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〈学校・政府・規則など〉‘を'『設ける』,設立する,制定する / 〈調査・訴訟など〉‘を'始める,起こす / (学校・研究所・学会などの)『教育』)『学術』『機関』

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/06/07 23:49:24」(JST)

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Basic structure of a bisphosphonate on top. To compare the structure of pyrophosphate below. Note the similarity in structure.

Bisphosphonates (also called diphosphonates) 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
3) groups and are similar in structure to pyrophosphate.

Evidence shows that they reduce the risk of osteoporotic fracture in those who have had previous fractures.^[2]^[3]

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.^[4]

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, fibrous dysplasia, and other conditions that feature bone fragility.

Medical uses

Most physicians use bisphosphonates 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 (Merck) and risedronate. If these are ineffective or if the patient develops digestive tract problems, intravenous pamidronate (Novartis) may be used. Strontium ranelate or teriparatide (Eli Lilly) are used for refractory disease; and in postmenopausal women, the selective estrogen receptor modulator raloxifene is occasionally administered instead of bisphosphonates.

High-potency intravenous bisphosphonates have been shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer. In one randomized control trial, women with breast cancer who received zoledronic acid had a 36% reduction in risk for a recurrence of breast cancer in the same breast, a new cancer in the other breast, or metastasis to bone compared to women who did not receive zoledronic acid.^[5]

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,^[6] to treat otosclerosis.,^[7] and by crew members on long-duration missions on the International Space Station^{[citation needed]} to minimize bone loss.

Efficacy

For prevention of fractures three Cochrane reviews of biphosphonates came to the conclusion that there was no significant reduction in hip fracture for primary prevention and a small but statistically significant reduction in hip fracture for secondary prevention.^[8]^[9]^[10] Another systematic review of all biphosphonates found there were no proven clinically meaningful benefits for bisphosphonates in postmenopausal women without a prior fracture or vertebral compression. Because of the small magnitude of effect and the high risk of bias in the RCTs, it was unclear whether bisphosphonates caused a clinically meaningful reduction of hip fractures in women with a prior fracture or vertebral compression. In those RCTs with mostly secondary prevention hip fracture risk was reduced. The mean age of women was 72 years. The absolute risk reduction was 1% and number needed to threat was 100 for 2,9 year of treatment. So to prevent 1 hip fracture 100 people had to be treated during 2,9 years. For any new class of drugs indicated to prevent bone fractures, it was found essential that a clinically meaningful reduction in hip fractures should be demonstrated before licensing. In secondary prevention risk of wrist fracture was also reduced: absolute risk reduction was 1,3% and NNT 77 for 3 years.^[11]

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. These symptoms do not recur with subsequent infusions.^{[citation needed]}

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).^[12]

A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes^[13] Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaw, 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]

Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women.^[15]^[16]^[17] The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.^[16] One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.^[16] 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).^[16] FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.^[18]^[19]

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 head of the bone, 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.^[20] 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.^[20]^[21] In cases where there is concern of such fractures occurring, teriparatide is potentially a good alternative due to it reducing damage caused by suppression of bone turnover.^[22]

A 2010 study suggests that the risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five-year period. In Europe and North America, the incidence of oesophageal cancer at age 60–79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years' use of oral bisphosphonates.^[23] There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates.^[24]

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 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.^[25]

Nitrogenous

N-containing bisphosphonates:

Pamidronate (APD, Aredia) — 100
Neridronate (Nerixia^[26]) — 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).^[27]

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).^[28]

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.^[29]

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..^[30]

