Download 1,25[OH] 2 D

Agents That Affect Bone
Mineral Homeostasis
Dr Safaeian
Bone
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Principal structural support for body and provides
space for hematopoiesis.
Major mineral constituents: Calcium (98% of 1–2
kg) and Phosphorus (85% of 1 kg)
Complex set of mechanisms for homeostasis of
calcium and phosphate
Bone cells: Osteoclast (bone resorption: removing
mineralized matrix and breaking up organic bone)
Osteoblasts (bone formation)
Bone Remodeling
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Growth and development of endochondral bone are
driven by a process called modeling. Once new bone is
laid down, it is subject to a continuous process of
breakdown and renewal called remodeling, by which
bone mass is adjusted throughout adult life.
Abnormalities in bone mineral
homeostasis
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Cellular dysfunctions (tetany, coma, muscle
weakness)
Disturbances in structural support of body
(osteoporosis with fractures)
Loss of hematopoietic
capacity
Calcium and Phosphate
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Enter body from intestine.
Ca: absorption → principally in duodenum and upper
jejunum, secretion →principally in ileum)
P: absorption → principally in jejunum
98% of filtered Ca and 85% of filtered P reabsorbed
by kidney.
Intestinal absorption and Renal excretion of Ca and P
is closely regulated.
Principal hormonal regulators
of bone mineral homeostasis
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Parathyroid hormone (PTH)
Fibroblast growth factor 23 (FGF23)
Vitamin D
Parathyroid Hormone
(PTH)
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1.
2.
3.
Parathormon 100 uspU/ml AMP
Teriparatide 250 mcg/ml, Prefilled Disposable
Injectional Pen (Recombinant PTH 1-34)
PTH: a single-chain peptide hormone (84 amino acids)
Regulation of PTH:
Cleavage of PTH in the gland through a Ca-sensitive
protease
↓ PTH production and secretion through Ca-sensing
receptor
Parathyroid gland contains Vit D receptor and also
activates Vit D ► suppress PTH production.
Parathyroid Hormone
(PTH)
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Rapid metabolic clearance in liver and kidney
Regulates Ca and P flux across cellular
membranes in bone and kidney
PTH ►↑Serum Ca and ↓Serum P
PTH in the bone
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PTH ► both catabolic and anabolic effects on bone.
Excess endogenous PTH ► ↑Activity and number
of osteoclasts, ↑bone turnover indirectly through
induction of a protein called RANK (receptor for
activation of nuclear factor-κB) ligand
Denosumab: An antibody that inhibits action of RANKL
has been developed for treatment of excess bone
resorption in osteoporosis and certain cancers.
Low and intermittent exogenous PTH ► ↑ bone
formation indirectly through insulin-like growth factor
1 (IGF-1) ► Teriparatide: for treatment of
osteoporosis.
PTH in the kidney
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↑Ability of nephron to reabsorb Ca and Mg
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↓Ability to reabsorb phosphate, amino acids,
bicarbonate, Na, Cl, and sulfate
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Stimulation of 1,25-dihydroxyvitamin D
(1,25[OH]2D) production
Vitamin D (Vit D3)
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A secosteroid produced in skin from 7dehydrocholesterol under influence of UV.
Also found in diet as natural form (Vit D3:
Cholecalciferol) and plant-derived form (Vit D2:
Ergocalciferol [less potent])
A prohormone is first hydroxylated in liver to 25hydroxyvitamin D3 (25[OH]D: Calcifediol): major
circulating form of Vit D3.
Further converted in kidney to 1,25dihydroxyvitamin D3 (1,25[OH]2D: Calcitriol) and
24,25-dihydroxyvitamin D3 (24,25[OH]2D:
Secalcifediol).
Conversion of 7-dehydrocholesterol to Vit D3 and its
metabolism
Vitamin D Preparations
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Vitamin D3 300,000 U AMP
Vitamin D3 50,000 U CAP (Pearl)
Calcitriol 0.25 mcg, 1, 2 mcg/ml CAP, AMP
Dihydrotachysterol 1 mg/ml Oral Solution
Calcipotriol (Calcipotriene) Topical Gel,
OINT, Solution (for psoriasis)
Vitamin D
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The recommended dietary allowance of vit D for
infants and children is 400 IU, or 10 g, daily.
The adult dose was set arbitrarily at 200 IU.
Maximum daily intake: up to 4000 IU/day
In osteoporosis ► Vit D: 600-800 IU daily
In hypocalcemia due to vit D deficiency ► 50,000 U
D2 or D3 orally once per week for 6-8 weeks, and
then 800 to 1000 U of D3 daily.
Vitamin D
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Vit D and its metabolites tightly bound to vit Dbinding protein in plasma.
Principal organ for clearance: liver
Prolonged terminal half-life = weeks to months
(store in fat depots).
Biological actions of vit D are mediated by a
nuclear receptor.
Vit D: Mechanism of action
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Calcitriol: most potent agent in stimulation of
intestinal Ca and P transport and bone resorption.
