Bone and new markers

  • Created by: hadar
  • Created on: 12-02-18 16:50
What is the purpose of bone?
1) structural support 2) protection of vital organs 3)blood cell production via marrow 4) storage for minerals- calcium
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What are the 3 types of bone composition?
1) cortical bone 2) trabecular bone 3) cancellous bone
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What is the composition of bone?
1) cells--> bone forming and resorbing 2) extracellular- organic matrix (collagen) and inorganic components (hydroxyapatite and minerals such as calcium and phosphate)
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What is cortical bone?
hard outer layer- compact bone- usually found on the outer cortex layer.
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What is trabecular bone?
spongy inner layer- consists of multiple microscopic columns (osteon)- cortical bone covered by periosteum on its outer surface- endosteum on inner surface.
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What is an osteoblast?
a cell that makes bone (from mesenchymal stem cell)- makes osteoid (non-mineralised organic matrix, consists of mainly Type 1 collagen)
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What are osteoblasts a terminally differentiated product of?
Mesenchymal stem cells
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What do osteoblast make? (3)
Make hormones (e.g. osteocalcin), matrix proteins and alkaline phosphatase
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What are osteoclasts?
rge. Multi nucleated Ruffled-resorption border cells
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What is the function of osteoclasts?
Break down bone – critical for repair and maintenance of bone. Produce enzymes such as tartrate resistant acid phosphatase (TRAP) and Cathepsin K - secreted to breakdown extracellular matrix. help enhance blood calcium levels
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What are osteoclasts regulated by?
Regulated by hormones including PTH, calcitonin and IL-6
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What help osteoclastic maturation and activity?
RANK ligand and osteoprotegrin
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What are osteocytes?
Star shaped Trapped/buried osteoblasts Communicate with each other via cytoplasmic extensions Mechanosensory properties Involved with regulating bone matrix turnover
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Why is bone a dynamic tissue?
Constant remodelling Highly vascular tissue Metabolically active Osteoblasts constantly producing and secreting matrix and helping with mineralisation Osteoclasts causing bone resorption
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Describe the bone cycle
resting- lining cells --> resorption-multinuclear osteoclast with ruffled boarder, adhesion zine with resorption pit --> osteoid formation- by osteoblasts --> mineralisation --> resting -->
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Describe bone with age
peak bone mass in males at 20-50 and females 30-50- decrease after that- female have large bone loss due to menopause
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What happens to bone with increasing age?
bone formation decreases and bone resorption increases
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How is bone disease investigates? (4)
1)gross structure- X-ray 2)Bone mass- DEXA 3) cellular function/ turnover- biochemistry 4) Microstructure/ cellular function- biopsy, qCT
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What is the biochemical marker showing bone formation?(3)
1)Alkaline phosphatase (TAP, BAP) 2) Osteocalcin (OC) 3) Procollagen type I propeptides (P1NP)
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What is the biochemical marker showing 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
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What releases bone alkaline phosphate?
Osteoblasts- Release stimulated by increased bone remodelling Childhood / Pubertal growth spurt Fractures Hyperparathyroidism Primary Secondary Pagets Disease of the Bone
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What is phosphatase involved in?
Bone mineralisation
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Describe P1NP (Procollagen type 1N propeptide) as a marker
Synthesized by osteoblasts - precursor molecule of type 1 collagen Has low diurnal and intraindividual variation Serum concentrations not affected by food intake Increased with increased osteoblast activity Decreased by reduced osteoblast activity
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Describe Collagen Cross-links (NTX, CTX) as a marker
Cross-linking molecules which are released with bone resorption, correlate highly with bone resorption Increased in periods of high bone turnover - hyperthyroidism, adolescents, menopause Have diurnal variation Do not predict bone mineral density
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Why would you see decreased Collagen Cross-links (NTX, CTX)?
Decrease seen in anti-resorptive therapy
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What do bone markers show?
They show whats happening with the osteoblast and osteoclasts at the time of marker But do not show the bone quality
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Wha are bone marker results used for?
