BONES AND OSTEOPOROSIS Flashcards
What is a definition of osteoporosis? The Who score
A skeletal disease characterised by low bone mass and microarchitecture deterioration in bone tissue leading to bone fragility and increased fracture risk.
WHO definied as T score (number of SD below young adult reference range). <-2.5 is osteoporosis. Imaged QCT.
What are the properties of bond?
collagen, cross linking, advanced glycation end products and cross link isomerization. Macro and micro architecture.
What is a good determinant of osteoporosis
Peak bone mass that has many influences such as genetics, exercise, milk consumption in childhood
What is the difference between male and female bone deposition?
Boys mainly deposition periosteally with resorption medullary whereas in women most deposition occurs endosteally.
What is milk avoidance associated with (3)
Increased rate of childhood fractures
Decreased peak bone mass
Increased adult fractures
What is worth noting about calcium and vitamin D
Small RCTS with supplementation for calcium show small effects that do not persist and vitamin D show little effect
What bone loss occurs from puberty/ menopause? And the type that all older men and women get 3?
Puberty - trabecular
Menopause - cortical (CANCELLOUS, UP TO 30% IN 4-8 YEARS)
2) Asymptomatic indefinite slow loss of mainly cortical bone due to SECONDARY HYPERPARATHYROIDISM (kidney function decreases with time). This is because there is increased renal calcium losses, reduced intestinal calcium uptake and low vitamin D levels in the older population. (Elderly need 0.5g of calcium extra to 2mg daily to prevent this)
What are the changes in oestrogen that occur after menopause?
• Sources of Oestrogen – 1: 17b oestradiol (E2) – is the main form pre-menopausally and is secreted from the ovaries, E1 (oestrone) is 4x less active and is converted from adrenal androgen peripherally by aromatase enzyme, main post menopause despite 70% reduction in levels.
What are four changes that occur in menopause?
- 1)Increased activation frequency of bone remodelling units. This increases osteoclast formation and decreases apoptosis. More bone surfaces involved and prolonged resorption phase. Increased osteoblast apoptosis
- 2) Causes remodelling imbalance – increased bone resorption (90%) but less bone formation (45%)
- 3) Remodelling errors: trabecular perforation, excess Haversian excavation and porosity
- 4) Decreased osteocyte sensing
What is the main form of male oestrogen?
1) Aromatization of testosterone from testes 20%
2) Aromatization of DHEA from adrenal in peripheral tissues is 80%
What happens to male testosterone levels?
They drop 1% each year also because SHBG levels rise
What is necessary for to maintain male bone patterns? EVIDENCE
Male ER alpha mutants have osteoporosis and delayed epiphyseal fusion despite normal oestrogen and testosterone levels. Bone mass density in elderly men correlates with oestrogen levels not testosterone. Evidence from giving GnRH agonists, aromatase inhibitors, Oestrogen and testosterone patches
What happens when a microcrack forms?
local factors form lining cells and Osteocyte apoptosis→osteoclasts→ osteoblasts→new lining cells and osteocytes
Where do osteoclasts come from? How are they activated?
Osteoclasts are differentiated from haemopoietic stem cells. Become activate when osteoblast/ stromal cell’s RANK LIGAND binds to the osteoCLAST’S RANK RECEPTOR. OPG from OSTEOBLAST is a down regulator that stops RANK from being activated.
How else can the Rank ligand be activated?
Multiple pathways converge: 25(OH2)D3, adrenalin and noradrenaline through cAMP, PKA and inflammatory cytokines.
What experimental evidence is there for the importance of RANK? What is an equivalent human condition?
In a mouse KO of rank ligand there is osteopetrosis (too high BMD) and growth failure since osteoclasts are inhibited. Lack bone marrow cavity and there is extramedullary haematopoiesis. Disruption of epiphyseal growth plates, shortened club shaped long bones.
Less OPG – Juveunile Paget’s Disease
Increased RANK – familial expansile osteolysis, early onset paget’s disease and expansile skeletal hyperphosphatasia. Excesssive osteoclast activity causing OSTEOLYTIC AND SCLEROTIC AREAS. Can get cranial nerve impingement.
What is oestrogen’s main activities?
- Promotes mesenchymal differentiation into osteoblast lineage, promotes pre-osteoblast differenetiation and inhibits osteoblast apoptosis
- Associated with a reduction in sclerostin
What happens in oestrogen deficiency?
- Increases Rank Ligand levels in OSTEOBLASTS, also b and t cells, via ER alpha. This leads to decreased OPG
- Menopause – proinflammatory: T cells produce TNF alpha, IL1 and oestrogen regulates T cell activation. TNFa causes increased differentiation of osteoclasts from osteoblase precursors. IL1 leads to activation of these osteoblasts
- Secondary osteoporosis is common in pro inflammatory states, liver disease
- TREATMENT: OPG infusions/stimulators and Rank L inhibitors. Eg DENOSUMAB binds to Rank Ligand with high affinity and specificity and thus inhibits rank ligand action. Studies that show increases BMD
Why is peak bone mass important?
An increase in peak bone mass of 10% will delay the onset of osteoporosis by 13 years
What creates peak bone mass? When is it established?
Bone modeling during growth shapes bone
and creates peak bone mass. Like height it is established during first 2 years of life
What is a big determinant of peak bone mass?
Race
What does vitamin D do?
Drive calcium absorbtion
What are the effects of HRT?
E2 acts on extraskeletal calcium homeostasis
E2 replacement in menopause:
increases PTH-independent renal Ca resorption
increases 1,25 Vit D levels
increases intestinal Ca absorption
reverses secondary hyperparathyroidism
