper decrease in bone mass in women at around the age of 50?
Due to menopause
32
Why is there a decrease in bone mass with increasing age? A
As there is increased bone resorption but decreased bone formation
33
What 4 things about bone might you want to investigate?
- gross structure
- bone mass (calcium)
- cellular function/turnover
- microstructure/cellular function
34
How is bone gross structure investigated?
X-ray
35
How is bone mass (calcium) investigated?
DEXA
36
How is bone cellular function/turnover investigated?
Biochemistry
37
How is bone microstructure/cellular function investigated?
Biopsy, qCT
38
What are the biochemical markers of bone formation?
Products of active OB:
- alkaline phosphatase (TAP, BAP)
- osteocalcin (OC)
- procollagen type 1 prepeptides (P1NP)
39
What are the biochemical markers of bone resorption?
Degradation products of bone collagen:
- hydroxyproline
- pyridinium crosslinks
- crosslinked telopeptides of type I collagen (NTX, CTX)
+ osteoclast enzymes
40
What are the osteoclast enzymes?
- tartrate-resistant acid phosphatase (TRACP 5b)
| - cathepsin K
41
When is alkaline phosphatase measured?
Measured by the lab in LFTs and bone profiles
Specific isoenzymes can be measured where there is diagnostic doubt
42
In health, what are the alkaline phosphatase levels?
50% liver
50% bone
43
What is bone alkaline phosphatase involved in?
Mineralisation
44
What is bone alkaline phosphatase released by?
Osteoblasts
45
Release of bone alkaline phosphatase is stimulated by increase bone remodelling in...
- childhood/pubertal growth spurt
- fractures
- hyperparathyroidism (primary or secondary)
- Paget's disease of the bone
46
What is P1NP?
Procollagen type 1N propeptide
47
What is P1NP synthesised by?
Osteoblasts
48
P1NP is the precursor molecule of what?
Type 1 collagen
49
P1NP levels are affected by what?
- increased with increased osteoblast activity
- decreased by reduced osteoblast activity
- serum concentrations not affected by food intake
- has low diurnal and intraindividual variation
50
What are collagen cross-links (NTX, CTX)?
Cross-linking molecules which are released with bone resorption
51
What do collagen cross-links levels correlate with?
Correlate highly with bone resorption
52
When do collagen cross-links levels change?
- increased in periods of high bone turnover (hyperthyroidism, adolescents, menopause)
- decrease with anti-resorptive therapy
- have diurnal variation
53
Collagen cross-links levels do not predict what?
Bone mineral density
54
Collagen cross-links (NTX, CTX) are increased in periods of high bone turnover. Give 3 examples of this
- hyperthyroidism
- adolescents
- menopause
55
Collagen-related bone markers are based primarily on what?
On type 1 collagen, which is widely distributed in several tissues
56
Are changes in bone markers disease-specific?
Changes in bone markers are not disease specific, but reflect alterations in skeletal metabolism
Some markers are characterised by significant intra-individual variability
57
What are the uses of new bone markers?
- evaluation of bone turnover and bone loss
- evaluation of treatment effect
- evaluation of compliance with medication
58
Bone markers can be used to evaluate treatment effect. Give and example
CTX used to monitor response to anti-resorptive therapy
59
Bone markers can be used to evaluate compliance with medication. Give 2 examples
- P1NP used to monitor compliance with teriparatide
| - CTX used to monitor compliance/response to anti-resorptive therapy
60
What is teriparatide?
A recombinant form of parathyroid hormone - an effective anabolic (bone growing) agent used in the treatment of some forms of osteoporosis
61
What do T scores mean?
- 1 and above = normal born density
- 1 to -2.5 = low bone mass (osteopenia)
- 2.5 and below = osteoporosis
62
What is osteopenia?
When the protein and mineral content of bone tissue is reduced, but less severely than in osteoporosis
63
Which scan gives you T scores?
DEXA
64
What are the different types of bone disorders?
- metastatic disease
- hyperparathyroidism
- osteomalacia/Rickets
- osteoporosis
- Paget's disease
65
What is osteomalacia?
Softening of the bones, typically through a deficiency of vitamin D or calcium
66
Why is hyperparathyroidism?
An abnormally high concentration of parathyroid hormone in the blood, resulting in weakening of the bones through loss of calcium.
67
What is Paget's disease of the bone?
Disrupts the normal cycle of bone renewal and repair, causing bones to become weakened and deformed
68
What is osteoporosis?
The bones become brittle and fragile from loss of tissue, typically as a result of hormonal changes, or deficiency of calcium or vitamin D
69
What might the spine of an osteoporosis patient show?
