Bone diseases and bone markers Flashcards
What are the 4 purposes of bone?
1) Structural support for the body
2) Protection of vital organs
3) Blood marrow production (via marrow)
4) Storage bank for minerals (especially calcium)
What are the 2 types of bone, making up bone?
1) Cortical bone - hard outer layer
2) Trabecular bone - spongy, inner layer
What 3 types of cells are found within bone?
Osteoblasts, osteoclasts and osteocytes
What makes up the extracellular space of bone?
Organic matrix made up mainly of collagen
Inorganic components including hydroxyapatite and minerals (calcium and phosphate)
What is the main role of trabecular bone?
Bone marrow is held within trabecular bone, it is highly porous with a large surface area - for high rate of metabolic activity
The extracellular matrix of bone is made up of mainly what substance and why?
Collagen - provides tensile strength
What surrounds cortical bone?
Periosteum
What s the process of bone formation? 3
1) Osteoblasts secrete matrix - protein and minerals, mainly collagen
2) Before mineralization this is called osteoid
3) Matrix is then mineralized by hydroxyapatite (calcium-phosphate-hydroxide salt) which hardens the osteoid
What are osteoblasts formed from?
Terminally differentiated products of mesenchymal stem cells
What is osteoid?
Non mineralized organic matric consisting mainly of type 1 collagen
What are osteocytes?
Osteoblasts which are buried/ trapped within the bone matrix after it undergoes mineralization
What are the 3 roles of osteoblasts?
1) Make osteoid
2) Make hormones (eg. osteocalcin), matrix proteins and alkaline phosphatase
3) Communicate with other bone cells
What is the morphology of osteoclasts?
Large, multinucleated cell with a ruffled-resorption border
Which 2 substances help with osteoclastic maturation?
RANK ligand and osteoprotegrin
Which 3 hormones are osteoclasts regulated by?
1) PTH
2) Calcitonin
3) IL-6
Where are osteoclasts found within bone?
In bone pits - resorption border
What is the role of osteoclasts?
Break down bone - critical for repair and maintenance of bone
How do osteoclasts break down bone?
By production of enzymes such as tartrate resistant acid phosphatase (TRAP), and Cathepsin K - secreted to breakdown extracellular matrix
How do osteocytes communicate with eachother?
Via cytoplasmic extensions
What is the role of osteocytes?
Involved with regulating bone matrix turnover
What shape are osteocytes?
Star shaped
What is the rough process of bone remodeling?
1) Osteoclasts recruited to bone - lie in absorption pits and breakdown bone
2) Osteoclasts also signal to osteoblasts which then arrive and make osteoid
3) Mineralisation of the osteoid occurs and osteoblasts get trapped in the bone thus becoming osteocytes
The adult skeleton is replaced once every how many years?
10 years
What is key about the activity of osteoblasts and osteoclasts?
Normal bone is a constant state of turnover caused by resorption by osteoclasts and formation by osteoblasts
Thus as activity of osteoclasts increases so does activity of osteoblasts
What are the 4 stages in the circular bone cycle?
1) Resting
2) Resorption
3) Osteoid formation
4) Mineralisation
How does bone mass change with age in men and women?
- As we age bone mass increases to reach a peak bone density at age 20
- After peak bone mass there is a gradual decline with time
- In this is a more gradual change
- In females there is an accelerated change after menopause then this levels off to become more gradual at about 65
What 2 mechanisms lead to the decrease in bone mass with age?
1) Decreased bone formation
2) Increased bone resorption
What are 4 techniques used in investigating bone disease?
1) Gross structure - using X ray
2) Bone mass (Calcium) - using a DEXA scan
3) Cellular function/ rate of turnover - using biochemistry and bone markers
4) Microstructure/ cellular function - biopsy and qCT
Biomarkers of bone formation are produced by what cells?
Osteoblasts
Give the 3 biomarkers of bone formation?
