関: alendronate、alendronate sodium

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a tablet (trade name Fosamax) prescribed to prevent or treat osteoporosis in women after menopause (同)Fosamax

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/06/12 22:09:56」(JST)

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Alendronic acid (INN) or alendronate sodium (USAN) — sold as Fosamax by Merck — is a bisphosphonate drug used for osteoporosis, osteogenesis imperfecta, and several other bone diseases. It is marketed alone as well as in combination with vitamin D (2,800 IU and 5,600 IU, under the name Fosamax+D). Merck's U.S. patent on alendronate expired in 2008 and the drug is now available as a generic. This is the most widely prescribed bisphosphonate medicine in the United States .

Pharmaceutical analysis

As with all potent bisphosphonates, the fraction of the drug that reaches the circulatory system intact (systemic bioavailability) after oral dosing is low, averaging only 0.6–0.7% in women and in men under fasting conditions. Intake together with meals and beverages other than water further reduces the bioavailability. The absorbed drug rapidly partitions, with approximately 50% binding to the exposed bone surface; the remainder is excreted unchanged by the kidneys. Unlike with most drugs, the strong negative charge on the two phosphonate moieties limits oral bioavailability, and, in turn, the exposure to tissues other than bone is very low. After absorption in the bone, alendronate has an estimated terminal elimination half-life of 10 years.^[1]

Pharmacology

Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates, it is chemically related to inorganic pyrophosphate, the endogenous regulator of bone turnover. But while pyrophosphate inhibits both osteoclastic bone resorption and the mineralization of the bone newly formed by osteoblasts, alendronate specifically inhibits bone resorption without any effect on mineralization at pharmacologically achievable doses. Its inhibition of bone-resorption is dose-dependent and approximately 1,000 times stronger than the equimolar effect of the first bisphosphonate drug, etidronate. Under therapy, normal bone tissue develops, and alendronate is deposited in the bone-matrix in a pharmacologically inactive form. For optimal action, enough calcium and vitamin D are needed in the body in order to promote normal bone development. Hypocalcemia should, therefore, be corrected before starting therapy.

Etidronate has the same disadvantage as pyrophosphate in inhibiting mineralization, but all of the potent N-containing bisphosphonates including Alendronate and also risedronate, ibandronate, and zoledronate, do not.

Clinical data

Treatment of post-menopausal women and people with osteogenesis imperfecta over the age of 22 with alendronic acid has demonstrated normalization of the rate of bone turnover, significant increase in BMD (bone mineral density) of the spine, hip, wrist and total body, and significant reductions in the risk of vertebral (spine) fractures, wrist fractures, hip fractures, and all non-vertebral fractures. In the Fracture Intervention Trial, the women with the highest risk of fracture (by virtue of pre-existing vertebral fractures) were treated with Fosamax 5 mg/day for two years followed by 10 mg/day for the third year. This resulted in approximately 50% reductions in fractures of the spine, hip, and wrist compared with the control group taking placebos. Both groups also took calcium and vitamin D.^[2]

Uses

Prophylaxis and treatment of female osteoporosis
Treatment of male osteoporosis
Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D
Paget's disease
Treatment for Osteogenesis imperfecta in patients of 18 years or older
Dental implants coating (experimental)

Contraindications and precautions

Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
Clinically manifest osteomalacia
Certain malformations and malfunctions of the esophagus (strictures, achalasia)
Inability to stand, walk, or sit for 30 minutes after oral administration
Renal impairment with a creatinine clearance below 30ml/min
Hypersensitivity to alendronate or another ingredient
Hypocalcemia
Pregnancy and breastfeeding
Patients below 18 yrs. of age, as no clinical data exists

