Metabolic bone disease histopathology Flashcards
Functions of bone
STRUCTURE structure and shape to body MECHANICAL site for muscle attachment PROTECTIVE vital organs and bone marrow METABOLIC reserve of calcium
State the composition of bone
Outline what is contained in the metaphysis
Composition:
INORGANIC - 65%
- calcium hydroxyapatite (10Ca 6PO4 OH2)
- is storehouse for 99% of Ca in the body
- 85% of the phosphorous, 65% Na & Mg
ORGANIC - 35%
-bone cells and protein matrix
Metaphysis:
The region joining the diaphysis to the epiphysis is known as the Metapyhsis and during growth this will contain the cartilage structure known as the growth plate during and is the region in long bones that contains the bulk of the trabecular or cancellous bone.
What type of proteins in bone
collagen (Type 1 mostly with some type V) 10-20% water and ~5% non-collagenous protein & carbohydrate.
What can cause bone marrow failure
Certain cations rg radium strontium and lead are ‘bone seeking’. They can be radioactive or toxic and cause bone marrow failure.
What are condyles and trochlea
Condyles are knuckle shaped and a trochlea is grooved like a pulley
What type of bone on the outside of the shaft and the medullary region
Outside: cortical
Inside: bone marrow and trabecular bone
When do bones show in X ray
Bone has to be 50% mineralised to be seen on X-ray
Image on slide 7
The image shows a lytic poorly circumscribed lesion in the diaphysis which has eroded cortex and caused a periosteal reaction.
Classify cortical vs. cancellous
- Where
- % of skeleton
- Appendicular/axial
- % calciied
- function
finish
..1. Cortical=long bones
Cancellous= vertebrae and pelvis
- Cortical= 80% of skeleton, cancellous=20%
- Cort.=appendicular cancell=axial
- cort=80-90% calcifified, cancell=15-25% calcified
- Cort=mainly structural, mechanical, and protective
cancell=mainly metabolic and large SA
Classify types of anatomical bone
Flat (cranial/rib… protect organs), long (femur/tib… support weight and facilitate ovement), short/cupoid (carpals and tarsals, stabalise and facilitate movement), irregular (complex shape like the vertebrae or the pelvis. That allows them to protect a specific organ or set of organs), sesamoid (patella… protective function)
Mascroscopic classification of bone
Trabcular/cancellous/spongy
cortical/compact
Microscopic classification of bone
when do you get non-lamellar bone
Woven (immature)
Lamellar (mature)
Collagen fibres are laid down in a disorganized fashion: such as states of high bone turnover(Pagets disease of bone, certain stages of fluoride treatment, tumours) not so tightly packed, random bundles
Microanatomy of bone
How big are osteons
Outline the mechanosensory network in bone
Osteons=structured, circular layers of lamellar bone, centreed around harvesian canal containing blood vessels … 0.2mm diameter
Circumferential lamaellea near periosteum
Interstital lamellae in between the osteons
Trabecular lamellae not in circular layers, but still lamellar layers
Dendritic structures found in lacunae in the lamellae are bone cells called osteocytes and the processes from them are the osteocyte canalicular network that spans throughout the bone and is thought to form a mechanosensory network allowing the repair of damaged bone or remodeling of structure to respond to new stresses being place on a bone.
Differentiate lamallar vs woven bone.
When might one find woven bone
Not in layers, much weaker, collgen disorganised
Woven bone is most often found in the developing skeleton as the cartilage scaffold is first converted to bone, but can also be found in states of rapid grow, or high bone turnover.
Types of bone cell ….and what percentage of them are osteocytes
Which differentiate into what
Osteocytes= mechanosensory netweok embedded in mature bone… 90% of bone cells (t1/2=25 years!)
Osteoclasts=multinuclear cells that resorb bone.!! Haematopoietic lineage
Osteoblasts- produce osteoid to form new bone
OSTEOBLAST (produce osteoid around then, which becomes mineralised and then they form)–> OSTEOCYTE
OSTEOCLAST is of haematopoietic lineage
Outline the bone remodelling cycle
PHYSIOLOGICALLY, THEN when some bone is a bit damaged THEN during bone disease
PHYSIOLOGICA:
BALANCED osteoclastic bone resorption and osteoblastic bone formation…. these processes are also COUPLED through interactions: osteoblasts mediate osteoclast formation and activity by producing RANKL, M-CSF (MACROPHAGE colony stimulating factor, as osteoclast is a macrophage) and RANKL decoy receptor OPG.
Remodelling occurs when osteocytes sense damage, and also produce RANKL as they apoptose, actvating osteoclasts. These then resorb the old bone, and then die away once they have resorbed to the required depth. Then the reversal phase: osteoblasts are recruited to the site and form new bone with some being trapped to become new osteocytes.
Bone disease then occurs if the balance between osteoclastic resorbtion and osteoblastic bone formation is lost.
