Pharmacology Of Bone And Calcium Homestasis

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Parathyroid hormone

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-Polypeptide made by parathyroid gland
-Released in response to decreased plasma calcium
-Causes increased calcium and phosphate mobilization from bone

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PTH effect on osteoblasts and osteoclasts

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Increased number of osteoblasts and osteoclasts which causes calcium mobilization

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PTH effects on kidney

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Decrease ca and increasd phosphate excretion

Increased activation of Vitamin D

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Active Vitamin D

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1,25 dihydroxyvitamin D

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PTH affect on GI tract

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Vitamin D activation, which indirectly increases calcium absorption

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Two forms of vitamin D

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Ergocalciferol-D2-plants
Cholecalciferol-D3-animals

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Synthesis of Vitamin D

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Formed from cholesterol by 7-dehydrocholesterol enzyme, along with UV radiation

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Calcitriol

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Most active form of vitamin D

1,25 dihydroxyvitamin D

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Activation of Vitamin D

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Requires Liver (25 hydroxyvitaminD) and kidney (1,25)

Kidney is rate limiting step

Activation in kidney is increased with PTH, low plasma ca and phosphate

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Estrogen Effects on calcium homeostasis

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Preserves calcium in bone (unknown mechanism)

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Glucocortoid effects on calcium homeostasis

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At pharmacological levels (not physiological levels) it increases calcium resorption from bone

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Calcitonin

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-Polypeptide produced in thyroid
-Not vital to Calcium homeostasis
-Modulates Vitamin D and PTH regulation
-Released in response to increased plasma calcium

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Calcitonin's effects on bone

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Direct inhibition of osteoclast activity-> decreased bone resorption

-may stimulate osteoblast formation

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Calcitonin's effects on Kidney

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Increases calcium, phosphate, and other ion excretion

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Net result of Calcitonin releases

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Tones down serum calcium (and phosphate)

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Is PTH orally available

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NO, It's a polypeptide

-low oral availability
-Rapid metabolism in KIDNEY and liver

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PTH administration

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Must be by injection (parenteral)

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PTH Mechanism of Action

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Increases osteoblast number->increases plasma calcium levels

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PTH indications

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-Osteoporosis

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Adverse affects of PTH

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Hypercalcemia

(uncommon at low dose used)

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Contraindications of PTH use

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Use with diphoshonates

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Is Calcitonin orally available?

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NO, It's a polypeptide

-low oral availability
-Rapid metabolism

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Calcitonin Mechanism of action

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-increases excretion of calcium and phosphate (and sodium, Mg, Cl)
-Decreases activity of osteoclasts->decreased bone resorption

-Decreases plasma calcium levels

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Calcitonin half life

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Very short T1/2, but salmon ct has longer halflife

metabolized in liver and kidney

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indications for Calcitonin

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Pagets Disease
Osteoporosis

To decrease Ca loss from bone and bone turnover

Hypercalcemia of malignancy

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Adverse effects of Calcitonin

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Hypocalcemia, uncommon due to escape of calcitonin in kidney

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Vitamin D

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pro-drug that must by activatied by 2 steps of hydroxylation 25-liver, 1-kidney

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Calcifedial

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25 hydroxyvitamin D

Converted to calcitriol in a HEALTHY KIDNEY

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Calcitriol

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Most active vitamin D

1, 25 dihydroxy vitamin D

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Dihydrotachysterol (DHT)

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Reduced form of Vitamin D2, activated by 25 hydroxylation in liver

useful in renal disease because it doesn't need a kidney

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Mechanism of action of Vitamin D

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Increased plasma calcium by
-increasing absorption through the gut and bone deposition
-increased release of Calcium from bone
-Decreased excretion from kidneys

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Vitamin D bioavailability?

