In
pharmacologyPharmacology is the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and exogenous chemicals that alter normal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals...
,
bisphosphonates (also called
diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases.
Bone has constant turnover, and is kept in balance (
homeostasisHomeostasis is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition...
) by osteoblasts creating bone and osteoclasts digesting bone. Bisphosphonates inhibit the digestion of bone by osteoclasts.
Osteoclasts also have constant turnover and normally destroy themselves by a process called cell suicide (
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
). Bisphosphonates encourage osteoclasts to undergo apoptosis.
The uses of bisphosphonates include the prevention and treatment of
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
, osteitis deformans ("
Paget's diseaseSir James Paget, a prolific surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
of bone"), bone
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
(with or without
hypercalcaemiaHypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a diagnosis should be undertaken if it persists...
),
multiple myelomaMultiple myeloma , also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease is a cancer of the white blood cells known as plasma cells. A type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates...
,
primary hyperparathyroidismPrimary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands. Its incidence is approximately 42 per 100,000 people...
,
osteogenesis imperfectaOsteogenesis imperfecta is a genetic bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen...
and other conditions that feature bone fragility.
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 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
hydroxylapatiteHydroxylapatite, also called hydroxyapatite, is a naturally occurring mineral form of calcium apatite with the formula Ca53, but is usually written Ca1062 to denote that the crystal unit cell comprises two entities. Hydroxylapatite is the...
, the principal bone mineral, thus 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 PO
3 (
phosphonatePhosphonates or phosphonic acids are organic compounds containing C-PO2 or C-PO2 groups . Bisphosphonates were first synthesized in 1897 by Von Baeyer and Hofmann. An example of such a bisphosphonate is HEDP. Since the work of Schwarzenbach in 1949, phosphonic acids are known...
) groups covalently linked to
carbonCarbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
determine both the name "bis
phosphonate" 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 (R
1), often called the 'hook', mainly influences chemical properties and
pharmacokineticsPharmacokinetics 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 adsorbed onto the bone surface.
Mechanism of action
Bisphosphonates, when attached to bone tissue, are "ingested" by
osteoclastAn osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption...
s, the bone cell that breaks down bone tissue.
There are two classes of
bisphosphonate: the
NNitrogen is a chemical element that has the symbol N and atomic number 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless and mostly inert diatomic gas at standard conditions, constituting 78% by volume of Earth's atmosphere.Many industrially important...
-containing and non-
N-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells.
Non-nitrogenous
Non-
N-containing bisphosphonates:
- Etidronate
Etidronic acid or 1-hydroxyethane 1,1-diphosphonic acid is a bisphosphonate used in detergents, water treatment, cosmetics and pharmaceutical treatment....
(Didronel) - 1 (potency relative to that of etidronate)
- Clodronate (Bonefos, Loron) - 10
- Tiludronate (Skelid) - 10
The non-nitrogenous bisphosphonates(disphosphonates) are
metabolisedMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
in the
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos...
to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional molecule that competes with
adenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleotide that plays an important role in cell biology as a coenzyme, that is, the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP) in the cellular energy metabolism. The osteoclast initiates
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
and dies, leading to an overall decrease in the breakdown of bone.
Nitrogenous
N-containing bisphosphonates:
- Pamidronate (APD, Aredia) - 100
- Neridronate - 100
- Olpadronate - 500
- Alendronate
Alendronic acid or alendronate sodium is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...
(Fosamax) - 500
- Ibandronate (Boniva) - 1000
- Risedronate
Risedronic acid or risedronate sodium is a bisphosphonate used to strengthen bone, treat or prevent osteoporosis, and treat Paget's disease of bone. It is produced and marketed by Procter & Gamble and Sanofi-Aventis....
(Actonel) - 2000
- Zoledronate
Zoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer...
(Zometa, Aclasta) - 10000
Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the
HMG-CoA reductase pathwayThe mevalonate pathway or HMG-CoA reductase pathway or mevalonate-dependent route or isoprenoid pathway, is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria...
(also known as the mevalonate pathway).
Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (
farnesolFarnesol is a natural organic compound which is an acyclic sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils. Farnesol is the alcohol derivative of Farnesol Pyrophosphate...
and geranylgeraniol) that are essential for connecting some small proteins to the
cell membraneThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see "
lipid anchored proteinIn lipid anchored proteins, a covalently attached fatty acid such as palmitate or myristate serves to anchor them to either face of the cell membrane. Examples include G proteins and certain kinases. It is believed that the fatty acid chain inserts and assumes a place in the bilayer structure of...
" for the principles of this phenomenon).
While inhibition of protein prenylation may affect many proteins found in an
osteoclastAn osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption...
, disruption to the lipid modification of
RasRas is a family of genes encoding small GTPases that are involved in cellular signal transduction. Activation of Ras signalling causes cell growth, differentiation and survival...
,
RhoRho may refer to:*Rho , a letter of the Greek alphabet, upper case Ρ, lower case ρ-Symbols:in mathematics* Spectral radius in a spherical coordinate systemin physics* Density of a material* Volume charge density* Resistivity of a material...
