Bisphosphonates are classes of drugs that prevent loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drug used to treat osteoporosis. They are called bisphosphonates because they have two phosphonates ( PO (OH)
2 ) group. They are also called diphosphonate ( bis - or in - phosphonates ).
The evidence suggests that they reduce the risk of fractures in post-menopausal women with osteoporosis.
Bone tissue undergoes constant remodeling and is stored in equilibrium (homeostasis) by osteoblasts that create bone and osteoclasts destroy bone. Bisphosphonates inhibit bone digestion by encouraging osteoclasts to undergo apoptosis, or cell death, thus slowing bone loss.
The use of bisphosphonates includes the prevention and treatment of osteoporosis, Paget's bone disease, bone metastasis (with or without hypercalcemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrosa dysplasia, and other conditions suggesting bone fragility.
Video Bisphosphonate
Medical use
Bisphosphonates are used to treat osteoporosis, osteitis deformans (bone Paget's disease), bone metastases (with or without hypercalcemia), multiple myeloma, and other conditions involving fragile and fragile bones.
In osteoporosis and Paget, the most popular first-line bisphosphonate drugs are alendronate and risedronate. If this is not effective or if people develop gastrointestinal problems, intravenous pamidronate may be used. Strontium ranelate or teriparatide is used for refractory disease. The use of strontium ranelate is limited due to increased risk of venous thromboembolism, pulmonary embolism and serious cardiovascular disorders, including myocardial infarction. In postmenopausal women, selective estrogen receptor modulator raloxifene is sometimes given in lieu of bisphosphonates. Bisphosphonates are useful in reducing the risk of vertebral fractures in steroid-induced osteoporosis.
Postmenopausal Osteoporosis
Bisphosphonates are recommended as first-line treatment for post-menopausal osteoporosis.
Long-term treatment with bisphosponates produces an anti-fracture and bone mineral density that persists for 3-5 years after the first 3-5 years of treatment. Alendronate bisphosphonates reduce the risk of hip, vertebral, and wrist fractures by 35-39%; zoledronate reduces the risk of hip fractures by 38% and 62% of vertebral fractures. Risedronate has also been shown to reduce the risk of hip fracture.
After five years of oral treatment or three years of intravenous treatment among those at low risk, bisphosphonate treatment may be discontinued. In those at high risk ten years of oral treatment or six years of intravenous care may be used.
Cancer
Bisphosphonates reduce the risk of bone fractures 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 as to whether bisphosphonates improve survival. A Cochrane 2017 review found that for people with early breast cancer, bisphosphonate treatment may reduce the risk of spreading cancer to people's bones, however, for people who have advanced bisphosphonate treatment of breast cancer does not seem to reduce the risk of cancer. spread to the bone. Side effects associated with bisphosphonate treatment for people with mild and rare breast cancer.
Bisphosphonates can also reduce mortality in those with multiple myeloma and prostate cancer.
More
The evidence suggests that the use of bisphosphonates would be useful in the treatment of complex regional pain syndromes, neuro-immune problems with high MPQ scores, low treatment efficacy and symptoms that may include regional osteoporosis. In 2009 bisphosphonates were "among the only classes of drugs that had survived from a placebo-controlled study that showed statistically significant improvement (in CRPS) with therapy."
Bisphosphonates have been used to reduce fracture rates in children with osteogenesis imperfecta disease and to treat otosclerosis by minimizing bone loss.
Other bisphosphonates, including medronate ( R
1 = H, R
2 = H) and oxidronate ( R
1 = H, R
2 = OH), mixed with radioactive and injected technetium, as a way of describing bones and detecting bone diseases.
Maps Bisphosphonate
Adverse effects
General
Oral bisphosphonates can cause stomach pain and inflammation and esophageal erosion, which is a major problem of preparations that contain oral N . This can be prevented by sitting upright for 30 to 60 minutes after taking the drug. Intravenous bisphosphonates can provide flu-like fevers and symptoms after the first infusion, which is thought to be due to their potential for human activation? T. Cells
Bisphosphonates, when given intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw (ONJ), with mandibles twice as common as the upper jaw and most cases occur after high-dose intravenous administration is used for some cancer patients. Approximately 60% of cases are preceded by dental procedures (which involve bone), and it has been suggested that bisphosphonate treatment should be suspended until after every dental treatment to remove potential sites of infection (antibiotic use may otherwise be indicated). before any operation).
Severe cases of bone, joint, or musculoskeletal pain have been reported, which causes labeling to change.
Recent studies have reported the use of bisphosphonates (especially zoledronate and alendronate) as risk factors for atrial fibrillation in women. An inflammatory response to bisphosphonates or fluctuations in blood calcium levels has been suggested as a possible mechanism. To date, however, the benefits of bisphosphonates, in general, outweigh these risks, although care should be taken on certain populations at high risk of serious side effects of atrial fibrillation (such as patients with heart failure, coronary artery disease, or diabetes). The FDA has not confirmed a causal relationship between bisphosphonates and atrial fibrillation.