1) Alkaline phosphatase
2) Osteocalcin
3) Procollagen type 1 propeptides (P1NP)
What are the 2 types of markers of bone resorption?
1) Degradation products of bone collagen
2) Osteoclast enzymes
Give the 3 bone resorption markers which are degradation products of collagen?
1) Hydroxyproline
2) Pyridinium cross links
3) Crosslinked telopeptides of type 1 collagen (NTX, CTX)
Give the 2 bone resorption markers which are osteoclast enzymes?
1) Tartrate resistant acid phosphatase (TRACP 5b)
2) Cathepsin K
If CTX is raised, is P1NP likely to be raised or lowered?
Raised as well - raised CTX indicates increased bone resorption thus osteoclast activity, this would mean concurrent increased osteoblast activity and thus raised P1NP
Alkaline phosphatase is measured in what 2 blood profiles, and is produced by what 2 organs in what proportion?
- Measured in bone profiles and LFTs
- Produced 50% by liver and 50% by bone in health
How can we distinguish between raised alkaline phosphatase due to liver and that due to bone?
Measure specific isoenzymes specific to bone and to liver
What is the role of bone alkaline phosphatase, what cells is it produced by?
Phosphatase involved in mineralization
Released by osteoblasts
Release of alkaline phosphatase is stimulated by what, in what 4 situations?
Stimulated by increased bone remodeling in:
1) Childhood/ pubertal growth spurt
2) Fractures
3) Hyperparathyroidism
4) Paget’s disease of the bone
Is raised bone alkaline phosphatase normally physiological or pathological?
Pathological
What is the role of P1NP and what cells is it produced by?
Precursor molecule of type 1 collagen
Synthesized by osteoblasts
How is P1NP used as a bone marker, give 2 reasons why is it useful in this way?
Indicates osteoblast activity - increases with increased and decreases with decreased activity
Useful because:
1) Has low diurnal variation
2) Serum concentrations not affected by food intake
How are CTX and NTX (collagen cross links) used as bone markers?
They are cross linking molecules which are released with bone resorption, correlate highly with bone resorption, increased in periods of high bone turnover
Give 3 situations involving high bone turnover with CTX and NTX are likely to be high?
1) Hyperthyroidism
2) Adolescents
3) Menopause
How are levels of CTX and NTX affected by the use of anti-resorptive therapy?
CTX and BTX decrease with anti-resorptive therapy
What are the 2 disadvantages of the use of CTX and NTX as bone markers?
1) Do not predict bone mineral density
2) Have diurnal variation
What are the 3 important considerations to remember when using bone markers?
1) Collagen related bone markers are based primarily on type 1 collagen which is widely distributed in several tissues
2) Changes in bone markers are not disease specific but reflect alterations in skeletal metabolism
3) Some markers are characterized by significant intra-individual variability
What are the 3 uses of new bone markers?
1) Evaluation of bone turnover and bone loss
2) Evaluation of treatment effect - CTX used to monitor response to anti-resorptive therapy
3) Evaluation of compliance with medication- P1NP used to monitor compliance with teriparatide, CTX used to monitor compliance/response to anti-resorptive therapy
What does a DEXA scan T score tell you?
In terms of bone density - The number of standard deviations that the patient is away from a young healthy patient of the same sex
WHO classify T score into what 3 classes?
-1 and above = Bone density is considered normal
Between -1 and -2.5 = osteopenia (thin bones)
-2.5 and below = osteoporosis
What T score defines osteoporosis?
-2.5 and below
Give the 5 most common bone disorders?
1) Metastatic disease
2) Hyperparathyroidism
3) Osteomalacia (adults)/ Rickets (children)
4) Osteoporosis
5) Paget’s disease
The use of what long term drug is associated with bone depletion and thus osteoporosis?
Glucocorticoids
What 2 vertebral fractures can commonly occur in osteoporosis?
1) Wedge fracture (appears as increased bone density where bone has collapsed in on itself)
2) End plate fracture
What blood test abnormalities are seen in osteoporosis?
