Bone Minerals

Question 1

Ions in bone mineral homeostasis

Answer 1

Calcium
Phosphate

Bone is principal reservoir for ions
make up matrix that composes bone structure

Question 2

importance of ion regulation

Answer 2

health/strength of bones - osteoporosis, osteopenia, osteopetrosis
Ca2+ balance - binds to membrane glycoproteins to impact electrical excitability of cells
Ca2+ = intracellular signal that can regulate expression of genes

Question 3

bone diseases

Answer 3

osteoporosis - bones become weak (low density)
osteopenia - mild step on progression to osteoporosis
osteopetrosis - bone is too dense → subject to breaks (brittle and inflexible

Question 4

control sites for plasma Ca2+ and PO4 (3-)

Answer 4

gut → uptake, excretion
bone = reservoir
kidney → uptake, excretion

Question 5

bone remodeling

Answer 5

bone is dynamic tissue → regenerated and resorbed
vitamin D metabolites and PTH are regulators of bone remodeling → stimulate bone resorption

resorption: release of Ca2+/PO4(3-) from bone

Question 6

osteoblasts + osteoclasts

Answer 6

osteoblasts: deposition of bone
osteoclasts: resorption of bone

activation of osteoclasts is indirect - hormones (PTH) activate osteoblasts → secrete RANK ligand → activates osteoclasts

Question 7

Parathyroid hormone

Answer 7

peptide hormone

bone: promotes bone resorption (through RANKL) = increases Ca2+, increases PO4 (3-)
kidney: stimulates vitD processing, promotes Ca2+ absorption, PO4 (3-) excretion = increases Ca2+, decreases PO4 (3-)

Question 8

PTH feedback loop

Answer 8

receptors on parathyroid gland sense decrease in circulating Ca2+ → release PTH
stimulates bone resorption, kidney reabsorption of Ca2+ and excretion of PO4(3-)
circulating levels of Ca2+ increase → relieves signal

Question 9

vitamin D metabolites → metabolism

Answer 9

‘steroid’ hormone - missing ring
metabolized in liver (add OH) then kidney to generate:
- calcitriol (active form) if low Ca2+ and high PTH
- secalciferol (weak activity) if high Ca2+

Question 10

vit D metabolites - action

Answer 10

kidney: decreased Ca2+ and PO4(3-) excretion = increases Ca2+, increases PO4 (3-)
bone: promotes bone resorption = increases Ca2+, increases PO4 (3-)
gut: promotes uptake of Ca2+ and PO4(3-) = increases Ca2+, increases PO4 (3-)

Question 11

bone remodeling regulation

Answer 11

Ca2+ levels are sensed by Ca2+ receptors on parathyroid and regulated
PTH acts on receptors in kidney and osteoblasts; stimulates Vitamin D metabolism → vitD effects in gut, kidney, bone
= restoration of circulating Ca2+ to normal levels

Question 12

secondary regulators of bone mineral homeostasis

Answer 12

FGF23
calcitonin
glucocorticoids
estrogens

Question 13

FGF23

Answer 13

inhibits phosphate uptake
inhibits D3 metabolism
inhibits PTH production

Question 14

calcitonin

Answer 14

secreted from thyroid (parafollicular cells)
inhibits bone resorption
inhibits calcium and phosphate reabsorption in kidney

Question 15

glucocorticoids

Answer 15

prolonged administration causes osteoporosis
blocks calcium uptake in gut, promotes excretion in kidney

Question 16

estrogens

Answer 16

prevent bone loss in post-menopausal women
direct effects in bone, prevents PTH-stimulated resorption

Question 17

disruptions of Ca2+ homeostasis

Answer 17

normal circulating levels are ~2.2 mM total Ca2+ and ~1mM free Ca2+ = tightly regulated

hypocalcemia
hypercalcemia

Question 18

hypocalcemia

Answer 18

low levels of circulating calcium
causes hyperexcitability of cells
unresolved → seizures, muscle spasms

short term resolution: calcium or active D2 metabolite

long term → can develop secondary hyperparathyroidism: due to low plasma Ca2+; will lead to breakdown and weakening of bones
causes: hypoparathyroidism, vit D deficiency

Question 19

Trousseau’s sign

Answer 19

calcium’s effect on membrane voltage leads to spasm in hand when pressure is applied to arm

Question 20

hypercalcemia

Answer 20

too much circulating Ca2+
loss of cellular excitability → lethargy, coma, pain in bones

primary hyperparathyroidism: overactivity of parathyroid → too much PTH
therapy: resection of gland; therapeutics to protect bone; calcimimetics: negative regulation of parathyroid

Question 21

osteoporosis

Answer 21

low bone density → abnormal bone loss → fractures
loss of balance between formation (decline) and resorption (incline) of bone

common in aging females - hormone replacements (risk of cancer); estrogen mimics

causes: long term-glucocorticoid administration; hyperparathyroidism

Question 22

teriparatide

Answer 22

therapy for osteoporosis
recombinent, fully active PTH fragment → stimulates osteoblasts without activating osteoclasts to promote deposition rather than resorption

Question 23

biphosphanates

Answer 23

therapy for osteoporosis
inhibition of osteoclast resorption of bone

might also inhibit glucocorticoids
side effects

two phosphonate groups
ex. alendronate
phosphate groups have high affinity for Ca2+ → drugs accumulate in bone

Question 24

osteoprotegerin

Answer 24

endogenous inhibitor of RANK/RANKL system
binds to RANKL → inhibits stimulation of osteoclasts = inhibition of bone resorption

OPG knockout = decreased expression → low bone density
OPG transgenic = increased (over-) expression → high bone density

Question 25

denosumab

Answer 25

osteoprotegerin mimetic
osteoporosis treatment

monoclonal antibody directed against RANKL (mimics effects of OPG) → decoy receptor

promotes protection of bone