Endocrine and Metabolic Bone Disorders Flashcards
What percentage of the body’s calcium is stored in the bone?
>95% of body’s Ca2+
What are the two main components of bone and what proportion of its mass is made up by these?
Organic component/osteoid(unmineralised bone) - makes up 35% bone mass; mostly made of type 1 collagen fibres (95%)
Inorganic mineral component - makes up 65% of bone mass; calcium hydroxyapatite crystals fill the space between collagen fibrils
What are the two main cells involved in bone remodelling? Describe their functions.
Osteoblasts - synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)
Osteoclasts - release lysosomal enzymes whihc break down bone (bone resporption)
What is required for the formation of an osteoclast?
RANKL found on onsteoblasts
Describe the process of osteoclast differentiation.
RANKL expressed on osteoblast surface
RANKL binds to RANK-R (on the osteoclast precursor) to stimulate osteoclast formation and activity
Activated osteoclast is invovled in bone resorption
How do osteoblasts help regulate bone formation and resorption?
Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) – regulate balance between bone formation & resorption
What is the RANK ligand?
- An osteoclast-activating factor – it increases the activation of osteoclasts
- It stimulates the maturation of osteoclasts from osteoclast precursors
- If there are more mature osteoclasts, you get more bone resorption
What are the two types of bone? What are the two ways in which collagen fibrils are laid down?
Cortical - hard bone
Trabecular - spongy bone
Both formed in lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong.
Woven bone =disorganised collagen fibrils, wekaer.
What are the effects of Vit D deficiency on bone, in adults and children?
Inadequate mineralisation of newly formed bone matrix/osteoid:
Children –> rickets
- Epiphyseal growth plates + bone affected
- Skeletal abnormalities, pain
- Growth retardation and increased fractures
Adults –> osteomalacia
- After epiphyseal closure but affects bone
- Skeletal pain
- Increased fracture risk
- Proximal myopathy
What are the zones where insufficiency fractures are common?
Looser zones
What type of gait is typical in a pelvic fracture caused by Vit D deficiency?
Waddling gait
Summarise the three types of hyperparathyroidism.
Name a hyperparathyroid bone disease.
Osteitis fibrosa cystica
How can renal disease cause osteitif fibrosa cystica? Name another consequence.
Vascular calcification
NB: in patients with renal failure you need to monitor clacium deficiency and monitor the parathyroid and ensure that they do not develop tertiary hyperparathyroidism.
What is the cellular cause of osteoitis fibrosa cystica?
Excess osteoclastic bone resorption secondary to high PTH
What are Brown tumours?
Radiolucent bone lesions
What is the treatment of hyperparathyroid bone disease?
- Low phosphate diet + Phosphate binders (reduce GI phosphate absorption) - to treat the hyperphosphataemia
- Alphacalcidol – ie calcitriol analogues
- Parathyroidectomy in 3o hyperparathyroidism - Indicated for hypercalcaemia &/or hyperparathyroid bone disease
What are the bone features in osteoporosis?
- Fewer trabeculae
- Reduced bone mass
- Bone mineral density >2.5 SDs below the average value for young healthy adults (a T score of -2.5 or lower)
–> weaker bone predisposed to fractures after minimal trauma
What is measured to predict future fracture risk in osteoporosis? How?
Bone mineral density
DEXA - Dual Energy X-ray Absorptiometry of femoral neck and lumbar spine
Ca content of bone is measured - the more mineral the greater the bone density.
Compare and contrast osteomalacia and osteoporosis.
- Osteomalacia is Vid D deficiency –> inadequately mineralised bone. In osteoporosis the cause is bone reabsorption exceeding formation.
- In osteomalacia the serum biochemistry is ABNORMAL (low 25(OH)D, low Ca and high PTH i.e. secondary hyperparathyroidism) whereas in osteoporosis the serum biochemistry in normal.
BOTH predispose to fracture.
What are the predisposing factors for osteoporosis?
- Postmenopausal oestrogen deficiency –> loss of bone matrix + risk of fracture
- Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence
- Hypogonadism in young women and in men
- Endocrine conditions e.g. Cushing’s syndrome, Hyperthyroidism, Primary hyperparathyroidism
- Iatrogenic - Prolonged use of glucocorticoids, Heparin
How debilitating are hip fractures one year later?
- 20% die within a year
- 80% are unable to carry out at least one independent activity of daily living
List the treatment options for osteoporosis.
