Bisphosphonates are a class of drugs that prevent the loss of
bone density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
, used to treat
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis.
They are called bisphosphonates because they have two
phosphonate
In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...
() groups. They are thus also called diphosphonates (''
bis-'' or ''
di-'' + ''
phosphonate
In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...
'').
Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.
Bone tissue
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
undergoes constant remodeling and is kept in balance (homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
) by osteoblasts
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
creating bone and osteoclasts
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...
destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, or cell death, thereby slowing bone loss.
The uses of bisphosphonates include the prevention and treatment of osteoporosis, Paget's disease of bone
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the ...
, bone metastasis (with or without hypercalcemia
Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L defined as hypercalcemi ...
), multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
, primary hyperparathyroidism
Primary hyperparathyroidism (or PHPT) is a medical condition where the parathyroid gland (or a benign tumor within it) produce excess amounts of parathyroid hormone (PTH). The symptoms of the condition relate to the resulting elevated serum calcium ...
, osteogenesis imperfecta
Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mi ...
, fibrous dysplasia
Fibrous dysplasia is a disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fracture, deformity, functional impairm ...
, and other conditions that exhibit bone fragility.
Medical uses
Bisphosphonates are used to treat osteoporosis, osteitis deformans
Paget's disease of bone (commonly known as Paget's disease or, historically, osteitis deformans) is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the ...
(Paget's disease of the bone), bone metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
(with or without hypercalcemia), multiple myeloma, and other conditions involving fragile, breakable bone.
In osteoporosis and Paget's, the most popular first-line bisphosphonate drugs are alendronate
Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementati ...
and risedronate
Risedronic acid, often used as its sodium salt risedronate sodium, is a bisphosphonate. It slows down the cells which break down bone. It's used to treat or prevent osteoporosis, and treat Paget's disease of bone. It is taken by mouth.
It was pa ...
. If these are ineffective or if the person develops digestive tract problems, intravenous pamidronate
Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis.
It was patented in 1971 and approved for medical use in 1987.
Medical uses
It is used to pre ...
may be used. Strontium ranelate
Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it bo ...
or teriparatide
Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first ( N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) ag ...
are used for refractory disease. The use of strontium ranelate is restricted because of increased risk of venous thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
and serious cardiovascular disorders, including myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
. In postmenopausal women, the selective estrogen receptor modulator
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists a ...
raloxifene
Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to ...
is occasionally administered instead of bisphosphonates. Bisphosphonates are beneficial in reducing the risk of vertebral fracture
A spinal fracture, also called a vertebral fracture or a broken back, is a fracture affecting the vertebrae of the spinal column. Most types of spinal fracture confer a significant risk of spinal cord injury. After the immediate trauma, there i ...
in steroid induced osteoporosis
Steroid-induced osteoporosis is osteoporosis arising from the use of glucocorticoids (a class of steroid hormones) analogous to Cushing's syndrome but involving mainly the axial skeleton. The synthetic glucocorticoid prescription drug prednisone ...
.
Post-menopausal osteoporosis
Bisphosphonates are recommended as a first line treatments for post-menopausal osteoporosis.
Long-term treatment with bisphosphonates produces anti-fracture and bone mineral density effects that persist for 3–5 years after an initial 3–5 years of treatment. The bisphosphonate alendronate reduces the risk of hip, vertebral, and wrist fractures by 35-39%; zoledronate reduces the risk of hip fractures by 38% and of vertebral fractures by 62%. Risedronate has also been shown to reduce the risk of hip fractures.
After five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped.[ In those at higher risk ten years of medication by mouth or six years of intravenous treatment may be used.]
Cancer
Bisphosphonates reduce the risk of fracture and bone pain in people with breast, lung, and other metastatic cancers as well as in people with multiple myeloma. In breast cancer there is mixed evidence regarding whether bisphosphonates improve survival. A 2017 Cochrane review found that for people with early breast cancer, bisphosphonate treatment may reduce the risk of the cancer spreading to the person's bone, however, for people who had advanced breast cancer bisphosphonate treatment did not appear to reduce the risk of the cancer spreading to the bone. Side effects associated with bisphosphonate treatment for people with breast cancer are mild and rare.
