Pharm of Parathyroid and Bone Flashcards
Calcium and Phosphate Ions
Important minerals for general cellular function as well as major constituents of bone. Plasma levels of calcium are regulated within narrow limits [8.8-10.4 mg/dl].
a. Intracellular Ca++ involved in muscular contraction, fusion and release of storage vesicles for hormones and neurotransmitters, and as critical 2nd messenger; in extracellular fluids, Ca++ promotes blood coagulation and supports formation and remodeling of skeleton.
b. Intracellular PO43- component of: phospholipids, phosphorylated nucleotides, glycolytic pathway intermediates, phosphate buffer systems
c. 98% of Ca++ and 85% of PO4— stored in bone
d. Plasma Ca++: Ionized (50%), protein-bound (46%), complexed with organic ions (4%)
Direct actions of Vit D, PTH
a. D stimulates the intestinal absorption of Ca and P
b. Both PTH and D promote bone formation and resorption by stimulating osteoblasts and osteoclasts
c. At the kidney, both D and PTH enhance reabsorption of Ca - D enhances P retention while PTH and FGF23 stimulate renal excretion of P
NET EFFECT on Serum Levels:
PTH: ↑ Ca and ↓ P D: ↑ Ca and ↑ P FGF23: ↓ P
Feedback loops include:
- PTH stimulation of activation of D via the kidney
- D and Ca++ inhibition of PTH synthesis and release from parathyroid glands
- FGF23 inhibition of D activation in the kidney.
- CT is less critical for calcium homeostasis but in pharmacologic concentrations can reduce serum Ca and P by inhibiting bone resorption.
Parathyroid Hormone
a. Structure / Pharmacokinetics. Single chain 84 AA; 1-34 fragment is biologically active [teriparatide]. Cleared from liver and kidneys with t1/2 of minutes.
b. Primary stimulus for synthesis and secretion is hypocalcemia (decreased PTH if hypercalcemia). Vitamin D interacts with receptor on parathyroid gland to decrease PTH release
c. In bone, PTH increases the number and activity of osteoclasts via actions on osteoblasts to induce a membrane-bound protein called RANK (receptor activator of nuclear factor B) ligand (RANKL).
i. This factor then acts on osteoclasts precursors and osteoclasts, increasing their number and activity, and increasing bone remodeling. This is a specific sequence of cellular events initiated by bone resorption and followed by osteoblastic bone formation.
ii. Net effect of excess PTH is to increase bone resorption, BUT low and intermittent doses of PTH stimulate formation without first increasing bone resorption
d. In kidney, PTH increases ability of nephron to reabsorb calcium, but reduces reabsorption of phosphate.
i. Also important action to stimulate renal production of active D3 [1,25(OH)2D3]
Vitamin D [1,25(OH)2D3]
Biosynthesis / Pharmacokinetics
. Dietary vitamin D requires metabolism to active form.
- 7-dehydrocholesterol is photoconverted via ultraviolet irradiation in skin to form Vitamin D3
- Vitamin D3 (dietary vitamin D) is converted to 25(OH) Vitamin D3 in liver
- 25(OH) Vitamin D3 is converted to 1,25(OH)2 Vitamin D3 in kidney (most potent agent)
Vitamin D Preparations for Repletion and Supplementation
a. Vitamin D3 - cholecalciferol (Delta-D): Preferred over vitamin D metabolites because of modest cost.
b. Vitamin D2 - ergocalciferol [from plant ergosterol]: Studies have shown that ergocalciferol is LESS efficient than D3 in elevating serum 25-OHD3, thus D3 should be used when possible.
25-Hydroxyvitamin D3 - calcifediol: Does not require hepatic 25-hydroxylation and is most *useful in patients with liver disease. Onset of action is more rapid and half-life is shorter than D3. Alfacalcidol only available in Canada.
c. 1,25-Dihydroxyvitamin D3 - calcitriol: Most useful in patients with decreased synthesis of calcitriol (chronic renal failure or type 1 vitamin D-dependent rickets).
i. Calcitriol has a rapid onset of action and a half-life of only 6 hours. Associated with hypercalcemia so patients should be followed closely.
d. Dihydrotachysterol: Functionally equivalent to 1α-OHD3, requires hepatic 25-hydroxylation to become therapeutically active.
i. *Alternative for use in disorders that calcitriol is used. Rapid onset of action and relatively short duration of action.
Vitamin D Pharmacodynamics
a. Synthesis of calcitriol (1,25-dihydroxyvitamin D3, most active form of vitamin D) in kidney is stimulated by PTH (released in response to hypocalcemia).
i. Hypophosphatemia also stimulates calcitriol synthesis directly
b. In intestine, calcitriol appears to act by induction of new protein synthesis (calcium binding-protein and TRPV6-intestinal calcium channel) and by modulating calcium flux across brush border
i. These actions result in enhanced absorption of calcium and phosphate
ii. This effect occurs at lower concentrations of vitamin D and is the basis for its use in the treatment of rickets (osteomalacia). The increase in serum concentrations of Ca++ and PO43- leads to increased bone mineralization.
c. In bone, calcitriol has effects similar to PTH.
