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In pharmacology, bisphosphonates (also called: diphosphonates) is a class of drugs that inhibits osteoclast action and the resorption of bone. Its uses include the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bone metastasis (with or without hypercalcemia), multiple myeloma and other conditions that feature bone fragility.
Additional recommended knowledge
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 included water softening 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, and hence arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated.
Chemistry and classes
All bisphosphonate drugs share a common P-C-P "backbone":
The two PO3 (phosphate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs.
The long side chain (R2 in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side chain (R1), often called the 'hook,' mainly influences chemical properties and pharmacokinetics.
Of the bisphosphonate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface.
Mechanism of action
Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cell that breaks down bone tissue.
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.
The non-nitrogenous bisphosphonates(disphosphonates) are metabolised in the cell to compounds that compete 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.
Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase pathway (also known as the mevalonate pathway).
Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol and geranylgeraniol) that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see "lipid anchored protein" for the principles of this phenomenon).
While inhibition of protein prenylation may affect many proteins found in an osteoclast, disruption to the lipid modification of Ras, Rho, Rac proteins has been speculated to underlie the effects of bisphosphonates. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between a resorbing osteoclast and a bone surface.
Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind to bone surfaces with high affinity, and are thus not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture (an indicator of osteoporosis) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment osteoporosis remains controversial.
Bisphosphonates are used clinically for the treatment of osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcemia), multiple myeloma and other conditions that feature bone fragility.
In osteoporosis and Paget's, alendronate and risedronate are the most popular first-line drugs. If these are ineffective or the patient develops digestive tract problems, intravenous pamidronate may be used. Alternatively, strontium ranelate or teriparatide are used for refractory disease, and the SERM raloxifene is occasionally administered in postmenopausal women instead of bisphosphonates.
High-potency intravenous bisphosphonates have shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer.
Other bisphosphonates, medronate (R1, R2 = H) and oxidronate (R1 = H, R2 = OH) are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease.
More recently, bisphosphonates have been used to reduce fracture rates in children with osteogenesis imperfecta.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Bisphosphonate". A list of authors is available in Wikipedia.|