,
RacRAC as a three letter acronym that may refer to:* Royal Automobile Club plc, a British motorist's organisation** Royal Automobile Club Foundation, a British motoring advocacy group* Royal Automobile Club, a private club in Pall Mall, London...
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.
StatinThe statins are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease...
s 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
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment osteoporosis remains controversial.
Uses
Bisphosphonates are used clinically for the treatment of
osteoporosisOsteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered...
, osteitis deformans (Paget's disease of the bone), bone
metastasisMetastasis , or metastatic disease, sometimes abbreviated mets, is the spread of a disease from one organ or part to another non-adjacent organ or part...
(with or without
hypercalcaemiaHypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a diagnosis should be undertaken if it persists...
),
multiple myelomaMultiple myeloma , also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease is a cancer of the white blood cells known as plasma cells. A type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates...
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 ranelateStrontium ranelate, a strontium salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. It is unusual in the sense that it both increases deposition of new bone osteoblasts and reduces the resorption of bone by osteoclasts...
or
teriparatideTeriparatide is a recombinant form of parathyroid hormone, used in the treatment of some forms of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.-Administration:...
are used for refractory disease, and the SERM
raloxifeneRaloxifene is an oral selective estrogen receptor modulator that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women...
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 cancerBreast cancer is a cancer that starts in the breast, usually in the inner lining of the milk ducts or lobules. There are different types of breast cancer, with different stages , aggressiveness, and genetic makeup. With best treatment, 10-year disease-free survival varies from 98% to 10%...
. In a randomized control trial, women with breast cancer who received zoledronic acid had a 36% reduction of risk for a recurrence of their breast cancer, a new cancer in the opposite breast, or metastasis to bone compared to women who did not receive that therapy.
Other bisphosphonates, medronate (R
1, R
2 = H) and oxidronate (R
1 = H, R
2 = OH) are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease.
Bisphosphonates are used on the International Space station by crew members on long duration missions.
More recently, bisphosphonates have been used to reduce fracture rates in children with
osteogenesis imperfectaOsteogenesis imperfecta is a genetic bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen...
.
Side-effects
- Oral bisphosphonates can cause upset stomach
In most mammals, the stomach is a hollow, muscular organ of the gastrointestinal tract , between the esophagus and the small intestine. It is involved in the second phase of digestion, following mastication . The word stomach is derived from the Latin stomachus, which derives from the Greek word...
and inflammation- Causes :* The most common cause is gastroesophageal reflux disease . If caused by GERD, the diseases is also called reflux esophagitis....
and erosions of the esophagusThe esophagus or oesophagus , sometimes known as the gullet, is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. The word esophagus is derived from the Latin œsophagus, which derives from the Greek word oisophagos , lit...
, 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
In chemistry, an electrolyte is any substance containing free ions that behaves as an electrically conductive medium, usually when in a solution...
disturbances, but not enough to warrant regular monitoring.
- In chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss of renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
, the drugs are excreted much more slowly, and dose adjustment is required.
- Bisphosphonates have been associated with osteonecrosis of the jaw
Osteonecrosis of the jaws is a severe bone disease that affects the jaws, including the maxilla and the mandible. Jaw bone damage and death occurs as a result of reduced local blood supply...
; 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 (the use of antibiotics may otherwise be indicated prior to any surgery).
- A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes
- Recent studies have reported bisphosphonate use (specifically zoledronate
Zoledronic acid or zoledronate is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer...
and alendronateAlendronic acid or alendronate sodium is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D . Merck's U.S...
) as a risk factor for atrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia and involves the two upper chambers of the heart. Its name comes from the fibrillating of the heart muscles of the atria, instead of a coordinated contraction...
in women. The inflammatory response to bisphosphonates or fluctuations in calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft grey alkaline earth metal, and is the fifth most abundant element by mass in the Earth's crust...
blood levels have been suggested as possible mechanisms. One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use. Until now however, the benefits of bisphosphonates generally outweigh this possible risk, although care needs to be taken in certain populations at high risk of serious adverse effects from atrial fibrillation (such as patients with heart failure, coronary artery disease or diabetes). FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.
- Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
2 may be a candidate gene for Bisphosphonate-associated osteonecrosis of the jawsBisphosphonate-associated osteonecrosis of the jaw, often abbreviated as BON of the jaw or even BRONJ, is a recently discovered dental phenomenon that may lead to surgical complication in the form of impaired wound healing following oral or periodontal surgery or endodontic therapy.There is...
, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of bisphosphonates.
- There are concerns of long-term bisphosphonate use resulting in severe or over suppression of bone turnover especially at the femur
The femur, or thigh bone, is the most proximal bone of the leg in vertebrates capable of walking or jumping, such as most land mammals, birds, many reptiles such as lizards, and amphibians such as frogs...
sub-trochanteric region. It is thought that micro-cracks in the bone are unable to heal and eventually unite and propagate, resulting in atypical fractures. Such fractures tend to heal poorly and often require some form of bone stimulation, for example bone graftingBone grafting is a surgical procedure that replaces missing bone with material from the patient's own body, an artificial, synthetic, or natural substitute...
as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.
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