Bone Remodeling and Osteoporosis Flashcards
What is cortical bone?
Compact bone found at diaphysis of long bones
What is trabecular bone?
Spongy bone that makes up vertebral bodies and end of long bones
Is cortical or trabecular bone remodelled quicker?
Trabecular
What are the bone cell types and their function?
- Osteocytes: Mature osteoblast, sensors of mechanical strain on skeleton embedded in bone matrix
- Osteoblasts: bone forming
- Osteoclasts: bone removing
What phases can the remodelling of bone be put into?
- Quiescence
- Resorption
- Reversal
- Formation
How long can the remodelling cycle last?
around 6 months
What cells are osteoclasts and osteoblasts derived from?
- Osteoclasts = cells of monocyte/macrophage lineage
- Osteoblasts = derived from mesenchymal stem cells
What are osteoclasts rich in?
TRAP enzymes
What type of cell are osteoclasts?
Multinucleated phagocytes
What are molecules important in regulation of osteoclast differentiation and activity?
- Transcription factor PU-1
- M-Csf
- C-fos
- Nuclear factor kappa B
- RANK and RANK ligand
- OPG
What does PU-1 do?
Needed for differentiation of early osteoclast precursors from haematopoetic stem cells.
What does RANK and RANK ligand do?
- Stimulate activity of osteoclasts
- Influence later stages of osteoclastogenesis by promoting differentiation oof comitted precursors to mature osteoclasts
What does OPG do?
Inhibit osteoclast formation and activity by binding to RANK ligand.
What expresses OPG?
Osteoblasts, marrow stromal cells and others.
How does resorption occur?
- Occurs through HCL and proteolytic enzyme secretion.
- Acid dissolves hydroyapatite, allowing enzymes to degrade collagen and other matrix proteins.
What are some important molecules in bone resorption?
- Carbonic anhydrase II needed for acid generation
- Cathepsin K a proteolitic enyme needed for resorption
What is cbfa 1?
The key trigger for osteoblasts.
-Is a trnascription factor that expresses genes characteristic of osteoblast phenotype eg. osteocalcin, type 1 collagen, alkaline phosphatase
What are some molecules important in controlling osteoblast proliferation and differentiation?
-PTH, glucocorticoids, Wnt, IGF, FGF
Define osteoperosis?
A skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fatigue.
What does bone strength reflect?
The integration of bone density and bone quality.
Why and how is OPG produced?
Produced naturally to neutralise RANK effects, to defend against bone loss.
How is RANK expressed?
Several factors (PTH, TNF, IL 1) stimulate expression by cells of osteoblast lineage (activated T cell).
Do osteotropic growth factors, cytokines and hormones up or down regulate RANK expression?
Upregulate.
In premenopausal state what regulates RANK ligand expression?
Estrogen
How is bone fully mineralised?
After basic structural matrix is formed a secondary mineralisation process starts which is much slower.
How do bones and bone mineral acquisition change during puberty?
- Mineral aquisition increases
- Spine increases in size and trabecular thickness
- Long bones increase in length and diameter
When do we attain peak bone mass?
Around 30-40
What are some determinants of peak bone mass?
- Lifestyle
- Genetics
- Nutrition
- Hormones
How does bone mass change after peak in men and women?
Men = steady decline -Women = accelerated decrease post menopause, can often drop below fracture threshold
Why is estrogen important?
-Needed for normal bone maturation and mineral acquisition
-Can modulate expression of factors that stimulate osteoclast formation.
Deficiency can negtively influence OPG.
What are some risk factors for Osteopoorotic fractures?
- Age
- Hypogonadism
- Smoking
- Excessive alcohol
- Menopause
- Malabsorption syndrome
- Rheumatoid
- Family history
What are determinats of fracture risk?
- Bone strength
- Extraskeletal conditions: propensity to fall and fall conditions
What is the DXA system used fro?
Bone strenght measutremnt by estimateing BMD.
What can T scores indicate?
- Normal is -1 or above
- Osteopenia is -1 to -2.5
- Osteoporosis is less or equal to than -2.5
- Established osteoporosis is less than oor equal to -2.5 with prescnece of 1 or more fractures
What can the FRAX tool do?
Predict future fracture risk.
What are non pharmaceutical ways to decrease fracture risk?
- Lifestyle changes
- Reduce fall risks
- Hip protectors
When are pharmaceutical ways to decrease fracture risk often used?
In post menopause osteoporosis patients for whom non pharmaceutical methods have not worked.
What are pharmaceutical ways to decrease fracture risk?
- Ca and Vit D supplementation
- HRT
- SERM’s
- Romosozumab
- Strontium ranalate
How do we know if our treatment is working for this?
- Fewer fractures
- Bone density (DXA) measurement
- Use of bone markers
What are the initial effects of mechanical stress/micro crack?
-Before crack, quiescent surface with embedded osteocytes secreting sclerostin to inhibit Wnt.
Pre osteoclasts circulating in blood vessel
-Sudden stress causes microcrack
-Causes osteocytes near crack to apoptose
What happens after osteocytes apoptose in micro crack?
- Stromal cells released from sclerostin inhibition and/or exposed to other factors eg. IL 1.
- They generate pre osteoblasts
- Also secrete M-Csf to help generate pre osteo clasts
- Lining cells pull away from bone matrix to form a canopy that merges with blood vessels.
What happens after canopy forms after micro crack?
-Pre osteoblasts start to express RANK ligand on their surfaces.
-Pre osteoclasts have receptors on their surfaces
-Pre osteoblasts proliferate and secrete more factors eg. Wnt
-Pre osteoclasts enlarge and fuse into mature osteoclasts
-Osteoclasts bind to bone matrix with integrins.
They resorb bone, takes around 2 weeks. Bone derived growth factors are released eg. IGF, TGF B.
What happens after bone resorption after micro crack?
- Eventually osteoclast apoptoses, lifespan regulated by estrogen and other factors.
- Pre osteoblasts mature and stop making RANK ligand and secrete OPG. Blocking activation of pre osteoclasts.
- Pre osteoblasts proliferate linng cavity. They secrete osteoid then mineralise it, filling cavity takes 3-4 months.
What happens after osteoblasts proliferate and line cavity after micro crack?
- Some osteoblasts apoptose, others turn into osteocytes, others become lining cells.
- Meanwhile, osteocytes have been re-establishing network with each other and lining cells.
- Microdamage repaired
How long will new matrix continue to accumulate mineral and increase in density for?
3 years
What other proteins and growth factors are in the matrix?
- IGF
- TGF B
