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
What is oestrogen’s role in the slow loss versus fast phase?
Oestrogen deficiency is major cause of age related bone loss in both sexes, both slow and accelerated phases
Reversal of secondary hyperparathyroidism with oestrogen
What other conditions are associated with osteoporosis?
Pro-inflammatory such as liver disease
Cortisol excess such as Cushings
What post menopausal treatment can be used for osteoporosis?
• 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
What factors influence the pool of active osteoclasts?
Rank Ligand increases (stimulatory Glucocorticoids, PTH and prostaglandins and inhibitory TGFb) and OPG decreases (glucocorticoids and prostanglandins are inhibitory whilst OESTROGEN IS STIMULATORY, and TGFb)
What is the role of TNF alpha? Oestrogen
T cells produce effect through TNF-a and IL-1
Levels in bone marrow increased markedly in ovx mice
TNF-a KO mice do not develop bone loss on ovx.
IL-1R KO mice have reduced bone loss on ovx. (§
What does oestrogen deficiency do?
E2 Deficiency increases RANKL level in osteoblasts, but also in T and B cells
What evidence is there of denosumab’s effect?
Reduced vertebral fracture rate and hip fracture rate
What is the major anabolic system in bone? How? What is another important factor?
WNT, promote the formation of mature osteoblasts. IGF1 also important.
What signalling pathway does WNT use?
Wnt–β-catenin signaling pathway
What does WNT do?
Wnt binds to specific receptors, called frizzled, and to (LRP5 and LRP6). These interactions lead to the stabilization of β-catenin, which translocates to the nucleus and regulates gene expression (Figure 4)
How can the importance of the WNT be known? Evidence?
- LRP5 Mutations – inactivating cause low bone mass, fractures and idiopathic jeuveunile osteoporosis and osteoporosis pseudoglioma syndrome.
- Activating can cause high bone mass and no fractures (reduced DKK-1 and sclerostin binding so increased activation of Wnt)
What is a natural inhibitor of WNT?
sclerotin (from SOST gene) expressed by osteoblasts and osteocytes, prevent Wnt signaling by binding to LPR 5/6
What is a clinical condition involving sclerostin?
SCLEROSTEOSIS is due to mutations in the SOST gene leading to less sclerostin. Leads to overgrowth of skull bones, frontal bossing, mandible enlarged, facial nerve palsy and progressive hearing loss. Raised ICP may require surgery.
What is a milder phenotype of sclerosteosis?
A milder phenotype is Van Buchem Disease but carriers still have high BMD
What way can sclerostin be therapeutically targeted?
AMG, a monoclonal Ab against sclerostinincreases BMD in healthy women and men
What are another two actions of oestrogen?
- Inhibits osteoblast apoptosis
* Enhances osteoblast response to loading (ERα KO)
What actions does oestrogen have on sclerstin?
E2 replacement in the menopause is associated with a reduction in sclerostin
What is the only anabolic therapy currently available?
PTH (teriparatide) increases BMD at the spine and femur and decreases at the radius and decreases fracture rate.. Improves trabecular architecture.
What is the hypothesised mechanism of action of PTH?
PTH suppresses sclerostin at osteocyte level. • Interacts with WNT co receptor LRP6 and activates signalling PTH effect on bone gain is blunted in SOST KO mice
What is another therapy?
Cathepsin K inhibitor eg odanacatib
A protease that is responsible for the degradation of the bone matrix by osteoCLASTS (COLLAGEN)
What are bisphosphonates currently in use for?
Currently in use for osteoporosis, Paget’s, bone metastasies, multiple myeloma and hypercalcaemia of malignancy.
What is the absorption of bisphosphonates like?
ABSORPTION – very hydrophilic and thus are poorly absorbed from the GI tract. Half of the remainder goes to the skeleton and the other half to the urine without being metabolised.
What do bisphosphonates do?
reduce bone resorption and/or increase bone formation in order to reduce the risk of fractures
What are side effects of bisphosphonates?
SE are osteonecrosis of the jaw, pathological fractures and GI complaints and bone pain
How do bisphosphonates work?
Bisphosphonates, when attached to bone tissue, are “ingested” by osteoclasts and then induce APOPTOSIS
What do bisphosphonates with a nitrogen group do?
Those with a NITROGEN group bind to and inhibit the activity of FARNESYL PYROPHOSPHATE SYNTHASE which is key in the production of CHOLESTROL and other lipids. Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol and geranylgeraniol) that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see “lipid-anchored protein” for the principles of this phenomenon
How do bisphosphonates go to bone?
pyrophosphate crystals have a high affinity for bone mineral as they bind to hydroxyappetite crystals (retention depends on binding sites)
How do statins fit into bisphosphonates?
Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and thus are not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture (an indicator of osteoporosis) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment of osteoporosis remains controversial
Conversely what may bisphosphonates have an effect on?
Improving atherosclerosis
What is another drug that can be used?
strontium – to increase synthesis of bone and decrease resorption. it also inhibits blast apoptosis.
What is in HRT?
- Either natural (eg conjugated equine oestrogens) or synthetic (ethinyl oestradiol) but only natural are used
- Progestins are also used (including spironolactone derivatives) to stop the uterus lining from building up
- Different forms can be anti-glucocorticoid, mineralocorticoid and anti-androgen
What are benefits?
• Benefits – symptomatic relief, preventing osteoporosis, cardiovascular and neurocognitive
What cardiovascular benefit are there?
- Less cholesterol, less LDL, either less or more HDL and triglycerides and decreased lipoprotein A.
- Improves atrial function
What HRT routes are there?
oral, impregnated pessary/ring, percutaneous gel, subcutaneous implants, transdermal patches
What was a negative study for the risks of HRT?
Women’s health initiative but started long after women had finished the menopause