i. Can induce RANK ligand in osteoblasts and proteins such as osteocalcin which may regulate the bone mineralization process
ii. This effect on RANKL occurs at higher concentrations of vitamin D that stimulate release of calcium from bone
d. In kidney, calcitriol decreases excretion of calcium and phosphate
e. In parathyroid gland, calcitriol decreases release of PTH, thus reducing its own synthesis (negative feedback)
i. Analogs of calcitriol are available for the treatment of secondary hyperparathyroidism
ii. They inhibit release of PTH, but will NOT cause hypercalcemia (NO increase in intestinal Ca++ absorption or bone Ca++ mobilization (Paracalcitol , Doxercalciferol)
Review of Parathyroid Hormone Actions
a. Parathyroid Gland
i. Hypocalcemia is major stimulus for release
ii. Vit D and increased Ca++ inhibit PTH release via distinct receptors
b. Sites of PTH action
1) Intestine
i. Increased Ca++ absorption via—> 1,25(OH)2 D3 synthesis
- Bone
i. Activates OCs–> increase bone remodeling
ii. Acute effect–> increase bone resorption—> Increased Ca++ - Kidney
i. Increased reabsorption of Ca++ at DCT
ii. Increased excretion of PO4
Review of Vitamin D Actions
a. Parathyroid Gland
i. Decreased release of PTH (via feedback inhibition of PTH synthesis)
b. Intestine *
i. Increased synthesis of Ca++-binding protein and channel
ii. Enhanced dietary absorption of Ca++ and PO4
c. Bone
i. Induce RANK ligand in OBs –> role in bone mineralization
d. Kidney
i. Decreased excretion of Ca++ and PO4
Vitamin D Preparations
Repletion and Maintenance
a. Vitamin D3 – cholecalciferol
i. Preferred over other vitamin D metabolites for repletion – modest cost
b. Vitamin D2 – ergocalciferol (from plants)
i. Less efficient in elevating 25-OHD levels than D3 in repletion states
c. 1,25-Dihydroxyvitamin D3 – calcitriol
i. Active form of Vitamin D - also as parenteral formulation
ii. Most useful in CKD and vitamin D-dependent rickets
iii. Rapid onset of action, half-life of 6 hours
d. 25-Hydroxyvitamin D3 – calcidiol (not readily available in US)
i. Does not require hepatic hydroxylation
ii. *Useful in patients with liver disease
iii. More rapid onset, shorter duration than D3
e. Dihydrotachysterol
i. Activated by hepatic 25-OH - equivalent to 1-OHD3 in function
ii. Can be used in disorders for which calcitriol is used
Vitamin D Preparations for Repletion and Supplementation
*handout
Vitamin D3 - cholecalciferol: Preferred over vitamin D metabolites because of modest cost.
Vitamin D2 - ergocalciferol: Studies have shown that ergocalciferol is **LESS efficient than D3 in elevating serum 25-OHD3, thus D3 should be used when possible.
25-Hydroxyvitamin D3 - calcifediol: Does not require hepatic 25-hydroxylation and is most **useful in patients with liver disease. Onset of action is more rapid and half-life is shorter than D3.
i. Used in liver disease
1,25-Dihydroxyvitamin D3 - calcitriol:
i. Most useful in patients with decreased synthesis of calcitriol (chronic renal failure or type 1 vitamin D-dependent rickets).
Dihydrotachysterol: Functionally equivalent to 1α-OHD3, requires hepatic 25-hydroxylation to become therapeutically active.
i. Alternative for use in disorders that calcitriol is used.
Primary HyperparathyroidismTreatment
- Surgery
i. Adenoma - 1 Gland
ii. Hyperplasia - 3 1/2 Glands - Calcimimetic Drug (Cinacalcet)
- Anti-Resorptive Bone Drug
i. Bisphosphonate, Denosumab
Calcimimetics- Uses
Cinacalcet
a. *Binds allosterically to calcium-sensing receptor (CaSR) in PT gland
b. Increases sensitivity of CaSR to Ca++—> reduced release of PTH (no hypercalcemia)
c. Complementary mechanism to Vit D and analogs that target the VDR
d. *Used in secondary hyperparathyroidism and non-surgical option in primary hyperparathyroidism
Vitamin D Analogs
Other Uses
Calcitriol Analogs – Paracalcitol
a. Inhibits PTH release from gland via action at D3 receptor (VDR) - *used in secondary hyperparathyroidism
b. Does NOT increase Ca++ absorption or mobilization from bone—> *NO hypercalcemia
c. Clinical advantage over calcitriol uncertain
Secondary Renal Osteodystrophy - CVPR
a. Pathophysiology: Failing kidney cannot excrete PO4 or synthesize D3— Increased PO4 levels and decreased in plasma Ca++ —> Increased PTH release—> Increased one turnover—> bone disease
b. Vitamin D and metabolites—> decreased PTH release indirectly (Increased GI Ca++ absorption –> hypercalcemia) and directly (decreased synthesis)
c. Paracalcitol—> acts selectively at D3 receptors on PT gland - not at intestine - so no hypercalcemia
d. Calcimimetics—> bind Ca++-sensing cells on PT gland - increased Ca++ —> reduced release of PTH (no hypercalcemia)
e. Phosphate binding agents—> bind PO4 in gut –> decreased absorption —> decreased plasma levels
Calcitonin Actions on Bone
a. Released from parafollicular cells of thyroid–> primary stimulus for calcitonin release is hypercalcemia
b. Action of Calcitonin
1) Bone*
i. Inhibits osteoclastic bone resorption
- Kidney
i. Increases excretion of Ca++ and PO4
NOTE: No demonstrable problem in calcium homeostasis if deficiency (thyroidectomy) or excess (thyroid carcinoma)
Estrogen Actions on Bone
a. Positive effects on bone mass - agonist at ERα receptors on OBs-OCs
b. Estrogens directly regulate Osteoblasts—> increase differentiation - decrease apoptosis
c. *Major effect of estrogens–> decrease number and activity of OCs
i. lower osteoclast activity
d. Alters OB cytokines—> decrease stimulating signals [IL-6, TNF-α] and increase anti-resorptive BMP-2 and TGF-β
e. Estrogens increase OB production of osteoprotegerin (OPG)
i. OPG is “decoy” receptor–> binds RANK-L —> prevents OC activation
