WEEK 4 - MINI LECTURES - OSTEOPOROSIS Flashcards
What are the short terms of decrease calcium in extracellular fluid
- increase Na+ permeability of cells
- leads to partial depolarisation which in turn leads to muscle spasm tetany and pins and needles and seizures
What are the short term effects of increase calcium concentration in ECF
- decrease Na+ permeability of cells
- hyperpolariation -> neurolgical dysfunciton, cardiac arrythmias, constipation, anorexia, nausea -> dehydration
- long term effects induce diuresis -> Dehydration
Normal range of serum inorganic phosphate
0.8-1.4 mmol/L
High PO4 in the long term
Soft tiussue mineral deposition
Low PO4 in the long term
Inadequate bone mineralisation
Three systems involved in calcium homeostasis
- gut
- kidney
- bone
Role of bone in caclium homeostasis (2)
- structural requirement for hydroxyapaetite laying -> gives comrpessive strength
- alternative store: release in blood to make up for daily losses
Parathyroid hormone
- Peptide
- released from parathyroid glands
Can be synthesized by Vit D precursor
What triggers the release of PTH
- low Ca2+ via calcium sensing receptor
What inhibits the release of PTH
- calcitriol
- high Ca2+
Sources of Vit D
- sun exposure is the main source
- Diet as a minor source: fatty fish, meat, liver, eggs, fortified food
- supplements: 1000 daily
Vitamin D metabolism
7 dehydrocholesterol -> Vit D -> 25(OH) vit D -> 1.25(OH)2D (= calcitriol)
- the last conversion is promoted by PTH, low Ca 2+, low PO43-, growth and pregnancy mainly by kidney and other tissues
Groups at high risk of Vit D deficiency
- old people in hospital or care
- dark skinned people
- infants of motherswith low vit D are at risk of rickets
- ## chronically ill individuals
FGF 23
- produced predominantly in bone by osteocytes
- also produced by rare tumours
- acts predominantly in kidneys: increase phosphate wasting, decrease calcitriol production and increase calcitriol degradation
FGF23 production is stimulated by
- calcitriol
- PTH
- high phosphate
Calcitonin
- inhibits bone resorption
- peptide
- produced by parafollicular cells
What promotes the release of calcitonin
- gastric hormones
- pentagastrin
- increase Ca2+
Gut: role in mineral homeostasis
- ingestes calcium and phosphate
- absorb Ca2+ passively or actively ( when stimulated by calcitriol)
- main function of calcitriol is to acquire Ca 2+ and PO4 from food for bone mineral
- Vit D role: acquire calcium and phosphate from food
Bone: role in mineral homeostasois
- calcium and phosphate required for bone mineral and compressive strength
- acts as a store of cacium and phosphate in bone turnover
Short term release of calcium from bone
- increased by PTH and calcitriol
- inhibition of release by calcitonin
Kidney: role in mineral homeostasis
- modulate Ca 2+ and PO4 losses
- calcium filtration and reabsorption by PTH
- filter PO4 and reabsorb
- PTH: reduces PO4 reapsorption and causes dumping of PO4 in urine
- PTH also increases calcitriol production
Summary: 2 role of gut
- increase Ca 2+ abosrption
- increase PO4 absorption
- both of these effects are induced by calcitriol
SUMMARY: kidney role
- low blood calcium -> increase PTH
- PTH Acts on kidney
- increase calcitriol
- conserve Ca 2+
- dump PO4 in urine
Bone SUMMARY
- PTH increases resorption
- stimulates release of Ca2+
- stimulates release of PO4
Low blood phosphate mechanism
- sensed directly by kidney -> increase calcitriol production
- calcitriol acts on gut to increase PO4 absorption and on bone to increase resorption
- calcitriol also modulates PO4 losses in kidney
Affect of changes in hormones
- high PTH
- Low PTH
- High FGF23
- mild- mod low vitD
- severe low Vit D
- hypercalcemia
- hypocalcemia
- hypophosphatemia (RARE)
- increase in PTH which maintains blood ca for some time at the expense of bone resorption
- cant resorb bone anymore -> osteomalacia and rickets
Bone mass determinants
- genetics
- age
- mechanical loading
- mineral balance: vit D, PTH, Sex steroids
- balance between rate of bone resorption and rate of bone formation
Contributors to fracture risk
- bone mass (density)
- measured usually with DEXA
- T-score: bone mineral density less than 2.5SF below young normal mean - osteoporosis
- bone quality
Bone gometry - propensity to fall
- loss of horizontal struts
Minimum requirements for bone health
- adequate exercise
- adequate calcium intake
- adequate vit D
- normal sex steroids
- avoid smoking, excess alcohol, glucocoricoids
Adequate exercise
- mechanical loading -> resistance to deformity
- large changes at low activity levels
- gravity, weight bearing exercises
Regulation of bone mass by osteocytes and sclerostin
- osteocytes is 90% of bone cells
- secrete sclerostin - negative regulator of bone mass
