T3 - L4 Diseases of the bone and new markers Flashcards
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 (osteoblasts)
bone reabsorbing cells (osteoclasts)
4
Q
What is the extracellular component of bone composed of?
A
- organic matrix = mainly type 1 collagen
- inorganic components; hydroxyapatite and minerals
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
what do osteoblasts do?
A
- make osteoid
- communicate with other bone cells
- make hormones (e.g. osteocalcin), matrix proteins and alkaline phosphatase
- Prerequisite for mineralisation
8
Q
what are features of osteoclasts?
A
- large surface area
- multi nucleated
- ruffled-resorption border
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 is the name for osteoblasts that are buried/trapped within the matrix?
A
Osteocytes
14
Q
Where are osteoclasts found?
A
In bone pits (resorption bays)
15
Q
What do osteoclasts do?
A
- break down bone
- produce enzymes that are secreted to break down extracellular matrix
- help enhance blood calcium levels
16
Q
Which enzymes do osteoclasts produce? (secreted to break down extracellular matrix)
A
Tartrate resistant acid phosphatase (TRAP)
Cathepsin K
17
Q
Which hormones are osteoclasts regulated by?
A
PTH
calcitonin
IL-6
18
Q
RANK ligand and osteoprotegrin do what?
A
Help with osteoclastic maturation and activity
19
Q
What are osteocytes?
A
Trapped/buried osteoblasts
20
Q
Describe the appearance of osteocytes
A
Star-shaped
21
Q
How do osteocytes communicate with each other?
A
Via cytoplasmic extensions
22
Q
What are the functions of osteocytes?
A
- mechanosensory properties (know which bone is being used)
- involved with regulating bone matrix turnover
23
Q
Describe bone remodelling
A
Normal bone is in a constant state of turnover caused by resorption by osteoclasts and formation by osteoblasts
24
Q
How often is the adult skeleton completely replaced?
A
Every 10 years
25
Simply, what is osteoporosis?
When there is more bone destruction than there is formation
26
What are the 4 main stages in the bone cycle?
- resting - lining cells of inactive osteoblasts
- resorption - osteoclasts are signalled to reabsorb areas
- osteoid formation - osteoblasts are signalled to form osteoids (non-mineralised type 1 collagen)
- mineralisation - osteoid becomes mineralised to hard bone.
27
How is bone mass measured?
Total mass of skeletal calcium in grams
28
How does bone mass change with age?
Increases from birth until a peak at around 30-40 where it then starts declining
29
Where is there is an accelerated bone loss in women around 50 years of age?
Due to menopause/oestrogen levels decline
30
what happens with bone mass as an individual ages?
- under 25’s still acquire their peak bone mass
| - From 50’s onwards men and women are gradually losing bone mass year upon year
31
What 4 things about bone might you want to investigate?
- gross structure
- bone mass (calcium)
- cellular function/turnover
- microstructure/cellular function
32
How is bone gross structure investigated?
X-ray
33
How is bone mass (calcium) investigated?
DEXA Dual-Energy X-ray absorptiometry
[Shine two x-ray beams through bones to give a densitometry result of the bone]
34
How is bone cellular function/turnover investigated?
Biochemistry
35
How is bone microstructure/cellular function investigated?
Biopsy (rare)
Quantitative computed tomography (QCT)
36
What are the biochemical markers of bone formation?
Products of active Osteoblasts:
- alkaline phosphatase (TAP, BAP)
- osteocalcin (OC)
- procollagen type 1 prepeptides (P1NP)
37
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:
- Tartrate-resistant acid phosphatase (TRACP 5b)
- Cathepsin K
38
What are the osteoclast enzymes?
- tartrate-resistant acid phosphatase (TRACP 5b)
| - cathepsin K
39
When is alkaline phosphatase measured?
Measured by the lab in LFTs and bone profiles
40
In health, what are the alkaline phosphatase levels?
50% liver
50% bone
NB: elevated alkaline phosphatase can be due to the liver
41
What is bone alkaline phosphatase involved in?
phosphatase involved in Mineralisation
42
What is bone alkaline phosphatase released by?
Osteoblasts
43
what is release of bone alkaline phosphatase stimulated by?
stimulated by increased bone remodelling e.g.:
- growth spurt
- fractures
- hyperparathyroidism (primary/secondary)
- pagets disease
44
What is P1NP?
Procollagen type 1N propeptide
45
What is P1NP synthesised by?
Osteoblasts
46
P1NP is the precursor molecule of what?
Type 1 collagen
47
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
48
What are collagen cross-links (NTX, CTX)?
Cross-linking molecules which are released with bone resorption
49
What do collagen cross-links levels correlate with?
Correlate highly with bone resorption
50
When do levels of collagen cross-links change?