No abnormalities are seen in routine blood tests
What does the diagnosis of osteoporosis rely on?
DEXA scan
What is the definition of osteoporosis?
Decreased bone mass + deranged bone microarchitecture (not routinely tested for) leading to failure of structural integrity
What is a fragility fracture?
A fracture caused by an injury which would be insufficient to fracture a normal bone
Why can breathing problems occur with osteoporosis?
Patients can get vertebral fracture leading to thoracic kyphosis, patients can lose the ability to properly ventilate there lungs (restrictive lung disease) thus leading to increased chance of infections. Patients can also get abdominal bloating due to the thoracic kyphosis
Which 3 symptoms/signs should prompt investigation for vertebral fractures?
1) Unexplained loss of height
2) Kyphosis
3) Severe back pain
What is the FRAX calculation tool?
Used to calculate the risk of fracture in 10 years - based on a database of loads of patients
What 11 parameters is the FRAX calculation tool based on?
1) Age
2) Sex
3) Weight
4) Height
5) Previous fracture
6) Parent fractured hip
7) Current smoking
8) Glucocorticoids
9) Rheumatoid arthritis
10) Secondary osteoporosis
11) Alcohol 3 or more units
Why is smoking a risk factor for osteoporosis?
Increases bone depletion
Which rheumatological diseases are secondary causes of osteoporosis and why?
RA and other inflammatory arthropathies
Inflammatory conditions cause bone loss
Why is alcohol a risk factor for osteoporosis?
Causes bone depletion
What are the 11 tests used in investigation for secondary causes of osteoporosis?
)1)Calcium and bone profile
2) U&Es
3) TFTs
4) FBC
5) Vit D
6) PTH
7) Plasma viscocity (+/- myeloma screen)
8) Coeliac screen
9) In men: testosterone etc.
10) In young amenorrhoeic women: hormone tests
11) Lateral X ray - consider in loss of height, back pain or kyphosis
What are the 4 types of drugs used to treat osteoporosis?
1) Antiresorptive
2) Denosumab - Monoclonal Ab to RANKL
3) Raloxifene - SERM
4) Anabolic
What antiresorptive therapies are used to treat osteoporosis?
Bisphosphonates - oral/IV
Alendronic acid/Zoledronic acid
Anabolic therapies to treat osteoporosis act on what cells?
Affect the osteoblasts
Name 2 anabolic therapies used to treat osteoporosis?
Terparatide SC
Synthetic PTH
What is the mechanism of action of bisphosphonates? 6
1) Mimic pyrophosphate structure
2) Taken up by skeleton
3) Ingested by osteoclasts
4) Inhibit osteoclast formation, migration and osteolytic activity aswell as promoting apoptosis
5) Modulate signaling from osteoblasts to osteoclasts
6) Local release from osteoclasts during bone resorption
Give the 6 disadvantages of using bisphosphonates to treat osteoporosis?
1) Poor absorption
2) Difficult to take
3) Can cause oesophageal/upper GI problems
4) Flu-like side effects
5) Osteonecrosis of the jaw
6) Atypical femoral fractures
What test can be undertake to monitor a patients compliance to bisphosphonate therapy?
Measurement of serum CTX - if high, then increased osteoclast activity thus reduce compliance
What are the 5 usual sights of spread of bone mets?
1) Spine
2) Pelvis
3) Femur
4) Humerus
5) Skull
What are the 2 types of bone mets?
1) Lytic - destruction of normal tissue (osteoclasts)
2) Sclerotic/osteoblastic - deposition of new bone
In what 4 malignancies do lytic bone mets occur?
Breast, lung, kidney, thyroid
In what 4 malignancies do sclerotic bone mets occur?
Prostate, lymphoma, breast, lung
What kind of bone mets are classical of myeloma?
Osteolytic mets of the skull
What are the 5 presenting symptoms of bone mets?
