Calcium Phosphate Regulation Flashcards
describe the structural requirements of bone and how they’re met
needs to be both strong and flexible
80% cortical: outer layer of all bones, bulk of inner part of long bones dense tissue containing…
- bone mineral, ECM, blood vessels, canaliculi
20% trabecular: interior of bones, prominent in vertebral bodies
- always undergoing remodeling
- helps maintain structural integrity of bone AND maintain Ca/PO4 levels
hydroxyapatite: components and why they don’t combine anywhere else
storage form of bone salts: Ca and PO4
- both are found in plasma at saturated levels but dont precipitate anywhere except bone due to PYROPHOSPHATE
roles of osteoblasts, osteoclasts, and osteocytes
osteoclasts: large multinucleate cells concentrated around growth surfaces
- secrete acids to dissolve bone mineral, proteolytic enzymes to hyrolyze matrix proteins
- phagocytize micro particles of bone osteoblasts: bone deposition overseers
osteoblasts
- generate mineralized bone from Ca + PO4
- promote prolif of osteoclast precursors…
- produce RANKL
- stimulates diff of preosteoclasts into osteoclasts AND upregs osteoclast activity
- produce osteoprotegerin: RANKL-binder which keeps a leash on RANKL availability
osteocytes: derived from osteoblasts, communicate with each other/bone surface via dendritic processes that also sense bone shear stress
- orchestrate cycles of rabs and deposition
what mechanisms/actors regulate plasma Ca?
concerted actions of
- parathyroid hormone (PTH)
- 1, 25 dihydroxy vitamin D3 (calcitriol)
what is the normal range for plasma Ca? what forms of Ca does this measurement include?
normal blood Ca: 9-10.3 mg/dl
measured Ca includes…
- ionized Ca [bioavailable] - 45%
- Ca bound to albumin - majority
what is the relationship between hypoalbuminemia and Ca measurement?
how should you adjust your interpretation of Ca measurement in light of hypoalbuminema?
hypoalbuminemia is the most common reason for decrease in total blood Ca
in hypoalbuminemia, a larger proportion of the Ca measured is in the ionized/bioavailable form than in a healthy pt
THEREFORE…
- need to use a correction factor to account for the difference
- increase Ca by .8 for every 1 mg drop in albumin
describe the mechanisms/actors that affect PO4 concentration in blood?
- PTH
- calcitriol
- FGF23
target proximal tubules and affect phosphate reabs/excretion
what is the normal range for plasma PO4?
normal range = 2-3.5 mg/dl
where does parathyroid hormone come from? what is its function and how does it accomplish it?
- secreted by parathyroid chief cells
- fx: increase plasma Ca, lower plasma PO4
how??? direct and indirect (via calcitriol)
- increases PO4 excretion in prox tubule
- increases Ca reabs in distal tubule
- increases expression of renal CYP27B1
- catalyzes production of calcitriol (1, 25 dihydroxy vitamin D3)
- in turn stimulates small intestine Ca uptake AND augments distal nephron Ca reabs
- catalyzes production of calcitriol (1, 25 dihydroxy vitamin D3)
- also impacts bone resorption
describe the effects of chronic PTH elevation
leads to bone resorption
- stimulates osteoblasts via PTH receptors (blasts have, clasts do not)
- also causes osteoblast secretion of
- proteases to digest bone matrix
- cytokines to promose osteoclast diff and activity
- impairs collagen synthesis by osteocytes
rapid (osteolysis) and slow (osteoclas digestion of bone matrix tissue) phases
rapid and slow phases of bone resorption
[what condition does bone resorption stem from]
chronic PTH elevation = bone resorption
rapid phase aka osteolysis {PTH and calcitriol both involved)
- removal of hydroxyapatite from bone matrix and surface
- activation of Ca pumps that can mediate absorption from bone
slow phase
- osteoclasts (interacting with osteoblasts) mediate enzymatic digestion of bone matrix –> free up Ca
describe the effects of an acute elevation in PTH
bone deposition
- increase in osteoblast proliferation
- blocks apoptosis in osteoblasts
- up regulates Ca channel activity in osteocytes
- allows for transfer from cytes to blasts, which pump them into matrix = bone deposition!!
what is CaSR?
what is the action of CaSR in conditions of normal/elevated Ca?
Ca Sensing Receptors
- tonically impair PTH secretion and parathyroid cell prolif
what is the action of CaSR in conditions of low Ca?
