In pharmacology, bisphosphonates (also called: diphosphonates) is a class of drugs that inhibits 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. Pharmacology (in Greek: pharmakon (φάρμακον) meaning drug, and lego (λέγω) to tell (about)) is the study of how drugs interact with living organisms to produce a change in function. ... Bone resorption is the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood. ... Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. ... For the musical composition, see Metastasis (Xenakis composition). ... Hypercalcaemia is an elevated calcium level in the blood. ... Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahlers disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. ...

History

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.^[1] Hydroxylapatite is a naturally occurring form of calcium apatite with the formula Ca5(PO4)3(OH), but is usually written Ca10(PO4)6(OH)2 to denote that the crystal unit cell comprises two molecules. ...

Chemistry and classes

All bisphosphonate drugs share a common P-C-P "backbone":

Bisphosphonate basic chemical structure File links The following pages link to this file: Bisphosphonate Categories: GFDL images ...

The two PO₃ (phosphate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs. A phosphate, in inorganic chemistry, is a salt of phosphoric acid. ... Covalent bonding is a form of chemical bonding characterized by the sharing of one or more pairs of electrons between atoms, in order to produce a mutual attraction, which holds the resultant molecule together. ... For other uses, see Carbon (disambiguation). ...

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. The term Side chain can have different meanings depending on the context: In chemistry and biochemistry a side chain is a part of a molecule attached to a core structure. ... Pharmacokinetics (in Greek: pharmacon meaning drug, and kinetikos meaning putting in motion) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. ...

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. An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... For other uses of the word bone, see bone (disambiguation). ...

Mechanism of action

Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cell that breaks down bone tissue. An osteoclast (from the Greek words for bone and broken) is a type of bone cell that removes bone tissue by removing the bones mineralized matrix. ...

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. General Name, symbol, number nitrogen, N, 7 Chemical series nonmetals Group, period, block 15, 2, p Appearance colorless gas Standard atomic weight 14. ...

Bisphosphonate side chain forms File links The following pages link to this file: Bisphosphonate Categories: GFDL images ...

Non-nitrogenous

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 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.^[2] Etidronic acid (INN) or etidronate disodium (trade name Didronel®) is a bisphosphonate used to strengthen bone, treat osteoporosis, and treat Pagets disease of bone. ... Clodronate is a bisphosphonate. ... Tiludronate is a bisphosphonate. ... A few of the metabolic pathways in a cell. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell being used to describe the smallest unit of a living organism Cells in culture, stained for keratin (red) and DNA (green) The cell is the... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... A section of mouse liver showing an apoptotic cell indicated by an arrow Apoptosis (pronounced apo tō sis) is a process of suicide by a cell in a multicellular organism. ...

Nitrogenous

N-containing bisphosphonates:

• Pamidronate (APD, Aredia®) - 100
• Neridronate - 100
• Olpadronate - 500
• Alendronate (Fosamax®) - 500
• Ibandronate (Boniva®) - 1000
• Risedronate (Actonel®) - 2000
• Zoledronate (Zometa®) - 10000

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).^[3] Pamidronate disodium (brand name Aredia®) is a bisphosphonate used to prevent bone loss, and treat osteoporosis. ... Alendronate (Fosamax, Merck) is a bisphosphonate drug used for osteoporosis and several other bone diseases. ... Ibandronic acid (INN) or ibandronate sodium (USAN), marketed under the trade names Boniva®, Bondronat® and Bonviva®, is a potent bisphosphonate drug used in the prevention and treatment of osteoporosis. ... Risedronate sodium (Actonel®) is a bisphosphonate used to strengthen bone and treat or prevent osteoporosis, and to treat Pagets disease of bone. ... Zoledronate (INN: zoledronic acid, marketed by Novartis under the trade names Zometa® and Aclasta®) is a bisphosphonate. ... The HMG-CoA reductase pathway, also known as MVA pathway or mevalonate-dependent (MAD) route, is an important cellular metabolic pathway present in virtually all organisms. ...

HMG-CoA reductase 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).^[4] Download high resolution version (534x695, 17 KB) HMG-CoA reductase pathway ( cholesterol) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Download high resolution version (534x695, 17 KB) HMG-CoA reductase pathway ( cholesterol) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Farnesol is a natural organic compound which is a sesquiterpene alcohol found as a colorless liquid. ... Look up cell membrane in Wiktionary, the free dictionary. ... In lipid anchored proteins, a covalently attached fatty acid such as palmitate or myristate serves to anchor them to the cytoplasmic face of the cell membrane. ...

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. An osteoclast (from the Greek words for bone and broken) is a type of bone cell that removes bone tissue by removing the bones mineralized matrix. ... In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. ... 1. ... RAC is the name of several different things: Reservation against Cancellation related to railway tickets in India RAC plc, a UK motoring organisation Royal Automobile Club, a Gentlemens Club in Pall Mall, London RACA, the oldest motoring organisation in Australia Radio Amateurs of Canada, an association of Canadian amateur...

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. Lovastatin, the first statin to be marketed The statins (or HMG-CoA reductase inhibitors) form a class of hypolipidemic agents, used as pharmaceutical agents to lower cholesterol levels in people with or at risk for cardiovascular disease. ... A fractured bone in a living person is typically treated by restoring the fractured pieces of bone to their natural positions (if necessary), and maintaining those positions while the bone heals. ... Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. ... A bone mineral density (BMD) test, also called a bone mass measurement, is used to measure bone density and determine fracture risk for osteoporosis. ...

Uses

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. Osteoporosis is a disease of bone in which the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. ... For the musical composition, see Metastasis (Xenakis composition). ... Hypercalcaemia is an elevated calcium level in the blood. ... Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahlers disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. ...

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. Strontium ranelate is a medication for osteoporosis marketed as Protelos or Protos by Servier. ... Teriparatide (Forsteo®) is a recombinant form of parathyroid hormone, used in the treatment of advanced osteoporosis. ... Raloxifene is an oral selective estrogen receptor modulator which is used in the prevention of osteoporosis in postmenopausal women. ...

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

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. Osteogenesis imperfecta (OI and sometimes known as Brittle Bone Disease) is a genetic bone disorder. ...

Side-effects

• Oral bisphosphonates can give stomach upset 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. Notably, these symptoms do not recur with subsequent infusions.
• There is a slightly increased risk for electrolyte disturbances, but not enough to warrant regular monitoring.
• In chronic renal failure, the drugs are excreted much slower, and dose adjustment is required.
• Bisphosphonates have been associated with osteonecrosis of the jaw; 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 and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection.^[5]
• A number of cases of severe bone, joint or musculoskeletal pain have been reported, prompting labeling changes^[6]

In anatomy, the stomach is a bean-shaped hollow muscular organ of the gastrointestinal tract involved in the second phase of digestion, following mastication. ... Esophagitis (or Oesophagitis) is inflammation of the esophagus. ... The esophagus (also spelled oesophagus/œsophagus, Greek ), or gullet is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. ... γδ T cells represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. ... An electrolyte is a substance containing free ions that behaves as an electrically conductive medium. ... Osteonecrosis of the jaws (ONj) is a severe bone disease that affects the jaws, including the maxilla and the mandible. ...

Footnotes

External Links

• International Myeloma Foundation article on bisphosphonates
• Bisphosphonates Cause Small Cracks in Bones