Treatment of osteoporosis and drugs affecting calcium balance
Osteoporosis and treatment
-
Upload
fariha-shikoh -
Category
Health & Medicine
-
view
430 -
download
0
Transcript of Osteoporosis and treatment
OSTEOPOROSIS AND TREATMENT
by: Fariha FatimaJR-2
FDA-Approved Medications For Osteoporosis Treatment Treatment of osteoporosis should always include:
a well-balanced diet,
getting the right amounts of calcium and vitamin D,
being physically active every day,
not smoking, quitting if you do smoke,
limiting the amount of alcohol you drink, and
taking safety precautions to prevent falls.
However, if diagnosed with osteoporosis, these important lifestyle changes are
often not enough; medication may be needed to stop further bone loss and to
prevent broken bones.
•Two types of agent are currently used for treatment of osteoporosis:
Antiresorptive drugs that decrease bone loss, e.g.
bisphosphonates, calcitonin, selective oestrogen receptor
modulators (SERMs), calcium.
Anabolic agents that increase bone formation e.g. PTH,
teriparatide.
Strontium ranelate has both actions.
BISPHOSPHONATES :
Bisphosphonates inhibit bone resorption by an action mainly on the
osteoclasts.
They form tight complexes with calcium in the bone matrix, and are
released slowly as bone is resorbed by the osteoclasts, which are thus
exposed to high concentrations of the drugs.
•Mechanism of action:
• In terms of their molecular mechanism of action, the bisphosphonates can be
grouped into two classes:
• Simple compounds that are very similar to pyrophosphate (e.g. etidronate).
These are incorporated into ATP analogues that accumulate within the
osteoclasts and promote their apoptosis.
• Potent, nitrogen-containing bisphosphonates (e.g. alendronate, risedronate,
ibandronate, zoledronate).
• These prevent bone resorption by interfering with the anchoring of cell
surface proteins to the osteoclast membrane by prenylation, which is
necessary for their attachment to bone.
•Unwanted effects: include gastrointestinal disturbances including
peptic ulcers and oesophagitis.
• Bone pain occurs occasionally. Given intravenously, some
bisphosphonates (in particular zoledronate) can lead to osteonecrosis of
the jaw.
•Clinical use :
• Alendronate and risedronate are given orally for prophylaxis and treatment of
osteoporosis. Etidronate is an alternative.
• Clodronate is used in patients with malignant disease involving bone and
pamidronate is given by intravenous infusion to treat hypercalcaemia of
malignancy or for Paget's disease.
• Ibandronate is given intravenously every 3-4 weeks in patients with breast
cancer metastatic to bone or every 3 months to treat postmenopausal
osteoporosis.
• Zoledronate, which is given as an intravenous infusion, is used for advanced
malignancy involving bone, for Paget's disease and selected cases of osteoporosis
(postmenopausal or in men) when it is administered once a year.
OESTROGENS AND RELATED COMPOUNDS: • The decline in oestrogen levels is a major factor in postmenopausal
osteoporosis, and there is evidence that giving oestrogen as hormone
replacement therapy can ameliorate this condition.
• But HRT has actions on many systems, and newer non-hormonal agents (e.g.
raloxifene) have now been developed that exhibit agonist actions on some
tissues and antagonist actions on others.
• These are termed selective oestrogen receptor modulators (SERMs).
• The most important of these is raloxifene.
Raloxifene:• Raloxifene is a SERM that has agonist activity on bone, stimulating osteoblasts
and inhibiting osteoclasts. It also has agonist actions on the cardiovascular
system, and antagonist activity on mammary tissue and the uterus.
• It is well absorbed in the gastrointestinal tract, and undergoes extensive first-
pass metabolism in the liver to give the glucuronide-resulting in only about 2%
bioavailability. Colestyramine given with it, reduces the enterohepatic cycling of
raloxifene by 60%.
• Raloxifene is widely distributed in the tissues, and is converted to an active
metabolite in liver, lungs, bone, spleen, uterus and kidney. Its half-life averages
32 h. It is excreted mainly in the faeces
•Unwanted effects include hot flushes, leg cramps, flu-like symptoms and
peripheral oedema.
• Less common are thrombophlebitis and thromboembolism.
