Endocrinology 13 - Endocrine and Metabolic Bone Disorders Flashcards
What does bone contain?
- Organic components (osteoid - unmineralised bone) are 35% of bone mass, including 95% type 1 collagen fibres
- Inorganic mineral components are 65% bone mass, containing calcium hydroxyapatite crystals, which fill in the space between the collagen fibrils
Which cell types are present in bone?
- Osteoblasts (synthesise osteoid and participate in the mineralisation and calcification of osteoid)
- Osteoclasts (release lyosomal enzymes which break down bone - bone resorption)
Describe the process of osteoclast differentiation
- RANKL expressed on the osteoblast surface
- RANKL binds to RANK-R on the osteoclast precursor to stimulate osteoclast formation and activity
- Osteoblasts express receptors for PTH and calcitriol (regulates the balance between bone formation and resorption)
Describe the structure of bone
- Cortical (hard bone on the outside) or trabecular (spongy) bone
- Formed in a lamellar pattern, with collagen fibrils laid down in alternating orientations, they are mechanically strong
- Woven bone - disorganised collagen fibrils, weaker dysfunctional bone
What is the effect of vitamin D deficiency on bone?
- Inadequate mineralisation of the newly formed bone matrix (osteoid)
- Children get rickets
- Adults get ostomalacia
What happens in rickets?
- Effects epiphysial growth plates and bone
- Skeletal abnormalities and pain
- Growth retardation
- Increased fracture risk
What happens in osteomalacia?
- After epiphyseal closure, affects bone
- Skeletal pain
- Increased fracture risk
- Proximal myopathy
What features are typical in vitamin D deficiency?
- Insufficiency fractures caused by normal stresses on bone (looser zones)
- Waddling gait
Describe the relationship between renal failure and bone disease
- Decreased renal function results in decreased calcitriol (no a-hydroxylation step), decreased Ca2+ absorption and decreased PO4- excretion
- Plasma phosphate increasing causes vascular calcification
- Hypocalcaemia results in decreased bone mineralisation, and increased PTH (which leads to increased bone resorption) and therefore osteitis fibrosa cystica
- Leads to tertiary hyperparathyroidism
What is osteitis fibrosa cystica?
- Hyperparathyroid bone disease
- Brown tumours are seen on scans - radiolucent bone lesions
- Excess osteoclastic bone resorption secondary to high PTH
How is osteitis fibrosa cystica treated?
- Low phosphate diet
- Phosphate binders to reduce GI phosphate absorption
- Alphacalcidol
- Parathyroidectomy - tertiary hyperparathyroidism (in hypercalcaemia or hyperparathyroid bone disease)
What is osteoporosis?
- Loss of bony trabeculae, so bone is not as strong
- Reduced bone mass (less then 2.5 standard deviation below average value for a young healthy adult - T-score)
- Weaker bone predisposed to fracture after minimal trauma, not a painful problem
How is bone mineral density measured?
- Duel energy X-ray absorptiometry (femoral neck and lumbar spine) - DEXA scan
- Mineral (calcium) content of bone measured, the more mineral the greater the bone density
Compare osteoporosis with osteomalacia
[Both predispose to fracture]
Osteomalacia
- Vitamin D deficiency (in adults) causing inadequate bone mineralisation
- Serum biochemistry abnormal, diagnosed on a blood test (low calcitriol, low Ca2+ and high PTH)
Osteoporosis
- Bone reabsorption exceeds formation
- Decreased bone mass
- Serum biochemistry is normal
- Diagnosis via DEXA scan
List the predisposing conditions for osteoporosis
- Post menopausal oestrogen deficiency (loss of bone matrix)
- Age related deficiency in bone homeostasis (osteoblast senescence - men and women)
- Hypogonadism (young men and women)
- Endocrine conditions - cushings, hyperthyroidism, primary hyperparathyroidism
- Iatrogenic (glucocorticoid or heparin use)
List the treatment options for osteoporosis
- Ostrogen/selective oestrogen receptor modulators
- Bisphosphonates
- Denosumab
- Teriparatide
When is oestrogen used in osteoporosis treatment?