- increased in periods of high bone turnover (hyperthyroidism, adolescents, menopause)
- decrease with anti-resorptive therapy
- have diurnal variation (change according to the time of day)
51
what is a disadvantage of using collagen cross-links as a bone resorption marker?
Do not predict bone mineral density
Decrease with anti-resorptive therapy
52
Collagen cross-links (NTX, CTX) are increased in periods of high bone turnover. Give 3 examples of when the body will experience high bone turnover.
- hyperthyroidism
- adolescents
- menopause
53
Collagen-related bone markers are based primarily on what?
type 1 collagen
54
Are changes in bone markers disease-specific?
no
reflect alterations in skeletal metabolism
55
What are the uses of new bone markers?
- evaluation of bone turnover and bone loss
- evaluation of treatment effect
- evaluation of compliance with medication
56
what is the bone marker CTX used for?
CTX used to monitor compliance/response to anti-resorptive therapy
57
which bone marker us used to measure compliance with teriparatide?
P1NP
58
What is teriparatide?
A form of parathyroid hormone - an effective anabolic (bone growing) agent used in the treatment of some forms of osteoporosis
59
T scores are given when doing a DEXA scan. What do T scores indicate
The T score indicates how many standard deviations the person is
away from the mean compared to someone who’s young, healthy and of the same sex
- 1 and above = normal born density
- 1 to -2.5 = low bone mass (osteopenia)
- 2.5 and below = osteoporosis
60
What is osteopenia?
When the protein and mineral content of bone tissue is reduced, but less severely than in osteoporosis
61
Which scan gives you T scores?
DEXA
62
What is osteomalacia?
Softening of the bones, typically through a deficiency of vitamin D or calcium
63
Why is hyperparathyroidism?
An abnormally high concentration of parathyroid hormone in the blood, resulting in weakening of the bones through loss of calcium.
64
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
65
what are risk factors of osteoporosis?
[Risk factors of osteoporosis: steroids, early menopause (earlier then 45), age, female,
smoker, alcohol and inflammatory conditions e.g. ulcerative colitis]
66
What abnormalities are seen in routine biochemical tests in osteoporosis?
None - perhaps because they are too insensitive
67
Diagnosis of osteoporosis relies on what?
DEXA/X-ray
68
What is the actual definition of osteoporosis?
- LOW BONE MASS
- MICROARCHITECTURAL DETERIORATION of bone tissue,
- consequent increase in bone fragility and susceptibility to fracture
69
Where are the common sites of fracture in osteoporosis?
- spine
- neck of femur
- wrist
70
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
71
What should be suspected in any person with history of fragility fracture?
Low bone mass
72
What signs should prompt investigation for vertebral fractures?
- unexplained loss of height
- kyphosis
- severe back pain
73
What is the FRAX calculation tool?
[Helps calculate the risk of fracture in the next 10 years]
74
What are some endocrine secondary causes of osteoporosis?
- early menopause
- amennorrhoea
- hypogonadism
- Cushings
- diabetes
- hyperparathyroidism
- hyperthyroidism
75
What are some GI secondary causes of osteoporosis?
- coeliac disease
- IBD
- chronic liver disease
- malabsorption
76
What are some rheumatological secondary causes of osteoporosis?
- rheumatoid arthritis
| - other inflammatory arthropathies
77
What are some haematological secondary causes of osteoporosis?
- myeloma
- haemaglobinopathies
- systemic mastocytosis
78
What are some respiratory secondary causes of osteoporosis?
- COPD
| - cystic fibrosis
79
What are some drugs that can cause secondary osteoporosis?
- steroids
- heparin
- ciclosporin
- anti-convulsants
- aromatase inhibitors
- androgen deprivation therapy
80
What are some anabolic treatment options for the prevention of osteoporosis?
Parathyroid hormone analogue – teriparatide]
81
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
82
What is raloxifene?
An oral selective estrogen receptor modulator (SERM) that has oestrogenic actions on bone
83
Which mineral is also used in bone treatment?
Strontium
84
Describe the mechanism of action of bisphosphonates
- mimic pyrophosphate structure
- ingested by osteoclasts
- Causing the osteoclasts to be destroyed, stopping
the signalling of osteoclasts and osteoblasts
85
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
86
Describe 2 types of bone metastases
- lytic
| - sclerotic/osteoblastic
87
What are lytic bone metastases?
Destruction of normal bone (osteoclasts)
88
What are sclerotic/osteoblastic bone metastases?
Deposition of new bone
89
Which cancers causes lytic bone metastases?
- breast/lung
| - kidney/thyroid
90
Which cancers cause sclerotic bone metastases?
- prostate
- lymphoma
- breast/lung (15-25%)
91
Where are the usual sites of bone metastases?
