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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/04/25 08:33:07」(JST)
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Chemical structure of pyrophosphate (A, above) and bisphosphonates (B, below). P = phosphorus, O = oxygen, H = hydrogen, C = carbon, R = side chain. In bisphosphonates, the central oxygen atom is replaced with a carbon atom. All bisphosphonates share a common phosphorus-carbon-phosphorus motif with two side chains (R1 and R2 in the figure). The R2 side chain determines the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis.[1] They are called bisphosphonates because they have two phosphonate (PO(OH)
2) groups.
Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.[2][3][4][5][6]
Bone undergoes constant turnover and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.[7]
The uses of bisphosphonates include the prevention and treatment of osteoporosis, Paget's disease of bone, bone metastasis (with or without hypercalcaemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrous dysplasia, and other conditions that exhibit bone fragility.
Contents
- 1 Medical uses
- 1.1 Post-menopausal osteoporosis
- 1.2 Cancer
- 1.3 Other
- 2 Adverse effects
- 2.1 Common
- 2.2 Long-term risks
- 3 Chemistry and classes
- 4 Pharmacokinetics
- 5 Mechanism of action
- 5.1 Non-nitrogenous
- 5.2 Nitrogenous
- 6 History
- 7 References
- 8 External links
Medical uses
Bisphosphonates are used to treat osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), multiple myeloma, and other conditions involving fragile, breakable bone.
In osteoporosis and Paget's, the most popular first-line bisphosphonate drugs are alendronate and risedronate. If these are ineffective or if the person develops digestive tract problems, intravenous pamidronate may be used. Strontium ranelate or teriparatide are used for refractory disease. The use of strontium ranelate is restricted because of increased risk of venous thromboembolism, pulmonary embolism and serious cardiovascular disorders, including myocardial infarction.[8] In postmenopausal women, the selective estrogen receptor modulator raloxifene is occasionally administered instead of bisphosphonates.
Post-menopausal osteoporosis
Bisphosphonates are recommended as a first line treatments for post-menopausal osteoporosis.[9][10][11][12]
Long-term treatment with bisphosponates produces anti-fracture and bone mineral density effects that persist for 3–5 years after an initial 3–5 years of treatment.[2] 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%.[3][4] Risedronate has also been shown to reduce the risk of hip fractures.[6][13]
After five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped.[14] In those at higher risk ten years of medication by mouth or six years of intravenous treatment may be used.[14]
Cancer
Bisphosphonates reduce the risk of fracture and bone pain[15] in people with breast,[16] lung,[17] and other metastatic cancers as well as in people with multiple myeloma.[18] In breast cancer there is mixed evidence regarding whether bisphosphonates improve survival.[19][20]
Bisphosphonates can also reduce mortality in those with multiple myeloma, breast and prostate cancer.[21]
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."[22]
Other bisphosphonates, including medronate (R
1=H, R
2=H) and oxidronate (R
1=H, R
2=OH), are mixed with radioactive technetium and injected, as a way to image bone and detect bone disease. Bisphosphonates have been used to reduce fracture rates in children with the disease osteogenesis imperfecta[23] and to treat otosclerosis[24] by minimizing bone loss.
Adverse effects
Common
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.
Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw (ONJ), 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).[25]
A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes[26]
Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women.[27][28][29] The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.[28] Until now, however, the benefits of bisphosphonates, in general, outweigh this risk, although care must 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).[28] FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.[30][31]
Long-term risks
In large studies, women taking bisphosphonates for osteoporosis have had unusual fractures ("bisphosphonate fractures") in the femur (thigh bone) in the shaft (diaphysis or sub-trochanteric region) of the bone, rather than at the femoral neck, which is the most common site of fracture. However, these unusual fractures are extremely 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 far outweighed the unusual shaft fractures.[32] 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 as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.[32][33] In cases where there is concern of such fractures occurring, teriparatide is potentially a good alternative because it does not cause as much damage as a bisphosphonate does by suppressing bone turnover.[34]
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.[35][36][37]
Chemistry and classes
All bisphosphonate drugs share a common P-C-P "backbone":
The two PO
3 (phosphonate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs. Bis refers to the fact that there are two such groups in the molecule.