• Other rarer adverse effects are thrombocytopenia, gastrointestinal
disturbances, rashes, raised blood pressure and arterial thromboembolism.
• It is not recommended for primary prevention of osteoporotic fractures, but is
one alternative to a bisphosphonate for secondary prevention in
postmenopausal women who cannot tolerate a bisphosphonate
Vitamin D preparations :
Clinical uses of vitamin D :
• Deficiency states: prevention and treatment of rickets, osteomalacia and
vitamin D deficiency owing to malabsorption and liver disease
(ergocalciferol).
• Hypocalcaemia caused by hypoparathyroidism (ergocalciferol).
• Osteodystrophy of chronic renal failure, which is the consequence of
decreased calcitriol generation (calcitriol or alphacalcidol).
Strontium ranelate :• Strontium (given as the ranelate salt) inhibits bone resorption and also
stimulates bone formation. In recent trials, it has been shown to be effective in
preventing vertebral and non-vertebral fractures in older women.
• It is approved in the UK and recommended by the National Institute for
Health and Clinical Excellence as an alternative to a bisphosphonate in
primary or secondary prevention of osteoporotic fractures, when a
bisphosphonate is not tolerated, although some authors consider it to be first-
line treatment for osteoporosis because of its positive risk-benefit ratio.
Parathyroid hormone and Teriparatide:
• PTH and fragments of PTH given in small doses paradoxically stimulate
osteoblast activity and enhance bone formation, and are used to treat selected
patients with osteoporosis. The main compound currently used is teriparatide-
the peptide fragment (1-34) of recombinant PTH.
• Teriparatide has anabolic effects on bone. It reverses osteoporosis by
stimulating new bone formation (Yasothan & Santwana, 2008). It increases
bone mass, structural integrity and bone strength by increasing the number of
osteoblasts and by activating those osteoblasts already in bone. It also reduces
osteoblast apoptosis.
CALCITONIN: • The main preparation available for clinical use is salcatonin (synthetic salmon
calcitonin).
• Synthetic human calcitonin is now also available.
• Calcitonin is given by subcutaneous or intramuscular injection, and there may
be a local inflammatory action at the injection site.
• It can also be given intranasally. Its plasma half-life is 4-12 min, but its action
lasts for several hours.
• Unwanted effects include nausea and vomiting. Facial flushing may occur, as
may a tingling sensation in the hands and an unpleasant taste in the mouth.
Clinical uses of calcitonin/salcatonin :
• Hypercalcaemia (e.g. associated with neoplasia).
• Paget's disease of bone (to relieve pain and reduce neurological
complications).
• Postmenopausal and corticosteroid-induced osteoporosis (with other agents).
CALCIUM SALTS Clinical uses of calcium salts :
• Dietary deficiency.
• Hypocalcaemia caused by hypoparathyroidism or malabsorption (intravenous
for acute tetany).
• Calcium carbonate is an antacid; it is poorly absorbed and binds phosphate in
the gut. It is used to treat hyperphosphataemia.
• Prevention and treatment of osteoporosis (often with oestrogen,
bisphosphonate, vitamin D or calcitonin).
• Cardiac dysrhythmias caused by severe hyperkalaemia (intravenous)
CALCIMIMETIC COMPOUNDS :• Calcimimetics enhance the sensitivity of the parathyroid Ca2+-sensing
receptor to the concentration of blood Ca2+. The effect is to decrease the
secretion of PTH and reduce the serum Ca2+ concentration.
• There are two types of calcimimetics:
Type I are agonists, and include various inorganic and organic cations. They
are not used clinically.
Type II are allosteric activators that activate the receptor indirectly. One such
compound is cinacalcet, which is used for the treatment of
hyperparathyroidism.
• Denosumab was first approved by the FDA in June 2010 for the treatment of
osteoporosis, and later that year for use in preventing skeletal-related events in
adults with solid tumors and bone metastases.
• Romosozumab is an investigational bone-forming agent that is designed to
work by inhibiting the protein sclerostin, thereby increasing bone formation
and decreasing bone breakdown.
• Romosozumab is being studied for its potential to reduce the risk of fractures
in an extensive global Phase 3 program.
•A new peptide analogue (ostabolin-cyclic PTH1-35, which increases
bone mass with less effect on plasma calcium concentration than PTH)
is in development.