Increase in biconcavity of the lower thoracic bodies and in anterior compression of the mid-thoracic vertebral bodies
70
What might the T scores of an osteoporosis patient be from a DXA scan?
T = -3.3 spine
T = -4.2 hip
71
What might the blood tests of an osteoporosis patient show?
Unremarkable apart from vitamin D deficiency
72
How might something to do with hormones cause osteoporosis?
Early menopause (before age 45)
73
Generalised loss of bone in osteoporosis gives propensity to what?
Fractures of the hip and spine, even from simple falls
74
What abnormalities are seen in routine biochemical tests in osteoporosis?
None - perhaps because they are too insensitive
75
Diagnosis of osteoporosis relies on what?
DEXA/X-ray
76
There is an increasing use of what in osteoporosis management?
Bone markers
77
What is the actual definition of osteoporosis?
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 (FAILURE OF STRUCTURAL INTEGRITY)
78
Where are the common sites of fracture in osteoporosis?
- spine
- neck of femur
- wrist
79
What is the definition of a fragility fracture?
A fracture caused by injury that would be insufficient to fracture a normal bone/ occurs as a result of minimal trauma, such as a fall from standing height or less, or no identifiable trauma
80
What should be suspected in any person with history of fragility fracture?
Low bone mass
81
What signs should prompt investigation for vertebral fractures?
- unexplained loss of height
- kyphosis
- severe back pain
82
What is the FRAX calculation tool?
```
Fracture risk assessment - calculates 10 year probability of fracture. Takes into account:
- previous fracture
- smoking
- glucocorticoids
- rheumatoid arthritis
- osteoporosis
- alcohol
- femoral neck BMD
etc
```
83
What are some endocrine secondary causes of osteoporosis?
- early menopause
- amennorrhoea
- hypogonadism
- Cushings
- diabetes
- hyperparathyroidism
- hyperthyroidism
etc
84
What are some GI secondary causes of osteoporosis?
- coeliac disease
- IBD
- chronic liver disease
- malabsorption
85
What are some rheumatological secondary causes of osteoporosis?
- rheumatoid arthritis
| - other inflammatory arthropathies
86
What are some haematological secondary causes of osteoporosis?
- myeloma
- haemaglobinopathies
- systemic mastocytosis
87
What are some respiratory secondary causes of osteoporosis?
- COPD
| - cystic fibrosis
88
What are some drugs that can cause secondary osteoporosis?
- steroids
- heparin
- ciclosporin
- anti-convulsants
89
What are the investigations done into secondary causes of osteoporosis?
- calcium and bone profile
- U&Es (estimated GFR)
- TFTs
- FBC
- vitamin D
- PTH
- plasma viscosity (+/- myeloma screen)
- coeliac screen
- lateral X-ray T5-L5
- testosterone, SHGB, LH, FSH, LFTs (male)
- LH, FSH, estradiol, prolactin (female)
90
What are some antiresorptive treatments?
- bisphosphonates (oral/IV) - (alendronic acid/zoledronic acid)
91
What are some anabolic treatments?
- terparatide (subcut)
| - synthetic PTH (parathyroid hormone)
92
What is denosumab?
Used in preventing fractures and other cancer related bone problems in adults with cancer that has spread to the bone
- monoclonal antibody to RANK ligand
93
What is raloxifene?
An oral selective estrogen receptor modulator (SERM) that has oestrogenic actions on bone
94
Which mineral is also used in bone treatment?
Strontium
95
Describe the efficacy of bone treatments
- 50-70% reduction in vertebral fractures
| - 25-35% reduction in hip fractures
96
Describe the mechanism of action of bisphosphonates
- mimic pyrophosphate structure
- ingested by osteoclasts
- bisphosphonate released from osteoclast during bone resorption
- impairs osteoclasts' ability to form ruffled border etc.
- inhibit osteoclast formation, migration, osteolytic activity and promote apoptosis
97
Describe some problems with the use of bisphosphonates
- poor absorption
- difficult to take
- can cause oesophageal/upper GI problems
- flu-like side effects
- osteonecrosis of the jaw
- atypical femur fractures
98
Describe 2 types of bone metastases
- lytic
| - sclerotic/osteoblastic
99
What are lytic bone metastases?
Destruction of normal bone (osteoclasts)
100
What are sclerotic/osteoblastic bone metastases?
Deposition of new bone
101
Which cancers causes lytic bone metastases?
- breast/lung
| - kidney/thyroid
102
Which cancers cause sclerotic bone metastases?
- prostate
- lymphoma
- breast/lung (15-25%)
103
Where are the usual sites of bone metastases?
