Bisphosphonates in medicine - Студенческий научный форум

IV Международная студенческая научная конференция Студенческий научный форум - 2012

Bisphosphonates in medicine

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Bisphosphonates (also called diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. They are called bisphosphonates because they have two phosphonate (PO3) groups and are similar in structure to pyrophosphate. Bisphosphonates all have in common the P-C-P structure, which is similar to the P-O-P structure of native pyrophosphate . Bisphosphonates differ from each other only at the two "R" groups in the accompanying  

Evidence shows that they reduce the risk of osteoporotic fracture in those who have had previous fractures. However, they do not reduce fracture risk in those with osteoporosis who have not previously had a fracture.Bone undergoes constant turnover and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.

The following are the medical  uses:

*The uses of bisphosphonates include the prevention and treatment of osteoporosis, osteopenia, osteitis deformans ("Paget´s disease of bone"), bone metastasis (with or without hypercalcaemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, and other conditions that feature bone fragility.

*Bisphosphonates have been used to reduce fracture rates in children with the disease osteogenesis imperfecta, to treat otosclerosis., and by crew members on long-duration missions on the International Space Station to minimize bone loss.

*Clinical manifestations and diagnosis of Paget disease of bone. In osteoporosis and Paget´s, the most popular first-line bisphosphonate drugs are alendronate (Merck) and risedronate.

* High-potency intravenous bisphosphonates have been shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer.

* Bisphosphonates in the management of osteoporosis in postmenopausal women. Postmenopausal women with vertebral compression fractures and decrease in the  total hip bone density .

* Elderly men with non-traumatic fractures.
Some  patients with secondary osteoporosis due to corticosteroids  .

HOW IT WORKS? Bisphosphonates are antiresorptive medicines, which means they slow or stop the natural process that dissolves bone tissue, resulting in maintained or increased bone density and strength. This may prevent the development osteoporosis. If osteoporosis already has developed, slowing the rate of bone thinning reduces the risk of broken bones. Bisphosphonates´ mechanisms of action all stem from their structures´ similarity to pyrophosphate .

 A bisphosphonate group mimics pyrophosphate´s structure, thereby inhibiting activation of enzymes that utilize pyrophosphate . Bisphosphonate-based drugs´ specificity comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially "stick" to calcium and bind to it. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration only in bones.Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cells that break down bone tissue .Bisphosphonates may be taken by men or women

 The bisphosphonates inhibit osteoclastic bone resorption via a mechanism that differs from that of other antiresorptive agents . Bisphosphonates attach to hydroxyapatite binding sites on bony surfaces, especially surfaces undergoing active resorption. When osteoclasts begin to resorb bone that is impregnated with bisphosphonate, the bisphosphonate released during resorption impairs the ability of the osteoclasts to form the ruffled border, to adhere to the bony surface, and to produce the protons necessary for continued bone resorption . Bisphosphonates also reduce osteoclast activity by decreasing osteoclast progenitor development and recruitment and by promoting osteoclast apoptosis .In addition to their inhibitory effect on osteoclasts, bisphosphonates appear to have a beneficial effect on osteoblasts. In a murine model of glucocorticoid-induced osteoporosis, bisphosphonates prevented osteocyte and osteoblast apoptosis . The mechanism of this effect involves connexin 43, a gap junction protein that facilitates activation of protein kinases. This anti-apoptotic effect, however, probably does not contribute significantly to the anti-osteoporotic efficacy of bisphosphonates, above their potent antiresorptive actions.Bone formation is often reduced by bisphosphonates, which is probably an indirect effect of inhibition of bone resorption. In normal bone remodeling, bone resorption and formation are coupled. Changes in resorption drive formation, so, when bone resorption decreases, bone formation also decreases.

There are two classes of bisphosphonate: the N-containing and non-N-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells.


Non-N-containing bisphosphonates:

Etidronate (Didronel) - 1 (potency relative to that of etidronate)

Clodronate (Bonefos, Loron) - 10

Tiludronate (Skelid) - 10

The non-nitrogenous bisphosphonates(disphosphonates) are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone.                                                                                                    


N-containing bisphosphonates:

Pamidronate (APD, Aredia) - 100

Neridronate - 100

Olpadronate - 500

Alendronate (Fosamax) - 500

Ibandronate (Boniva) - 1000

Risedronate (Actonel) - 2000

Zoledronate (Zometa, Aclasta) - 10000

Bisphosphonates are avoided in such cases:

*Women who are pregnant or planning pregnancy 
 *Chronic kidney disease stages 4 or 5 
 *Low serum calcium 
*Vitamin D deficiency (until it is corrected) 
*Oral bisphosphonates should not be used in: -Patients with serious esophageal disease 
-Patients at bedrest who can´t stay upright for an hour .*People with severe heartburn or inflammation of the esophagus (the tube that connects the throat to the stomach).

*Pregnant women


-Patients with abnormal white blood cells 
-Patients with high PTH 
-Patients with gastric or intestinal bypass surgery 
-Children (no long-term safety data) 
The following are the side effects: Oral bisphosphonates can cause upset stomach and inflammation and erosions of the esophagus, which is the main problem of oral N-containing preparations. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication. Intravenous bisphosphonates can give fever and flu-like symptoms after the first infusion, which is thought to occur because of their potential to activate human γδ T cells. These symptoms do not recur with subsequent infusions.Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw (ONJ), with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure (that involve the bone), and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection.

Side effect in case of  oral uptake of bisphosphonates:                

1. Trouble swallowing (dysphagia)  2.Muscle pain or cramps   3.Stomach pain     

 Side effect in case of intravenous(i.v) bisphosphonates:

1. Blood in the urine.   2.  Dizziness   3. Unusual tiredness or weakness.  4.  Muscle pain or cramps.

Common side effects of this medicine include:

Heartburn and irritation of esophageal mucous membrane ,if you are taking bisphosphonate pills. Headache;constipation,diarrhea, and flatulence; and muscle andjoint pain, if you are taking intravenous (IV) bisphosphonate shots.

Bisphosphonates were developed in the 19th century but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxylapatite, the principal bone mineral, thus arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated with the initial launch of Fosamax (alendronate) by Merck.

 This topic review provides an overview of the pharmacology of the bisphosphonates and of the differences between the preparations that are either currently available or undergoing clinical testing. Bisphosphonates are a unique class of drugs. As a family, they are characterized pharmacologically by their ability to inhibit bone resorption, whereas, pharmacokinetically, they are classified by their similarity in absorption, distribution, and elimination. Although all bisphosphonates have similar physicochemical properties, their antiresorbing activities differ substantially.

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