What do osteoclasts and osteoblasts look like on sldie 18
Osteolast is multinucleated , big
Osteoblasts cuboidal, more flat and on surface
Osteocyte sort of on their own, separate
Indications for bone biopsy
Evaluate bone pain or tenderness
Investigate an abnormality seen on X-ray
For bone tumour diagnosis (benign vs malignant)
To determine the cause of an unexplained infection
To evaluate therapy
Types of bone bopsy
Where is typical location for bone biopsy
CLOSED - needle, core bopsy (jamshidi needle)
OPEN- for sclerotic/inaccessible lesion (surgery)
Bone biopsy may be performed at any site of interest, but if the reason is general and not bone specific then the typical location would be a transilliac biopsy allowing a core sample with plenty of cortical and trabecular bone to study as shown here.
Types of histological stains
H&E (decalcified samples)
Masson-Goldner Trichrome (labels mineralised and unmineralised one)
Tetracycline/calcein leblling (for rate of bone turnover)
What is green on masson-goldner trichrome
How would this differ on osteomalacia
Green-mineralised bone
Orange-unmeralied osteoid recently produced by osteoblasts ….
In osteomalacia there would be more orange due to Ca2+ deficiency
Explain tetracycline labelling.
Green!
Admiistered, incorporated into mineralising front of osteoid currently being mineralised.
Administering it a second time allows us to determine much about the dynamic formation of bone in a patient.
1 line= was only forming bone at the time of 1 injection
2 lines= was forming bone at time of both injections
Distance b/w bone shows how much mineral accrued b/w the 2 injections= MINERAL APPOSITION RATE
Look at mineral apposition rate and quantity of bone surface labelled, to tell you BONE FORMATION RATE (how much bone formed in total in the sample)…
useful for determining if bone turnover is fast, or slow, or if there is a defect in mineralisation
What is metabolic bone disease
Conditions causing reduced bone mass and strength
Disordered bone turnover due to imbalance of various chemicals in the body (vitamins, hormones, minerals etc)
Cause altered bone cell activity, rate of mineralisation, or changes in bone structure
Give 3 main categories of metabolic bone disease
as well as
common metabolic bone diseases
MAIN TYPES
- Related to endocrine abnormality (Vit D; Parathyroid hormone)
- Non-endocrine (e.g. age related osteoporosis)
- Disuse osteopaenia
COMMON:
Osteoporosis
Osteomalacia/Rickets
Primary hyperparathyroidism
Renal osteodystrophy
Paget’s disease
Define osteoporosis
finish
BMD T score of -2.5 or lower (through DXA)
means that the patient has a BMD more than 2.5 standard deviations below the population mean BMD at peak bone mass
NOT compared to age, compared to average peak bone mass
Primary vs secondary osteoporosis
1º - age, post-menopause
2º - nutritional deficits, certain drugs, genetic conditions, and of course endocrine or metabolic disorders
2 types of osteoporosis
due to imbalance in bone remodelling meaning more resorption than formation:
High turnover- high osteoblastic formation but higher osteoclastic reabsorption
Low turnover- low osteoclast resorption, but lower osteblast bone formation
Where is most obvious impact of osteoporosis
TRABECULAR BONE
trabeculae tend to be thinner and less interconnected. This weakens the bone and as the osteoporosis progresses there will be a further loss of trabecular bone, the cortical bone will thin and you will see compression fractures in the spine, and low impact fragility fractures in the long bones.
Histology of osteoporotic bone
How could you determine if the osteoporosis is high turnover or low turnvoer
Masson- Goldner
the trabeculae are thinner and there are fewer than you would expect in normal bone and they will often be ‘free floating’ disconnected from any other bone.
Could then use tetracycline to determine if it is high or low turnover bone.
high turnover osteoporosis as you can see there are large areas of unmineralised osteoid in orange
(presumably unmineralised because bone also formed at a greater rate than it can be mineralised… but the resorption is still greater)
slide 35
What is osteomalacia
Defective mineralisation of newly synthesised bone
BOTH CALCIUMA ND PHOSPHATE comprise the bone mineral
2 types of osteomalacia
- Deficiency of vitamin D (causing hypocalcaemia)
2 Deficiency of PO4 (phosphate wasting)
What will histo look like in osteomalacia
Hardly any green… lots of unmineralised osteoid (orange)
As cannot mineralise the osteoid due to calcium deficiency
Why does vitamin D lead to osteomalacia
Symptoms of hypocalcaemia
We get vitamin D from sunlight exposure and in our diets. Activated Vitamin D acts to increase Calcium absorbtion in the intestine and re-absorbtion in the kidneys so increasing serum calcium levels.
Vit D deficiency from whatever cause results in increased parathyroid hormone (PTH) release and subsequent increased bone resorption.
Hypocalcaemia: muscle twitching, spasms, tingling and numbness…. most common cause it vit D defic.
Imaging on osteomalacia
Consequences of osteomalacia
X-ray of rickets
What are looser’s zone fractures
Insufficient calcium or phosphate to form the hydroxyapatite crystals necessary to mineralise bone. be observed histologically as the osteoid produced by the osteoblasts remains unmineralised and so orange on this Masson-Trichrome stain.
