13 - Endocrine and metabolic bone disorders Flashcards
What is stored in bones?
calcium (over 95% of the body’s Ca2+)
What are the roles of osteoclasts and osteoblasts and what impact does this have on the amount of calcium in bone?
osteoblasts - synthesise bone (make and mineralise osteoid)
—–> assist with deposition of calcium
osteoclasts - consume bone thought release lysosomal enzymes
—–> liberates calcium from the bone
What are the 2 components of bone?
- osteoid
this is the organic component of bone - unmineralised bone made up of type 1 collagen - calcium hydroxyapatite crystals
inorganic compound of bone - fills the space between the collagen fibrils
What is the mechanism of action of PTH on the bone?
(indirectly activates osteoclasts) works on osteoblasts and inhibits various activities
Stimulates osteoblasts to produce OAF (osteoclast activating factors)
What is the action of OAF (osteoclast activating factors)
(produced by osteoblasts) move to osteoclasts and stimulate the breakdown of bone matrix to release Ca2+
Give an example of an OAF
RANKL
Describe the process of osteoclast differentiation, by which osteoclasts require the action of ostoblasts
- osteoblasts express RANK
- osteoclasts have a receptor for RANK
- on binding, the osteoclasts precursor becomes activated
- osteoclast formation and activity
What 2 substances regulate the balance between bone formation and resorption
and what are the corresponding receptors for these located?
PTH and calcitriol regulate the balance
their receptors are located on osteoblasts
Describe the structure of regular bone
How is the strength maintained?
- hard cortical bone around the outside
- spongy, trabecular bone on the inside
bone is formed in a lamellar pattern - collagen fibrils are laid down in altering orientations - this gives the maximum mechanical strength
Name and describe the type of bone with much less mechanical strength
woven bone
collagen fibrils are organised randomly
What is the effect of vitamin D deficiency on bone?
inadequate mineralisation of newly formed bone matrix (osteoid)
Describe the presentation of vitamin D deficiency in children
RICKETS
- affects cartilage of epiphyseal growth plates and bone
- skeletal abnormalities (tibia bowing) and pain, growth retardation. increased fracture risk (‘bendy bones’)
- particularly problematic in legs (weight bearing)
Describe the presentation of vitamin D deficiency in adults
OSTEOMALACIA
- occurs after epiphyseal closure
- skeletal pain, increased risk fracture, proxoimal myopathy
(- not the same bone deformities that are seen in rickets - epiphyseal growth closure)
What are the effects of vitamin D deficiency on bone?What are the typical fracture sites?
stress fractures - due to normal stresses i.e. bearing weight
typical fracture sites are in areas of high bone load
abnormal pelvic fractures - patients walk with a ‘waddling gait’
Describe what happens in primary hyperparathyroidism
- the problem is with one of the parathyroid glands
- autonomous secretion of PTH (e.g. parathyroid adenoma)
- patients have high serum calcium and high PTH
Describe what happens in secondary hyperparathyroidism
- normal physiological response to low calcium
- —-> this is due to either renal failure or Via D deficiency
- high PTH secondary to low Ca2+
Describe what happens in tertiary hyperparathyroidism
- (seen in chronic renal failure)
- chronically low calcium because calcitriol cannot be made
- PTH increases in response to low calcium
What is the treatment for tertiary hyperparathyroidism
need to have a parathyroidectomy
What are the 2 main effects of kidney failure on calcium serum levels?
- calcitriol cannot be made, so calcium is not absorbed well from the gut
- (reduced excretion of phosphate =) increased serum phosphate —–> decreases bioavailable serum calcium (phosphate binds to calcium)
inadequate bone mineralisation and increased PTH release (-> increased bone reabsorption)
leads to osteitis fibrosa cystica (rare)
In what way do patients with chronic kidney failure need to manage their diet?
try to reduce serum phosphate
What can result because of high serum phosphate?
vascular calcification
When is osteitis fibrosa cystica seen?
in people with very high PTH e.g. in renal failure
What is osteitis fibrosa cystica?
What causes it?
hyperparathyroid bone disease
high PTH —> osteoclast stimulation —> increased bone resorption
What is the treatment for osteitis fibrosa cystica?
- hyperphosphataemia - low phosphate diet and phosphate binders
- alfacalcidol - active vitamin D/calcitriol analogues
- parathryoidectomy (when tertiary hyperparathyroidism)
Define osteoporosis.
(reduction in bone mass)
Having a bone mineral density (BMD) that is 2.5 standard deviations (SD) or more below the average for young healthy adults
Describe the features of bone in someone who has osteoporosis
loss of bony trabeculae
weaker bone
predisposed to fracture after minimal trauma
Who is most likely to have problems caused by osteoporosis?
post-menopausal women
elderly
How is bone mineral density measured?
Name the key areas that are looked at during this test
using Dual Energy X-ray Absorptiometry (DEXA)
the scan looks at the mineral (calcium) content of the bone
the femoral neck and lumbar spine are scanned
What are the similarities between osteomalacia and osteoporosis?
both predispose to fractures
How can you differentiate between osteomalacia and osteoporosis?
