Endrocrine and metabolic bone disorders Flashcards
what 2 components make up bone?
It is composed of 2 components – the inorganic component formed predominantly by hydroxyapatite crystals and the organic osteoid formed predominantly from type 1 collagen fibres
what is the purpose of bone?
As well as providing a skeleton, bone is a reservoir for calcium and phosphorus
what do osteoblasts do?
synthesise osteoid and participate
in mineralisation/calcification
of osteoid
-bone formation
what do osteoclasts do?
release lysosomal enzymes
which break down bone
-bone resorption
Osteoblasts express receptors for PTH & calcitriol (1,25 (OH)2 vit D) – regulate balance between bone formation & resorption
how do osteoclasts become activated?
osteoclasts are switched on by osteoblasts
RANKL expressed on osteoblast surface
RANKL binds to RANK-R (on osteoclast) to stimulate osteoclast formation and activity
define the following:
Cortical :
Trabecular:
Woven bone:
Cortical (hard) bone
Trabecular (spongy or trabecular) bone
Both formed in a lamellar pattern = collagen fibrils laid down in alternating orientations, mechanically strong
Woven bone – disorganised collagen fibrils, weaker
what is the effect on bone of vit D deficiency?
what is it called in children and adults
Inadequate mineralisation of newly formed bone matrix (osteoid)
Normal stresses on abnormal bone cause insufficiency fractures - Looser zones
Waddling gait - typical
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 are the three types of hyperparathyroidism and what happens in them?
- adenoma (primary hyperparathyroidism)
- high PTH
- high Cal
- neg feedback does not occur, parathyroid gland does its own thing
- normal kidney function - low plasma Cal eg renal failure, vit deficiency (secondary hyperparathyroidism)
- high PTH
- low Cal (cannot get higher) - chronic low plasma cal (tertiary hyperparathyroidism)
- high PTH
- high Cal
- parathyroid glands get really big and cannot be switched off so there is no neg feedback . difference between this and the first one is that this is accompanied with chronic kidney failure
what condition can arise due to renal failure and bone disease?
vascular calcification
and osteitis fibrosa cystica
what is osteitis fibrosa cystica
see slide
Osteitis fibrosa cystica (hyperparathyroid bone disease) – rare
= XS osteoclastic bone resorption 2o to high PTH
due to decreased bone mineralisation and caused by a surplus of parathyroid hormone (PTH) from overactive parathyroid gland(s)
side note:‘Brown tumours’ = radiolucent bone lesions
what is the treatment for osteitis fibrosa cystica (hyperparathyroid bone disease)?
Hyperphosphataemia
Low phosphate diet
Phosphate binders – reduce GI phosphate absorption
Alphacalcidol – ie calcitriol analogues
Parathyroidectomy in 3o hyperparathyroidism
Indicated for hypercalcaemia &/or hyperparathyroid bone disease
what is osteoporosis?
Loss of bony trabeculae, reduced bone mass, weaker bone predisposed to fracture after minimal trauma
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 BMD do?
BMD predicts future fracture risk
how do you measure BMD?
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)
what are the differences between osteomalacia ad osteoporosis?
Both predispose to fracture
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- hence cannot be diagnosed using a blood test Diagnosis via DEXA scan
predisposing conditions for osteoporosis
Postmenopausal oestrogen deficiency: Oestrogen deficiency leads to a loss of bone matrix and Subsequent increased risk of fracture
Age-related deficiency in bone homeostasis (men and women) eg osteoblast senescence
Hypogonadism in young women and in men
Endocrine conditions: Cushing’s syndrome, Hyperthyroidism, Primary hyperparathyroidism
Iatrogenic
Prolonged use of glucocorticoids and Heparin
treatment options for osteoporosis
Oestrogen/Selective Oestrogen Receptor Modulators
Bisphosphonates
Denosumab
Teriparatide
how does oestrogen help with osteoporosis?
-what are the risks and precautions that need to be taken?
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
how do bisphosphonates work?
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.
what are the uses of bisphosponates?
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)
what are the pharmacokinetics of bisphosphonates?
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
what are 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 denosumab?
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 s 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 paget’s disease (of bone)?
Accelerated, localised but disorganised bone remodelling
Excessive bone resorption (osteoclastic overactivity) followed by a compensatory increase in bone formation (osteoblasts)
New bone formed = WOVEN bone
structurally disorganised
mechanically weaker than normal adult lamellar bone
BONE FRAILTY
BONE HYPERTROPHY & DEFORMITY
what is paget’s disease characterised by histologically?
Characterised by abnormal, large osteoclasts – excessive in number
clinical features of paget’s disease
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
how is paget’s disease diagnosed?
Plasma [Ca2+] normal
*Plasma [alkaline phosphatase] usually increased (this is a bone enzyme)
Plain x rays = Lytic lesions (early), thickened, enlarged, deformed bones (later)
Radionuclide bone scan demonstrates extent of skeletal involvement
suggest a treatment option for paget’s disease?
Bisphosphonates – very helpful for reducing bony pain and disease activity
Simple analgesia