CONSEQUENCES: bone pain/tenderness fracture proximal weakness bone deformity
X-ray: widening of growth plate and bowing of long bones in leg
Looser’s zone: are pseudo-fractures at locations of high tensile stress, normally at right angles to the cortex and extending only part way through the bone
What happens in hyperparathyroidism
T/f there is reduced urinary excretion of calcium in primary HPT
What is osteitis fibrosa cystica
Excess PTH
F: increased Ca and PO4 excretion in urine
hypercalcaemia
hypophosphataemia
skeletal changes of osteitis fibrosa cystica (Resorption of bone and replacement with fibrous tissue and the formation of cysts like ‘brown tumours)
Which organs are affected by PTH
Differentiate calcitriol and PTH in terms of type effect on phosphate and calcium
What happens to ca2+ and phopshate in primary hyperpara.
Parathyroid glands
Bones
Kidneys
Proximal small intestine
PTH increases Ca2+ absorption and PO4 excretion
Calcitriol increases absorption of bot Ca2+ and Po4
Normally the serum calcium acts to reduce PTH, but when this feedback mechanism is lost in primary HPT the result is hypercalcemia and hypophosphatemia.
Types of hyperparathyroidism
1º -
parathyroid adenoma (85-90%)
chief cell hyperplasia
2º -
chronic renal deficiency
vit D deficiency
(i.e. just increases as there’s low vitamin D…)
Symptoms of hyperparathyroidism
Stones (Ca oxalate renal stones)
Bones (osteitis fibrosa cystica, bone resorption)
Abdominal groans (acute pancreatitis)
Psychic moans (psychosis & depression)
Bone lesions in hyperparathyroidism
Earliest: Sub periosteal erosions
Tunnel erosions (osteoclasts penetrate the middle of the trabeculae and resorb a central channel)
What are brown cell tumours
extensive resorption causes lytic bone lesions with reparative tissue called giant cell reparative granuloma. Because the giant cells are often associated with extravasated red blood cells and their brown hemosiderin breakdown products, these tumors have been known as brown tumors
ZONAL pattern distinguishes this lesion from other giant cell containing neoplasms. In addition, giant cell reparative granulomas are not localized to the ends of long bones as are conventional giant cell tumors of bone.
…
….
What is renal osteodystrophy
Comprises all the skeletal changes of chronic renal disease:-
- Increased bone resorption (osteitis fibrosa cystica.. due to vit D def. due to chronic renal disease causing secondary HPT)
- Osteomalacia (due to hypocalcaemia due to insufficient vit D)
- Osteosclerosis
- Growth retardation
- Osteoporosis
Cuases of renal osteosydrophy
Consequences of chronic renal disease:-
PO4 retention – hyperphosphataemia
Hypocalcaemia as a result of ↓vit D
2o hyperparathyroidism
Metabolic acidosis
Aluminium deposition
3 stages of paget’s disease and how can this disease be described
FOCAL disorder of BONE TURNOVER
- Osteolytic
- Osteolytic-osteosclerotic
- Quiescent osteosclerotic
Onset, proportion of mono-ostotic vs polyostotic
Onset > 40y (affects 3% Caucasians > 55y) M=F Rare in Asians and Africans Mono-ostotic 15% Remainder polyostotic
Cause of paget’s
Aetiology is unknown
Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutations in SQSTM1 or RANK)
Parvomyxovirus type particles have been seen on EM in Pagetic bone (doubt.. probably not.. was probs contamination)
Overuse of previous bone injury
Symptoms of paget’s disease
pain
microfractures
nerve compression (incl. Spinal N and cord)
skull changes
may put medulla at risk
deafness
+/-
haemodynamic changes,
cardiac failure
hypercalcaemia
Development of sarcoma in area of involvement 1%
Histology of paget’s
Here we see images of a patient diagnosed with Paget’s disease. (A) AP radiograph of the left proximal femur shows increased width of the femoral shaft, markedly thickened cortices, coarse but disorganized trabeculae, and small lytic areas within the medullary canal. (B) The photomicrograph illustrates the active phase of Paget’s disease with numerous trabeculae undergoing resorption by osteoclasts (arrows) and a thin layer of surface-related osteoblasts (arrowheads). Subsequent osteoblastic activity results in cement lines and the “mosaic” pattern apparent in sclerotic phases (Stain, hematoxylin and eosin; original magnification, ×10).
Where is pagets most likely to occur
Tib, femur, pelvis, humerus, vertebrae, skull
What is OPG exactly
OPG is a receptor. It competes with RANK for RANKL binding. When it is bound to RANKL, RANK cannot bind to it, so osteocytes cannot mature and thus there is reduced bone resorbsorption
OPG is synthesised in response to oestrogen…. this is lost in the menopause so more RANKL binds RANK and more osteoclasts are activated and more resorption
There is up-regulation of RANK ligand that may occur in response to many stimuli (e.g. infection, trauma etc.).