- Treatment of postmenopausal women (HRT)
- Prevents bone mass, anti-resorptive effects
- Women with an intact uterus also need progestogen to prvent endometrial cancer/hypoplasia
- Limited use due to increased breast cancer and venous thromboembolism risk, therefore cannot be used long term
How do bisphosphonates work?
- Bind avidly to hydroxyapatite and ingested by osteoclasts
- Impair ability of osteoclasts to reabsorb bone
- Decreased osteocalst progenitor development and recruitment
- Promote osteoclast apoptosis
- Net result = reduced bone turnover
When are bisphosphonates used in osteoporosis treatment?
- First line treatment in osteoporosis
- Malignancy (associated hypercalcaemia, reduced bone pain from metastases)
- Pagets disease (reduce bony pain)
- Severe hypercalcaemic emergency (IV first)
Describe the pharmacokinetics of bisphosphonates
- Orally active but poorly absorbed (taken on empty stomach)
- Accumulates at site of bone mineralisation until it is resorbed (months/years)
List the unwanted actions of bisphosphonates
- Oesophagitis (switch to IV)
- Osteonecrosis of the jaw as bone becomes adynamic (risk to cancer patients recieving IV)
- Atypical fractures (oversuppression of bone remodelling)
How does denosumab work and when is it used?
- Human monoclonal antibody which binds to RANKL inhibiting osteoclast formation and activity
- Inhibits osteoclast mediated bone resorption
- Subcutaneous injection every 6 months
- 2nd line to bisphosphonates
What is teriparatide and how does it work?
- Recombinant PTH fragment - amino terminal 34 amino acids of native PTH
- Increases bone formation and resorption, formation outweighs resorption
- 3rd line of treatment
- Daily subcutaneous injection
- Expensive
What is Pagets disease of bone?
- Accellerated, localised but disorganised bone remodelling
- Excessive bone resorption (osteoclast overactivity) and compensatory increase in bone formation (osteoblasts)
- New bone formed is woven bone, which is disorganised and weaker than adult healthy bone
- Therefore, bone fraility, hypertrophy and deformity
Describe epidemiology and characteristics of Pagets
- Positive family history
- Evidence for viral origin (measles)
- Highest in UK, normal america, australia and new zealand
- Lowest and asia and scandinavia
- Men and women affected equally
- Not apparent under age 50
- Most patients are asymptomatic - characterised by an excessive number of abnormal, large osteoclasts
List the clinical features of Pagets disease of bone
- Skull, thoracolumbar spine, pelvis, femur and tibia are most commonly affected
- Arthritis
- Fracture
- Pain
- Bone deformity
- Increased vascularity (warmth over the affected bone)
- Deafness, blindness
- Radiculopathy (nerve root pain)
- Enlargement of the skull
- Kyphosis
- Bowing of limbs (deformed due to abnormal bone remodelling)
How is pagets disease of bone diagnosed?
- Plasma Calcium is normal
- Plasma alkaline phosphate increased (due to bone remodelling - also present in the plasma in liver disease)
- Lytic lesions on x-ray, thickened enlarged and deformed bones later
- Radionuclide bone scan demonstrates the effect of skeletal involvement
What are the treatment options for Pagets disease?
- Bisphosphates (helpful to reduce pain and disease activity)
- Analgesia
What is osteopenia?
Low bone density, which will progress to osteoporosis
List risk factors for osteomalacia
- Age
- Vegan diet
- Ethnicity (South Asian predisposed)
- Not getting enough sun
Why is PTH increased in vitamin D deficiency?
Lack of negative feedback on PTH release due to low calcium
Why is calcium increased in hypercalcaemia of malignancy?
Damaged bone releases cytokines and peptides which cause calcium release