Side-effects

Gastrointestinal tract:
- Ulceration of the esophagus; this may require hospitalization and intensive treatment. Gastric and duodenal ulceration may also occur.
- Esophageal cancer, a meta-analysis concluded that bisphosphonate treatment is not significantly associated with excess risk of esophageal cancer.^[3]^[4]
General: infrequent cases of skin rash, rarely manifesting as Stevens–Johnson syndrome and toxic epidermal necrolysis, eye problems (uveitis, scleritis) and generalized muscle, joint, and bone pain ^[5] (rarely severe) have been seen. In laboratory tests decreased calcium and phosphate values may be obtained but reflect action of the drug and are harmless.
Osteonecrosis of the jaw (deterioration of the temporomandibular joint or TMJ) may occur while on this drug, if dental work of any kind is carried out.^[6] Although this side effect is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.^[7]^[8]
Bone: alendronate has been linked in long-term users to the development of low-impact femoral fractures.^[9] Further, studies suggest that users of alendronate have an increase in the numbers of osteoclasts and develop giant, more multinucleated osteoclasts; the significance of this development is unclear.^[10] Fosamax has been linked to a rare type of leg fracture that cuts straight across the upper thigh bone after little or no trauma (subtrochanteric fractures).^[11]

Interactions

Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminium (antacids): the absorption of alendronate is decreased. At least half an hour should pass after intake of alendronate before taking the supplement or drug.
Highly active vitamin D analogues or fluorides: no data is available. Concomitant treatment should be avoided.
The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen. The combination is therefore possible.
Intravenous ranitidine increases the oral bioavailability of alendronate. No clinical consequences are known.
The combination of NSAIDs and alendronate may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

Dosage

Prophylaxis of osteoporosis in women: 5–10 mg daily or 35–70 mg weekly.
Therapy of osteoporosis in women and men : 10 mg daily or 70 mg weekly.
Osteoporosis under corticosteroids: 5–10 mg daily or 35–70 mg weekly in men and premenopausal women or those receiving concomitant HRT. In postmenopausal women not receiving HRT, the recommended dose is 10 mg daily or 70 mg weekly.
Paget's disease: 40 mg daily for 6 months.

The risk of esophageal irritation places special requirements on how this oral drug is taken. The patient should take the drug only upon rising for the day with 8 oz. of water, and stand, walk, or sit, and remain fasting for 30–45 minutes afterwards (preferably 1–2 hours), then eat breakfast. No other medications should be taken for this time. Lying down or reclining after taking the drug and prior to eating breakfast may cause gastroesophageal reflux and esophageal irritation.

Alendronic acid 35 mg (as alendronate sodium 45.7 mg) oral tablet

Dosage forms

Fosamax solution 70 mg/75ml
Fosamax tablets 5 mg, 10 mg, 35 mg, 40 mg, and 70 mg

References

^ Shinkai I, Ohta Y (January 1996). "New drugs--reports of new drugs recently approved by the FDA. Alendronate". Bioorg. Med. Chem. 4 (1): 3–4. PMID 8689235. doi:10.1016/0968-0896(96)00042-9.
^ Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (December 1996). "Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group". Lancet. 348 (9041): 1535–41. PMID 8950879. doi:10.1016/S0140-6736(96)07088-2.
^ Sun K, Liu JM, Sun HX, Lu N, Ning G (October 2012). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies". Osteoporosis International. 24 (1): 279–86. PMID 23052941. doi:10.1007/s00198-012-2158-8.
^ Haber SL, McNatty D (March 2012). "An evaluation of the use of oral bisphosphonates and risk of esophageal cancer". Ann Pharmacother. 46 (3): 419–23. PMID 22333262. doi:10.1345/aph.1Q482.
^ FDA Patient Safety News, March 2008
^ Fosamax product description, Merck & Co
^ Pazianas, M.; Miller P; Blumentals WA; Bernal M; Kothawala P (August 29, 2007). "A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics". Clinical Therapy. 29 (8): 1548–58. PMID 17919538. doi:10.1016/j.clinthera.2007.08.008.
^ Carini, F.; Barbano L; Saggese V; Monai D; Porcaro G. (2012-04-03). "Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report.". Ann Stomatol (Roma). 3 (2 Suppl): 32–6. PMC 3512552 . PMID 23285320.
^ 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. PMID 18354114. doi:10.1056/NEJMc0707493. Lay summary – US News & World Report.
^ 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. PMC 2866022 . PMID 19118304. doi:10.1056/NEJMoa0802633. Lay summary – Washington Post.
^ Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (February 2008). "An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy?". Injury. 39 (2): 224–31. PMID 18222447. doi:10.1016/j.injury.2007.08.036.

