1 + 3. Metabolic bone disease - histopathology + biochemistry Flashcards
What are 4 of the functions of bone?
- Structure
- Mechanical (support and site for muscle attachment)
- Protective
- Metabolic (reserve of calcium)
What is the bone composed of?
Inorganic (65%)
• Calcium hydroxyapatite
• Stores 99% of Ca, 85% of P, 65% of Na + Mg
Organic (35%)
• Bone cells
• Protein matrix
• (collagen, osteoid)
When does the epiphyseal line fuse and what does this mean?
- Fusion of growth plate
- Happens in early 20s
- Until then, bone grows and elongates from the epiphysis (end of long bone)
What is the diaphysis?
Central, long part of the bone (shaft)
What is the metaphysis?
Slightly flared part of the bone below the growth plate (between epiphysis and diaphysis)
Which tissue does the blood supply to the bone come through?
Periosteum - dense layer of vascular connective tissue enveloping bones (not at joints)
What is cortical bone?
- Long bones
- 80% of skeleton
- Appendicular (limbs)
- 80-90% calcified
- Mainly mechanical and protective
What is cancellous/trabecular bone?
- Vertebrae + pelvis
- 20% of skeleton
- Axial (torso and head)
- 15-25% calcified (shorter turnover)
- Mainly metabolic function
- Large SA - can be used as a mineral store
What does ‘anatomical bones’ describe as a level of classification?
- Flat - protective e.g. cranial, ribs
- Long - support weight, facilitate movement
- Short/cuboid - stabilise and facilitate movement e.g. tarsals and carpals
- Irregular - specific shape to protect organs e.g. vertebrae and pelvis
- Sesamoid - embedded in tendons, protective e.g. patella
What does the macroscopic structure of bone describe?
- Cancellous/trabecular/spongy - low strength and disorganised structure
- Cortical/compact - makes up outside of the bone
What does the microscopic structure of bone describe?
- Woven bone (immature) - low strength and disorganised structure
- Lamellar bone (mature) - makes up most of the bone in the body
What are osteons?
- Functional unit of bone
- Circular regions formed of concentric layers of lamellar bone
- Form in response to mechanical forces
- Give the bone strength in cortical bone
Describe osteons
• Haversian canal at centre of each lamellae ring - contains blood vessels
• Circumferential lamellae on the outside of the bone
• Interstitial lamellae between osteons
(• Trabecular lamellae don’t have haversian canals and form layers)
Where are osteocytes located and how are they connected?
- Sit between layers of lamellar bone
- Contain dendritic processes which forms the canalicular network throughout the bone with other osteocytes
- This forms mechano-sensory function to determine where bone needs to be repaired
Where are bone biopsies usually done and what are they done for?
- Usually in ASIS area (transiliac)
- Evaluate ongoing bone pain or tenderness
- Investigate abnormality seen on X-ray
- Bone tumour diagnosis
- Determine cause of unexplained infection
- Evaluate theraoy
What are the different types of bone biopsies?
- Closed - needle: core biopsy (Jamshidi needle)
* Open - large sample of bone, for sclerotic or inaccessible lesions (requires general anaesthetic)
What stain do you use to look at bone?
- Haematoxylin + eosin stain
* Can use Masson-Goldner Trichrome stain to look at mineralised and unmineralised bone
Describe the histology of the femoral head?
- Trabecular bone on inside
- Cortical bone on outside (thick + dense)
- Cartilage on the surface between the two articular surfaces
What are the 3 main bone cells?
- Osteoblasts - build bone
- Osteoclasts - resorb bone (multinucleate, macrophage)
- Osteocytes - osteoblast-like cells, sit in lacunae, look inert
What are osteoprogenitor cells and what do osteocytes do to them?
- Stem cells in the marrow
* Osteocytes produce messengers to change them into osteoblasts or osteoclasts
What is ‘RANK’ and ‘OPG’?
- RANK - receptor activator for nuclear factor kappa b
* OPG - osteoprotegerin
What does OPG do?