Bisphosphonates can also reduce mortality in those with multiple myeloma and prostate cancer.
Other
Evidence suggests that the use of bisphosphonates would be useful in the treatment of complex regional pain syndrome, a neuro-immune problem with high MPQ scores, low treatment efficacy and symptoms which can include regional osteoporosis. In 2009 bisphosphonates were "among the only class of medications that has survived placebo-controlled studies showing statistically significant improvement (in CRPS) with therapy."
Bisphosphonates have been used to reduce fracture rates in children with the disease osteogenesis imperfecta
Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mi ...
and to treat otosclerosis
Otosclerosis is a condition of the middle ear where portions of the dense enchondral layer of the bony labyrinth remodel into one or more lesions of irregularly-laid spongy bone. As the lesions reach the stapes the bone is resorbed, then har ...
by minimizing bone loss.
Other bisphosphonates, including medronate (R1=H, R2=H) and oxidronate (R1=H, R2=OH), are mixed with radioactive technetium
Technetium is a chemical element with the symbol Tc and atomic number 43. It is the lightest element whose isotopes are all radioactive. All available technetium is produced as a synthetic element. Naturally occurring technetium is a spontaneous ...
and injected, as a way to image bone and detect bone disease.
Adverse effects
Common
Oral bisphosphonates can cause upset stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
and inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and erosions of the esophagus
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
, which is the main problem of oral ''N''-containing preparations, that is ones containing "normal" unbranched chains. 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
Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss ...
after the first infusion, which is thought to occur because of their potential to activate human γδ T cells.
Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws (the maxilla and the mandible). Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.
Osteo ...
(ONJ), with the mandible
In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower tooth, teeth in place. The mandible sits beneath the maxilla. It is the only movabl ...
twice as frequently affected as the maxilla
The maxilla (plural: ''maxillae'' ) in vertebrates is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. The t ...
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 involves 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.
Some studies have identified bisphosphonate use as a risk factor for atrial fibrillation (AF), though meta-analysis of them finds conflicting reports. , the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
did not recommend any alteration in prescribing of bisphosphonates based on AF concerns. More recent meta-analyses have found strong correlations between bisphosphonate use and development of AF, especially when administered intravenously, but that a significantly increased risk of AF that required hospitalization did not have an attendant increased risk of stroke or cardiovascular mortality.
Long-term risks
In large studies, women taking bisphosphonates for osteoporosis have had unusual fractures ("bisphosphonate fractures") in the femur
The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates with ...
(thigh bone) in the shaft (diaphysis
The diaphysis is the main or midsection (shaft) of a long bone. It is made up of cortical bone and usually contains bone marrow and adipose tissue (fat).
It is a middle tubular part composed of compact bone which surrounds a central marrow cavit ...
or sub-trochanteric region) of the bone, rather than at the femoral neck, which is the most common site of fracture. However, these fractures are rare (12 in 14,195 women) compared to the common hip fractures (272 in 14,195 women), and the overall reduction in hip fractures caused by bisphosphonate is more than the increase in unusual shaft fractures. There are concerns that long-term bisphosphonate use can result in over-suppression of bone turnover. It is hypothesized 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 grafting
Bone grafting is a surgical procedure that replaces missing bone in order to repair bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly. Some small or acute fractures can be cured wit ...
as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds. In cases where there is concern of such fractures occurring, teriparatide
Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first ( N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) ag ...
is potentially a good alternative because it does not cause as much damage as a bisphosphonate does by suppressing bone turnover.
Three meta analyses have evaluated whether bisphosphonate use is associated with an increased risk of esophageal cancer. Two studies concluded that there was no evidence of increased risk.
Chemistry and classes
All bisphosphonate drugs share a common phosphorus-carbon-phosphorus "backbone":
The two (phosphonate
In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...
) groups covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
ly linked to carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...
determine both the name "bis''phospho''nate" and the function of the drugs. ''Bis'' refers to the fact that there are two such groups in the molecule.