Footnotes

^ National Osteoporosis Society. "Drug Treatment". U.K. National Osteoporosis Society. Retrieved 7 August 2012.
^ Wells G, Cranney A, Peterson J, et al. (2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD004523. doi:10.1002/14651858.CD004523.pub3. PMID 18254053.
^ Wells GA, Cranney A, Peterson J, et al. (2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD001155. doi:10.1002/14651858.CD001155.pub2. PMID 18253985.
^ Weinstein RS, Roberson PK, Manolagas SC (January 2009). "Giant osteoclast formation and long-term oral bisphosphonate therapy". N. Engl. J. Med. 360 (1): 53–62. doi:10.1056/NEJMoa0802633. PMC 2866022. PMID 19118304.
^ Gnant M, Mlineritsch B, Schippinger W, et al. (February 2009). "Endocrine therapy plus zoledronic acid in premenopausal breast cancer". N. Engl. J. Med. 360 (7): 679–91. doi:10.1056/NEJMoa0806285. PMID 19213681.
^ Shapiro JR, Sponsellor PD (December 2009). "Osteogenesis imperfecta: questions and answers". Current Opinion in Pediatrics 21 (6): 709–16. doi:10.1097/MOP.0b013e328332c68f. PMID 19907330.
^ Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J 14 (2): 92–6. PMID 19205157.
^ Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD001155. PMID 18253985. Cite uses deprecated parameters (help)
^ Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD003376. PMID 18254018. Cite uses deprecated parameters (help)
^ Wells, G; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD004523. PMID 18254053. Cite uses deprecated parameters (help)
^ "A Systematic Review of the Efficacy of Bisphosphonates Sep - Oct 2011". Therapeutics Letter.
^ Woo S, Hellstein J, Kalmar J (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med 144 (10): 753–61. doi:10.7326/0003-4819-144-10-200605160-00009. PMID 16702591.
^ Wysowski D, Chang J (2005). "Alendronate and risedronate: reports of severe bone, joint, and muscle pain". Arch Intern Med 165 (3): 346–7. doi:10.1001/archinte.165.3.346-b. PMID 15710802.
^ Lehrer S, Montazem A, Ramanathan L, et al. (January 2009). "Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene". J. Oral Maxillofac. Surg. 67 (1): 159–61. doi:10.1016/j.joms.2008.09.015. PMID 19070762.
^ Black DM, Delmas PD, Eastell R, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". N. Engl. J. Med. 356 (18): 1809–22. doi:10.1056/NEJMoa067312. PMID 17476007.
^ ^a ^b ^c ^d Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (April 2008). "Use of alendronate and risk of incident atrial fibrillation in women". Arch. Intern. Med. 168 (8): 826–31. doi:10.1001/archinte.168.8.826. PMID 18443257.
^ Cummings SR, Schwartz AV, Black DM (May 2007). "Alendronate and atrial fibrillation". N. Engl. J. Med. 356 (18): 1895–6. doi:10.1056/NEJMc076132. PMID 17476024.
^ "Early Communication of an Ongoing Safety Review on Bisphosphonates: Alendronate (Fosamax, Fosamax Plus D), Etidronate (Didronel), Ibandronate (Boniva), Pamidronate (Aredia), Risedronate (Actonel, Actonel W/Calcium), Tiludronate (Skelid), and Zoledronic acid (Reclast, Zometa)". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). 2007-10-01. Retrieved 2009-07-15.
^ "Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). October 2008. Retrieved 2009-07-15.
^ ^a ^b Shane E (May 2010). "Evolving data about subtrochanteric fractures and bisphosphonates". N. Engl. J. Med. 362 (19): 1825–7. doi:10.1056/NEJMe1003064. PMID 20335574.
^ Lenart BA, Lorich DG, Lane JM (March 2008). "Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate". N. Engl. J. Med. 358 (12): 1304–6. doi:10.1056/NEJMc0707493. PMID 18354114.
^ Arkan S Sayed-Noor; Bakir K Kadum; Göran O Sjödén (31 March 2010). "Bisphosphonate-induced femoral fragility fractures: What do we know?". Orthopedic Research and Reviews 2 (1): 27–34. doi:10.2147/ORRS7521. Retrieved 26 April 2012.
^ Green, J.; Czanner, G.; Reeves, G.; Watson, J.; Wise, L.; Beral, V. (2010). "Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort". BMJ 341: c4444. doi:10.1136/bmj.c4444. PMC 2933354. PMID 20813820. edit
^ http://www.drugs.com/fda/oral-osteoporosis-bisphosphonates-safety-communication-potential-increased-risk-esophageal-cancer-13003.html
^ Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M (1997). "Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro". J Bone Miner Res 12 (9): 1358–67. doi:10.1359/jbmr.1997.12.9.1358. PMID 9286751.
^ (not sold in the United States)
^ van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S (November 2003). "Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates". Bone 33 (5): 805–11. doi:10.1016/j.bone.2003.07.007. PMID 14623056.
^ Van Beek E, Löwik C, van der Pluijm G, Papapoulos S (1999). "The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates". J Bone Miner Res 14 (5): 722–9. doi:10.1359/jbmr.1999.14.5.722. PMID 10320520.
^ Uzzan, B; et al. (2007). "Effects of statins on bone mineral density: a meta-analysis of clinical studies". Bone 40 (6): 1581–7. doi:10.1016/j.bone.2007.02.019. PMID 17409043. Retrieved 2012-07-13.
^ Fleisch H (2002). "Development of bisphosphonates". Breast Cancer Res 4 (1): 30–4. doi:10.1186/bcr414. PMC 138713. PMID 11879557.