- Found on osteoblasts
- Competes with RANK for RANKL, preventing it from binding
- Therefore inhibits osteoclastogenesis
What can cause an up-regulation of RANKL?
Many stimuli e.g. infection or trauma
=> differentiation of osteoclast
What happens to OPG in menopause?
- Oestrogen levels fall
- OPG levels fall
- More resorption
Where are osteocytes and osteoblasts located in the bone?
- Osteocytes - bone matrix
- Osteoblasts - surface of the bone
- Osteoclasts - Howship’s lacunae
What are reversal lines?
Lines left when the bone is remodelled
What are lamellae?
Lines that form in response to gravity
What is tetracycline labelling?
- Give tetracycline antibiotic, related to a fluorescent stain
- Look at bone turnover and growth
- Forms a bright green layer on the slide
- Normally give 2 doses a few days apart then can measure the average distance between the layer to calculary bone growth
- Contraindicated in children - turn teeth black
How does reduction in calcium affect the kidneys?
• More PTH release • PTH activates 1-α hydroxylase in the kidney (• Hydroxylated vitamin D) • Stimulated reabsorption of calcium • Inhibited reabsorption of phosphate
What is the rank system?
- Receptor Activator of a Nuclear Factor Kappa
- PTH causes bone resorption through the RANK system
- Ligand on osteoblasts is RANK-L (RANK of osteoclasts)
- Binding causes activation and differentiation of osteoclasts
- Slowed down by a dummy receptor - OPG - blocks ligand but has no effect
What happens in metabolic bone disease and what causes it?
- Disordered bone turnover
- Imbalance of various chemicals in the body (vitamins, hormones, minerals etc.)
- Can altered bone cell activity, rate of mineralisation and changes in bone structure
- Overall reduced bone mass (osteopenia) => fractures with little or no trauma
- Patients present with bone pain and difficulty performing normal tasks
Name some common metabolic bone diseases?
- Osteoporosis
- Rickets/osteomalacia
- Primary hyperparathyroidism
- Renal osteodystrophy
- Paget’s disease
What are the 3 main categories of bone disease?
1) Related to endocrine abnormality
2) Non-endocrine e.g. age related
3) Disuse osteopenia (reduced use of bones)
What is secondary hyperparathyroidism caused by?
Vitamin D deficiency
=> hypocalcaemia
=> excessive PTH
What defines osteoporosis and what are the different types?
Bone mineral density T-score of 2.5 or more SD below average
- Primary - age related/due to post-menopausal changes
- Secondary - seen with drugs and in systemic disease
- High turnover - increased activity of osteoblasts/clasts (more osteoclasts)
- Low turnover - decreased activity of osteoblasts/clasts (more osteoblasts)
How does mineralisation change in osteoporosis
It doesn’t
How does the calcium:phosphate:protein ratio change in osteoporosis?
It doesn’t
How much of the bone is calcified and osteoid in a normal bone biopsy and osteoporosis biopsy?
Both normal and osteoporosis
• 2/3 calcified
• 1/3 osteoid
• Only less bone in total in osteoporosis
What proportion of the bone is calcified in osteomalacia?
- 1/3 calcified (as opposed to 2/3 normally)
* Less bone in total as well
Describe the main tool to assess for osteoporosis
- BMD (bone mineral density)
- Represents 70% of total fracture risk
- Measured using X-rays ‘DEXA’ bone scan
- T-score = (measured BMD - young adult mean BMD)/young adult SD
- Anything above -1 is normal (average 25 year old in UK is 0)
- Between -1 and -2.5 is osteopenia
- Anything below -2.5 is osteoporosis
- z-score compares you to average person of the same age
Describe osteomalacia?
- Defective bone mineralisation
- Bendy bone, which is mostly osteoid
- Can result from deficiency of vitamin D or phosphate
What are the sequelae (consequences) of osteomalacia?
- Bone pain/tenderness
- Fracture and microfracture
- Proximal weakness
- Bone deformity
How do bone changes differ in rickets compared to osteomalacia?
- Epiphyses haven’t fused in children - so they start to bend
- Tibial bowing and wide wrists/ankles stay with patient for life
- Permanent damage to growth plates
What skeletal disease can hyperparathyroidism lead to if not treated?