External links

Fosamax information from Merck
RxList page
MedlinePlus listing

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. ステロイド誘発性骨粗鬆症の予防および治療 prevention and treatment of glucocorticoid induced osteoporosis
3. HIV感染患者における骨およびカルシウム異常 bone and calcium disorders in hiv infected patients
4. ビスホスホネートの薬理学 pharmacology of bisphosphonates
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

Pulmonary delivery of nanosized alendronate for decorporation of inhaled heavy metals: formulation development, characterization and gamma scintigraphic evaluation.

Sultana S, Bhatnagar A, Rawat H, Nishad DK, Talegaonkar S, Ahmad FJ, Mittal G.Author information Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University , New Delhi , India and.AbstractAbstract Context: Medical management of heavy metal toxicity including radioactive ones is the cause of concern because of their increased use in energy production, healthcare and mining. As inhalation is one of the primary routes for internalization, a formulation is needed to trap metal(s) at the portal of entry itself. Objective: Objective was to formulate and characterize a nanonized dry powder inhaler (DPI) formulation of alendronate sodium as potential inhalable antidote for chelating metal toxicants. Methods. In vitro binding studies of alendronate with respect to seven non-radioactive heavy metals were carried out using UV-spectroscopy and HPLC. Nanonizing of alendronate particles was achieved by antisolvent precipitation using Pluronic-F68 as stabilizer. Characterization was done with the help of SEM, TEM FT-IR, XRD, DSC, NMR spectroscopy and PSD studies. In vitro and in vivo pulmonary deposition studies were carried out using gamma scintigraphy, followed by a limited pharmacokinetic study in humans. Results. In vitro binding studies confirmed the chelating action of alendronate. Anderson cascade impaction showed that nano-alendronate exhibited significantly higher respirable fraction (58.25 ± 1.32%) compared to the micronized form (28.7 ± 0.59%). Scintigraphy results showed significant increase in the alveolar deposition of drug post-nanonizing. Conclusion: Results strongly indicate the role of nano-alendronate DPI as potential inhalable antidote for neutralizing heavy metal toxicity, including radio-metal contamination.
Pharmaceutical development and technology.Pharm Dev Technol.2014 Aug;19(5):623-33. doi: 10.3109/10837450.2013.819013. Epub 2013 Jul 25.
Abstract Context: Medical management of heavy metal toxicity including radioactive ones is the cause of concern because of their increased use in energy production, healthcare and mining. As inhalation is one of the primary routes for internalization, a formulation is needed to trap metal(s) at the
PMID 23883097

Effects of clodronate and alendronate on osteoclast and osteoblast co-cultures on silk-hydroxyapatite films.

Hayden RS, Vollrath M, Kaplan DL.Author information Department of Biomedical Engineering, Tufts University, 4 Colby St., Medford, MA 02155, USA.AbstractThe goal of this study was to explore the effects of osteoporosis-related therapeutics on bone remodeling in vitro. A previously established bone-tissue mimetic system consisting of silk protein biomaterials in combination with hydroxyapatite and human cells was used for the study. Silk-hydroxyapatite films were pre-complexed with the non-nitrogenous bisphosphonate clodronate or the nitrogenous bisphosphonate alendronate and cultured with THP-1 human acute monocytic leukemia cell line-derived osteoclasts, human mesenchymal stem cell derived osteoblasts or a direct co-culture of the two cell types. Metabolic activity, calcium deposition and alkaline phosphatase activity were assessed over 12weeks, and reconstructed remodeled biomaterial surfaces were also evaluated for quantitative morphological changes. Increased metabolic activity and increased roughness were found on the clodronate-complexed biomaterial substrates remodeled by osteoblasts and co-cultures of osteoblasts with osteoclasts, even at doses high enough to cause a 90% decrease in osteoclast metabolic activity. Films complexed with low doses of alendronate resulted in increased metabolic activity and calcium deposition by osteoblasts, while higher doses were similarly toxic among osteoclasts, osteoblasts and co-cultures. These results point to the utility of these well-defined bone-mimetic in vitro cultures as useful screens for therapeutics for bone-related diseases, particularly with the ability to conduct studies for extended duration (here for 12weeks) and with pre-complexed drugs to mimic conditions found in vivo.
Acta biomaterialia.Acta Biomater.2014 Jan;10(1):486-93. doi: 10.1016/j.actbio.2013.09.028. Epub 2013 Oct 1.
The goal of this study was to explore the effects of osteoporosis-related therapeutics on bone remodeling in vitro. A previously established bone-tissue mimetic system consisting of silk protein biomaterials in combination with hydroxyapatite and human cells was used for the study. Silk-hydroxyapati
PMID 24096150

Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: Efficacy and safety results from a randomized open-label study.

Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A, Hawkins F, Micaelo M, Minisola S, Papaioannou N, Stone M, Ferreira I, Siddhanti S, Wagman RB, Brown JP.Author information Paris Descartes University, Department of Rheumatology, Cochin Hospital, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. Electronic address: christian.roux@cch.aphp.fr.AbstractDenosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers when compared with alendronate-treated subjects. This trial was designed to compare the efficacy and safety of denosumab with risedronate over 12months in postmenopausal women who transitioned from daily or weekly alendronate treatment and were considered to be suboptimally adherent to therapy. In this randomized, open-label study, postmenopausal women aged ≥55years received denosumab 60mg subcutaneously every 6months or risedronate 150mg orally every month for 12months. Endpoints included percentage change from baseline in total hip BMD (primary endpoint), femoral neck, and lumbar spine BMD at month 12, and percentage change from baseline in sCTX-1 at months 1 and 6. Safety was also assessed. A total of 870 subjects were randomized (435, risedronate; 435, denosumab) who had a mean (SD) age of 67.7 (6.9) years, mean (SD) BMD T-scores of -1.6 (0.9), -1.9 (0.7), and -2.2 (1.2) at the total hip, femoral neck, and lumbar spine, respectively, and median sCTX-1 of 0.3ng/mL at baseline. At month 12, denosumab significantly increased BMD compared with risedronate at the total hip (2.0% vs 0.5%), femoral neck (1.4% vs 0%), and lumbar spine (3.4% vs 1.1%; p<0.0001 at all sites). Denosumab significantly decreased sCTX-1 compared with risedronate at month 1 (median change from baseline of -78% vs -17%; p<0.0001) and month 6 (-61% vs -23%; p<0.0001). Overall and serious adverse events were similar between groups. In postmenopausal women who were suboptimally adherent to alendronate therapy, transitioning to denosumab was well tolerated and more effective than risedronate in increasing BMD and reducing bone turnover.
Bone.Bone.2014 Jan;58:48-54. doi: 10.1016/j.bone.2013.10.006. Epub 2013 Oct 17.
Denosumab has been shown to reduce new vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis. In subjects who were treatment-naïve or previously treated with alendronate, denosumab was associated with greater gains in bone mineral density (BMD) and decreases in bone t
PMID 24141036

Japanese Journal

ラットにおけるアレンドロネート経口投与時のミネラルウォーターによる吸収率への影響

YAKUGAKU ZASSHI 131(5), 801-807, 2011
NAID 130000678862

Fosamax Actonel Comparison Trial Investigators. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis. A randomized double-blind study

J Bone Miner Res. 20, 141-151, 2005
NAID 30030100373

Cost effectiveness of alendronate (fosamax) for the treatment of osteoporosis and prevention of fractures

