13. Endocrine and metabolic bone disorders Flashcards
What are the two components to bone?
- Osteoid - organic component, unmineralised bone, type 1 collagen
- Calcium hydroxyapatite crystals - inorganic component, fills the space between collagen fibrils
What are osteoblasts and osteoclasts?
- Osteoblasts - synthesise bone, mineralisation of osteoid
* Osteoclasts - bone resorption, release lysosomal enzymes to break down bone
How does PTH act on bone?
(indirect effect on osteoclasts)
- PTH stimulates osteoblasts to produce various osteoclast activating factors (OAFs) e.g. RANKL
- OAFs move to the the osteoclasts and stimulate the breakdown of bone matrix
- Release of Ca
How does the osteoblast activate the osteoclast with regards to RANK?
- RANK ligand (RANKL) expressed on osteoblast surface
- RANKL binds to RANK receptor (RANK-R) on osteoclast precursor
- Osteoclast becomes activated
What do osteoblasts express receptors for apart from those for PTH?
Receptors for calcitriol (1,25(OH)2D3)
How is the outside of bone different to the inside?
- Outside - hard, cortical bone
* Inside - spongy, trabecular bone
What pattern is bone formed in?
- Lamellar pattern
- Collagen fibrils laid down in altering orientation
- Most mechanical strength possible
- ‘Woven bone’ is also a type, but it is weaker
Compare rickets to osteomalacia
Rickets
• Affects cartilage of epiphysial growth plates and bone
• Skeletal abnormalities (tibia bowing)
• Skeletal pain, growth retardation, increased fracture risk
Osteomalacia
• After epiphyseal closure, affects bone
• Skeletal pain, increased fracture risk, proximal myopathy
• Don’t get the same bony deformities seen in rickets
What are the typical bone effects of severe vitamin D deficiency?
- Normally where there it is a lot of bone loading
- Insufficiency fractures at looser zones
- ‘Waddling gait’ due to pain from abnormal pelvis fractures
How does kidney failure affect the bones?
- Calcitriol cannot be made - calcium isn’t absorbed from the gut well = hypocalcaemia
- Kidneys can’t excrete phosphate - increased serum phosphate - phosphate binds to calcium = decreased bioavailable serum calcium
- Inadequate bone mineralisation = osteitis fibrosa cystica (rare disease)
- Increased PTH release as a response to low calcium - this increases bone resorption (breakdown) = osteitis fibrosa cystica
What affect can high serum phosphate have on blood vessels?
• Vascular calcificaiton
• high rate of macrovascular disease in kidney failure, partly due to phosphate that can’t be excreted
How can osteitis fibrosa cystica be treated?
- Treat hyperphosphataemia - low phosphate diet, phosphate binders (reduce GI phosphate absorption by collating phosphate on the gut)
- Alphacalcidol - calcitriol analogues (must be active vitamin D)
- Parathyroidectomy (in 3°)
What is osteoporosis?
- Reduction in bone mass
- Loss of bony trabeculae - weaker bone - predisposed to fracture after minimal trauma
- Everyone becomes osteoporotic with age
- Problem especially in post-menopausal women
How do you measure if someone has osteoporosis?
- Measure bone mineral density (predicts fracture risk)
- Use DEXA scan (dual energy x-ray absorptiometry)
- Scan the femoral neck and lumbar spine
- Looks at mineral (calcium) content of bone
- BMD of >2.5 SD below the average (T-score) shows osteoporosis
How is osteoporosis different to osteomalacia?
- Unbalanced bone formation in osteoporosis, inadequate mineralisation due to serum biochemistry in osteomalacia
- Serum biochemistry is normal in osteoporosis
What are the pre-disposing conditions for osteoporosis?
- Post-menopausal oestrogen deficiency (loss of bone matrix)
- Age-related deficiency in bone homeostasis e.g. osteoblast senescence
- Hypogonadism
- Endocrine conditions e.g. Cushing’s
- Iatrogenic - prolonged use of glucocorticoids, heparin
How can osteoporosis be treated?
- Oestrogen/selective receptor modulators
- Bisphosphonates
- Denosumab
- Teriparatide
What is the effect of oestrogen (HRT) on women?
- Anti-resorptive effects on bone - prevents bone loss
- Women with an intact uterus need additional progesterone to prevent endometrial hyperplasia/cancer
- Use limited due to increased risk of breast cancer and VTE
How are selective oestrogen receptor modulators (SERMS) used in treating osteoporosis?
1) Tissue selective ER antagonist e.g. tamoxifen
• antagonises ERs in breast but has oestrogenic activity in bone
• oestrogenic effects on endometrium - limit its use in osteoporosis management
2) Tissue selective ER agonist e.g. raloxifene (further developed)
• Oestrogenic activity in bone, and anti-oestrogenic at breast and uterus
• Reduces breast cancer risk but still increased risk of VTE
How are bisphosphonates used in treating osteoporosis?
- First line treatment
- Bind to hydroxyapaptite and ingested by osteoclasts - impair ability of osteoclasts to resorb bone
- Decrease osteoclast progenitor development and recruitment
- Promote osteoclast apoptosis
- Also stop osteoclasts from forming a ruffled border / secreting enzymes to resorb bone
- Net result = reduced bone turnover
What can bisphosphonates be used for apart from osteoporosis?
- Malignancy associated with hypercalcaemia (reduces bone pain)
- Paget’s disease - reduces bone pain
- Severe hypercalcaemic emergency (but after re-hydration)
Why should you take bisphosphonates on an empty stomach?
Even though they are orally active - poorly absorbed
How long can bisphosphonates remain at the site of bone mineralisation?
- Stay until resorbed
* Can be months, years
What are the unwanted actions of bisphosphonates?
• Oesophagitis (heart burn)
• Osteonecrosis of the jaw - greatest risk in cancer patients receiving IV
• Atypical fractures - over-suppression of bone remodelling
- make bone more brittle
- prevents microfractures from being repaired
Patients can be given a ‘bisphosphonate holiday’ for recovery from treatment
What is denosumab and how does it work?
• Human monoclonal antibody
• Binds RANKL, inhibiting osteoclast activity
- inhibited bone resorption
• Subcutaneous injection every 6 months
• 2nd line to bisphosphonates (mainly due to price)
What is teriparatide and how does it work?
- Recombinant parathyroid hormone fragment - amino-terminal 34 amino acids of native PTH
- Increases bone formation and resorption, but formation outweighs resorption
- Daily subcutaneous injection
- 3rd line treatment
- Very expensive
What is Paget’s disease, and outline the cause and prevalence?
• Accelerated, localised but disorganised bone remodelling
• Excessive bone resorption (osteoclastic over-activity) followed by a compensatory increase in bone formation
- woven, disorganised, weak
• Evidence for viral origin
• Most patients are asymptomatic
• Characterised by abnormal, large osteoclasts
What are the 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
- Radiculopathy - due to nerve compression
How can Paget’s disease be diagnosed?
- Normal plasma [Ca2+]
- Increased plasma [alkaline phosphatase] - bone isoenzymes
- X-rays - early lytic lesions, later thickening, enlargement and deformities
- Radionuclide bone scan can demonstrate extent of skeletal involvement
How can Paget’s disease be treated?
- Bisphosphonates
* Simple analgesia