Supplementation with cholecalciferol (D3) is
suggested because D3 increases serum 25[OH]D
more efficiently than ergocalciferol (D2).
Acts on intestine through intracellular receptor
by induction of new protein synthesis (Ca-binding
protein and intestinal Ca channel) and by modulation
of Ca flux across membranes.
On bone like PTH, regulate mineralization process.
Vit D: Mechanism of action
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Calcifediol (25(OH)D) is more potent than
1,25(OH)2D in stimulating renal reabsorption of
Ca and P and regulating Ca flux and contractility
in muscle.
Vit D ►↑Serum Ca and ↑Serum P
Vit D: Side effects
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Safe Upper Limit for vit D: 4000 IU/day
However, higher doses are sometimes required
for initial treatment of vit D deficiency.
Excessive vit D, especially + Ca ►
hypercalcemia, hypercalciuria, kidney
stones. (weakness, headache, somnolence,
nausea, cardiac rhythm disturbance)
Fibroblast Growth Factor 23
(FGF23)
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A single-chain protein produced primarily by
osteoblasts and osteocytes in bone.
Inhibits 1,25(OH)2D3 production and phosphate
reabsorption (via Na phosphate co-transporters) in
kidney
► ↓Serum P and ↓circulating 1,25(OH)2D3
Actions of PTH, Vit D, and FGF23 on
Gut, Bone, and Kidney
PTH
Intestine
↑Ca and P absorption
(by ↑1,25[OH]2D
production)
Vitamin D
FGF23
Kidney
↓Ca excretion, ↑P
excretion
↓Ca and P excretion ↑P excretion
by 25(OH)D and
1,25(OH)2D1
Bone
↑Ca and P resorption
high doses. Low doses
may increase bone
formation.
↑Ca and P resorption ↓mineralization due
by 1,25(OH)2D;
to
↑bone formation by hypophosphatemia
1,25(OH)2D and
24,25(OH)2D
Net effect
on serum
levels
↑Serum Ca ,↓Serum P ↑Serum Ca and P ↓Serum P
↑Ca and phosphate ↓Ca and P
absorption by 1,25 absorption by
↓1,25(OH)2
(OH)2D
production
Secondary Hormonal Regulators
of Bone Mineral Homeostasis
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Calcitonin
Glucocorticoids
Estrogens
Calcitonin
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Calcitonin 50, 100 IU/ml AMP
Calcitonin, Salmon100, 200 IU/dose NASAL
SPRAY
A single-chain peptide hormone secreted by
parafollicular cells of thyroid.
Half-life of human calcitonin monomer=10 min
Salmon calcitonin: longer half-life and a
↓metabolic clearance → more attractive as a
therapeutic agent.
Much of clearance occurs in kidney.
Calcitonin
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Principal effects ►↓Serum Ca and P by actions
on bone and kidney.
Inhibits osteoclastic bone resorption at first after
its administration, with time►↓both formation
and resorption of bone.
In kidney► ↓Ca, P, Na, K and Mg reabsorption
Useful in treatment of Paget's disease,
hypercalcemia, and osteoporosis.
Glucocorticoids
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Alter bone mineral homeostasis.
Antagonize Vit D-stimulated intestinal Ca
transport.
Stimulate renal Ca excretion.
Block bone formation.
Prolonged administration ► Osteoporosis
Useful in reversing hypercalcemia associated
with lymphomas or in Vit D intoxication.
Estrogens
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Prevent accelerated bone loss during
immediate postmenopausal period and at
least transiently increase bone in
postmenopausal woman.
Reduce bone-resorbing action of PTH.
Lead to ↑1,25(OH)2D level in blood.
Estrogen receptors have been found in bone
► direct effects on bone remodeling.
Estrogens
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Long-term use of estrogen is discouraged
because of its deleterious adverse effects.
But, selective estrogen receptor
modulators (SERMs) such as Raloxifene
have beneficial effects on bone while
minimizing these deleterious adverse effects
on breast, uterus.
Nonhormonal agents
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Bisphosphonates
Calcimimetics
Thiazides
Fluoride
Other drugs
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Gallium nitrate
Plicamycin (Mithramycin)
Strontium Ranelate
Bisphosphonates:
Analogs of pyrophosphate
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Etidronate TAB
Pamidronate AMP
AlendronateTAB
Risedronate TAB
Zoledronate AMP
Bisphosphonates:
Pharmacodynamic
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Retard formation and dissolution of
hydroxyapatite crystals within and outside
skeletal system.
Localize to regions of bone resorption and so
exert their greatest effects on osteoclasts.
Amino bisphosphonates such as alendronate
and risedronate ►block farnesyl pyrophosphate
synthase, an enzyme in mevalonate pathway is
critical for osteoclast survival.
Bisphosphonates:
Pharmacokinetics
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Less than 10% of an oral dose is absorbed.
Food reduces absorption.
Pamidronate is not available as an oral
preparation due to gastric irritation.
