Lecture 32: Bone Mineral Homeostasis Flashcards
What are the two main ions in bone mineral homeostasis?
calcium (Ca2+)
phosphate (PO4 3-)
bone is the principal reservoir for these ions
Why is the regulation of calcium and phosphate ions important?
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
How is bone a dynamic tissue?
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
What are the actions of parathyroid hormone (PTH)?
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
What are vitamin D metabolites?
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
What are the actions of vitamin D metabolites?
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
What is the D3 response to Ca2+ excursion?
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
What are the secondary regulators of bone mineral homeostasis?
FGF23
Calcitonin
Glucocorticoids
Estrogens
What is FGF23?
“anti-PTH/D3”
inhibits phosphate uptake
inhibits D3 metabolism
inhibits PTH production
What is calcitonin?
secreted from thyroid (parafollicular cells)
inhibits bone resorption
inhibits calcium and phosphate reabsorption in kidney
What are glucocorticoids?
prolonged administration causes osteoporosis (common)
blocks calcium uptake in gut, promotes excretion in kidney
What are estrogens?
prevent bone loss in post-menopausal women
direct effects in bone, prevents PTH-stimulated resorption
What are acute disruptions of Ca2+ homeostasis?
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
What is hypocalcemia?
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
What is the long term danger is development of secondary hyperparathyroidism?
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
What are the long term underlying defects of hypocalcemia?
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
What are the symptoms of hypercalcemia?
effects related to loss of cellular excitability: lethargy, coma, also pain in bones if due to excessive PTH
What is primary hyperparathyroidism?
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)
What is osteoporosis?
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
What is teriparatide?
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
What are biphosphonates?
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
What is osteoprotegerin?
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
What is denosumab?
monoclonal antibody directed against RANKL
same mechanism as the native protein (DECOY receptor for RANKL)
