Lecture 32: Bone Mineral Homeostasis

Question 1

What are the two main ions in bone mineral homeostasis?

Answer 1

calcium (Ca2+)
phosphate (PO4 3-)

bone is the principal reservoir for these ions

Question 2

Why is the regulation of calcium and phosphate ions important?

Answer 2

health/strength of bones - osteoporosis, osteopenia, osteopetrosis - (long-term, chronic effects)

Ca2+ balance has significant effects on electrical excitability of cells, by binding to membrane glycoproteins (can lead to acute crises when Ca2+ levels are abnormal)

Ca2+ is an essential intracellular signal that can regulate expression of many genes

Question 3

How is bone a dynamic tissue?

Answer 3

bone is a dynamic tissue, constantly regenerated and resorbed

osteoblasts: deposition of bone
osteoclasts: resorption of bone

major regulators of bone remodeling are vitamin D metabolites and PTH (stimulate bone reabsorption)

activation of osteoclasts is indirect - the hormones activate osteoblasts; secretion of RANK ligand (RANKL) from osteoblasts activates osteoclasts

Question 4

What are the actions of parathyroid hormone (PTH)?

Answer 4

bone: promotes bone resorption (indirect effect through RANKL), increased Ca, increased PO4

kidney: promotes Ca absorption, promotes PO4 excretion, increased Ca, decreased PO4

net effect: increased Ca, decreased PO4

kidney: stimulation of Vitamin D processing

synthetic PTH 1-34 is marketed as a therapeutic (teriparatide) for osteoporosis

Question 5

What are vitamin D metabolites?

Answer 5

Vitamin D: “steroid” hormone (secosteroid, steroid with a missing ring), metabolized in liver, than kidney, to generate:

calcitriol (1,25-hydroxy vitamin D3) - active form

secalciferol (24,25-hydroxy D3) - weak activity

Question 6

What are the actions of vitamin D metabolites?

Answer 6

kidney: decreased Ca and PO4 excretion, increased Ca, increased PO4

bone: promotes bone resorption, increased Ca, increased PO4

gut: promotes uptake of Ca and PO4, increased Ca, increased PO4

net effect: increased Ca, increased PO4

Question 7

What is the D3 response to Ca2+ excursion?

Answer 7

Ca2+ levels are sensed by Ca2+ receptors in the parathyroid… PTH levels are regulated accordingly

PTH exerts effects on PTH receptors in kidney and osteoblasts

PTH stimulation of Vitamin D metabolism (to 1,25 form) leads to Vit D effects in gut, kidney, bone

restoration of circulating Ca2+ to normal levels

Question 8

What are the secondary regulators of bone mineral homeostasis?

Answer 8

FGF23

Calcitonin

Glucocorticoids

Estrogens

Question 9

What is FGF23?

Answer 9

“anti-PTH/D3”

inhibits phosphate uptake

inhibits D3 metabolism

inhibits PTH production

Question 10

What is calcitonin?

Answer 10

secreted from thyroid (parafollicular cells)

inhibits bone resorption

inhibits calcium and phosphate reabsorption in kidney

Question 11

What are glucocorticoids?

Answer 11

prolonged administration causes osteoporosis (common)

blocks calcium uptake in gut, promotes excretion in kidney

Question 12

What are estrogens?

Answer 12

prevent bone loss in post-menopausal women

direct effects in bone, prevents PTH-stimulated resorption

Question 13

What are acute disruptions of Ca2+ homeostasis?

Answer 13

acute disruptions can be severe and often need to be resolved quickly - short term

normal circulating levels are ~2.2 mM total Ca2+, ~1 mM free Ca2+

however, there are typically underlying defects that are a long term problem and need resolution

Question 14

What is hypocalcemia?

Answer 14

short term resolution: calcium (oral, i.v., i.m.), or active D3 metabolite

causes hyperexcitability of cells - early symptom is Trousseau’s sign

unresolved hypocalcemia can lead to seizures, muscle tetany/spasms

Question 15

What is the long term danger is development of secondary hyperparathyroidism?

Answer 15

hyperactive parathyroid due to low plasma Ca2+ (normally resulting from kidney failure and poor renal reabsorption of Ca2+)

secondary hyperparathyroidism will lead to breakdown and weakening of bones

Question 16

What are the long term underlying defects of hypocalcemia?

Answer 16

hypoparathyroidism: intrinsic defect of parathyroid, treat with Vitamin D supplementation, Ca2+ supplementation

vitamin D deficiency: inability to generate Vit D metabolites, resolve by dietary correction, ingestion of active Vit D3 metabolites (calcitriol), sunshine

Question 17

What are the symptoms of hypercalcemia?

Answer 17

effects related to loss of cellular excitability: lethargy, coma, also pain in bones if due to excessive PTH

Question 18

What is primary hyperparathyroidism?

Answer 18

overactivity of the parathyroid - typically due to tumor

therapy is resection of the gland

therapeutics might also be used to “protect bone” (biphosphonates, calcitonin, inhibitors of bone reabsorption)

second possible therapy is calcimimetrics (mimic calcium effects on CaR, negative feedback regulation of parathyroid)

Question 19

What is osteoporosis?

Answer 19

abnormal bone loss –> fractures

long-term gradual disorder, loss of balance between formation (decreased) and resorption (increase) of bone

we will briefly discuss therapeutics that target each of these processes

most familiar in aging females

other common causes: long-term glucocorticoid administration, hyperparathyroidism

Question 20

What is teriparatide?

Answer 20

recombinant, fully active PTH fragment (1-34)

counterintuitive? (doesn’t PTH increase circulating Ca2+ by resorbing bone)

PTH acts primarily as a stimulus on osteoblasts, and acts via ANKL to activate osteoclasts; mechanism of action requires proper timing of dosage (once daily), tought to “tip the balance” towards osteoblast activity

Question 21

What are biphosphonates?

Answer 21

mechanism of action is inhibition of osteoclast resorption of bone

specific target is unclear, some recent concerns about side effects (cancers, abnormal fractures)

speculation that these may also act to inhibit glucocorticoid effects

trials have combined bisphosphonates with teraparatide, but effects are inconclusive

all share a similar structure (two phosphonate groups)

alendronate is the most commonly prescribed bisphosphonate

the phosphonate groups have a high affinity for Ca2+, so these drugs accumulate in bone

this targets them to osteoclasts during bone resorption, and have a variety of toxic effects on osteoclasts

Question 22

What is osteoprotegerin?

Answer 22

naturally occurring “scavenger” of RANKL

by binding to RANKL, it competes with RANK

osteoprotegerin can prevent RANKL binding and activating osteoclasts, and this inhibits bone resorption

Question 23

What is denosumab?

Answer 23

monoclonal antibody directed against RANKL

same mechanism as the native protein (DECOY receptor for RANKL)