Endo 14: Endocrine and metaboic bone disorders Flashcards
Outline component of bone
Organic components
(osteoid – unmineralised bone)
(35% bone mass)
Inorganic mineral component
(65% bone mass)
Outline composition of organic and inorganic component of bone
Organic: Type 1 collagen fibres (95%)
Inorganic: Calcium hydroxyapatite crystals
fill the space between collagen fibrils
Function of osteoblast
synthesise osteoid and participate
in mineralisation/calcification
of osteoid
(bone formation)
Function of osteoclast
Osteoclasts
release lysosomal enzymes
which break down bone
bone resorption
How do you activate an osteoclast
The osteoclast must recognise RANKL expressed on osteoblast/stromal cell by its RANK receptor
T/f Osteoclasts contain RANKL
False, osteoblasts do
How do osteoblasts regulate balance between been formation and resorption
Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) in response to which RANKL expression can be altered
Differentiate type of bone
Cortical (hard) bone… around side
Trabecular (spongy or trabecular) bone
Outline formation of normal bone
collagen fibrils laid down in alternating orientations, mechanically strong and then mineralisation occurs
What is woven bone
Woven bone – disorganised collagen fibrils, weaker
Effect of vitamin D deficiency on bone… in
Children
Adults
Inadequate mineralisation of newly formed bone matrix (osteoid)
Children: RICKETS:
- affects cartilage of epiphysial growth plates and bone
- skeletal abnormalities and pain, growth retardation, increased fracture risk
Adults: OSTEOMALACIA
- after epiphyseal closure, affects bone
- skeletal pain, increased fracture risk, prox myopathy
What is a looser zone and where does this occur
Normal stresses on abnormal bone cause insufficiency fractures…..
femur and pelvis
What is a symptom of vitamin D deficiency on bone
Waddling gait - typical
Looser zones
Differentiate 1o, 2o and 3o hyperparathyroidism
1o- lack of -ve feedback
2o- vit D defic or renal failure
3o- parathyroids revved up due to kidney failure for example (because not enough vit D) and stay revved up even after kidney failure cured
Effect of renal failure on bone disease
Can’t make calcitriol, not enough Ca2+ reabsorption, hypocalcaemia, less bone mineralisation
If kideys aren’t working, you can’t excrete phosphate, so increased phosphate (which binds calcium and reduces free calcium in blood) so hypocalcaemia, so high PTH so bone resoprtion of Ca2+ (active osteoclasts).
These 2 combined= OSTEITIS FIBROSA CYSTICA
Increased plasma PO43- leads to VASCULAR CALCIFICATION (bad for heart)
What is Osteitis fibrosa cystica what is it caused by and what is seen radiologically
Due to hyperparathyroid bone disease
XS osteoclastic bone resorption secondary to high PTH- Peppered skull
‘Brown tumours’ = radiolucent bone lesions
How is osteitis fibrosa cystica treated
Hyperphosphataemia
- Low phosphate diet
- Phosphate binders – reduce GI phosphate absorption
Alphacalcidol – ie calcitriol analogues
Parathyroidectomy in 3o hyperparathyroidism
-Indicated for hypercalcaemia and/or hyperparathyroid bone disease
What is osteoporosis
Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
How is osteoporosis classified
Bone mineral density (BMD) > 2.5 standard deviations below the average value for young healthy adults (usually referred to as a T-score of -2.5 or lower)
What does bone mineral density predict
Fracture risk
How is BMD measured
Dual Energy X-ray Absorptiometry (DEXA) - femoral neck and lumbar spine
Mineral (calcium) content of bone measured, the more mineral, the greater the bone density (bone mass)
Differentiate osteomalacia and osteoporosis biochemistry
OSTEOMALACIA
Vitamin D deficiency (adults) causing inadequately mineralised bone
Serum biochemistry abnormal (low 25(OH) vit D, low/low N Ca2+, high PTH (2o hyperparathyroidism)
