Diseases of the Bone Flashcards
What are the purposes of bone?
- to support the body structurally
- protection of vital organs
- allows movement
- provides an environment for bone marrow, where blood cells are produced
- acts as a storage area for minerals, particularly calcium
What are the 2 different forms of bone and where are they found?
cortical bone:
- this is the hard outer layer
trabecular bone:
- this is the spongy inner layer
What are the 3 different types of cells found within bone?
- bone forming cells
- bone resorbing cells
- bone co-ordinating cells
What is the extracellular composition of bone like?
organic matrix (30%):
- mainly collagen (osteoid)
- ground substance
inorganic components (70%):
- hydroxyapatite (calcium and phosphate)
- minerals (magnesium, sodium and potassium)
What is the extracellular matrix made up from?
the extracellular matrix (osteoid) is mainly collagen
this provides tensile strength
it is produced by osteoblasts
What is involved in mineralisation of bone?
hydroxyapatite
this is a calcium-phosphate hydroxide salt
WHat is involved in bone remodelling?
bone is vascular and metabollically active
this is a cellular process
What is the role of the osteoblast?
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
What is the role of the osteoclast?
it breaks down old bone
What component are involved in the osteoclasts breaking down old bone?
RANKL and osteoprotegrin
RANKL is an apoptosis regulator gene
osteoprotegrin binds and opposes RANKL and controls cell proliferation levels
What hormones influence the osteoclasts to breakdown old bone?
- PTH
- calcitonin
- IL-6
How do osteoclasts break down bone?
they remove bone by dissolving the mineral and breaking down the matrix in a process called bone resorption
Where do osteocytes originate from?
the osteoprogenitor cell becomes an osteoblast
the osteoblast then becomes an osteocyte
Where are osteocytes found in bone?
the osteocytes are found closer towards the centre than the osteoblasts, which are found on the outside
How often is the human skeleton replaced?
How does remodelling occur in normal bone?
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
What are the 3 stages involved in the bone remodelling cycle?
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
What components are involved in osteoclast stimulation and inhibition?
osteoclast stimulation:
- RANK
- RANKL (ligand)
osteoclast inhibition:
- OPG
- denosumab
What are the systemic regulators of the bone remodelling cycle?
- parathyroid hormone
- calcitrol
- other hormones including thyroid hormones, sex hormones, glucocorticoid
- insulin-like growth factors, prostaglandins, tumour growth factor-beta and cytokines
What is the role of RANK in the bone remodelling cycle?
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
How does ageing affect bone?
there is decreasing bone mass with age
peak bone mass is around 30-40 years of age
females experience bone loss due to menopause
How does bone resorption and formation change with age?
with increasing age there is decreased bone formation and increased bone resorption
What is involved in the investigation of bone disease?
gross structure:
- X-ray
- MRI
- CT
bone mass (calcium):
- DEXA
cellular function / turnover:
- biochemistry
microstructure / cellular function:
- biopsy
- qCT
What are the biochemical markers of bone formation?
products of active osteoblasts:
- alkaline phosphatase (TAP, BAP)
- osteocalcin (OC)
- procollagen type I propeptides (P1NP)
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
How is alkaline phosphatase measured?
it is measured in LFTs and bone profiles
specific isoenzymes can be measured where there is diagnostic doubt
What is the purpose of bone alkaline phosphatase?
What is its release stimulated by?
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
What is P1NP?
How does it vary?
What will increase and decrease it?
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
What are collagen cross-links (NTX, CTX)?
How do they vary?
cross-linking molecules which are released with bone resorption
they correlate highly with bone resorption
they have diurnal variation
When would collagen cross-links (NTX, CTX) be increased and decreased?
What can they not be used to predict?
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
What are most bone markers based on?
How do changes in bone markers relate to diseases?
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
What are the uses of new bone markers?
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
What is a DEXA scan?
a DEXA scan is also called a bone density scan
it is a common technique used to measure bone density
What is a T score?
How is it interpreted?
- 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
What are the 5 main bone disorders?
- metastatic disease
- hyperparathyroidism
- osteomalacia / rickets
- osteoporosis
- paget’s disease
What is the definition of osteoporosis?
