Calcium homeostasis Flashcards
PTH
A peptide- secreted by the parathyroid gland in response to low serum calcium
Binds with PTH receptors in the bones and the kidneys, leads to increase in cAMP level
PTH actions
In bone, PTH can increase both the rate of bone formation and the rate of bone resorption -
pulsatile exposure and low dose- results in net bone formation (increases osteoblastic activity)
continuous exposure results in net bone resorption (increases osteoclastic activity)
Teriparatide
Recombinant analog of human PTH (34 AA)
Administered once a day
this intermittent exposure results in net bone formation (increases the osteoblastic activity).
Teriparatide use
the treatment of osteoporosis (increases spinal bone density and decreases the risk of vertebral fracture and its recurrence).
First approved treatment for osteoporosis that stimulate bone formation (osteoblastic activity)
treatment of glucocorticoid-induced osteoporosis
Teriparatide ADR
Major adverse effects: Hypercalcemia (transient)
Frequent adverse effects: nausea, vomiting, dizziness, depression, limb pain, headache and leg cramps
Report of increased risk of osteosarcoma in rats.
should be reserved for patients at high risks of fractures or who can not tolerate other osteoporosis therapies
Must not be used for more than 2 years
Abaloparatide
An analog of parathyroid hormone-related peptide
Increases the osteoblastic activity
Abaloparatide use
treatment of postmenopausal women with osteoporosis at high risk for fracture, or patients who have failed or are intolerant to other agents
Abaloparatide reduced the risk of new vertebral and non-vertebral fractures over a period of 18 months
Calcitonin
Peptide secreted by parafollicular cells of the thyroid gland in response to elevated Ca2+
Calcitonin actions
Reduces serum Ca2+ and PO4
Antagonizes the actions of PTH through independent mechanism:
Interacts with specific receptors on osteoclasts to decrease net resorption of bone. May also stimulate bone formation.
Increases renal excretion of Ca2+, Na+, and PO4
Calcitonin pharmalogical properties
Synthetic salmon calcitonin differs from human calcitonin by 13 of 32 amino acids and has a longer half-life
Route- intranasal
Reduces bone resorption and improves bone architecture, relieves bone pain*** (unique property) associated with osteoporotic fracture and, increases function
Decreases serum Ca2+ in 2 hours that persists for 6-8 hours
Therapeutic uses of calcitonin
treat hypercalcemia due to Paget’s disease, hyperparathyroidism, idiopathic juvenile hypercalcemia, vitamin D intoxication, osteolytic bone disorders
Used for prevention of osteoporosis (in women who are postmenopausal for>5 years***)
Tolerance develops to the action of calcitonin when it is administered continuously over a long period of time (due to the production of anticalcitonin antibodies).
Vitamin D is a derivative of?
7-dehydrocholesterol
Considered as a pro-hormone
Hydroxylation in the liver → 25-hydroxyvitamin D
Then Hydroxylation in kidneys yields 1,25-dihydroxyvitamin D
Vitamin D actions
Increases calcium and phosphate absorption from the intestine
Increases calcium and phosphate reabsorption from kidneys
Decreases calcium and phosphate excretion by kidneys
Net result: increases serum calcium as well as phosphate
Increases bone formation
Forms of Vitamin D
Calcifediol (25-hydroxy)
Calcitriol (1,25 dihydroxy)***
Other analogs
Calcipotriene: used in psoriasis topically
Doxercalciferol
Paricalcitol
Bisphosphonates
P-C-P bond which is non-hydrolyzable compared to Pyrophosphate
P-O-P bond found in bone hydroxyapatite.
Bisphosphonate MOA
They bind directly to hydroxyapatite crystals in bone and impair resorption
Increase bone density and reduce fractures
Inhibit osteoclastic proton pump (necessary for dissolution of hydroxyapatite crystals)
Inhibit the activity of farnesyl pyro-phosphate synthase (mevalonic acid biosynthetic pathway) important for osteoclastic function (esp. amino biphosphonates)
increase osteoclastic apoptosis
Etidronate, Tiludrontate
First gen bisphosphonates
Alendronate, pamidronate, Ibandronate
Second gen bisphosphonates
Risedrontate, Zoledronate
3rd gen bisphosphonates
Bisphosphonate indications
Paget’s disease
Osteoporosis: For prevention and treatment (preferred in postmenopausal osteoporosis)
Hypercalcemia
Cancer metastases to bone
Other bone diseases with high bone resorption
Pharmacokinetics of Bisphosphonates
VERY poor oral absorption <10% (all bisphosphonates); Pamidronate given IV
Food significantly interferes with absorption (hence administered on empty stomach with 6-8 Oz of water at least 1 hr before breakfast) and patient should remain upright at least for 30 minutes (to prevent esophagitis)
Nearly half of the absorbed drug accumulates in bone
Elimination solely through renal clearance (should not be given to individuals with severe renal impairment)
Bisphosphonate ADR
GI disturbances including GI bleeding, diarrhea, abdominal pain
Esophageal ulceration and erosion*** (esp. with oral bisphosphonates (risedronate, alendronate and Ibandronate)
to minimize the risk of esophageal irritation, patients should remain upright for at least 30 mins (60 mins for Ibandronate)
Osteomalacia and bone pain (esp Etidronate on prolonged treatment)
Fracture of femoral shaft (“Chalk stick fracture”)
Musculoskeletal pain and chest pain
Osteonecrosis of Jaw (ONJ)- esp with zoledronate on high IV dose
Bisphosphonate contraindication
Women who are pregnant or planning pregnancy (although no concrete evidence in human available)
Renal insufficiency
Low serum calcium
Osteomalacia
Oral bisphosphonates should not be used by?