- spine
- pelvis
- femur
- humerus
- skull
104
Describe 5 groups of presenting symptoms of bone mets
- pain
- broken bones
- numbness, paralysis, trouble urinating
- loss of appetite, nausea, thirst, confusion, fatigue
- anaemia
105
Describe the pain that occurs in born mets
- often worse at night
- gets better with movement initially
- usually becomes constant
106
Which bones get commonly broken in bone mets
- femur
- humerus
- vertebral column
Pathological fractures
107
Why do you get numbness, paralysis and trouble urinating in bone mets?
Spinal cord compression from bone metastases
108
Why do you get loss of appetite, nausea, thirst, confusion and fatigue in bone mets?
Symptoms of hypercalcaemia
109
Why do you get anaemia in bone mets?
Disruption of bone marrow
110
What do the parathyroid glands do?
Control the body's calcium levels - produce parathyroid hormone (PTH)
111
What are the mild symptoms of hypercalcaemia?
- polyuria, polydipsia
- mood disturbance
- anorexia
- nausea
- fatigue
- constipation
112
What are the severe symptoms of hypercalcaemia?
- abdominal pain
- vomiting
- coma
- pancreatitis
- dehydration
- cardiac arrhythmias
113
What are the non-PTH mediated causes of hypercalcaemia?
- malignancy
- vitamin D intoxication
- chronic granulomatous disorders eg. sarcoidosis
- medications eg. thiazide diuretics, teriparatide
- immobilisation
- other endocrine conditions eg. hyperthyroidism, acromegaly
114
What are the PTH-mediated causes of hypercalcaemia?
- sporadic primary hyperparathyroidism
| - familial (MEN1 and 2A, familial hypocalciuric hypercalcaemia, familial isolated hyperparathyroidism)
115
Where are the parathyroid glands?
2 on each side of the thyroid gland, at the back
116
What is parathyroid hormone (PTH) secreted by?
Chief cell of parathyroid gland
117
What type of molecule is PTH?
Polypeptide containing 84 amino acids
118
What stimulates the parathyroid gland to release PTH?
- low levels of blood calcium
- decreased serum magnesium
- increased vitamin D
119
What 3 main things does PTH do?
- increases decomposition of bone, releasing calcium
- increases absorption of calcium from food by intestines
- increases reabsorption of calcium from urine by kidneys
These all increase levels of blood calcium
120
What effect does increasing levels of calcium have on the parathyroid gland?
Negative feedback back to the parathyroid gland so less PTH produced
121
What are the 3 different types of hyperparathyroidism (HPT)?
- primary
- secondary
- tertiary
122
What are the calcium levels in hyperparathyroidism?
primary = high
secondary = normal or low
tertiary = high
123
What are the PTH levels in hyperparathyroidism?
primary = inappropriately high
secondary = appropriately high
tertiary = inappropriately high
124
What are the phosphate levels in HPT?
primary = low phosphate and high alkaline phosphate
secondary = high phosphate if due to chronic kidney disease
tertiary = phosphate can be high or low
125
What are the causes of primary HPT?
Sporadic or familial
126
What are the causes of secondary hyperthyroidism?
Mainly CKD or vitamin D deficiency
127
What are the causes of tertiary HPT?
After prolonged secondary HPT, usually in CKD
128
What is tertiary hyperthyroidism?
A state of excessive secretion of parathyroid hormone (PTH) after a long period of secondary hyperparathyroidism and resulting in a high blood calcium level
129
What is secondary hyperparathyroidism?
Excessive secretion of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcemia (low blood calcium levels) and associated hyperplasia of the gland
130
How does primary hyperparathyroidism present?
Used to present with severe hypercalcaemia and/or symptomatic renal and skeletal disease
Now presentation is much earlier and is usually asymptomatic
131
Majority of cases of PHPT present at what age?
Over 45
132
Which gender is more affected by PHPT?
Women are 2x as likely to be affected compared to men
133
What blood test results suggest PHTP?
Inappropriately elevated PTH in the presence of high calcium
134
What accounts for 90% of cases of primary HPT?
Benign adenomas
```
85% = single adenoma
5% = double parathyroid adenomas
```
135
Describe typical parathyroid adenomas
Most adenomas are encapsulated and consist of parathyroid chief cells
136
What accounts for 1-2% of PHPT?
Parathyroid carcinomas (malignant)
137
Describe the features of PHPT caused by carcinoma
- features of invasion on histology
| - usually aggressive disease, with significant hypercalcaemia, and possibility of distant metastases
138
What account for 6-10% of cases of primary HPT?
