Calcemic Hormones

Leonard Waite, PhD

Dept. of Pharmacology
And Toxicology
 Slow
Very Slow

Fast
Blood calcium Concentrations
Major hormones involved in calcium homeostasis

Hormone Target Effect

PTH Bone Increases bone resorption
Increases bone formation

Kidney Increases Ca++ reabsorption

Decreases PO4--- reabsorption
Intestine Indirectly increases Ca++ and
PO4--- absorption
CT Bone Decreases bone resorption
Vitamin D Intestine Increases Ca++ and PO4---
absorption
 Effects of Hormones on Blood Calcium and Phosphate

Hormone Calcium Phosphate

PTH (1)* Increases Decreases

Vit. D (2) Increases Increases

CT (3) Decreases Decreases

* Order of importance in human calcium homeostasis

PTH and Calcium Homeostasis
Bone resorption and formation cycle

1 = reduced formation 2= normal formation 3= excess formation

Osteoporosis = slightly less than 2

Osteoclastic bone resorption
Decrease in
Plasma Ca++
Cinacalcet (Sensipar)
A calcimimetic
Sensitizes the parathyroid calcium receptor to
calcium
Decreases the release of parathyroid hormone
Approved for use in dialysis patients who develop
secondary hyperparathyroidism and parathyroid
carcinoma
Calcilytics- calcium receptor antagonists
Experimental
Potential use – short term stimulation of PTH
secretion to stimulate bone formation
Parathyroid Hormone related protein (PTHrP)
Originally discovered to be a secretory product of
various cancer cells
Also secreted by nonmal cells
Combines with PTH receptors and mimics the
effects of PTH
Thought to be responsible for the hypercalcemia
associated with some malignancies( Humoral
Hypercalcemia of Malignancy, HHM)
Hypercalcemia of malignancy is also caused by
skeletal metastases
Parathyroid Hormone related Protein (PTHrP) continued
PTH like protein secreted by several types of cancer
cells
Binds to PTH receptors in bone and stimulates
osteoclastic bone resorption
Binds to renal PTH receptors and increases calcium
reabsorption
Now know to be a family of proteins that bind to PTH
receptors and many other receptors resulting in
smooth muscle relaxation, placental calcium
transfer, normal eruption of teeth, etc.
PTH / PTHrP receptor
Bone receptor is on osteoblasts
Osteoblasts signal the recruitment and activation
of osteoclasts
Clinical use of PTH
Constant PTH – stimulates bone resorption
Intermittent PTH – stimulates bone formation

Teriparatide (Forteo) – AAs 1-34 of human PTH

Treatment of osteoporosis (intermittent use)
Best stimulator of bone formation
Other agents inhibit resorption
Cinacalcet (Sensipar)
A calcimimetic
Sensitizes the parathyroid calcium receptor to
calcium
Decreases the release of parathyroid hormone
Approved for use in dialysis patients who develop
secondary hyperparathyroidism and parathyroid
carcinoma
Calcilytics- calcium receptor antagonists
Experimental
Potential use – short term stimulation of PTH
secretion to stimulate bone formation
Calcitonin
 Structures of some animal calcitonins

Human
Mouse
Porcine
Salmon
Eel
Calcitonin receptor

Osteoclast membrane
Stimulation decreases resorption
Salmon calcitonin better agonist than human
calcitonin
Available as a nasal spray
Not very efficacious for hypercalcemia
Clinical use of calcitonin
Treatment of hypercalcemia
Treatment of osteoporosis
Treatment of Pagets disease

Use is limited by “calcitonin escape”

Drug is effective for days to weeks but effect
then decreases
Thought to be due to receptor down
regulation
Medullary carcinoma of the thyroid
Vitamin D
Necessary for PTH mediated bone resorption
Necessary for proper bone mineralization
Indirect effect
Helps maintain sufficient blood calcium for
proper bone mineralization
Deficiency
Children – rickets
Adults- osteomalacia
Activation of vitamin D

Major circulating form

Clinical use of vitamin D
Most people respond adequately to vitamin D
(cheap)
If a rapid response is needed calcitriol is the choice
but is more expensive