1) Pain - often worse at night and gets better with movement initially and then becomes constant
2) Broken bones - commonly femur,humerus and vertebral
3) Numbness, paralysis and trouble urinating - spinal cord compression from bone mets
4) Loss of appetite, nausea, thirst, confusion and fatigue - symptoms of hyperclacemia
5) Anaemia - disruption of bone marrow
If a patient presents with hypercalcemia, what is the next necessary blood tests?
PTH
What are the 6 symptoms of mild hypercalcemia?
1) Polyuria, polydipsia
2) Mood disturbance
3) Anorexia
4) Nausea
5) Fatigue
6) Constipation
What are the 6 symptoms of severe hypercalcemia?
1) Abdo pain
2) Vomiting
3) Coma
4) Pancreatitis
5) Dehydration
6) Cardiac arrhythmias
What are the 2 categories of causes of hypercalcemia?
1) Non-PTH mediated
2) PTH- mediated
What are the 6 non PTH mediated causes of hypercalcemia?
1) Malignancy
2) Vit D intoxication
3) Medication: lithium being the main one
4) Immobilisaion
5) Other endocrine conditions incl. hyperthyroidism, acromegaly
6) Chronic granulomatous disorders eg. sarcoidosis
What are the 2 types of PTH mediated hypercalcemia?
1) Sporadic primary hyperparathyroidism
2) Familial: MEN1 and 2A, familial hypocalciuric hypercalcemia, familial isolated hyperparathyroidism
What is a possible complication of parathyroid surgery and why?
Loss of voice - lies close to the laryngeal nerve
What is the structure of PTH and where is it secreted from?
Polypeptide - 84 amino acids
Secreted by chief cells of the parathyroid gland
What are the 3 main effects of PTH?
1) Increased decomposition of bone releasing calcium
2) Increased resorption of calcium from urine by kidneys
3) Mediated by vit D = increased absorption of calcium from food by intestines
What are the levels of calcium and PTH in primary hyperparathyroidism and what are the causes?
Calcium usually high
PTH: inappropriately high (doesn’t respond to negative feedback from calcium)
Low phosphate and high alk phos common
Causes = sporadic or familial
What are the levels of calcium and PTH in secondary hyperparathyroidism, what are the causes?
Calcium: normal or low
PTH: appropriately high ĭe. as a result of the low calcium
Phosphate also high if due to CKD
Causes = CKD or vit D deficiency
Tertiary hyperparathyroidism can also occur, what are the levels of calcium, PTH and what are the causes?
Calcium is usually high
PTH is inappropriately high
Causes = after prolonged secondary HPT, usually in CKD
How did primary hyperparathyroidism (PHPT) used to present and how does it generally present now?
Used to present with severe hypercalcemia and/or symptomatic renal and skeletal disease
Now presentation is much earlier in disease course and is asymptomatic
What 2 blood test findings suggest PHPT?
1) Inappropriately elevated PTH
2) With high calcium
What group is most commonly affected by PHPT?
Women over the age of 45
What are the 4 possible causes of PHPT?
1) Adenomas (benign)
2) Parathyroid carcinoma (malignant) - have significant hypercalcemia
3) Glandular hyperplasia
4) Ectopic adenomas
What is the most common cause of PHPT?
Single adenoma
What cells do adenomas consist of?
Mainly chief cells
Are parathyroid carcinomas a common cause of PHPT?
No -account for 1-2% of cases
What is glandular hyperplasia of the PT gland?
All 4 glands are enlarged, lower glands usually larger than the upper ones and usually composed of chief cells
What is the treatment for PT glandular hyperplasia?
Medical or surgery
If surgery - 3.5 of the glands removed
Is glandular hyperplasia a genetic condition?
Can be sporadic or genetic, genes involved = MEN1, MEN2a or familial hyperparathyroidism
Where do ectopic PT adenomas most commonly occur, why do they form?