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
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
.
See nitrogenous and non-nitrogenous sections in ''Mechanism of action'' below.
Pharmacokinetics
Of the bisphosphonate that is resorbed (from oral preparation) or infused (for intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, an ...
, and is rapidly adsorbed onto the bone surface. Once bisphosphonates are in bone, they have a very long elimination half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
that can exceed ten years.
Mechanism of action
Bisphosphonates are structurally similar to pyrophosphate
In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among other ...
, but with a central carbon that can have up to two substituent
A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''side ...
s (R1 and R2) instead of an oxygen atom. Because a bisphosphonate group mimics the structure of pyrophosphate, it can inhibit activation of enzymes that utilize pyrophosphate.
The specificity of bisphosphonate-based drugs comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially bind to calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
ions. 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 released by osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
s, the bone cells that break down bone tissue. Bisphosphonate molecules then attach to and enter osteoclasts where they disrupt intracellular enzymatic functions needed for bone resorption
Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood.
The osteoclasts are multi-nucleated ...
.
There are two classes of bisphosphonate compounds: non-nitrogenous (no nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
in R2) and nitrogenous (R2 contains nitrogen). The two types of bisphosphonates work differently in killing osteoclasts.
Non-nitrogenous
The non-nitrogenous bisphosphonates (diphosphonates) are metabolised in the cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
to compounds that replace the terminal pyrophosphate moiety of ATP, forming a non-functional molecule that competes with adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
and dies, leading to an overall decrease in the breakdown of bone. This type of bisphosphonate has overall more negative effects than the nitrogen containing group, and is prescribed far less often.
Nitrogenous
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).
Bisphosphonates that contain isoprene
Isoprene, or 2-methyl-1,3-butadiene, is a common volatile organic compound with the formula CH2=C(CH3)−CH=CH2. In its pure form it is a colorless volatile liquid. Isoprene is an unsaturated hydrocarbon. It is produced by many plants and animals ...
chains at the R1 or R2 position can impart specificity for inhibition of GGPS1
Geranylgeranyl pyrophosphate synthase is an enzyme that in humans is encoded by the ''GGPS1'' gene.
Function
This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. ...
.
Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol
Farnesol is a natural 15-carbon organic compound which is an acyclic sesquiterpene alcohol. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils.
Farnesol is produced from 5- ...
and geranylgeraniol
Geranylgeraniol is a diterpenoid alcohol. It is a colorless waxy solid.
Geranylgeraniol is an important intermediate in the biosynthesis of other diterpenes, of vitamins E, and of K. It also used in the post-translational modification known ...
) that are essential for connecting some small proteins to the cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see "''lipid-anchored protein
Lipid-anchored proteins (also known as lipid-linked proteins) are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilay ...
''" for the principles of this phenomenon).
While inhibition of protein prenylation may affect many proteins found in an osteoclast
An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...
, disruption to the lipid modification of Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
, Rho
Rho (uppercase Ρ, lowercase ρ or ; el, ρο or el, ρω, label=none) is the 17th letter of the Greek alphabet. In the system of Greek numerals it has a value of 100. It is derived from Phoenician letter res . Its uppercase form uses the sa ...
, 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.
Statin
Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.
Low- ...
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 thus are not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture
Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displa ...
(an indicator of osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
) and/or an increased bone mineral density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
in statin users. The overall efficacy of statins in the treatment of osteoporosis remains controversial.
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 hydroxylapatite
Hydroxyapatite, also called hydroxylapatite (HA), is a naturally occurring mineral form of calcium apatite with the formula Ca5(PO4)3(OH), but it is usually written Ca10(PO4)6(OH)2 to denote that the crystal unit cell comprises two entities. ...
, the principal bone mineral, thus arresting bone loss. In the 1990s their actual mechanism of action was demonstrated with the initial launch of alendronate
Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementati ...
by Merck & Co.
Notes
References
External links
International Myeloma Foundation article on bisphosphonates
{{Bisphosphonates
Farnesyl pyrophosphate synthase inhibitors