- production/release of PTH
- upregulates vit D receptor (VDR) in chief cells
- in turn, calcitriol upregulates CaSR! cyclical
list the roles of CaSR in the kidney
- downreg CYP27B1 activity
- downreg calcitriol production
- mediate aspects of cation transport which affect:
- JG cell fx (renin secretion)
- urine conentrating mechs
- urine acidification
how is calcitriol synthesized?
inactive precursors made on 15+ min exposure to sun
precursors are converted to 1,25 dihydroxy vitamin D3 in presecence of CYP27B1 (in kidney) = calcitriol!!!
main stimulus: PTH (associated with CYP27 expression in kidney)
what are the main functions of calcitriol?
how does calcitriol fulfill these functions?
maintain plasma calcium and phosphate
- stimulates bone resorption
- releases Ca and PO4
- stimulates reabs of Ca
- independent in prox nephron
- augments PTH stimulus of Ca reabs in distal nephron
- prevents excretion of PO4
- blocks action of PTH on PO4 excretion in prox tubule
- stimulates uptake of Ca and PO4 from small intestine
- can block PTH secretion - mostly likely mediated by FGF23 (fibroblast growth factor 23)
calcitonin : origin and function
- secreted by parafollicular cells of thyroid gland
- aka C cells
- no certain physio fx in adults
- can block Ca reabs
- can impair osteoclast activity, formation of new osteoclasts/diff of new osteoblasts
FGF23 : origin and effects
major determinant of PO4 homeostasis
- secreted by osteocytes in response to hyperphosphatemia and/or calcitriol
- dependent on coreceptor Klotho to bind to and activate FGFR
lowers plasma phosphate
- knocks out CYP27 expression in nephron: blocks new calcitriol formation
- upreg 24-hydroxylase : breaks existing calcitriol down into inactive components
- inhibit NaPi2a and NaPi2c in prox tubule (PO4 reabs channels) : decreases PO4 reabs
- impair PTH secretion : knock out bone resorption
- FGF is also likely the middleman in the effects of E2 (estradiol 17beta) in knocking out bone resorption
what are some of the risks of chronic FGF23 elevation?
evidence in rats: chronically elevated FGF23 linked to LVH
hypertensive rats with elevated FGF23 have LVH…block the FGFR and they stay hypertensive but LOSE LVH!!
potential mechanism:
- might shift metabolism from use of FFA to glucose [stress condition metabolism]
how might FGF23 (and conditions stemming from elevated FGF23) become involved in individuals with chronic kidney disease?
chronic kidney disease - cant reabs Ca - PTH secreted - can’t make calcitriol - no way to block PTH secretion….
secondary hyperparathyroidism (hypocalcemia, hyperphosphatemia)
FGF23 is secreted in response to hyperphosphatemia…so could get elevated FGF23 in chronic kidney disease…and the LVH that comes with it
describe the effects of estradiol17beta (E2) on bone growth and bone density
overall: prevent osteoclast mediated resorption AND bolsters Ca uptake
- in duodenum: upreg VDR, increases Ca reabs
- in bone, E2 hits ERalpha to…
- stimulate longitudinal bone growth
- also terminates this by induing epiphysial closure over time
- downreg clasts and upreg blasts
- impairs clast differentiation and RANKL synthesis
- promotes clast apop
- promotes blast diff
- promotes osteoprotegerin production [binds RANKL up, prevents its action]
- cytes
- prevent apoptosis of cytes
- trigger release of TGFbeta, which blocks clast differentiation
- stimulate longitudinal bone growth
what is the effect of androgens (testosterone, DHT) on bone growth and density?
associated with increases in bone growth and density BUT unknown whether effects are direct
POTENTIAL MECHANISM:
testosterone can be converted to E2 via aromatase in many tissues….the effects seen might be accounted to E2
evidence: total E2 deficiency men with normal test levels have severe osteopenia
* when given E2 exogenously, get bone growth and epiphyseal closure
what are some factors that can increase bone density and strength?
- E2
- testosterone, DHT (direct or indirect…? possibly indirect through conversion to E2)
- biomechanical stress due to effects of androgens on body mass
describe the effects of glucocorticoids on bone
enhance bone resorption through a few avenues (bone, sk muscle, kidneys, sm intestines, inhibition of estrogen/androgen production)
Ca Balance
- kidneys: impairs Ca reabs
- sm intestine: impairs Ca abs
Skeletal Muscle
- drives catabolism = lower ability to perform load bearing/bone building exercises = loss of potential bone growth
Bone (blasts, clasts, cytes all express GRalpha and GRbeta)
- blasts/cytes: upregulate apoptosis
- clasts: extend lifespan
- promote RANKL production, which promotes osteoclast activity
where/how are GH and IGF1 synthesized? where do they have their effects?
growth hormone
- synthesized in ant pituitary (variety of endocrine/metabolic factors)
insulin-like growth factor 1
- mostly synthesized in liver in response to GH
- also expressed in osteocytes and chondrocytes
what are the effects of GH and/or IGF1 on bone growth?
late adolescence/early adulthood:
stimulate longitudinal bone growth
- chondrocytes: mitogenic effects in epiphyseal cartilage AND stimulates local IGF1
- osteocytes: GH stimulates IGF1 and promotes mineralization
- GH/IGF1 also regulate modeling/remodeling of trabecular and cortical bone throughout life
***anabolic effects of GH depend on IGF1
what are the effects of thyroid hormone on bone growth?
two avenues. TH has…
- stimulatory action on GH and IGF1
- regulatory role with cohort of genes involved in mediating bone remodeling
- affects both blasts and clasts
describe the effects of:
- childhood hypothyroidism
- childhood hyperthyroidism
- adult hyperthyroidism
- childhood hypothyroidism
- blunted bone growth
- childhood hyperthyroidism
- accelerated bone growth
- adult hyperthyroidism
- increased mineralization leading to increased resorption!