Pharmacoeconomics 21, 305-314, 2003
NAID 30019831855

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Alendronic acid
Clinical data
Trade names	Fosamax
AHFS/Drugs.com	Monograph
MedlinePlus	a601011
Pregnancy; category	C;
Routes of; administration	Oral
ATC code	M05BA04 (WHO);
Legal status
Legal status	UK: POM (Prescription only);
Pharmacokinetic data
Bioavailability	0.6%
Metabolism	excreted unchanged
Biological half-life	126 months
Excretion	renal
Identifiers
	IUPAC name sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate;
CAS Number	121268-17-5 ;
PubChem CID	2088;
IUPHAR/BPS	3141;
DrugBank	DB00630 ;
ChemSpider	2004 ;
UNII	X1J18R4W8P;
KEGG	D07119 ;
ChEBI	CHEBI:2567 ;
ChEMBL	CHEMBL870 ;
ECHA InfoCard	100.128.415
Chemical and physical data
Formula	C4H13NO7P2
Molar mass	249.097
3D model (Jmol)	Interactive image;
	SMILES O=P(O)(O)C(O)(CCCN)P(=O)(O)O ;
	InChI InChI=1S/C4H13NO7P2/c5-3-1-2-4(6,13(7,8)9)14(10,11)12/h6H,1-3,5H2,(H2,7,8,9)(H2,10,11,12) ; Key:OGSPWJRAVKPPFI-UHFFFAOYSA-N ;
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英: Fosamax
関: アレンドロネート、アレンドロン酸ナトリウム

[pmid8689235-1] Shinkai I, Ohta Y (January 1996). "New drugs--reports of new drugs recently approved by the FDA. Alendronate". Bioorg. Med. Chem. 4 (1): 3–4. PMID 8689235. doi:10.1016/0968-0896(96)00042-9.

[pmid8950879-2] Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (December 1996). "Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group". Lancet. 348 (9041): 1535–41. PMID 8950879. doi:10.1016/S0140-6736(96)07088-2.

[pmid23052941-3] Sun K, Liu JM, Sun HX, Lu N, Ning G (October 2012). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies". Osteoporosis International. 24 (1): 279–86. PMID 23052941. doi:10.1007/s00198-012-2158-8.

[pmid22333262-4] Haber SL, McNatty D (March 2012). "An evaluation of the use of oral bisphosphonates and risk of esophageal cancer". Ann Pharmacother. 46 (3): 419–23. PMID 22333262. doi:10.1345/aph.1Q482.

[5] FDA Patient Safety News, March 2008

[6] Fosamax product description, Merck & Co

[7] Pazianas, M.; Miller P; Blumentals WA; Bernal M; Kothawala P (August 29, 2007). "A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics". Clinical Therapy. 29 (8): 1548–58. PMID 17919538. doi:10.1016/j.clinthera.2007.08.008.

[8] Carini, F.; Barbano L; Saggese V; Monai D; Porcaro G. (2012-04-03). "Multiple systemic diseases complicated by bisphosphonate osteonecrosis: a case report.". Ann Stomatol (Roma). 3 (2 Suppl): 32–6. PMC 3512552 . PMID 23285320.

[pmid18354114-9] 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. PMID 18354114. doi:10.1056/NEJMc0707493. Lay summary – US News & World Report.

[pmid19118304-10] 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. PMC 2866022 . PMID 19118304. doi:10.1056/NEJMoa0802633. Lay summary – Washington Post.

[pmid18222447-11] Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (February 2008). "An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy?". Injury. 39 (2): 224–31. PMID 18222447. doi:10.1016/j.injury.2007.08.036.

v t e Merck & Co., Inc.
Corporate directors:	Richard Clark Johnnetta Cole William Harrison William Kelley Rochelle Lazarus Thomas Shenk Anne Tatlock Samuel Thier Wendell Weeks Peter Wendell
Products:	Alendronate Aprepitant Ertapenem Ezetimibe Ezetimibe/simvastatin Finasteride Fosaprepitant Indinavir Losartan Lovastatin Montelukast Omarigliptin Raltegravir Rizatriptan Rofecoxib Simvastatin Sitagliptin Vorinostat
Publications:	The Merck Manuals Index Manual Veterinary Geriatrics

v t 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) RANKL inhibitor (Denosumab) Cathepsin K inhibitor (Odanacatib) Calcium Vitamin D

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Fosamax