The long side-chain (R
2 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 pharmacokinetics.
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' mechanisms of action all stem from their structures' similarity to pyrophosphate (see figure above). A bisphosphonate group mimics pyrophosphate's structure, thereby inhibiting activation of enzymes that utilize pyrophosphate.
Bisphosphonate-based drugs' specificity comes from the two phosphonate groups (and possibly a hydroxyl at R
1) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially "stick" to calcium and bind to it. 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 "ingested" by osteoclasts, the bone cells that break 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.
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 non-functional 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. This type of bisphosphonate has overall more negative effects than the nitrogen containing group, and is prescribed far less often.[38]
Nitrogenous
N-containing bisphosphonates:
- Pamidronate (APD, Aredia) — 100
- Neridronate (Nerixia[39]) — 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).[40]
Bisphosphonates that contain isoprene chains at the R1 or R2 position can impart specificity for inhibition of GGPS1.[41]
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).[42]
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 thus are 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 of osteoporosis remains controversial.[43]
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 & Co.[44]
References
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External links
- International Myeloma Foundation article on bisphosphonates
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UpToDate Contents
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- 1. 閉経後女性における骨粗鬆症に対するビスホスホネート投与 the use of bisphosphonates in postmenopausal women with osteoporosis
- 2. ビスホスホネートの薬理学 pharmacology of bisphosphonates
- 3. 転移性癌患者におけるビスホスホネートおよびデノスマブ bisphosphonates and denosumab in patients with metastatic cancer
- 4. 多発性骨髄腫患者のビスフォスフォネート製剤の使用 the use of bisphosphonates in patients with multiple myeloma
- 5. 閉経後の女性における骨粗鬆症のマネージメントの概要 overview of the management of osteoporosis in postmenopausal women
English Journal
- (177)Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment.
- Bergmann R1, Meckel M2, Kubíček V3, Pietzsch J1, Steinbach J1, Hermann P3, Rösch F4.
- EJNMMI research.EJNMMI Res.2016 Dec;6(1):5. doi: 10.1186/s13550-016-0161-3. Epub 2016 Jan 16.
- BACKGROUND: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs a
- PMID 26780082
- Nonunion of the Femur and Tibia: An Update.
- Bell A1, Templeman D2, Weinlein JC3.
- The Orthopedic clinics of North America.Orthop Clin North Am.2016 Apr;47(2):365-75. doi: 10.1016/j.ocl.2015.09.010.
- Delayed union and nonunion of tibial and femoral shaft fractures are common orthopedic problems. Numerous publications address lower extremity long bone nonunions. This review presents current trends and recent literature on the evaluation and treatment of nonunions of the tibia and femur. New studi
- PMID 26772945
- The bisphosphonate zoledronic acid regulates key angiogenesis-related genes in primary human gingival fibroblasts.
- Ohlrich EJ1, Coates DE2, Cullinan MP1, Milne TJ1, Zafar S1, Zhao Y1, Duncan WD1, Seymour GJ1.
- Archives of oral biology.Arch Oral Biol.2016 Mar;63:7-14. doi: 10.1016/j.archoralbio.2015.11.013. Epub 2015 Nov 23.
- BACKGROUND: Osteonecrosis of the jaws is recognised as a serious complication for patients receiving bisphosphonates. The anti-angiogenic effects of bisphosphonates have been implicated in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The purpose of this study was to d
- PMID 26658366
Japanese Journal
- O.li.v.e. PLUS SERMに関する最新論文の要約と解説 バゼドキシフェンと経口ビスホスホネートの椎体骨折発生抑制効果の間接比較
- 太田 博明
- O.li.v.e. : osteo lipid vascular & endocrinology : 骨代謝と生活習慣病の連関 5(3), 193-199, 2015-08
- NAID 40020594543
- 四肢発生の転移性骨腫瘍に対する治療法の選択 (シンポジウム 四肢転移性骨腫瘍に対する手術適応を考える)
- 藤田 郁夫,藤本 卓也,深瀬 直政 [他]
- 日本整形外科学会雑誌 89(4), 203-209, 2015-04
- NAID 40020482609
- 画像検査 男性の低骨密度 (特集 内分泌疾患に関するコンサルテーションQ&A)
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