Treatment of rickets and osteomalacia

Treatment of hypocalcemia
Stimulate intestinal calcium absorption
Often used with a calcium supplement
Stimulate bone resorption
Requires larger doses
Nonhypercalcemic analogues of vitamin D
Calcipotriol*
Paracalcitol**
22-Oxacalcitol**

Uses
**Treatment of hyperparathyroidism
Inhibits the secretion of PTH
*Treatment of psoriasis
**Treatment of cancer*
Treatment of hypercalcemia

Causes of hypercalcemia
Hyperparathyroidism
Malignancy
Bone metastases
Humural Hypercalcemia of Malignancy (HHM)
PTHrP
Other causes
Agents used to treat hypercalcemia

Rehydration
Diuretics and sodium loading
Phosphate
Plicamycin
Gallium nitrate
Calcitonin
Bisphosphonates
Diuretics for treating hypercalcemia
Loop diuretics – drugs of choice
Thiazide diuretics – contraindicated
Increase blood calcium
Loop diuretics –furosemide
Inhibit sodium reabsorption in the ascending
limb of the loop of Henle
Calcium reabsorption is coupled to sodium
reabsorption in the loop
Sodium infusion leads to increased sodium
loss and increased calcium loss
Phosphate therapy for hypercalcemia
Oral phosphate supplements
Exceeds the solubility of calcium phosphate
and the salt precipitates in the intestine
May increase blood phosphate and cause
soft tissue calcification
IV phosphate
Crystal seeds in bone cause precipitation
from a metastable solution of blood calcium
and phosphate
Soft tissue calcification is a major problem
Rarely used
Plicamycin
Introduced for the treatment of testicular cancer
Inhibits bone resorption
Some use in resistant cases of Pagets disease
Toxicity limits use
Cortical steroids
Are lytic to some cancers (breast, lymphoid, others)
Inhibits intestinal calcium absorption
Treat sarcoidosis, vitamin D overdose and
vitamin A overdose
Bisphosphonates
Derivatives of pyrophosphate
Bisphosphonates
Nonamino – inhibit formation and resorption
Amino – inhibit resorption
Ring amino- inhibit resorption, longer DOA, more efficacious
Bisphosphonates continued
Mechanism
Bind to bone hydroxyapatite at active sites of
resorption
Incorporated into osteoclasts
Non-amino bisphosphonates are metabolized
to a cytotoxic product that is cytotoxic to
osteoclasts
Amino bisphosphonates are not metabolized
Amino bisphosphonates inhibit the
prenylation of small osteoclastic GTP
binding proteins that are essential for
normal osteoclastic function
Prenyl- functional group
Geranyl-geryanyl pyrophosphate
Protein Prenylation
Mechanism of action of aminobisphosphonates

Derivatives of
pyrophosphate

Farnesyl
Pyrophosphate
Synthase
Adverse effects of bisphosphonates
Low bioavailability < 5%
Patient must remain ambulatory for 30-60 minutes to
avoid unpleasant GI effects
Osteonecrosis (dead jaw syndrome)
Bisphosphonates disrupt the normal
resorption – formation cycle
When teeth are removed normal bone
overgrowth is deficient, infection may
develop and bone resorption increases
Mainly associated with the chronic IV use of
zoledronate and/or pamidronate in
cancer patients
Drugs used in the treatment of osteoporosis
Inhibitors of bone resorption
Hormone replacement therapy – estrogen
Abandoned by most
Raloxifene
Bisphosphonates
Calcitonin
Stimulators of bone formation
Teriparatide
Only FDA approved drug that stimulates bone
formation
Raloxifene
SERM – Selective Estrogen Receptor
Modifier
SERMs stimulate some estrogen receptors
and inhibit other estrogen receptors
Raloxifene stimulates bone estrogen
receptors and inhibits breast and uterine
estrogen receptors
It increases bone mineral density by
inhibiting bone mineral loss (resorption)
Teriparatide
Amino acids 1-34 of PTH ( 84 AAs)
PTH stimulates osteoclastic bone resorption
Intermittent treatment with PTH stimulates
osteoblastic bone formation
Teriparatide currently a drug of choice for treating
osteoporosis
Only drug with a primary mechanism of action of
increasing bone formation
Must be injected
Effect of various drugs on spinal bone mineral density