patients with serious esophageal diseases
patients at bed rest who can not stay upright for an hour
Bisphosphonates don’ts:
Not with food in your stomach
Not with a little sip of water (drink at least 4 oz)
Not within 1 hour before you go to bed
Cinacalcet
Calcium sensing receptor activators/calcimimetics
CaSR is widely distributed but has its greatest concentration in parathyroid gland
Inhibits PTH secretion and hence is approved for use in patients with hyperparathyroidism secondary to renal disease and for the treatment of parathyroid carcinoma
Primary hyperparathyroidism in patients unable to be managed surgically
Hypocalcemia- major adverse effect
Calcium and Vit D supplements
Calcium and Vitamin D: essential for optimal bone formation in children and prevention of and treatment of osteoporosis in adults
Also used for prevention and treatment of Hypocalcemia
by ingesting optimal calcium and vitamin D, young adults can have increased bone mass and older adults can have decreased rate of bone loss.
Calcium carbonate
Calcium citrate
Calcium gluconate
Calcium carbonate requires stomach acidity for absorption.
Calcium citrate does not require acidity.
Calcium gluconate is the preferred i.v. preparation
Calcium supplement ADR
constipation and hypercalcemia (with long-term use)
Denosumab
Recombinant humanmonoclonal antibody against RANKL
First RANKL inhibitor to be approved by the FDA
Inhibits maturation of osteoclasts by binding to and inhibiting RANKL
Denosumab treats
osteoporosis, bone metastases (from breast cancer), multiple myeloma, drug induced osteoporosis andgiant cell tumor of bone
SC injection every 6 months for osteoporosis
Patient should use it along with Calcium and vitamin D
Denosumab ADR
Joint and muscle pain in the arms/legs Increased risk of infections Hypocalcemia Hypersensitivity, allergic reactions, Osteonecrosis of the jaw Atypical hip fractures
Secondary agents affecting Ca homeostasis
Thiazide diuretics: decrease the renal excretion of Ca2+ and the incidence of kidney stone formation in patients with idiopathic hypercalciuria
Loop diuretics: Furosemide increases the renal excretion of Ca2+
Estrogens: Effective therapy for the prevention of postmenopausal bone loss
Estrogen receptors found?
When estrogen initiated immediately in postmenopausal …?
receptors are found in bone and have direct effects on bone remodeling.
When initiated immediately in postmenopausal period, prevent osteoporosis and reduce the risk of hip fracture
Reduce the bone resorbing action of PTH
Increase bone density
Why are estrogens no longer the used
increased risk of breast cancer, endometrial cancer, stroke, venous thromboembolism, and coronary disease
Estrogen deficiency
Increases the release of IL-1, IL-6 and IL-7 from stroma cells in bone marrow. IL-7 increases the proliferation of T-cells and TNF
Decreases the production of osteoprotegerin (OPG), increases the production of RANKL and facilitates its binding to RANK (osteoblast secrets RANK L and binds to osteoclast RANK to activate it)
The net result is increase in the osteoblast apoptosis and augmentation of the activity of osteoclasts
Raloxifene
SERM: approved for the prevention and treatment of osteoporosis
It protects against fractures of spine but not hip
alternative for postmenopausal osteoporosis in women who are intolerant to bisphosphonates or denosumab
increases bone density without increasing risk of endometrial cancer and reduces the risk of invasive breast cancer
Raloxifene ADR
Hot flashes, inc of pulmonary embolism, leg cramps, inc risk of deep vein thrombosis
Strontium ranelate
being used in Europe for the treatment of osteoporosis
Acts on both osteoblasts and osteoclasts (Dual action bone agent-DABA)
appears to block osteoclast differentiation while promoting their apoptosis and thus inhibits bone resorption
also promotes bone formation