External links

International Myeloma Foundation article on bisphosphonates

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

Bisphosphonate-functionalized gold nanoparticles for contrast-enhanced X-ray detection of breast microcalcifications.

Cole LE1, Vargo-Gogola T2, Roeder RK3.Author information 1Department of Aerospace and Mechanical Engineering, Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.2Department of Biochemistry and Molecular Biology, Indiana University Simon Cancer Center, Indiana University School of Medicine - South Bend, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.3Department of Aerospace and Mechanical Engineering, Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA. Electronic address: rroeder@nd.edu.AbstractMicrocalcifications are one of the most common abnormalities detected by mammography for the diagnosis of breast cancer. However, the detection of microcalcifications and correct diagnosis of breast cancer are limited by the sensitivity and specificity of mammography. Therefore, the objective of this study was to investigate the potential of bisphosphonate-functionalized gold nanoparticles (BP-Au NPs) for contrast-enhanced radiographic detection of breast microcalcifications using two models of breast microcalcifications, which allowed for precise control over levels of hydroxyapatite (HA) mineral within a low attenuating matrix. First, an in vitro imaging phantom was prepared with varying concentrations of HA uniformly dispersed in an agarose hydrogel. The X-ray attenuation of HA-agarose compositions labeled by BP-Au NPs was increased by up to 26 HU compared to unlabeled compositions for HA concentrations ranging from 1 to 10 mg/mL. Second, an ex vivo tissue model was developed to more closely mimic the heterogeneity of breast tissue by injecting varying concentrations of HA in a Matrigel carrier into murine mammary glands. The X-ray attenuation of HA-Matrigel compositions labeled by BP-Au NPs was increased by up to 289 HU compared to unlabeled compositions for HA concentrations ranging from 0.5 to 25 mg/mL, which included an HA concentration (0.5 mg/mL) that was otherwise undetectable by micro-computed tomography. Cumulatively, both models demonstrated the ability of BP-Au NPs to enhance contrast for radiographic detection of microcalcifications, including at a clinically-relevant imaging resolution. Therefore, BP-Au NPs may have potential to improve clinical detection of breast microcalcifications by mammography.
Biomaterials.Biomaterials.2014 Feb;35(7):2312-21. doi: 10.1016/j.biomaterials.2013.11.077. Epub 2013 Dec 18.
Microcalcifications are one of the most common abnormalities detected by mammography for the diagnosis of breast cancer. However, the detection of microcalcifications and correct diagnosis of breast cancer are limited by the sensitivity and specificity of mammography. Therefore, the objective of thi
PMID 24360718

Denosumab: A cost-effective alternative for older men with osteoporosis from a Swedish payer perspective.