Oestrogen
Bisphosphonates
Denosumab
Teriparatide
When would you treat osteoporosis with HRT?
Post-menopausal women - osteorgen is given to have anti-resoprtive effects on the skeleton and to prevent bone loss.
Additional progestogen needed if INTACT uterus to prevent endometrial hyperplasia/cancer.
Describe the mechanism of action of bisphosphonates.
- Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to reabsorb bone
- Decrease osteoclast progenitor development and recruitment
- Promote osteoclast apoptosis (programmed cell death)
- Net result = reduced bone turnover.
Lsit 4 uses of bisphosphonates.
- Osteoporosis – first line treatment
- Malignancy - if associated hypercalcaemia or to reduce bone pain from metastases
- Paget’s disease – reduce bony pain
- Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)
Descirbe the pharmacokinetics of bisphosphonates. Why are they not used much in younger people?
Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally)
Accumulates at site of bone mineralisation and remains part of bone until it is resorbed - months, years (unsure about long term effects so not used as much in younger people)
List and explain the unwanted actions of bisphosphonates.
- Oesophagitis - may require switch from oral to iv preparation
- Osteonecrosis of the jaw - greatest risk in cancer patients receiving iv bisphosphonates
- Atypical fractures - may reflect over-suppression of bone remodelling in prolonged bisphosphonate use
What is the mechanism of action of Denosumab?
- Human monoclonal antibody
- Binds RANKL, inhibiting osteoclast formation and activity
- Hence inhibits osteoclast-mediated bone resorption
Describe the administration of denosumab.
- SC injection 6/12ly
- 2nd line to bisphosphonates
What type drug is teripartide? How does it act?
- Recombinant PTH fragment - amino-terminal 34 aa’s of native PTH
- Increases bone formation and bone resorption, but formation outweighs resorption
- 3rd line for osteoporosis
How is teripartide administered?
SC injection
DAILY
Describe Paget’s Disease.
Accelerated, localised but disorganised bone remodelling.
- Excessivee resorption (by osteoclastic overactivity)
- Then compensatory increase in bone formation (by osteoblasts)
- New bone = WOVEN so structurally disorganised and mechanically wekaer than adult lamellar bone
- Causes bone frailty, hypertrophy and deformity.
Describe the prevalence of Paget’s Disease of bone.
- Highest in UK, N America, Australia and NZ
- Lowest in Asian and Scandinavia
- Men and women equally
- Disease not apparent under 50 - most asymptomatic
What is a characteristic cellular feature of Paget’s?
Abnormal, large osteoclasts – excessive in number
Why would you feel warmth over bone in Paget’s ?
Increased vascularity
What bones are most commonly affected in Paget’s?
Skull, thoracolumbar spine, pelvis, femur and tibia
What are the clinical features of Paget’s?
- Arthritis
- Fracture
- Pain
- Bone deformity
- Increased vascularity (warmth over affected bone)
- Deafness – cochlear involvement
- Radiculopathy – due to nerve compression
How is Paget’s Disease diagnosed?
Blood test:
- Plasma Ca normal
- But plasma ALKALINE PHOSPHATASE increased
Plain X ray:
- Lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionucleotide bone scan
- Shows extent of skeletal involvement
What are the treatment options for Paget’s disease?
- Bisphosphonates – very helpful for reducing bony pain and disease activity
- Simple analgesia
What are the possible causes of Paget’s?
- Could be genetic (often positive family history)
- Viral origin - measles ?
Vitamin D deficiency:
- is relatively common in the elderly
- can be associated with renal failure
- is called rickets in children
- is usually confirmed by the presence of a low
circulating 1,25(OH)2D level
- can be a cause of proximal myopathy
True
True
True
False
True
Paget’s disease:
- is defined as demineralisation of bone
- is caused by inadequate levels of calcitriol
- may be associated with a localized vasodilatation
- is often asymptomatic
- may be treated with bisphosphonates
False
False
True
False
True
Response Feedback:
Inadequate levels of calcitriol cause rickets in children or osteomalacia in adult, not Paget’s disease of bone
Can be asymptomatic, but often presents with bone pain
Parathyroid hormone:
- is low in hypercalcaemia of malignancy
- inhibits synthesis of calcitriol
- stimulates renal excretion of phosphate
- is usually low in renal failure
- stimulates bone resorption
True
False
True
False
True