Long-term risk
In a large study, women taking bisphosphonates for osteoporosis had an unusual fracture ("biphosphonate fracture") in the femur (thighbone) of the shaft (diaphysis or sub-trochanteric region) of the bone, rather than in the femoral neck, the fracture site most common. However, this unusual fracture is extremely rare (12 in 14,195 women) compared with a general pelvic fracture (272 in 14,195 women), and overall reduction in pelvic fractures caused by bisphosphonates far exceeds unusual shaft fractures. There is concern that long-term bisphosphonate use may lead to over-suppression of bone turnover. It is hypothesized that micro fractures in bone can not heal and eventually merge and spread, resulting in atypical fractures. Such fractures tend to heal poorly and often require some form of bone stimulation, eg bone grafting as a secondary procedure. These complications are uncommon, and the benefits of overall fracture reduction still apply. In cases where there are concerns such fractures occur, teriparatide is potentially a good alternative because it does not cause much damage like bisphosphonates by suppressing bone turnover.
Three meta-analyzes have evaluated whether the use of bisphosphonates is associated with an increased risk of esophageal cancer. Two studies concluded that there was no evidence of increased risk.
Chemistry and class
All bisphosphonate drugs share a common P-C-P "spine":
Two PO
3 (phosphonate ) groups that are covalently connected to carbon determine the name "bis phospho nate" and the function of drugs. Bus refers to the fact that there are two such groups in the molecule.
Chain long ( R
2 in the diagram) determines the chemical properties, workings and strength of the bisphosphonate drug. Short side chains ( R
1 ), often called a 'hook', primarily affecting chemical and pharmacokinetic properties.
Pharmacokinetics
Of bisphosphonates absorbed (from oral dosage) or infused (for intravenous drugs), about 50% are excreted unchanged by the kidney. The rest have a very high affinity for bone tissue, and are rapidly adsorbed onto the bone surface.
Action mechanism
Bisphosphonates are structurally similar to pyrophosphates (see figure above). A group of bisphosphonates mimics the structure of the pyrophosphate, thereby inhibiting the activation of enzymes that utilize pyrophosphates.
The specificity of bisphosphonate-based drugs is derived from two phosphonate groups (and possibly hydroxyl at R
1 ) that work together to coordinate calcium ions. Molecular bisphosphonates preferentially "stick" to calcium and bind it. The largest calcium deposits in the human body are bones, so the bisphosphonates accumulate into high concentrations only in the bone.
Bisphosphonates, when attached to bone tissue, are "swallowed" by osteoclasts, bone cells that break down bone tissue.
There are two classes of bisphosphonates : bisphosphonates containing N and do not contain N . Two types of bisphosphonates work differently in killing osteoclasts.
Non-nitrogen
Non-N & apos; -berbent biphosphonate:
- Etidronate (Didronel) - 1 (potential relatif terhadap etidronate)
- Clodronate (Bonefos, Loron) - 10
- Tiludronate (Skelid) - 10
Non-nitrogen bisphosphonates (dysphosphonates) are metabolized in cells for compounds that replace the ATP terminal pyrophosphate portion, forming a non-functional molecule that competes with adenosine triphosphate (ATP) in cellular energy metabolism. Osteoclasts initiate apoptosis and die, which causes a complete decrease in bone damage. This type of bisphosphonate as a whole has more negative effects than a group containing nitrogen, and is prescribed much less frequently.
Nitrogenous
N - mengandung bifosfonat:
- Pamidronate (APD, Aredia) - 100
- Neridronate (Nerixia) - 100
- Olpadronate - 500
- Alendronate (Fosamax) - 500
- Ibandronate (Boniva - AS, Bonviva - Asia) - 1000
- Risedronate (Actonel) - 2000
- Zoledronate (Zometa, Aclasta) - 10000
Nitrogen 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 containing an isoprene chain at the position of R 1 or R 2 may give specificity to GGPS1 inhibition.
Impaired HMG CoA-reductase pathways at the FPPS level prevent the formation of two metabolites (farnesol and geranylgeraniol) which are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and it is important to trade appropriate sub-cellular proteins (see "lipid protein-anchored " for the principles of this phenomenon).
While inhibition of protein prenylation may affect many proteins found in osteoclasts, disruption to lipid modification of Ras, Rho, Rac proteins has been speculated to underlie the bisphosphonate effect. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is essential to maintain the "ruffled border" necessary for contact between the osteoclast of the impregnation and bone surface.
Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike bisphosphonates, statins do not bind bony surfaces with high affinity, and thus are not specific to bone. Nevertheless, several studies have reported a decrease in fracture (indicator of osteoporosis) and/or increased bone mineral density 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 1960 for use in bone metabolic disorders. Their non-medical use is to soften water in the irrigation systems used in citrus orchards. The initial reason for its use in humans is their potential in preventing the dissolution of hydroxylapatite, the major bone mineral, thus retaining bone loss. Only in the 1990s were their actual action mechanisms indicated by the early launch of Fosamax (alendronate) by Merck & amp; Together.
References
External links
- Myeloma Foundation International Articles on bisphosphonates
Source of the article : Wikipedia
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