- Osteitis fibrosa cystica
* Replacement of bone with fibrous cyst-like tissue
What are the symptoms of hyperparathyroidism?
- Ca oxalate renal stones
- Osteitis fibrosa cystica, bone resorption
- Acute pancreatitis
- Psychosis + depression
(stones, bones, abdominal groans, psychic moans)
What did the test for suspected hyperparathyroidism use to involve?
- X-ray of the hand
* Small, brown cell tumours (lytic lesions) on radial side of the digits and thumb
What are the brown cell tumours of hyperparaythyroidism?
- Composed of osteoclast cells
* Become out of control - form tumours on a background of fibrous tissue and blood
What causes 80% of primary hyperparathyroidism cases?
Adenoma in just one gland
What can happen if (too much) calcium enters the urine?
- Nephrocalcinosis (renal parenchymal calcification)
* Renal colic (pain from stones any part of urinary tract, mainly ureter)
What is renal osteodystrophy and what happens in the condition?
• Bone disease related to CKD (chronic kidney disease)
• Comprises all the skeletal changes of CKD
- increased bone resorption
- osteomalacia
- osteosclerosis (osteoblasts not functioning properly)
- growth retardation
- osteoporosis
- PO4 retention - hyperphosphatemia
- Hypocalcaemia (due to low vitamin D)
- Secondary hyperparathyroidism
- Metabolic acidosis
- Aluminium deposition
How does renal failure lead to renal osteodystrophy?
- Renal failure
- Less 1-α hydroxylase
- Calcium levels fall
- Secondary hyperparathyroidism (attempt to increase Ca and reduce PO4)
- Kidneys fail to excrete PO4 => low Ca, high PO4, hight PTH
- PTH becomes autonomous
- Tertiary hyperparathyroidism
- Leads to renal osteodystrophy over time (mainly due to low PO4 excretion)
What affect will giving vitamin D supplements to someone with CKD have on calcium?
None, can’t be hydroxylated
What is the deposition of calcium salts in tissues around the body called?
Metastatic calcification
What are the 3 stages of Paget’s disease?
1) Osteolytic - osteoclast predominant
2) Osteolytic-osteosclerotic - osteoblasts try to build bone
3) Quiescent osteosclerotic - disorganised, mineralised bone
Describe the histology of Paget’s disease?
- Osteolytic phase - bone remodelled in disorganised way
- Lots of osteoclast giant cells, and multinucleated osteoclasts
- Osteoblasts fight back and build none
- Left with paving pattern - reversal lines where bone is remodelled
What is the usual age of onset for Paget’s disease?
Over 40
What proportion of Paget’s disease are mono-ostotic?
15% (remainder is polyostotic)
What causes Paget’s disease?
- Aetiology unknown
- Familial cases show autosomal pattern of inheritance with incomplete penetrance
- Mutation 5q35-qter - sequestosome 1 gene (on long arm of chr5
- Parvomyxovirus type particles have been seen on EM in Pagetic bone, but dismissed
What is the site predilection in Paget’s disease?
- Affects the skull quite often
- Vertebrae (particularly lower)
- Long bones in the leg
What are the clinical symptoms in Paget’s disease?
- Pain
- Microfractures
- Nerve compression
- Skull changes - medullat risk
- Deafness - temporal bone
- Haemodynamic changes
- Cardiac failure
- Hypercalcaemia
- Sarcoma in area of involvement
How does cardiac output change in Paget’s disease?
If disease is extensive within skeleton, a lot of CO can go into the bones instead of around the body
How can Paget’s diseas affect the tibia?
- Bowing
- Bone becomes osteomalacic - not mineralising properly
- Bone can’t respond to gravitational forces
- Looser’s zone fractures
Summarise what happens to the bone in Paget’s disease?
- Increased bone turnover
- Increase osteoblast and osteoclast activity
- Spreads around the body
- High alkaline phosphatase (making lots of osteoblasts)
- Normal calcium handling
- Bones get bigger and weaker