- spine
- pelvis
- femur
- humerus
- skull
92
Describe 5 groups of presenting symptoms of bone mets
- pain
- broken bones
- numbness, paralysis, trouble urinating
- loss of appetite, nausea, thirst, confusion, fatigue
- anaemia
93
Describe the pain that occurs in born mets
- often worse at night
- gets better with movement initially
- usually becomes constant
94
Which bones get commonly broken in bone mets
- femur
- humerus
- vertebral column
Pathological fractures
95
Why do you get numbness, paralysis and trouble urinating in bone mets?
Spinal cord compression from bone metastases
96
Why do you get anaemia in bone mets?
Disruption of bone marrow
97
What are the mild symptoms of hypercalcaemia?
- polyuria, polydipsia
- mood disturbance
- anorexia
- nausea
- fatigue
- constipation
98
What are the severe symptoms of hypercalcaemia?
- abdominal pain
- vomiting
- coma
- pancreatitis
- dehydration
- cardiac arrhythmias
99
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
100
What are the PTH-mediated causes of hypercalcaemia?
- sporadic primary hyperparathyroidism
| - familial (MEN1 and 2A, familial hypocalciuric hypercalcaemia, familial isolated hyperparathyroidism)
101
Where are the parathyroid glands?
2 on each side of the thyroid gland, at the back
102
What is parathyroid hormone (PTH) secreted by?
Chief cell of parathyroid gland
103
What type of molecule is PTH?
Polypeptide containing 84 amino acids
104
What stimulates the parathyroid gland to release PTH?
- low levels of blood calcium
- decreased serum magnesium
- increased vitamin D
105
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
106
What effect does increasing levels of calcium have on the parathyroid gland?
Negative feedback back to the parathyroid gland so less PTH produced
107
What are the 3 different types of hyperparathyroidism (HPT)?
- primary
- secondary
- tertiary
108
What are the calcium levels in hyperparathyroidism?
primary = high
secondary = normal or low
tertiary = high
109
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
110
What are the causes of primary HPT?
Sporadic or familial
111
What are the causes of secondary hyperthyroidism?
Mainly CKD or vitamin D deficiency
112
What are the causes of tertiary HPT?
After prolonged secondary HPT, usually in CKD
113
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
114
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
115
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
116
Majority of cases of PHPT present at what age?
Over 45
117
Which gender is more affected by PHPT?
Women are 2x as likely to be affected compared to men
118
What blood test results suggest PHTP?
Inappropriately elevated PTH in the presence of high calcium
119
what is the most common cause of primary HPT?
Benign adenomas
```
85% = single adenoma
5% = double parathyroid adenomas
```
120
Describe typical parathyroid adenomas
Most adenomas are encapsulated and consist of parathyroid chief cells
121
Describe the features of glandular hyperplasia of the parathyroid gland, causing primary HPT
- all 4 glands enlarged
- lower glands usually larger than upper ones
- usually composed of chief cells
122
Glandular hyperplasia of the parathyroid gland, causing primary HPT, can be sporadic or caused by which genetic syndromes?
MEN1, MEN2A or familial hyperparathyroidism
123
what is an ectopic adenoma of the thyroid gland?
- any parathyroid gland that is not next to they thyroid (para) is "ectopic"
- adenoma of the "ectopic" parathyroid gland.
- Parathyroid cells which migrated during embryogenesis.
- rarely in the mediastinum
- often found around the thymus gland.
124
What are the classical clinical manifestations of PHPT?
- hypercalcaemia
- renal disease
- bone disease
- proximal muscle wasting
125
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
126
What are the indications, that a patient with an ectopic parathyroid adenoma, may need surgery?
- 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
127
Why are calcimimetics (cinacalcet) used in HPT?
Activates CaSR (calcium sensing receptor) in the parathyroid gland, therefore leading to reduced PTH secretion
128
When would you use calcimimetics for patients with 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
129
What are the limitations of calcimimetics?
GI side effects, particularly nausea
130
What happens in Paget's disease of bone?
- rapid bone turnover and formation
- leading to abnormal bone remodelling
Can be polyostotic or monostotic
131
What type of people does Paget's disease of bone often occur in?
- over 50 years old
| - higher prevalence in men
132
Does Paget's disease generally come with family history?
FH in 10-15% of cases
Probably genetic and environmental triggers
133
There are elevated levels of what in Paget's disease of bone?
Elevated alkaline phosphatase
- reflecting increased bone turnover
134
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
135
Which bones does Paget's disease most commonly affect?
- pelvis
- femur
- lower lumbar vertebrae
136
What investigations would you do into Paget's disease?
- lab assessment
- plain X-rays
- nuclear medicine bone scan
137
What is osteomalacia?
Lack of mineralisation of bone due to vitamin D deficiency or lack of calcium and/or phosphate
138
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
139
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
140
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)
141
What are the clinical features of osteomalacia?