- loss of trabecular bone thickness
- increased porosity
- dimished cortical bone thickness
describe the general pattern of bone density during normal lifespan
peaks around 16-17
little drop in 30s, plateaus for a decade or more
then decreases?
osteoporosis: definition
wasting of the bone matrix associated with age-dependent drop in E2 (and maybe androgen…though androgen effects prob mediated by E2…) production
why is there a decrease in E2/androgen production in elderly men and women?
women: menopause = loss of ovarian fx - decline in bioavailable E2
men: andropause = decreased androgen production
hallmark sign of osteoporosis
bone demineralization –> decreased bone density in spine, hip, pelvis, wrist making fractures more likely
vit D deficiency common
treatment options for osteoporosis
estrogen replacement therapy: ERT: evidence that it increases bone density but no evidence that it decreases fracture risk in post-menopausal women
bisphosphonates: prevent bone absorption by impairing osteoclas activity and accelerating osteoclast apoptosis
SERM: selective estrogen receptor modulators (ex. raloxifene): E2 agonist in bone, E2 antagonist in breast/uterine tissue
denosumab: human monoclonal antibody against RANKL
ERT
estrogen replacement therapy
-evidence that it increases bone density but no evidence that it decreases fracture risk in post-menopausal women
bisphosphonates
treating osteoporosis
- prevent bone absorption by impairing osteoclas activity and accelerating osteoclast apoptosis
SERM
treating osteoporosis
selective estrogen receptor modulators (ex. raloxifene): E2 agonist in bone, E2 antagonist in breast/uterine tissue
denosumab
treating osteoporosis
- human monoclonal antibody against RANKL
primary hyperparathyroidism: effects and basics of prevalence
- elevated PTH resulting in hypercalcemia due to increased bone resorption
-
hypercalciuria and hyperphosphaturia
- PTH stimulates Ca reabs in nephron, BUT increased serum Ca means saturation, so see HYPERCALCIURIA as well
- also predisposition to kidney stones
- more frequent above 50
- 3x more frequent in women
- most common symptoms: bone pain, arthralgia
effects of severe hypercalcemia
Ca has significant role in neuromuscular/cardiac fx as well as bone fx
- bone pain, arthralgia
- sk muscle weakness, ventricular myocyte arrhythmia
- short QT: hypercalcemia = high Ca which stimulates Ca channels
- shortens the plateau phase = phase 2 depol = ST segment
- constipation, depression
- hypercalciuria, hyperphosphaturia
- increased risk for kidney stones
- abnormal CaSR activity
- can lead to Ca-dependent diabetes insipidus
most common cause of hypocalcemia
loss of calcitriol synthesis
why?
chronic kidney disease! PTH cant upreg CYP27B1 to convert precursor to calcitriol!
signs and symptoms of hypocalcemia
hyperexcitability of nerves and muscles
how?
Ca has a role in stabilizing Na channels in skeletal muscles and neuron membranes
- hypocalcemia means membrane permeability to Na is increased and those cells become hyperexcitable
- in severe cases, ventricular myocyte contractility affected
- long QT
signs: Trousseau’s sign (carpal spasm), Chvostek’s sign (facial m contraction)
Trousseau’s sign
hypocalcemia
carpal spasm due to loss in brachial artery circulation
- occurs during sustains inflation of bp cuff over systolic pressure
- SEEN in 94% of hypocalcemic pt
- SEEN in 1% of eucalcemic pt
- pretty specific
Chvostek’s sign
ipsilateral facial muscle contraction when facial nerve is tapped anterior to the ear
- NOT SEEN in 1/3 of hypocalcemic patients
- SEEN in 10% of euvolemic patients
- therefore not very specific
control of plasma phosphate
PTH and absorption of PO4 from GI tract
signs/symptoms associated with hyperphosphatemia
- impaired calcitriol synthesis
- impeded PTH-mediated bone resorption
- precipiation of Ca
- collectively, get induced hypocalcemia
- typically, signs and symptoms are attributed to hypocalcemia
- in prolonged cases, imbalances in Ca and PO4 cna lead to calcifications in vasculature and heart
hypophosphatemia
increased PO4 excretion that accompanies hyperparathyroidism
- often accompanies alcoholism
connection between alcoholism and hypophosphatemia
- during acute alcohol withdrawal, combo of resp alkalosis, high plasma insulin, epi = shift in PO4 content
connection between hypophosphatemia and oxygen/muscles
severe hypophosphatemia decreases 2,3DPG concentration, leading to and INCREASED AFFINITY OF HB FOR OXYGEN
- messes with ability of Hb to offload oxygen
- can result in hyscle weakness and necrosis (rhabdomyolysis)
rickets/osteomalacia
(child/adult)
cause
calcitriol deficiency or resistance
- undernourishment
- not enough sunlight exposure
- cause can be metabolic, dietary, renal, genetic
physio
- increased PTH-dependent PO4 excretion
- decreased Ca uptake from intestines
signs and symptoms
bone pain, tenderness
low bone density, high bone min
hypophosphatemia
hypocalcemia
hypocalciuria
