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Drugs affecting Bone, ADR of bisphosphanates, Teriparatide, Denosumab:,…
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ADR of bisphosphanates
Distinctive toxicity of these agents is esophageal irritation that can lead to ulceration as well.
To prevent this complication, patient taking bisphosphonates are advised to take nothing by mouth except water and not to lie down at least for half an hour.
This minimises the chances of the drug touching the esophagus.
Zoledronate can result in renal toxicity and first generation bisphosphanates can result in osteomalacia
Osteonecrosis of jaw has been noted with the use of bisphosphanates particularly zoledronate.
Patients receiving bisphosphanates must receive regular dental care and try to avoid dental extraction.
Teriparatide
Teriparatide is a recombinant PTH1-34.
it has been noted that PTH in low and pulsatile doses stimulate bone formation whereas in excess it causes resorption of bones.
Teriparatide is available for the treatment of osteoporosis by intermittent S.C. administration.
Teriparatide stimulates the production of new collagenous bone matrix that must be mineralized.
Therefore, patients receiving teriparatide must have sufficient intake of Vitamin D and calcium.
When teriparatide administered to patients with osteoporosis in dose of 20mcg/day subcutaneously for 2 years,
teriparatide dramatically improves bone density in most bones except the distal radius.
Denosumab:
Denosumab: osteoclasts express a receptor called receptor for activated nuclear factor Kappa B RANK on its surface.
When this receptor is stimulated by RANK ligand, bone resorption results due to the activation of osteoclasts.
Denosumab is a monoclonal antibody against this ligand and is useful for the treatment of osteoporosis.
Osteoprotegrin acts as a decoy receptor for RANK ligand.
Binds it and thus prevents the binding of RANK-L to osteoclasts. It can also prevent osteoporosis.
Denosumab can decrease serum calcium therefore avoided in patients with hypocalcemia.
It has been approved for the treatment of giant cell tumour of bone unresectable.
Drugs
Drugs in this group include first generation drugs like medronate, clodronate and etidronate.
Second generation drugs like alendronate, ibadronate and pamidronate.
And third generation compounds like risedronate and zoledronate most potent.
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Uses of Bisphosphanates
These are used for the treatment of post menopausal and steroid induced osteoporosis,
pagets disease and hypercalcemia of malignancy.
Zoledronate and pamidronate given by IV route.
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Raloxifene
Raloxifene is a selective estrogen receptor modulator
with estrogen agonistic action on bone and antagonistic action on breast and endometrium.
Preferred drug for the treatment and prevention of postmenopausal osteoporosis.
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Cinacalcet:
Cinacalcet: calcium sensing receptors are present on parathyroid gland that regulates the secretion of PTH. Ca2+ activates these receptors and decreases the PTH secretion.
Hypocalcemia will have opposite effect i.e increased PTH secretion.
Cinacalcet acts as calcimimetic drug by directly activating calcium sensing receptors on parathyroid gland.
It has been approved for
the treatment of secondary hyperparathyroidism due to chronic renal disease and for hypercalcemia associated with parathyroid carcinoma.
Strontium ranelate
Strontium ranelate has a novel mechanism of action as It inhibits bone resorption as well as stimulates bone formation.
Strontium is incorporated into hydroxyapatite replacing calcium.
Small increased risk of venous thrombosis, seizures and abnormal cognition have been seen and require further studies
Calcium and calcitriol
Calcium and calcitriol(vitamin D) can be used in the prophylaxis and treatment of osteoporosis.
Calcium can be life saving in extreme hyperkalemia >7meq/L. reverse some of the cardiotoxic effects of K+.
Calcium is also approved for the IV treatment of black widow spider envenomation and magnesium toxicity.
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Vitamin D
causes increase in serum calcium and serum phosphate.
They act by increasing the intestinal absorption of calcium and phosphate and decrease the renal excretion of both.
PTH- parathyroid hormone
causes increase in the serum calcium and decrease in serum phosphate.
They act by decreasing the renal excretion of calcium and increasing the excretion of phosphate.
It increases the resorption of calcium from bone.
It increases the intestinal absorption of calcium by increasing the calcitriol.
Notes:
Thus vitamin D and calcitonin can be used to treat osteoporosis whereas PTH excess can result in osteoporosis
FGF-23
FGF-23 decreases the serum phosphate and has no effect in serum calcium.
It acts by decreasing the calcium and phosphate absorption by the intestine and increased phosphate excretion by kidneys.
Plasma calcium
Plasma calcium is the major factor regulating PTH secretion.
Hypocalcemia stimulates PTH secretion whereas hypercalcemia inhibits it.
Calcium inhibits PTH secretion by stimulating the calcium sensing receptors on parathyroid cells.
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Activation of Vitamin D
Vitamin D2 is ergocalciferol whereas D3 is cholecalciferol.
Vitamin D is converted to 25 OHD calcifediol in the liver with the help of 25-alpha hydroxylase
and then to 1,25 dihydroxy D3 calcitriol by the activation of 1 alpha hydroxylase in kidney.
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Bisphosphanates
Bisphosphanates agents are used for the treatment of osteoporosis due to their inhibitory effect on osteoclast mediated bone resorption.
These drugs accelerate the apoptosis of osteoclasts and also suppress differentiation of osteoclast precursors to mature osteoclast by inhibiting IL-6.
this results due to reduction of cholesterol synthesis via inhibition of farnesyl pyrophosphate synthase by bisphosphanates.
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Major contraindications
Major contraindications of bisphosphanates are renal dysfunction, esophageal motility disorders and peptic ulcer.
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Estrogen
Estrogen increases bone formation and its deficiency in old age may result in postmenopausal osteoporosis.
Use of hormone replacement therapy for this condition predisposes the patients to adverse effects of estrogens
on breast and endometrium(increased incidence of breast and endometrial carcinoma).
Bazedoxifene
Bazedoxifene is another SERM that has been approved
for the prevention of postmenopausal osteoporosis and to treat vasomotor symptoms of menopause.
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Risk of Osteosacroma
The recommended dose of teriparatide should not be exceeded since teriparatide has caused osteosarcoma in rats when administered in high doses.
Due to this potential risk of osteosarcoma teriparatide should be avoided in
pagets disease of bone, prior radiotherapy to the bone, past history of osteo or chondrosarcoma, unexplained increase in alkaline phosphate.
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Gallium nitrate
Gallium nitrate inhibits bone resorption and is useful in management of pagets disease and hypercalcemia of malignancy
but nephrotoxicity limits its use for this indication.
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Thiazides
Thiazides inhibit the renal excretion of calcium and thus can be used for the treatment of osteoporosis
apart from their use in recurrent calcium stones due to hypercalciuria.
Calcitonin
Calcitonin inhibits resorption of bone and thus can be used for the treatment of osteoporosis.
It can be administered by nasal route for this indication.
Calcitonin possess analgesic effects on bone pain from fractures.