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.