ETIDRONIC ACID MONOHYDRATE

US Previously Marketed

Details

Stereochemistry	ACHIRAL
Molecular Formula	C2H8O7P2.H2O
Molecular Weight	224.0435
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.CC(O)(P(O)(O)=O)P(O)(O)=O

InChI

InChIKey=KKNZXUHBWLPUFN-UHFFFAOYSA-N

InChI=1S/C2H8O7P2.H2O/c1-2(3,10(4,5)6)11(7,8)9;/h3H,1H3,(H2,4,5,6)(H2,7,8,9);1H2

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017831s058lbl.pdf |

Etidronate is a salt of etidronic acid (brand name Didronel, also known as EHDP) a diphosphonate, which is indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel is not approved for the treatment of osteoporosis. This drugs acts primarily on bone. It can inhibit the formation, growth, and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases. Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier. Didronel is not metabolized. The amount of drug absorbed after an oral dose is approximately 3 percent. Bisphosphonates, when attached to bone tissue, are absorbed by osteoclasts, the bone cells that breaks down bone tissue. Although the mechanism of action of non-nitrogenous bisphosphonates has not been fully elucidated, available data suggest that they bind strongly to hydroxyapatite crystals in the bone matrix, preferentially at the sites of increased bone turnover and inhibit the formation and dissolution of the crystals. Other actions may include direct inhibition of mature osteoclast function, promotion of osteoclast apoptosis, and interference with osteoblast-mediated osteoclast activation. Etidronic acid may promote osteoclast apoptosis by competing 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.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hydroxyapatite 20 Target ID: CHEMBL2363055 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16046206	Antagonist 2778
ATP 10 Target ID: CHEMBL2366048 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21111853	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Paget’s disease of bone 12 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017831s058lbl.pdf	Primary		Approved 8429	DIDRONEL Approved Use Didronel is indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel is not approved for the treatment of osteoporosis. Paget’s Disease: Didronel is indicated for the treatment of symptomatic Paget's disease of bone. Didronel therapy usually arrests or significantly impedes the disease process as evidenced by: --Symptomatic relief, including decreased pain and/or increased mobility (experienced by 3 out of 5 patients). --Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30 percent or more in 4 out of 5 patients). --Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and more lamellar bone formation. Bone scans showing reduced radionuclide uptake at pagetic lesions. In addition, reductions in pagetically elevated cardiac output and skin temperature have been observed in some patients. In many patients, the disease process will be suppressed for a period of at least 1 year following cessation of therapy. The upper limit of this period has not been determined. The effects of the Didronel treatment in patients with asymptomatic Paget's disease have not been studied. However, Didronel treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones. Heterotopic Ossification: Didronel is indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, Didronel retards the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months posttherapy) suggest these benefits persist. In total hip replacement patients, Didronel does not promote loosening of the prosthesis or impede trochanteric reattachment. In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of the spine. Launch Date 1977
Heterotopic ossification 7 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/017831s058lbl.pdf	Preventing		Approved 8429	DIDRONEL Approved Use Didronel is indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel is not approved for the treatment of osteoporosis. Paget’s Disease: Didronel is indicated for the treatment of symptomatic Paget's disease of bone. Didronel therapy usually arrests or significantly impedes the disease process as evidenced by: --Symptomatic relief, including decreased pain and/or increased mobility (experienced by 3 out of 5 patients). --Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30 percent or more in 4 out of 5 patients). --Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and more lamellar bone formation. Bone scans showing reduced radionuclide uptake at pagetic lesions. In addition, reductions in pagetically elevated cardiac output and skin temperature have been observed in some patients. In many patients, the disease process will be suppressed for a period of at least 1 year following cessation of therapy. The upper limit of this period has not been determined. The effects of the Didronel treatment in patients with asymptomatic Paget's disease have not been studied. However, Didronel treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones. Heterotopic Ossification: Didronel is indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Didronel reduces the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, Didronel retards the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months posttherapy) suggest these benefits persist. In total hip replacement patients, Didronel does not promote loosening of the prosthesis or impede trochanteric reattachment. In spinal cord injury patients, Didronel does not inhibit fracture healing or stabilization of the spine. Launch Date 1977

