In pharmacology, 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 (homeostasis) 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 (apoptosis). Bisphosphonates encourage osteoclasts to undergo apoptosis.^[1]

The uses of bisphosphonates include the prevention and treatment of osteoporosis, 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.

Contents 1 History 2 Chemistry and classes 3 Pharmacokinetics 4 Mechanism of action 4.1 Non-nitrogenous 4.2 Nitrogenous 5 Uses 6 Side-effects 7 Footnotes 8 External links

[edit] 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, 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.^[2]

[edit] Chemistry and classes

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

The two PO₃ (phosphonate) 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.

[edit] 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.

[edit] 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.

[edit] 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 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.^[3]

[edit] Nitrogenous

N-containing bisphosphonates:

• Pamidronate (APD, Aredia) - 100
• Neridronate - 100
• Olpadronate - 500
• Alendronate (Fosamax) - 500
• Ibandronate (Boniva) - 1000
• Risedronate (Actonel) - 2000
• Zoledronate (Zometa, Aclasta) - 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).^[4]

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).^[5]

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.

[edit] Uses

Bisphosphonates are used clinically for the treatment of osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), 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. 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.^[6]

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.

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 imperfecta.

[edit] 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. 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 more slowly, 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 (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).^[7]
• A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes^[8]
• Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women.^[9][10][11] The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.^[10] One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.^[10] 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).^[10] FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.^[12][13]
• Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side effects of bisphosphonates. ^[14]
• There are concerns of long-term bisphosphonate use resulting in severe or over suppression of bone turnover especially at the femur 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 grafting as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.^[15]

[edit] Footnotes

[edit] External links

• International Myeloma Foundation article on bisphosphonates

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v • d • e Drugs for treatment of bone diseases (M05) Bisphosphonates Nitrogenous (Alendronic acid, ibandronic acid, incadronic acid, pamidronic acid, risedronic acid, zoledronic acid) Non-nitrogenous (Etidronic acid, clodronic acid, tiludronic acid) Bone morphogenetic proteins Dibotermin alfa · Eptotermin alfa Other Resorption inhibitor (Ipriflavone) · Aluminium chlorohydrate · Dual action bone agent (Strontium ranelate) · Cathepsin K inhibitor (Odanacatib)