Parthan A1, Kruse M2, Agodoa I3, Silverman S4, Orwoll E5.Author information 1OptumInsight, One Main Street, Cambridge, MA 02142, USA. Electronic address: anju.parthan@optum.com.2OptumInsight, One Main Street, Cambridge, MA 02142, USA. Electronic address: morgan.kruse@optum.com.3Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: iagodoa@amgen.com.4Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address: stuarts@slsdss.net.5Oregon Health & Science University, 3181 SW Sam Jackson Park Road, L607, Portland, OR 97239, USA. Electronic address: orwoll@ohsu.edu.AbstractOBJECTIVE: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden.
Bone.Bone.2014 Feb;59:105-13. doi: 10.1016/j.bone.2013.11.002. Epub 2013 Nov 12.
OBJECTIVE: To assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥75years old from a payer perspective in Sweden.METHODS: A lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporot
PMID 24231131

Bisphosphonate-osteoclasts: Changes in osteoclast morphology and function induced by antiresorptive nitrogen-containing bisphosphonate treatment in osteoporosis patients.

Jobke B1, Milovanovic P2, Amling M1, Busse B3.Author information 1Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.2Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Laboratory for Anthropology, Institute of Anatomy, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.3Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: b.busse@uke.uni-hamburg.de.AbstractOsteoclasts are unique cells capable of bone resorption and therefore have become a major target in osteoporosis treatment strategies. Bisphosphonates suppress bone turnover via interference with the internal enzymatic cell system of osteoclasts leading to cytoskeletal disruption. This mechanism found its clinical relevance in reducing bone resorption, stabilizing bone mass and reducing fracture risk in osteoporosis patients. However, knowledge about specific in vivo changes in osteoclast cell morphology and function is still insufficient. We examined osteoclasts in 23 paired bone biopsies from osteoporosis patients (18 males, 5 females; age: 52.6±11.5yrs) under nitrogen-containing bisphosphonate administration with a mean treatment duration of three years. Formalin-fixed, undecalcified sections were assessed by qualitative and quantitative bone histomorphometry, where the osteoclast morphology, nuclei, distribution, location as well as resorption parameters were investigated to obtain information about cell function and viability. After three years of treatment, resorption parameters decreased significantly while the number of osteoclasts remained unchanged. Out of 23 patients, nine developed previously termed "giant-osteoclasts" with increased size, numerous nuclei (>10 nuclei/Oc) and oftentimes detachment from the bone surface. These cells frequently had pycnotic nuclei and other morphological signs suggestive of osteoclast apoptosis. Characteristic large-sized osteoclasts were uniquely found in patients treated with nitrogen-containing bisphosphonates, thus being clearly distinguishable from giant-osteoclasts in other bone disorders such as Paget disease, secondary hyperparathyroidism or osteopetrosis. The resorption indices of large-sized osteoclasts, specifically the eroded perimeter and erosion depth, revealed significantly reduced values but not an entirely inhibited resorption capability. Bisphosphonate-osteoclasts' viability and affinity to bone seem significantly disturbed while the apoptotic process may be prolonged for a yet unknown period of time in favor of maintaining a low bone turnover.
Bone.Bone.2014 Feb;59:37-43. doi: 10.1016/j.bone.2013.10.024. Epub 2013 Nov 6.
Osteoclasts are unique cells capable of bone resorption and therefore have become a major target in osteoporosis treatment strategies. Bisphosphonates suppress bone turnover via interference with the internal enzymatic cell system of osteoclasts leading to cytoskeletal disruption. This mechanism fou
PMID 24211427