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Yes-Readily absorpbed by gut IF bile salts present

-imparied absorption with biliary cirhosis, steatorrhea

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Vitamin D half-life and excretion

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-T1/2 1-3 days, but it's stored in body tissues for long periods
-Excreted in Bile

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Therapeutic Uses of Vitamin D

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-Rickets and osteomalacia
-osteoporosis
-hypocalcemia
-Hypoparathyroidism
-Renal Failure

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Adverse effects of Vitamin D

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-Hypercalcemia

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Contraindications of Vitamin D use

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Impaired renal function

(inc risk of hypercalcemia)

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Calcium salts indications

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-hypocalcemia
-osteoporosis
-osteomalacia
-hypoparathyroidism
-renal failure
-intestinal osteodystrophy

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Adverse Effects Calcium Salts

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Hypercalcemia

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Drug interactions Calcium Salts

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Thiazide Diuretics (dec calcium excretion)->HYPERCALCEMIA

When given IV, it can precipitate salts

-Digoxin sensitizes heart to Calcium, so Calcium Salts cause wierd, severe heart problems

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Diphosphonate Etidronate

(Didronel)

MOA

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-Analouge to Pyrophosphate
-Deacreases osteoclast activity and number->slows bone turnover

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Diphosphonate Etidronate

(Didronel)

Indications

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Use for osteoporosis (treatment and prophylaxis)

Hypercalcemia of Malignancy

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Diphosphonate Etidronate

(Didronel)

Administration

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Oral or IV

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Diphosphonate Etidronate

(Didronel)
Adverse Effects

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Decreased bone mineralization can lead to OSTEOMALACIA and BONE PAIN

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PTH effectiveness with or without Diphosphonates

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PTH alone is more effective than pth and diphosphonates together

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Selective Estrogen Receptor Modulators (SERMS) For?

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Women lacking estrogen who have increased bone resoprtion

-postmenopausal
-post hysterectomy

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SERMS
eg Raloxifene

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Estrogen agonist activity (full or partial) at bone and Cardiovascular tissues

antagonist activity ot other organs (uterine and breast)

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Loop Diuretics and Calcium

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Decreased calcium reabsorption (->increasd excretion)

Used for hypercalcemia

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Thiazide diuretics and calcium

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Increasd Calcium reabsorption
->decreased excretion

Used in hypercalCEURIA (ie stones)

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Causes of hypercalcemia

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-Hyperparathyroidism
-hypervitaminosis D
-Malignancies sometimes

-Immobilizations

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Treatment for hypercalcemia

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-Diphosphonates (chronic)
-Calcitonin (chronic)
-Loop Diuretics (acute)

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Treatment of HyperCALCIURIA

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Thiazide Diuretics

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Causes of HYPOcalcemia

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-Rickets(juv) and Osteomalacia(adult)
-Hypoparathyroidism
-Renal Failure

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Rickets and osteomalacia due to?

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Vitamin D deficiency
Lack of activation or resistance to Vitamin D
calcium malabsorption

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Treatment for hypocalcemia

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Vitamin D (or active analogs) and calcium supplements

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Osteoporosis

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Excessive resorption of calcium (and loss of bone)
Caused by aging, decreased estrogen (androgen?) and excess GC levels

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osteoporosis treatment

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Vitamin D, Dietary Calcium, diphosphonate, calcitonin, PTH, SERMs (women only)

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Pagets disease causes

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-excessive formation and resportion of bone
-abnormal mutinucleated osteoclasts
-pagetic bone (thick and abn)
-Also causes Deafness, spinal cord compression, High output heart failure, pain

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Pagets Disease Treatment

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Calcitonin, Diphosphonates to decrease bone mineralization

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Uses for Vitmin D

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Rickets, osteomalacia, hypocalcemia, hypoparathyroidism, osteoporosis, renal failure/disease

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uses for PTH

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Osteoporosis

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Uses for calcitonin

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Pagets Disease
Ostoeporosis
hypercalcemia of malignancy

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Uses for SERMs or Estrogen

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Osteoporosis

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Uses of Diphosphonates

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Osteoporosis, pagets disease, hypercalcemia

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Uses of Loop diuretics

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hypercalcemia

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Uses of thazide diuretics

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Hypercalceuria