- with deformity of bone - sclerostin secretion decreases
Wnt pathway in bone
- Wnt 3b secreted by bone cells
- when binds to receptor, inhibits GSK3b -> b catenin is freed from complex APC -> goes to nucleus -> acts on TF to stimulate bone cell and proliferation
- Wnt Signalling inhibited by Sclerostin -> b catenin is targetted for defradation
Adequate Vit D
- needed to absorb clacium from diet, to mineralize bone and for normal muscle function
- D3: cholecalciferol - animal sources
- D2: ergocaciferol: plant sources
Mild-moderate deficiency in Vit D
- increased. PTH
- increased bone resorption, decreae bone density
- impaired muscle function and increased risk of falls and fracture
Severe deficiency in but D
- gut calcium absorption impaired
- a lot of increase in PTH
- bone resorption impaired, no capacity to increase gut calcium or phosphate absorption
- phosphate loss in urine
- insufficient calcium and phosphare -> impaired bone mineralisation -> rickets and osteomalacia, impaired muscle function
Intermittent PTH stimulates bone formation
- main effect is on osteoblasts
- anabolic effect on bone
- unclear why, but suppresses sclerostin and stimulation of Wnt pathway
Sex steroids: estrogens, androgens
- help to maintain normal balance between bone formation and resorption
- help to keep bone cells alive
- estrogen are probably important in men as well
- androgens give men bigger, more mechanically strong bones
Actions of estrogens in bone
- reduce osteoclast generation and lifespan
- reduces rates of bone turnover
- promote coupling
- some evidence of increase formation
- keep osteoblasts and osteocytes alive longer
Glucocorticoids effects
- decrease calcium absorption in gut
- increase calcium loss in kidney
- decrease osteoblast and osteocyte viability in bone
Non modifiable risk factor for fracture
- advanced age
- female gender
- prevalent fractrures
- bad genes
- early menopause
- past comorbidity
- disability
Most important risk factor for fracture
- previous fractures
Modifiable risk factors for fracture
- life style and nutrition
- low bone mass
- high bone turnover
- high fall propensity
- treatable comorbidities
- bone adverse medicatin
T score
- comapred to mean peak bone mass
- used to assess fracture risk
Z score
- compared to age and gender matched congtrols
- used to assess what is expected
When is a bone density scan recomeded?
- in any person with a minimal trauma fracture
- in any person with significant risk factors for bone loss without a fracrture
Clinical examination of osteoporosis:
- early stages are asymptomatic
- late stages: complication and fracture
- severe acute or chronic back pain
- loss of height, stooped posture
- cardiovascular and respiratory complications
Thoracolumbar spine examination
- change in posture, height loss
- thoracic kyphosis
- abdominal distension
- lower ribs to pelvis distance
- para-spinal skin folds
- localised tenderness
- spinal mobility
Balance and risk of falling
- neuro-muscular examination
- sarcopenia, proprioception
- time-up-and-go
- gait and tandem speed
- visual acuity
- mini mental state
Laboratory investigations to exclude secondary causes
- ESR: exclude muyeloma
- C,P, M: look for problems with homeostasis metabolism
- Creatinine for renal function
- 25OH Vit D
- TFT
- urine: calcium, phosphate, creatinine
Management strategy
- analgesia -> physiotherapy -> life style changes -> Fall prevention -> calcium balance -> Vit D sufficiency -> pharmacotherapy
Non pharmaological management
- weight bearing exercise programs improve muscle strength, mobility, balance, bone density, future fracture risk
Calcium supplement effect
- decrease PTH secretion
- decrease bone resorption
Calcium and Vit D supplement and fracture risk
- each individually has no effect on fracture risk
- in combination can decrease fracture risk by 12%
Pharmacotherapy: Inhibitors of bone resorption
- SERM
- Biphosphonates
- Strontium Ranelate
- RANKL inhibitors
Specific pharmacotherapy: Stimulators of bone formation
- PTH
Effect of oral biphosphonates on incidence of vertebral fracture risk
- risk reduction of 50-60% for vertebral fractures
- 20-40% for non vertebral fractures
Persistence with oral anti-osteoporosis treatment is generally poor
- 50% after 1 year
- 40% after 2 years
- 20-35% after 5 years
- if miss half of the dose, its the same thing as not taking it
- solution is a non oral treatment
The true problem: we dont treat patients with osteoporosis
- 70% of patients who have suffered an osteoporotic fracture go untreated
- 30-50% of these patients fracture again, usually within 3-5 years: domino effect
- all osteoporotic fractures are associated with increased morbidity and excess mortality