Japanese Journal

若年者のびまん性硬化性下顎骨骨髄炎にパミドロネートが著効した1例

河野通秀,渡辺正人,浜田勇人 [他]
日本口腔外科学会雑誌 = Japanese journal of oral and maxillofacial surgery 61(7), 368-373, 2015-07
NAID 40020545344

上顎洞に炎症が波及したビスフォスフォネート関連顎骨骨髄炎の治療経験

福原紫津子,山崎亨,高橋克 [他]
日本口腔外科学会雑誌 = Japanese journal of oral and maxillofacial surgery 61(6), 310-318, 2015-06
NAID 40020518218

転移性骨腫瘍に対する薬物療法 (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)

中紀文,濱田健一郎,王谷英達
日本整形外科学会雑誌 89(4), 210-215, 2015-04
NAID 40020482637

Related Pictures

★リンクテーブル★

リンク元	「institute」「ビスホスフォネート」「diphosphonate」
関連記事	「bisphosphonates」

「institute」

　　[★]

vt.

(会、制度、法政などを)設ける、策定する

treatment with a bisphosphonate should be instituted when bone disease is identified.

(調査を)始める

The risk of side effects and the possibility of developing an infection with a drug-resistant organism or with more harmful, invasive bacteria make it more reasonable to institute an empirical short course of treatment if symptoms develop.

(訴訟を)起こす
教会/教区に(人を)任命する

n.

関: academy、commence、commencement、establish、establishment、foundation、initiate、initiation、institution、mount、onset、research institute、start

「ビスホスフォネート」

　　[★]

英: bisphosphonate
同: ビスフォスフォネート、ビスホスホネート、ビスホスホン酸、ビスホスホネート製剤
関: 骨粗鬆症

第1世代

エチドロネート etidronate

第2世代

第3世代

「diphosphonate」

　　[★] ジホスホン酸、ジホスホン酸塩、ジホスホン酸エステル

関: bisphosphonate

「bisphosphonates」

　　[★] ビスホスフォネート

[Nat_Osteo_Soc-1] National Osteoporosis Society. "Drug Treatment". U.K. National Osteoporosis Society. Retrieved 7 August 2012.

[2] Wells G, Cranney A, Peterson J, et al. (2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD004523. doi:10.1002/14651858.CD004523.pub3. PMID 18254053.

[3] Wells GA, Cranney A, Peterson J, et al. (2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD001155. doi:10.1002/14651858.CD001155.pub2. PMID 18253985.

[4] Weinstein RS, Roberson PK, Manolagas SC (January 2009). "Giant osteoclast formation and long-term oral bisphosphonate therapy". N. Engl. J. Med. 360 (1): 53–62. doi:10.1056/NEJMoa0802633. PMC 2866022. PMID 19118304.

[5] Gnant M, Mlineritsch B, Schippinger W, et al. (February 2009). "Endocrine therapy plus zoledronic acid in premenopausal breast cancer". N. Engl. J. Med. 360 (7): 679–91. doi:10.1056/NEJMoa0806285. PMID 19213681.

[6] Shapiro JR, Sponsellor PD (December 2009). "Osteogenesis imperfecta: questions and answers". Current Opinion in Pediatrics 21 (6): 709–16. doi:10.1097/MOP.0b013e328332c68f. PMID 19907330.

[7] Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J 14 (2): 92–6. PMID 19205157.

[8] Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD001155. PMID 18253985. Cite uses deprecated parameters (help)

[9] Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD003376. PMID 18254018. Cite uses deprecated parameters (help)

[10] Wells, G; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD004523. PMID 18254053. Cite uses deprecated parameters (help)

[11] "A Systematic Review of the Efficacy of Bisphosphonates Sep - Oct 2011". Therapeutics Letter.

[12] Woo S, Hellstein J, Kalmar J (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med 144 (10): 753–61. doi:10.7326/0003-4819-144-10-200605160-00009. PMID 16702591.