1) evaluation of bone turnover and loss 2) evaluation of treatment effect 3) evaluation of compliance with medication
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What medications impact bone turnover?
- P1NP used to monitor compliance with teriparatide - CTX used to monitor compliance/response to anti-resorptive therapy
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What does T-score show?
-1 and above: Bone density is considered normal. Between -1 and -2.5 = osteopenia. -2.5 and below = osteoporosis.- tells you how many SD person is form the standard of young healthy person
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Name some risk factors of osteoporosis
steroids, early menopause, smoker, alcohol(ore 20 units a weak), UC(any inflammatory condition), age, female
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How is osteoporosis diagnosed?
Diagnosis relies on DEXA/XRay Increasing use of bone markers in management
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What is the definition of osteoporosis?
systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture
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What is the equation for osteoporosis?
decreased bone mass + deranged bone microarchitecture = failure of structural integrity
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What is a fragility fracture?
A fracture caused by injury that would be insufficient to fracture a normal bone
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What is a fragility fracture a sign of?
Sign of low bone density/ quality low bone mass
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How do you assess fracture risk?
FRAX calculation tool
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What does FRAX calculation tool take into account?
age, sex, weight, height, previous fracture, smoker, steroids, RA, osteoporosis, alcohol, inflammatory conditions
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Broadly what are the 2 treatment options for prevention of osteoporotic fracture?
1) anti-resorptive treatment 2)anabolic treatment
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What is the first line treatment for prevention of osteoporotic fracture?
First line treatment= bisphosphonates usually oral therapy
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What are the 3 types of anti-resorptive treatments?
1)SERMS 2)Bisphosphonates 3)RANK-L inhibitor
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Give example of SERMS
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Give example of bisphosphonates
oral--> alendronate, risedronate, ibandronate IV--> zoledronate, ibandronate
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Give example of RANK-L inhibitor
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Give example of anabolic treatment
Teriparatide- parathyroid hormone analogue--> works on osteoblasts to try and stimulate production of new bone
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What is the mechanism of action of bisphonsphonates?
Mimic pyrophosphate structure Taken up by skeleton Ingested by osteoclasts- inhibit osteoclast formation, migrations activity and promote apoptosis
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What side effects can you get from bisphosphonates?
Can cause oesophageal/ upper GI problems Flu-like side effects Osteonecrosis of the jaw Atypical femur fractures
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What are the 2 main types of bone metastases?
1) Lytic 2) Sclerotic/ osteoblastic
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Give examples of lytic bone metastases
Breast / Lung/ Kidney/ Thyroid- destruction of normal bone (osteoclasts)
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Give examples of sclerotic/ osteoblastic bone metastases
Prostate Lymphoma Breast/lung (15-25%)- deposition of new bone
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What is the usual site of spread of bone metastases?
Spine, pelvis, femur, Humerus, skull
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What are the presenting symptoms with bone metastases?
1) pain- worse at night and gets better in day 2)broken bones 3)numbness, paralysis, trouble urinating- spinal cord compression 4) loss of appetite, nausea, vomiting, thirst, confusion, fatigue 5)anaemia- disruption bone marrow
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What blood test would you do for someone with a high calcium?
PTH- parathyroid
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What are the mild symptoms of hypercalcaemia?
Polyuria, polydipsia Mood disturbance Anorexia Nausea Fatigue Constipation
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What are the severe symptoms of hypercalcaemia?
Abdo pain Vomiting Coma Pancreatitis Dehydration Cardiac arrhythmias
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What are the causes of hypercalcaemia?
non-PTH mediated--> malignancy, vitamin D intoxication, chronic granulomatous disorders, medications, immobilisation, endocrine PTH-mediated--> sporadic primary hyperparathyroidism, familial
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What medications can cause hypercalcaemia?
Thiazide diuretics, Lithium, Teriparatide, Theophylline toxicity
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What familial conditions caused PTH-mediated hypercalcaemia?
MEN1 and 2A Familial hypocalciuric hypercalcaemia Familial isolated hyperparathyroidism
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Where is PTH secreted from?