OSTEOPOROSIS Bone reabsorption exceeds formation Decreased bone MASS Serum biochemistry normal Diagnosis via DEXA scan
What predisposes you to osteoporosis
Postmenopausal oestrogen deficiency
- Oestrogen deficiency leads to a loss of bone matrix
- Subsequent increased risk of fracture
Other pre-disposig conditions for osteoporosis
Postmenopausal oestrogen deficiency
Age-related deficiency in bone homeostasis (men and women) due to osteoblast senescence
Hypogonadism in young women and in men
Endocrine conditions
- Cushing’s syndrome
- Hyperthyroidism
- Primary hyperparathyroidism
Iatrogenic
- Prolonged use of glucocorticoids (i.e. not for replacement, for high GC dose for immunosupression i.e. rheumatoid)
- Heparin
Treatment for osteoporosis
Oestrogen/Selective Estrogen Receptor Modulators (SERMs….. also used for contraceptive)
Bisphosphonates
Denosumab
Teriparatide
Outline treatment of oestrogen for osteoporosis
Treatment of post-menopausal women with pharmacological doses of oestrogen
- Anti-resorptive effects on the skeleton
- Prevents bone loss
Women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer
Use limited largely due to concerns re:
- Increased risk of breast cancer
- Venous thromboembolism
Outline treatment of osteoporosis with bisphosphonates
Bind avidly to hydroxyapatite and ingested by osteoclasts – impair ability of osteoclasts to resorb bone
Decrease osteoclast progenitor development and recruitment
Promote osteoclast apoptosis (programmed cell death)
Net result = reduced bone turnover.
Use of bisphosphonates
Osteoporosis – first line treatment
Malignancy
- Associated hypercalcaemia
- Reduce bone pain from metastases
Paget’s disease – reduce bony pain
Severe hypercalcaemic emergency – i.v. initially (+++ re-hydration first)
Pharmacokinetics of bisphosphnates
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
Oral (or IV if oesophagitis)
Unwanted action of bisphonates
Oesophagitis
- may require switch from oral to iv preparation
Osteonecrosis of the jaw
- greatest risk in cancer patients receiving iv bisphosphonates to try to reduce their calcium
Atypical fractures
- may reflect over-suppression of bone remodelling in prolonged bisphosphonate use
How does denosumab work
Human monoclonal antibody
Binds RANKL, inhibiting osteoclast formation and activity
Hence inhibits osteoclast-mediated bone resorption
SC injection 6/12ly
2nd line to bisphosphonates
What is teriparatide
Recombinant PTH fragment - amino-terminal 34 amino acids of native PTH
Increases bone formation and bone resorption, but formation outweighs resorption
3rd line treatment for osteoporosis
Daily s.c. injection
£££
What is pagets disease of bone
Accelerated, localised but disorganised bone remodelling
Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts) ….
but the new bone is woven bone
Outline woven bone in paget’s disease
structurally disorganised
mechanically weaker than normal adult lamellar bone
Effects of paget’s disease on bone
BONE FRAILTY
BONE HYPERTROPHY & DEFORMITY (areas of resorbed bone next to areas of new, disorganised bone)
What causes paget’s
Maybe genetic…..
men and women equally affected
Most asymptomatic…
characteriesed by absormal, large osteoclasts, excessive in number
Clinical features of paget’s disease of bone
Skull, thoracolumbar spine, pelvis, femur and tibia most commonly affected
Arthritis
Fracture
Pain
Bone deformity
Increased vascularity (warmth over affected bone)
Deafness – cochlear involvement
Radiculopathy – due to nerve compression
Diagnosis of paget’s disease
Plasma [Ca2+] normal (as the bone resorption is only in certain areas)
*Plasma [alkaline phosphatase] usually increased (from bone not liver, different isoenzyme)
Plain x rays =
-Lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionuclide bone scan demonstrates extent of skeletal involvement
Treatment of paget’s
- Bisphosphonates – very helpful for reducing bony pain and disease activity
- Simple analgesia
