13. Endocrine and metabolic bone disorders Flashcards
what are the 2 components of bone?
- osteoid (organic component making up 35% bone mass - unmineralised bone made up of type 1 collagen)
- calcium hydroxyapatite crystals (inorganic component making up 65% bone mass - fills the space between collagen fibrils)
what are the 2 types of bone cells?
- osteoblasts - synthesise osteoid and participate in mineralisation/calcification of osteoid (bone formation)
- osteoclasts - release lysosomal enzymes which break down bone (bone resorption)
What is the action of PTH in bone?
PTH inhibits various activities of osteoblasts
PTH stimulates osteoblasts to produce various osteoclast activating factors (OAFs) e.g. RANKL which move to the osteoclasts and bind to the RANK receptor to stimulate the breakdown of bone matrix to release Ca
what does RANKL mean and what is its role?
RANK ligand
it is expressed on the osteoblast surface and binds to a RANK receptor expressed on the osteoclast surface to stimulate osteoclast formation and activity
what do osteoblasts express receptors for?
PTH
calcitriol (1,25 (OH)2 vitamin D)
what are the different types of bone?
- hard, CORTICAL bone around the outside
- spongy, TRABECULAR bone on the inside
what pattern is bone formed in and what does this mean?
lamellar pattern - collagen fibrils are laid down in alternating orientations giving as much mechanical strength as possible
what is woven bone?
an immature type of bone that is much weaker because it doesn’t have the same organisation of collagen fibrils (fibrils are laid randomly)
what is vitamin D deficiency?
inadequate mineralisation of newly formed bone matrix (osteoid)
what does vit D deficiency present as in children?
RICKETS
- affects cartilage of epiphysial growth plates and bones
- skeletal abnormalities (tibia bowing) and pain, growth retardation, increased fracture risk
what does vit D deficiency present as in adults?
OSTEOMALACIA
- affects bone after epiphyseal closure
- skeletal pain, increased fracture risk, proximal myopathy
where are fracture sites typically found?
in places where there is a lot of bone loading
what 2 things start to happen when the kidneys fail?
- calcitriol cannot be made so calcium is not absorbed from the gut very well - hypocalcaemia
- the kidneys excrete less phosphate resulting in raised serum phosphate which binds to calcium, further decreasing the bioavailability of serum calcium - hypocalcaemia
what does hypocalcaemia result in?
inadequate bone mineralisation and increased PTH release which increases bone resorption
both also result in osteitis fibrosa cystica
what can high serum phosphate contribute to?
vascular calcification - there is a high rate of microvascular disease in kidney failure
what is osteitis fibrosa cystica?
high PTH -> osteoclast stimulation -> increased bone resorption
this results in pepper-pot skull (thinning) and ‘brown tumours’ which are radiolucent bone lesions
what is the treatment of osteitis fibrosa cystica?
- hyperphosphataemia: low phosphate diet, phosphate binders which reduce GI phosphate absorption
- alphacalcidol (calcitriol analogues): gives the patient active Vit D
- parathyroidectomy in tertiary hyperparathyroidism
what is osteoporosis?
reduction in bone mass due to a loss of bone trabeculae leading to weaker bone and increased fracture risk
who is particularly susceptible to osteoporosis?
post-menopausal women
what is a measure of osteoporosis?
bone mineral density
how is bone mineral density measured?
- using a DEXA scan (dual energy x-ray absorptiometry)
- femoral neck and lumbar spine are scanned
- the scans look at the mineral (calcium) content of bone
- the more mineral, the greater the bone density (bone mass)
what is the difference between osteomalacia and osteoporosis?
- osteomalacia is when vitamin D deficiency in adults causes inadequately mineralised bone, whereas osteoporosis is when bone resorption exceeds bone formation to decrease bone mass
- in osteomalacia the serum biochemistry is abnormal (low 25(OH) vitamin D, low calcium, high PTH) whereas in osteoporosis the serum biochemistry is normal
- osteoporosis is diagnosed via a DEXA scan, osteomalacia is not
what are the pre-disposing conditions for osteoporosis?
- post-menopausal oestrogen deficiency
- age-related deficiency in bone homeostasis
- hypogonadism
- endocrine conditions: cushing’s syndrome, hyperthyroidism, primary hyperparathyroidism
- iatrogenic: prolonged use of glucocorticoids, heparin
what are the treatment options for osteoporosis?
- oestrogen/selective oestrogen receptor modulators
- bisphosponates
- denosumab
- teriparatide
how and why is oestrogen used to treat osteoporosis? what are the risks?
WHY
- anti-resorptive effects on the skeleton
- prevents bone loss
HOW
- pharmacological doses of oestrogen
- women with an intact uterus need additional progestogen to prevent endometrial hyperplasia/cancer
RISKS
- use is limited due to concerns of increase breast cancer risk and venous thromboembolism
what are the 2 types of selective oestrogen receptor modulators (SERMS) and what do they do?
- tissue selective ER antagonists/anti-estrogens (e.g. tamoxifen)
- antagonise ERs in breast but has oestrogenic activity in bone
- oestrogenic effects on endometrium limits its use in osteoporosis management - tissue selective ER agonist raloxifene
- oestrogenic activity in bone, anti-oestrogenic at breast and uterus
- reduces breast cancer risk but increases risk of venous thromboembolism
what do bisphosphonates do?
- bind to hydroxyapatite and are ingested by osteoclasts so impair the ability of osteoclasts to resorb bone
- decrease osteoclast progenitor development and recruitment
- promote osteoclast apoptosis
what illnesses can bisphosphonates be used for?
- osteoporosis
- malignancy
- paget’s disease
- severe hypercalcaemia emergency
describe the pharmacokinetics of bisphosphonates
- orally active but poorly absorbed, take on an empty stomach
- accumulates at site of bone mineralisation and remains part of bone until it is resorbed
what are the unwanted actions of bisphosphonates?
- oesophagitis (heart burn) due to oral consumption (may require shift to IV)
- osteonecrosis of the jaw
- atypical fractures due to the over-suppression of bone remodelling
what is Denosumab and how is it used to treat osteoporosis?
human monoclonal antibody
- binds RANKL, inhibiting osteoclast formation and activity
- inhibits osteoclast-mediated bone resorption
- subcutaneous injections every 6 months
- 2nd line to bisphosphonates (due to price)
what is Teriparatide and how is it used to treat osteoporosis?
recombinant parathyroid hormone fragment
- increases bone formation and bone resorption but bone formation outweighs resorption
- 3rd line treatment
- daily subcutaneous injection
- very expensive
what is Paget’s disease?
accelerated, localised but disorganised bone remodelling
excessive bone resorption followed by compensatory increase in bone formation but new bone is woven bone (weaker)
men and women are affected equally
what are the causes of Paget’s disease?
- often positive family history suggesting possible genetic cause
- evidence for viral origin (measles virus)
what are the clinical features of Paget’s disease?
- skull, thoracolumbar spine, pelvis, femur and tibia commonly affected
- arthritis
- fracture
- pain
- bone deformity
- increased vascularity
- deafness
- radiculopathy (due to nerve compression)
how is Paget’s disease diagnosed?
- plasma [Ca2+] is normal
- plasma [alkaline phosphatase] is usually increased (bone isoenzymes)
- plain x-rays show lytic lesions (early) and thickened, enlarged, deformed bones
- radionuclide bone scan shows extent of skeletal involvement
what is the treatment for Paget’s disease?
- bisphosphonates
- simple analgesia