[13] Wysowski D, Chang J (2005). "Alendronate and risedronate: reports of severe bone, joint, and muscle pain". Arch Intern Med 165 (3): 346–7. doi:10.1001/archinte.165.3.346-b. PMID 15710802.

[14] Lehrer S, Montazem A, Ramanathan L, et al. (January 2009). "Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene". J. Oral Maxillofac. Surg. 67 (1): 159–61. doi:10.1016/j.joms.2008.09.015. PMID 19070762.

[HORIZON-15] Black DM, Delmas PD, Eastell R, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". N. Engl. J. Med. 356 (18): 1809–22. doi:10.1056/NEJMoa067312. PMID 17476007.

[ArchIntMed2008-16] Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (April 2008). "Use of alendronate and risk of incident atrial fibrillation in women". Arch. Intern. Med. 168 (8): 826–31. doi:10.1001/archinte.168.8.826. PMID 18443257.

[FractureInterventionTrial-17] Cummings SR, Schwartz AV, Black DM (May 2007). "Alendronate and atrial fibrillation". N. Engl. J. Med. 356 (18): 1895–6. doi:10.1056/NEJMc076132. PMID 17476024.

[18] "Early Communication of an Ongoing Safety Review on Bisphosphonates: Alendronate (Fosamax, Fosamax Plus D), Etidronate (Didronel), Ibandronate (Boniva), Pamidronate (Aredia), Risedronate (Actonel, Actonel W/Calcium), Tiludronate (Skelid), and Zoledronic acid (Reclast, Zometa)". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). 2007-10-01. Retrieved 2009-07-15.

[19] "Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). October 2008. Retrieved 2009-07-15.

[Shane-20] Shane E (May 2010). "Evolving data about subtrochanteric fractures and bisphosphonates". N. Engl. J. Med. 362 (19): 1825–7. doi:10.1056/NEJMe1003064. PMID 20335574.

[21] Lenart BA, Lorich DG, Lane JM (March 2008). "Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate". N. Engl. J. Med. 358 (12): 1304–6. doi:10.1056/NEJMc0707493. PMID 18354114.

[Arkan-22] Arkan S Sayed-Noor; Bakir K Kadum; Göran O Sjödén (31 March 2010). "Bisphosphonate-induced femoral fragility fractures: What do we know?". Orthopedic Research and Reviews 2 (1): 27–34. doi:10.2147/ORRS7521. Retrieved 26 April 2012.

[23] Green, J.; Czanner, G.; Reeves, G.; Watson, J.; Wise, L.; Beral, V. (2010). "Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort". BMJ 341: c4444. doi:10.1136/bmj.c4444. PMC 2933354. PMID 20813820. edit

[24] ttp://www.drugs.com/fda/oral-osteoporosis-bisphosphonates-safety-communication-potential-increased-risk-esophageal-cancer-13003.html

[25] Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M (1997). "Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro". J Bone Miner Res 12 (9): 1358–67. doi:10.1359/jbmr.1997.12.9.1358. PMID 9286751.

[26] (not sold in the United States)

[27] van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S (November 2003). "Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates". Bone 33 (5): 805–11. doi:10.1016/j.bone.2003.07.007. PMID 14623056.

[28] Van Beek E, Löwik C, van der Pluijm G, Papapoulos S (1999). "The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates". J Bone Miner Res 14 (5): 722–9. doi:10.1359/jbmr.1999.14.5.722. PMID 10320520.

[Uzzan2007-29] Uzzan, B; et al. (2007). "Effects of statins on bone mineral density: a meta-analysis of clinical studies". Bone 40 (6): 1581–7. doi:10.1016/j.bone.2007.02.019. PMID 17409043. Retrieved 2012-07-13.

[30] Fleisch H (2002). "Development of bisphosphonates". Breast Cancer Res 4 (1): 30–4. doi:10.1186/bcr414. PMC 138713. PMID 11879557.

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bisphosphonate