½ Absorbed drug accumulates in bone for
months.
Remainder is excreted unchanged in urine.
Bisphosphonates:
Clinical Application
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Hypercalcemia associated with malignancy
Paget's disease
Osteoporosis
Contraindications:
 ↓Renal function, esophageal motility
disorders, and peptic ulcer disease→ can be
used IV administration of pamidronate.
Bisphosphonates: Adverse Effects
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Remarkably free of ADR in doses for osteoporosis.
Etidronate → Mineralization defect in higher doses
All (exception of etidronate) have gastric and
esophageal irritation ►taking drug with a full glass of
water and remaining upright for 30 min.
Rare osteonecrosis of jaw (1/100,000 patient-years)
by high iv doses of zoledronate
Rare femur fractures after long-term treatment due
to over-suppressing bone turnover.
↑Risk of new-onset atrial fibrillation (AF), especially in
IV therapy (zoledronate)- UpToDate 2016.
Calcimimetics: Cinacalcet TAB
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Activates calcium sensing receptor (CaR)
especially in parathyroid gland.
Blocks PTH secretion.
Approved for treatment of secondary
hyperparathyroidism in chronic kidney
disease and for treatment of parathyroid
carcinoma.
Thiazides
Reduce renal Ca excretion.
 Increase effectiveness of PTH in
stimulating renal Ca reabsorption.
 In distal tubule: block Na
reabsorption,↑Ca-Na exchange
►↑Ca reabsorption into blood
 Useful in reducing hypercalciuria
and incidence of stone formation
in idiopathic hypercalciuria
►↓Stone formation
by ↓urine oxalate excretion
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Fluoride
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Effective for prophylaxis of dental caries.
Accumulated by bones and teeth ► stabilizes
hydroxyapatite crystal.
Optimum concentration in drinking water
supplies = 0.5–1 ppm.
Excess fluoride in drinking water leads to
mottling of enamel.
Calcium Preparations
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Calcium Citrate
Calcium Gluconate 10%, 10ml, AMP, GEL
Calcium Carbonate 500 mg TAB, Eff TAB
Calcium Carbonate+Vit D3 500 mg+200IU TAB, Eff
Calcium Forte (Carbonate 0.3 g, Lactate
Gluconate 2.94 g) TAB, Eff TAB
Calcium (Glubionate, Lactobionate): 500 mg
Syrup
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The intake recommendations refer to amount of
elemental calcium in the calcium supplement.
Calcium
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Optimal intake of Ca: 1200 mg (total of diet and
supplement) should not routinely exceed 2000
mg/day.
The most widely available Ca supplements:
calcium carbonate and calcium citrate.
Calcium carbonate is cheapest► good first
choice in most individuals when taken with
meals.
Calcium citrate is well absorbed in fasting
state, is first line in patients taking proton
pump inhibitors or H2 blockers or who have
achlorhydria.
Intravenous Calcium Indication
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Acutely symptomatic patients (acute
hypoparathyroidism following surgery)
Asymptomatic hypocalcemia with acute ↓serum Ca to
≤7.5 mg/dL (1.9 mmol/L) may develop serious
complications if untreated
Patients with milder or chronic hypocalcemia unable
to take or absorb oral supplements (after complex
surgical procedures)
Calcitriol (0.25 to 0.5 mcg BID) is preferred for
patients with severe acute hypocalcemia because of
its rapid onset of action.
Intravenous Calcium Indication
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10% Ca gluconate (90 mg of elemental Ca/10
mL) can be infused over 10 to 20 mins ►
because of risk of serious cardiac dysfunction,
including systolic arrest.
Ca should be diluted in 5% dextrose or saline
because of irritating effect to veins.
IV solution should not contain bicarbonate or
phosphate, which can form insoluble calcium
salts. Another IV line (in another limb) could be
used.
Calcium Preparations:
Side effects of high calcium intake
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Headache, anorexia, weakness, dry mouth, metallic
taste, dyspepsia and constipation, abdominal
cramps, ataxia, ↑risk of nephrolithiasis
Cardiovascular disease (CVD) is controversial.
Interfere with absorption of iron and thyroid
hormone ► should be taken at different times.
Side effects following IV administration: dizziness,
flushing, sensation of warmth, irregular heartbeat,
nausea or vomiting, skin redness, rash, pain, or
burning at injection site, sweating, tingling sensation
Phosphate Preparations
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For treatment of Hypophosphatemia
Phosphate (Organic) AMP
Phosphate, Potassium AMP
Phosphate, Potassium Monobasic Bulk,
TAB
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Phosphate, Sodium Monobasic, Dibasic
Bulk
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Phosphate, Sodium TAB, EFFERVESCENT
Treatment of
Hyperphosphatemia
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Dialysis
Glucose and insulin infusions (seldom
necessary)
Restriction of dietary phosphate plus use of
phosphate-binding gels (Sevelamer
800mg, TAB)
Ca supplements.