Secreted by chief cells of parathyroid gland
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What regulates PTH?
magnesium, vitamin D, calcium levels
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Describe the levels in primary hyperparathyroidism
high calcium, inappropriate high PTH, low phosphate and high alk phosphatase
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What are the causes of primary hyperparathyroidism?
Sporadic or familial
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Describe the levels in secondary hyperparathyroidism
normal/low calcium, appropriately high PTH, phosphate high if due to kidney disease
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What are the causes of secondary hyperparathyroidism?
CKD or vitamin D deficiency
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Describe the levels in tertiary hyperparathyroidism
high calcium, inappropriately high PTH, phosphate can be high/low
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What are the causes of tertiary hyperparathyroidism?
After prolonged secondary HPT, usually in CKD
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How does primary hyperparathyroidism present?
Previously- severe hypercalcaemia, symptomatic renal and skeletal disease Now earlier in disease course- usually asymptomatic Majority >45 years of age Women X2 likely-Inappropriately elevated PTH in the presence of high calcium suggests PHPT
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What adenomas seen in primary hyperparathyroidism?
bening adenomas, glandular hyperplasia, ectopic adenomas, parathyroid carcinoma
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What are the clinical manifestations of primary hyperparathyroidism?
Symptoms related to hypercalcaemia(as described) Renal disease (nephrolithiasis, chronic kidney disease) Bone disease (osteoporosis, osteitis fibrosa cystica) Proximal muscle wasting
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What is the treatment for symptomatic hypercalcaemia?
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What the treatment for asymptomatic patients with primary hyperparathyroidism?
medical--> Calcimimetics (Cinacalcet)
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What is the mechanism of action of Calcimimetics (Cinacalcet)?
Activates CaSR in the parathyroid gland Therefore leads to reduced PTH secretion Use 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
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What is Pagets disease of bone?
Rapid bone turnover and formation Leading to abnormal bone remodelling
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What is seen in Pagets disease of bone?
Elevated alkaline phosphatase reflecting increased bone turnover
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What does imagine of Pagets disease of bone show?
Cotton wool appearance of excessive bone formation
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What is the epidemiology of Pagets disease of bone?
Mainly over 50 years old Higher prevalence in men Probable genetic and environmental triggers FH in 10-15% of cases Polyostotic or monostotic
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What are the clinical features of Pagets disease of bone?
Bone pain Bone deformity Fractures Arthritis Cranial nerve defects if skull affected Hearing and vision loss Risk of osteosarcoma Most commonly affects pelvis, femur and lower lumbar vertebrae
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How is Pagets disease of bone investigated?
Lab assessment Plain X-rays Nuclear medicine bone scan
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How do you monitor disease activity of Pagets disease of bone?
Monitor disease activity with a blood test looking at the osteoclast markers- ALKALINE PHOSPHATASE
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What treatment for Pagets disease of bone?
Bisphophonates are used since they are anti-osteoclastic activity
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What is osteomalacia?
Lack of mineralisation of bone Adult form - widened osteoid seams with lack of mineralisation Classic childhood rickets - widened epiphyses & poor skeletal growth
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What are the causes of osteomalacia?
Insufficient calcium absorption from intestine Due to lack of dietary calcium or Vit D deficiency/resistance Excessive renal phosphate excretion Rare genetic forms (e.g. hereditary hypophosphataemic rickets)
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What are the clinical features of osteomalacia?
Diffuse bone pains Usually symmetrical Muscle weakness Bone weakness High alk phos, low Vit D, possibly low Calcium and high PTH (secondary hyperparathyroidism)
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What is the biochemistry of hyperparathyroidism?
Increase alk phos, calcium, PTh decreased phosphate
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What is the biochemistry of osteomalacia?
Increased alk phos, PTH Decreased calcium, phosphate
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What is the biochemistry of osteoporosis?
normal biochemistry
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What is the biochemistry of Pagets disease?
normal biochemistry only increased alk phos
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What is the biochemistry of bone mets?
Increased alk phos, calcium Decreased PTH and normal phosphate
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