How can this be summarised?
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
In general, what is osteoporosis?
What are the common risk factors?
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
How is osteoporosis diagnosed?
no abnormalities are seen in routine biochemical tests
diagnosis relies on DEXA / X-ray
increasing use of bone markers in management
How can osteoporosis change someone’s life?
it can lead to loss of mobility, independence, increased social isolation and depression
What is a fragility fracture?
a fracture caused by injury that would be insufficient to fracture a normal bone
it occurs as a result of minimal trauma
What are the common sites for a fragility fracture?
- spine
- neck of femur
- wrist
What does osteoporotic fracture incidence correlate with?
osteoporotic fracture incidence correlates with progressive trabecular and cortical bone loss over time
When is vertebral fracture and hip fracture incidence high and why?
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
what are the 6 main risk factors for fracture?
- age
- sex
- recent fragility fracture
- vertebral fractures - number and severity
- smoking
- alcohol
What are 7 less prominent risk factors for fracture?
- falls
- drugs
- inflammatory conditions
- malabsorption
- type 1 diabetes mellitus
- family history
- BMI
What is the FRAX calculation tool used for?
the ten year probability of fracture with BMD (bone mineral density)
What are endocrine secondary causes of osteoporosis?
- early menopause
- amenorrhoea in pre-menopausal women
- hypogonadism
- hormone ablation for breast/prostate cancer
- hyperparathyroidism
- hyperthyroidism
- cushings disease
- hyperprolcatinaemia
- diabetes
What are gastrointestinal secondary causes of osteoporosis?
- coeliac disease
- IBD
- chronic liver disease
- any cause of malabsorption
What are rheumatological secondary causes of osteoporosis?
rheumatoid arthritis and other inflammatory arthropathies
What are haematological secondary causes of osteoporosis?
- myeloma
- haemoglobinopathies
- systemic mastocytosis
What are respiratory, metabolic and other secondary causes of osteoporosis?
respiratory:
- COPD
- cystic fibrosis
metabolic:
- homocystinuria
others:
- immobility
- CKD
What drugs can be secondary causes of osteoporosis?
- glucocorticoids
- heparin
- ciclosporin
- anti-convulsants
- aromatase inhibitors
- androgen deprivator
What are the investigations for secondary causes of osteoporosis in all patients?
- calcium and bone profile
- U&Es
- TFTs
- FBC
- vitamin D
- parathyroid hormone
- plasma viscosity (+/- myeloma screen)
- coeliac screen
What investigations for secondary causes of osteoporosis are only performed in men?
- 9am fasting testosterone
- SHBG
- LH, FSH
- LFTs
Which investigations for secondary causes of osteoporosis are only performed in young amenorrhoeic women?
- LH
- FSH
- oestradiol
- prolactin
What significant feature must be present to consider an X-ray to determine a secondary cause of osteoporosis?
loss of height, back pain or kyphosis
a lateral X-ray of T5-L5 spine is considered
What are the 2 categories of treatments to prevent osteoporotic fractures?
- antiresorptive treatments
- anabolic treatments
What are examples of anabolic treatments for prevention of osteoporotic fractures?
parathyroid hormone / PTHrP analogues
these are teriparatide and abaloparatide
What are the 3 categories of antiresorptive treatments for the prevention of osteoporotic fractures?
SERMS:
- selective oestrogen receptor modulators
- raloxifene
Bisphosphonates:
- for oral therapy - alendronate, risedronate, ibandronate
- for IV therapy - zoledronate, ibandronate
RANK-L inhibitor:
- denosumab
What is the mechanism of action of bisphosphonates?
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
How does denosumab work?
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
What is the main complication of treatment for osteoporosis?
What are the 2 different types and how do they arise?
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
What are the usual sites of spread for bone metastases?
- spine
- pelvis
- femur
- humerus
- skull
What are the 5 main presenting symptoms of bone metastases?
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
What are the mild symptoms of hypercalcaemia?
- polyuria and polydipsia (excessive thirst)
- mood disturbance
- anorexia
- nausea
- fatigue
- constipation
What are the severe symptoms of hypercalcaemia?