Glandular hyperplasia
139
Describe the features of glandular hyperplasia causing primary HPT
- all 4 glands enlarged
- lower glands usually larger than upper ones
- usually composed of chief cells
140
Is glandular hyperplasia causing primary HPT sporadic or familial?
Can occur sporadically or part of genetic syndromes (MEN1, MEN2A or familial hyperparathyroidism)
141
How is glandular hyperplasia causing primary HPT treated?
- medical or surgical therapy
| - if surgery, 3.5 glands often removed
142
Describe the features of ectopic adenomas causing primary HPT?
- rarely ectopic adenomas in mediastinum
- some parathyroid adenomas found in thymus gland
- parathyroid cells which migrated during embryogenesis
143
What are the classical clinical manifestations of PHPT?
- symptoms related to hypercalcaemia (as described)
- renal disease (nephrolithiasis, chronic kidney disease)
- bone disease (osteoporosis, osteitis, fibrosa cystica)
- proximal muscle wasting
144
What drug is used in imaging to identify parathyroid adenomas in primary HPT?
Tc 99 sestamibi
- can also identify ectopic parathyroid tissue in mediastinum for example
145
What are the indications for surgery in PHPT?
- symptomatic hypercalcaemia
- in asymptomatic patients with:
- calcium over 0.25mmol/L above normal
- renal stone disease
- creatinine clearance less than 60ml/min
- age under 50 yeas
- osteoporosis at any site or history of fragility fracture
146
Why are calcimimetics (cinacalcet) used in HPT?
Activates CaSR (calcium sensing receptor) in the parathyroid gland, therefore leading to reduced PTH secretion
147
What are calcimimetics used for in HPT?
Used to normalise calcium in symptomatic patients, or those who are not fit for or unwilling to have surgery
- does not seem to alter bone disease
- no data on renal outcomes or QoL
148
What are the limitations of calcimimetics?
GI side effects, particularly nausea
149
What happens in Paget's disease of bone?
- rapid bone turnover and formation
- leading to abnormal bone remodelling
Can be polyostotic or monostotic
150
Who does Paget's disease of bone occur in?
Mainly over 50 years old, higher prevalence in men
151
Does Paget's disease generally come with family history?
FH in 10-15% of cases
Probably genetic and environmental triggers
152
There are elevated levels of what in Paget's disease of bone?
Elevated alkaline phosphatase - reflecting increased bone turnover
153
What are the clinical features of Paget's disease of bone?
- bone pain
- bone deformity
- fractures
- arthritis
- cranial nerve defects if skull affected = hearing and vision loss
- risk of osteosarcoma
154
Which bones does Paget's disease most commonly affect?
- pelvis
- femur
- lower lumbar vertebrae
155
What are the investigations into Paget's disease?
- lab assessment
- plain X-rays
- nuclear medicine bone scan
156
What happens in osteomalacia?
Lack of mineralisation of bone due to vitamin D deficiency or lack of calcium and/or phosphate
157
What are the differences between the adult and child forms of osteomalacia?
adult form = widened osteoid seams with lack of mineralisation
classic childhood rickets = widened epiphyses and poor skeletal growth
158
What is an osteoid seam? (these are widened in osteomalacia)
On the surface of a bone, the narrow region of newly formed organic matrix not yet mineralised
159
What are the main causes of osteomalacia?
- insufficient calcium absorption from intestine (due to lack of dietary calcium or vit D deficiency/resistance)
- excessive renal phosphatase excretion (rare genetic forms eg. hereditary hypophosphataemic rickets)
160
What are the clinical features of osteomalacia?
- diffuse bone pains, usually symmetrical
- muscle weakness
- bone weakness
161
What are the levels of alkaline phosphatase, calcium etc that you would find in osteomalacia?
- high alkaline phosphatase
- low vitamin D
- possibly low calcium
- high PTH (secondary hyperparathyroidism)
162
Which of the adult population are more at risk of osteomalacia?
- nursing home residents/elderly
- asian population (Hijab/Burka wearing)
- malabsorption
163
Summarise the biochemistry of hyperparathyroidism
Alkaline phosphatase = increased
Calcium = increased
Phosphate = decreased
PTH = increased
164
Summarise the biochemistry of osteomalacia
Alkaline phosphatase = increased
Calcium = (low)
Phosphate = low
PTH = (high)
165
Summarise the biochemistry of osteoporosis
Alkaline phosphatase = nil
Calcium = nil
Phosphate = nil
PTH = nil
166
Summarise the biochemistry of Paget's
Alkaline phosphatase = high
Calcium = nil
Phosphate = nil
PTH = nil
167
Summarise the biochemistry of bone mets
Alkaline phosphatase = high
Calcium = (high)
Phosphate = nil
PTH = (low)
