Calcium homeostasis Flashcards
What are the primary regulators in Calcium homeostasis?
What are the secondary regulators?
Calcium & Phosphate homeostasis:
Primary regulators:
- PTH
- Vitamin D
Secondary roles:
- Calcitonin
- Glucocorticoids
- Estrogens
How does PTH influence Calcium homeostasis?
Intestine:
- Increased calcium and phosphate absorption (via increased 1,25[OH]2D production)
Kidney:
- Decreased calcium excretion, increased phosphate excretion, stimulation of 1,25(OH)2D production
Bone:
- Calcium and phosphate resorption increased by high doses. Low doses increase bone formation.
Net effect on serum levels:
- Serum calcium increased
- serum phosphate decreased
How does Vitamin D Influence Calcium homeostasis?
Intestine:
- Increased calcium and phosphate absorption by 1,25(OH)2D
Kidney:
- Calcium and phosphate excretion may be decreased by 25(OH)D and 1,25(OH)2D
Bone:
- Increased calcium and phosphate resorption by 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D
Net effect:
- Serum calcium and phosphate both increased
How do PTH & Vitamin D influence Bone remodeling?
Both PTH and 1,25(OH)2D regulate bone formation and resorption, with each capable of stimulating both processes
This is accomplished by their stimulation of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell
PTH also stimulates osteoblast formation indirectly by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway.
PTH and 1,25(OH)2D stimulate the expression of RANKL by the osteoblast, which with MCSF, stimulates the differentiation and subsequent activation of osteoclasts, the bone-resorbing cell
Describe the metabolism of Vitamin D
Skin: UV light
7-Dehydrocholesterol → Cholecalciferol (Vit. D3)
Liver: [25-Hydroxylase]
Cholecalciferol (Vit. D3) → Calcidiol (25 (OH) D)
Kidney: [1α-Hydroxylase]
Calcidiol (25 (OH) D) → Calcitriol (1,25 (OH)2 D)
How does Bone density change with age?
What are potential treatments?
Untreated:
- Bone density is lost during aging in both men & women
Treated:
Vitamin D, PTH, Sr2+:
- Promotes bone formation & can increase bone mineral density
- PTH & Vit. D @ high-doses can also activate bone resorption
Estrogen, calcitonin, Denosumab, & Bisphonsonates:
- Block bone resorption
- Leads to a transient increase in bone mineral density because bone formation is not initially decrease
- Over time, both bone formation & resorption decrease & a new bone mineral density plateau is reached
Describe the process of Bone remodeling
Bone remodeling consists of (2) phases:
- Bone resorption followed by Bone formation
Phase I: Bone Resorption:
- Growth factors induce circulating preosteoclasts to differentiate to osteoclasts and attach to bone
- Growth factors: RANKL, PTH, Vit. D,
- Osteoclasts erode the mineral and matrix of bone surfaces, creating small cavities.
Phase II: Bone Formation:
- Bone morphogenetic protein (BMP) and other factors induce mesenchymal cells to differentiate into preosteoblasts
- PTH induces preosteoblasts to become osteoblasts and are further stimulated by insulin-like growth factor (IGF) to fill the cavities with new bone matrix that is subsequently mineralized
Explain the effect of Teriparatide
Administration of Teriparatide:
- Short-term intermittent:
- Mimics the effect of PTH; increases bone mass
- Long-term Continuous:
- Increases bone resorption (reduces bone mass)
What is osteoporosis?
Osteoporosis: “Porous Bone”
Occurs when the body;
- Loses too much bone (Excessive Bone resorption)
- Makes too little bone (Deficient Bone formation)
- Both
Bones become fragile and brittle, greatly increasing the risk of fracture
Osteoporosis
- Most common bone disorder
- Characterized by a gradual loss of bone mass that leads to skeletal weakness and fractures
- Treated with a bisphosphonate drug, calcitonin, teriparatide, estrogen, raloxifene, denosumab, or strontium ranelate
- Most drugs reduce bone resorption, teriparatide stimulates bone formation, and strontium appears to do both
Explain the action of Denosumab
Denosumab: Inhibition of osteoclast activity
- An Ig G2 monoclonal Ab that binds to & inactivates RANK ligand (RANKL)
- Thereby preventing osteoclast-mediated bone resorption & subsequent increase in bone density
RANK ligand (RANKL):
- Membrane protein; member of the tumor necrosis factor (TNF) superfamily
- Activates the Receptor Activator of Nuclear factor κ-B (RANK)
- Leads to gene expression required for cell fusion and the formation of mature osteoclasts
Which supplements are used in replacement therapy for those deficient in Calcium or Vitamin D?
Calcium: Calcium Citrate (Citracal)
Cholecalciferol (Vit. D3)
What is the general action of Bisphosphonates?
What is the example drug given?
Bisphosphonates inhibit Osteoclast activity, thereby reducing bone resorption and subsequently increasing bone mineral density.
Ex. Alendronate (fosamax)
Lifelong intake of adequate calcium & vitamin D is essential for what?
Optimal bone formation, maintenance & prevention of osteoporosis.
Dietary vit. D is essential to prevent rickets in children