- abdominal pain
- vomiting
- coma
- pancreatitis
- dehydration
- cardiac arrhythmias
What are the 2 categories of causes of hypercalcaemia?
non-PTH mediated:
- PTH is low / suppressed
PTH mediated:
- PTH is high
What are the non-PTH mediated causes of hypercalcaemia?
- malignancy
- vitamin D intoxication
- chronic granulomatous diseases (e.g. sarcoidosis)
- medications
- immobilisation
- other endocrine conditions:
hyperthyroidism, acromegaly, phaeochromocytoma, adrenal insufficiency
What types of medications cause non-PTH mediated hypercalcaemia?
- thiazide diuretics
- lithium
- teriparatide
- theophylline toxicity
What are the causes of PTH-mediated hypercalcaemia?
- primary hyperparathyroidism
- also familial causes:
- MEN1 and 2A
- familial hypocalciuric hypercalcaemia
- familial isolated hyperparathyroidism
What is parathyroid hormone?
Where is it secreted from?
it is a polypeptide containing 84 amino acids
it is secreted by the chief cells of the parathyroid gland
What are the stages involved in the regulation of parathyroid hormone levels ?
- low levels of blood calcium stimulate the parathyroid gland to release PTH
- PTH increases the levels of blood calcium through several mechanisms
By which 3 mechanisms does PTH release increase the levels of blood calcium?
- increased decomposition of bone releases calcium
- increased absorption of calcium from food by intestines
- increased reabsorption of calcium from urine by kidneys
What are levels of calcium and PTH like in primary hyperparathyroidism?
What are the main causes?
calcium levels are usually high
PTH is inappropriately high
low phosphate and high alkaline phosphate
causes are sporadic or familial
What are the levels of calcium and PTH like in secondary hyperparathyroidism?
What are the causes?
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
What are the levels of calcium and PTH like in tertiary hyperparathyroidism?
What are the causes?
calcium is usually high
PTH is inappropriately high
phosphate can be high or low
it is usually caused by prolonged secondary hyperparathyroidism in CKD
What suggests primary hyperparathyroidism?
When do the majority of cases present?
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
What are the four types of adenomas that cause primary hyperparathyroidism?
- benign adenomas
- glandular hyperplasia
- ectopic adenomas
- parathyroid carcinoma (malignant)
What type of adenoma causes the most cases of primary hyperparathyroidism?
benign adenomas
single adenoma account for 85% of cases of primary HPT
What causes glandular hyperplasia?
How many cases of PHPT does this cause?
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
What are ectopic adenomas?
there are rarely ectopic adenomas in the mediastinum
some parathyroid adenomas are found in thymus gland
these are parathyroid cells which migrated during embryogenesis
What is parathyroid carcinoma?
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
What are the clinical manifesttions of classical primary hyperparathyroidism?
- symptoms related to hypercalcaemia
- renal disease - nephrolithiasis, chronic kidney disease
- bone disease - osteoporosis, osteitis, fibrosa cystica
- proximal muscle wasting
When is surgery used as a treatment for hyperparathyroidism?
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
What is the medical treatment for hyperparathyroidism?
calcimimetics (Cinacalcet)
this activates CaSR in the parathyroid gland and leads to reduced PTH secretion
When are calcimimetics used?
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
What is Paget’s disease of bone caused by?
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
Which types of patients tend to be affected by Paget’s disease of bone?
- mainly over 50 years old
- higher prevalence in men
- probable genetic and environmental triggers
- family history in 10-15% of cases
What are the clinical features of Paget’s disease?
- 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
What is osteomalacia?
How does it present in adult form and in childhood?
lack of mineralisation of bone
adult form:
- widened osteoid seams with lack of mineralisation
childhood:
- classic childhood rickets
- widened epiphyses and poor skeletal growth
What are the causes of osteomalacia?
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)
What are the clinical features of osteomalacia?
- diffuse bone pains (usually symmetrical)
- muscle weakness
- bone weakness
- high alkaline phosphatase, low vit D, possibly low calcium and high PTH (secondary hyperparathyroidism)
What is the adult population at risk from osteomalacia?
- nursing home residents / elderly
- asian population (hijab / burka wearing)
- malabsorption