In mediastinum - some found in the thymus gland, PT cells which migrated during embryogenesis
What are the 4 classical clinical manifestations of PHPT?
1) Symptoms related to hypercalcemia (as described)
2) Renal disease (nephrolithiasis, CKD)
3) Bone disease (osteoporosis, osteitis fribosa cystica)
4) Proximal muscle wasting
What 2 imaging techniques can be used to identify PHPT?
1) Imaging using a radio isotope which concentrates in the PT gland
2) CT imaging using a tracer
What are the indications for surgery in PHPT?
1) Symptomatic hypercalcemia Asymptomatic patients with: 1) Calcium >0/25mmol/L above normal 2) Renal stone disease 3) Calculated creatinine clearance
What is the medical treatment for PHPT?
Calcimimetics (Cinacalcet) - activates CaSR (calcium sensory receptors) in the PT gland therefor leads to reduced PTH secretion
When is medical treatment used for PHPT, what is its use limited by and what symptoms does it not effect?
- Used to normalise calcium in symptomatic pts or those who are not fit for or willing to have surgery
- Side effects: GI, mainly nausea
- Does not seem to alter bone disease and renal outcomes not known
What is Paget’s disease of the bone?
Disease with rapid bone turnover and formation leading to abnormal bone remodelling
Can be polyostotic - affects more than one bone - or monostotic - affects only one bone
What blood test abnormalities are seen in Paget’s disease?
Elevated alkaline phosphatase reflecting increased bone turnover
Is Paget’s disease of bone genetic?
Probable genetic and environmental triggers, FH in 5-10% of cases
Which group does Paget’s disease of bone mainly affect?
Males over 50
Which 3 bones does Paget’s disease most commonly affect?
1) Pelvis
2) Femur
3) Lower lumbar vertebrae
What malignant condition does Paget’s disease increase the risk of?
Osteosarcoma
What are the 5 clinical features of Paget’s disease?
1) Bone pain
2) Bone deformity
3) Arthritis (abnormal weight bearing)
4) Fractures
5) Cranial nerve defects if skull affected - hearing and vision loss
What are the 3 investigations in Paget’s disease of bone?
1) lab assessment
2) plain x rays
3) nuclear medicine bone scan
What is osteomalacia, and what is the term for the condition in children?
In children called Ricketts
Lack of mineralisation of bone due to vit D deficiency or lack of calcium and/or phosphate
How do the adult form and childhood form of osteomalacia differ?
Adult - widened osteoid seams with lack of mineralisation
Child - widened epiphyses and poor skeletal growth
What are the 2 main causes of osteomalacia?
1) Insufficient calcium absorption from the intestine - due to lack of dietary calcium or vit D deficiency/resistance
2) Excessive renal phosphate excretion - rare genetic forms
What 3 groups of the adult population are at risk of osteomalacia?
1) Nursing home residents/ elderly
2) Asian population - lack sunlight
3) Malabsorption
What are the 4 clinical features of osteomalacia?
1) Diffuse bone pains - usually symmetrical
2) Muscle weakness
3) Bone weakness
4) High alk phos, low vit D, possibly low calcium and high PTH (secondary hyperparathyroidism)
What are the alk phos, ca, phosphate and PTH levels in HyperPTH?
Alk phos = High
Calcium = High
Phosphate = Low
PTH = High
What are the alk phos, ca, phosphate and PTH levels in osteomalacia?
Alk phos = high
Calcium = Low
Phosphate = Low
PTH = High
What are the alk phos, ca, phosphate and PTH levels in osteoporosis?
Alk phos = Normal
Calcium = normal
Phosphate = normal
PTH = normal
What are the alk phos, ca, phosphate and PTH levels in Paget’s disease of bone?
Alk phos = High
Calcium = normal
Phosphate = normal
PTH = normal
What are the alk phos, ca, phosphate and PTH levels in Bone mets?
Alk phos = Increased
Calcium = Increased
Phosphate = Normal
PTH = Decreased