BIOCHEMISTRY IS COMPLETELY NORMAL IN OSTEOPOROSIS
osteomalacia - diagnosed using serum biochemistry
osteoporosis - diagnosed using DEXA scan
osteomalacia - caused by Vitamin D deficiency causing inadequately mineralised bones
osteoporosis - when bone reabsorption exceeds formation
List predisposing conditions for osteoporosis
- post menopausal oestrogen deficiency
- age-related deficiency in bone homeostasis
- hypogonadism
- endocrine conditions
- —-> Cushings
- —-> hyperthyroidism
- —-> primary hyperparathyroidism
- iatrogenic
- —-> prolonged use of glucocorticoids
- —-> heparin
What are the 1st, 2nd and 3rd line treatments for osteoporosis?
Bisphosphonates
Denusomab
Teriparatide
NOTE: with oestrogen replacement, there is risk of breast cancer and VTE
What are the benefits of oestrogen replacement to prevent osteoporosis in post-menopausal women?
It has an anti-resorptive effect in bone and, hence, prevents bone loss
What are some cautions and risks of oestrogen replacement?
In patients with a uterus (i.e. not had a hysterectomy), you must give additional progestogen to prevent endometrial hyperplasia and reduce the risk of endometrial carcinoma
Risks:
• Breast cancer
• Venous thromboembolism
What are the 2 types of SERMs?
Give an example of each
Selective Oestrogen Receptor Modulators 1- Tissue selective ER antagonists/anti-oestrogens e.g. tamoxifen 2- Tissue selector ER agonists e.g. raloxifene
Describe the effects of tissue selective ER antagonists/anti-oestrogens
- Antagonises ERs in breast but has oestrogenic activity in bone
- Oestrogenic effects on endometrium limit its use in osteoporosis management
Describe the effects of tissue selector ER agonists
- Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus
- Reduces breast cancer risk (anti-oestrogen) but increases risk of venous thromboembolism
What is the action of bisphosphonates in treatment of osteoporosis?
- Bind to hydroxyapatite and ingested by osteoclasts - impair ability of osteoclasts to reabsorb bone
- Decrease osteoclast progenitor development and recruitment
- Promote osteoclast apoptosis
Net result = reduced bone turnover
What conditions are bisphosphonates used to treat?
- Osteoporosis – first line treatment
- Malignancy (associated hypercalcaemia, reduce bone pain from metastase)
- Paget’s disease – reduce bony pain
- Severe hypercalcaemic emergency – i.v. Initially (+++ re-hydration first)
Describe the pharmacokinetics of bisphosphonates
- Orally active but poorly absorbed; take on an empty stomach (food, especially milk, reduces drug absorption generally) - so these tablets are a pain to take
- Accumulates at site of bone mineralisation and remains part of bone until it is resorbed – months, years
Give some of the unwanted actions of bisphosphonates
• Oesophagitis (heart burn): may require switch from oral to IV
• 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
—> hence, patients are given a bisphosphonate holiday so bones can recover from treatment
What is the action of Denosumab in treatment of osteoporosis?
• Human monoclonal antibody
• binds RANKL, inhibiting osteoclast formation and activity
—–> Hence inhibits osteoclast-mediated bone resorption
Describe the pharmacokinetics of Denosumab
Subcutaneous injection every 6 months
What is teriparatide?
What is its action in treatment of osteoporosis?
• Recombinant PTH fragment
• Increases bone formation and bone resorption, but formation outweighs resorption
(3rd line treatment for osteoporosis - very expensive)
Describe the pharmacokinetics of teriparatide
Daily subcutaneous injection
What is Paget’s disease?
Active/accelerated, localised but disorganised bone metabolism – usually slowly progressive.
There is increased bone breakdown and bone formation.
What happens in the bone in Paget’s disease?
- excessive bone resorption (over activity of osteoclasts)
- followed by compensatory increase in bone formation (osteoblasts)
BUT the new bone formed is woven bone
What is Paget’s disease characterised by histologically?
Abnormal, large osteoclasts - that are excessive in number
State some clinical features of Paget’s disease
(most patients are asymptomatic)
- Fracture
- Pain
- Bone deformity
- Increased vascularity (warmth over affected bone)
- Most commonly affected bones are: pelvis, femur, tibia, skull, and spine
- ^arthritis
- deafness: cochlear involvement
- radiculopathy - due to nerve compression
Describe how you would diagnose Paget’s disease.
Biochemical Findings:
- Plasma calcium = NORMAL
- Plasma ALP (alkaline phosphatase) = HIGH
Radiological findings:
- x-rays:
—–> (early) lytic lesions
—–> (later) thickened, early, deformed bones
- Radioisotope scanning can be performed to indicate areas of involvement
What is the treatment for Paget’s?
- bisphosphonates
- simple analgesia