- diffuse bone pains, usually symmetrical
- muscle weakness
- bone weakness
142
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)
143
Summarise the biochemistry of primary hyperparathyroidism, in terms of alkaline phosphatase, calcium, phosphate and parathyroid hormone.
Alkaline phosphatase = increased
Calcium = increased
Phosphate = decreased
PTH = increased
144
Summarise the biochemistry of osteomalacia, in terms of alkaline phosphatase, calcium, phosphate and parathyroid hormone.
Alkaline phosphatase = increased
Calcium = (low)
Phosphate = low
PTH = (high)
145
Summarise the biochemistry of osteoporosis, in terms of alkaline phosphatase, calcium, phosphate and parathyroid hormone.
Alkaline phosphatase = nil
Calcium = nil
Phosphate = nil
PTH = nil
146
Summarise the biochemistry of Paget's, in terms of alkaline phosphatase, calcium, phosphate and parathyroid hormone.
Alkaline phosphatase = high
Calcium = nil
Phosphate = nil
PTH = nil
147
Summarise the biochemistry of bone mets, in terms of alkaline phosphatase, calcium, phosphate and parathyroid hormone.
Alkaline phosphatase = high
Calcium = (high)
Phosphate = nil
PTH = (low)
148
what does cortical bone provide?
tensile strength
structural support
(80% of the body's bone mass)
149
what does trabecular bone provide?
provides a large surface area for metabolically active reactions to occur
home to the bone marrow (which gives blood cell production)
150
what is an osteocyte?
Osteoblasts that are buried/trapped within the matrix [osteoids]
151
individuals with less osteoblasts will result in what?
production of less bone
152
what is the bone called before mineralisation?
osteoid
153
what mineralises the bone matrix?
hydroxyapatite (calcium-phosphate-hydroxide salt)
154
bone is AVASCULAR, true or false?
false
generally highly vascular - highly metabolically active due to osteoblasts constantly building and osteoclasts constantly breaking
155
can bone be considered an endocrine organ?
yes it produces hormones
156
do women or men have a lower peak bone mass?
Women have lower peak bone mass than men
157
what effect does oestrogen have on bone mass?
protects bone density
158
what effect does the oral contraceptive pill have on bone density
- exposed to more oestrogen
| - higher bone density
159
what effect will a woman who started her menstrual cycle at an early age have on her bone density?
- exposed to more oestrogen
| - higher bone density
160
A young woman's menstrual periods have stopped due to extremely low body weight and excessive exercise, what affect will this have to her bone density?
- decline in oestrogen exposure
| - may lose significant amounts of bone density
161
what does Tartrate-resistant acid phosphatase (TRACP 5b) do?
TRAP prompts the dephosphorylation of bone matrix.
162
what does Cathepsin K do?
responsible for the proteolytic activation of TRAP.
163
what is pagets disease?
Paget's disease/osteitis deformans:
- excessive bone breakdown and subsequent disorganised new bone formation in one or more bones (but never the whole skeleton)
164
symptoms of pagets disease?
Mild or early cases of Pagets are asymptomatic
most common symptom: bone pain.
When symptoms do occur, they may be misdiagnosed with arthritis or other disorders.
Paget's disease affecting the skull may cause frontal bossing, increased hat size, and headaches. Often patients may develop loss of hearing in one or both ears[5] due to auditory foramen narrowing and resultant compression of the nerves in the inner ear. Rarely, skull involvement may lead to compression of the nerves that supply the eye, leading to vision loss.
165
what are the two main sites where a DEXA scan is performed?
- lumbar spine
| - hip
166
what anti-resorptive treatments are available for the prevention of osteoporosis?
● Bisphosphonates are the first line or oral therapy
● Denosumab – injections once a year
● Raloxifene
167
what are the 4 types of PHPT adenomas?
- adenoma (benign)
- glandular hyperplasia
- ectopic adenomas
- parathyroid carcinoma (malignant)
168
what is a malignant cancer of the thyroid glands called?
parathyroid carcinoma
169
what is a benign cancer of the thyroid glands called?
adenoma
170
what test would you use to detect parathyroid adenoma in patients with primary hyperparathyroidism (PHPT)?
CT SPECT (Tc-99m MIBI)
171
with reference to Paget's disease of bone, what does polyostotic mean?
many bones
172
with reference to Paget's disease of bone, what does monostatic mean?
one bone
173
what would be the best treatment for paget's bone disease?
Bisphosphonates
reduce osteoclastic and osteoblastic function
174
How could you monitor disease activity?
Bone markers: alkaline phosphatase or P1NP
175
how do bisphosphonates
| reduce osteoclastic and function?
- attach to hydroxyapatite bony surfaces
- when osteoclasts resorb bone impregnated with Bisphosphonate - it is released to impair ability of osteoclast
- osteoclast can not adhere to bony surface or produce protons necessary for continued bone resorption
- promotes osteoclast apoptosis