PubMed

Title	Date	PubMed
Possibility of "distraction arthrogenesis": first report in rabbit model.	2001	11793183
Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: a comparison with the effect of etidronate.	2001	11793169
Etidronate for treating and preventing postmenopausal osteoporosis.	2001	11687195
Guidelines for treatment of osteoporosis in men.	2001 Aug	11681154
186Re-1,4,8,11-tetraaza cyclotetradecyl-1,4,8,11-tetramethylene phosphonic acid: a novel agent for possible use in metastatic bone-pain palliation.	2001 Aug	11518653
Osteoporosis in children and adolescent girls: case report of idiopathic juvenile osteoporosis and review of the literature.	2001 Aug	11496161
Subcutaneous fat necrosis of the newborn following hypothermia and complicated by pain and hypercalcaemia.	2001 Aug	11488718
[Therapy of osteoporosis. Risk factors alone are not an indication].	2001 Dec 6	11813710
[Fluorides and bisphosphonates in the treatment of osteoporosis].	2001 Jul	11515184
[Tumor-induced hypercalcemia. Review of bisphosphonate treatment].	2001 Jul	11508158
A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer.	2001 Jul	11504074
Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis.	2001 Jul	11485341
[Bisphosphonate treatment prevents hip fractures in 70-79 year old women with osteoporotic vertebral fractures].	2001 Jul 14	11484428
The use of scintigraphy to demonstrate the rapid esophageal transit of the oval film-coated placebo risedronate tablet compared to a round uncoated placebo tablet when administered with minimal volumes of water.	2001 Jul 17	11427359
Clinical effect of etidronate on alveolar pyorrhoea associated with chronic marginal periodontitis: report of four cases.	2001 Jul-Aug	11675910
Prevalence and determinants of osteoporosis drug prescription among patients with high exposure to glucocorticoid drugs.	2001 Jun	11439733
Osteoporosis in men.	2001 Jun 15	11430449
[Alternatives to hormonal treatment for the prevention of postmenopausal osteoporosis: the bisphosphonates].	2001 Nov	11770280
Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage.	2001 Nov	11768198
Familial fibrodysplasia ossificans progressiva: trial with etidronate disodium.	2001 Nov	11721075
Role of alendronate and risedronate in preventing and treating osteoporosis.	2001 Nov	11718433
Extracellular signal-regulated kinases and calcium channels are involved in the proliferative effect of bisphosphonates on osteoblastic cells in vitro.	2001 Nov	11697801
Rhenium-188 HEDP to treat painful bone metastases.	2001 Nov	11595844
Conventional treatment of hypercalcemia of malignancy.	2001 Nov 15	11757206
Advances in the biology and treatment of myeloma bone disease.	2001 Nov 15	11757204
A method to assess the proportion of treatment effect explained by a surrogate endpoint.	2001 Nov 15	11746311
[Economic aspects of osteoporosis therapy. What does a prevented fracture cost?].	2001 Nov 22	11791359
Risedronate treatment and extended fracture protection in postmenopausal women.	2001 Nov-Dec	11791630
Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates.	2001 Oct	11730262
Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy.	2001 Oct	11730260
Alendronate for the treatment of osteoporosis in men.	2001 Oct	11730259
Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. effect of adding hormone replacement therapy.	2001 Oct	11707007
Low-dose oral etidronate therapy for immobilization hypercalcaemia associated with Guillain-Barré syndrome.	2001 Oct	11697437
Maintenance of cancellous bone in ovariectomized, human parathyroid hormone [hPTH(1-84)]-treated rats by estrogen, risedronate, or reduced hPTH.	2001 Oct	11595618
Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity.	2001 Oct	11595616
Painful multifocal arthritis: therapy with rhenium 186 hydroxyethylidenediphosphonate ((186)Re HEDP) after failed treatment with medication--initial results of a prospective study.	2001 Oct	11568349
[Osteoporosis. Fracture as alarm signal].	2001 Oct 11	11721665
Risedronate: a new oral bisphosphonate.	2001 Sep	11589256
Bisphosphonates for osteoporosis.	2001 Sep	11586803
The diagnosis of Paget's disease.	2001 Sep	11584586
Effects of high-dose etidronate treatment on microdamage accumulation and biomechanical properties in beagle bone before occurrence of spontaneous fractures.	2001 Sep	11557372
Alendronate does not interfere with 99mTc-methylene diphosphonate bone scanning.	2001 Sep	11535725
Pharmacologic therapy for the treatment and prevention of osteoporosis.	2001 Sep	11532658
Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates.	2001 Sep 1	11520816
Zinc diphosphonates templated by organic amines: syntheses and characterizations of [NH3(CH2)2NH3]Zn(hedpH2)22H2O and [NH3(CH2)nNH3(CH2)nNH3]Zn2(hedpH)22H2O (n=4,5,6) (hedp=1-hydroxyethylidenediphophonate).	2001 Sep 10	11531453
[Risedronate now also approved for hip fractures. Study discloses significant risk reduction in proximal femoral neck fractures].	2001 Sep 6	11584532
[Optimizing treatment of osteoporosis. Rapidly effective therapy lowers fracture risk in 1 year up to 70%].	2001 Sep 6	11584531
Refractory heterotopic ossification with complications.	2001 Summer	11587419
Positive effect of etidronate therapy is maintained after drug is terminated in patients using corticosteroids.	2001 Winter	11748341
Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats.	2002 Feb 8	11724771

Patents

Sample Use Guides

In Vivo Use Guide

should be taken as a single, oral dose. Paget’s Disease: Initial Treatment Regimens: 5 to 10 mg/kg/day, not to exceed 6 months, or 11 to 20 mg/kg/day, not to exceed 3 months. The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there is an overriding need to suppress rapid bone turnover (especially when irreversible neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20 mg/kg/day are not recommended.

Route of Administration: Oral

In Vitro Use Guide

In vitro cytotoxicity of etidronic acid to MCF-7 cells was estimated on the basis of clonogenicity assays, while cell cycle effects were determined by using flow cytometry. A 24-hour treatment with etidronic acid (10 mM) with or without strontium chloride was cytototoxic to MCF-7cells. Etidronic acid (1, 10 mM) caused a decrease in the S-phase population and an increase in the G2/M population. Treatment of MCF-7 human breast cancer cells with etidronic acid (10 mM) for six hours caused mutations in exons 6 and 8 of the p53 gene in MCF-7 cells.

Name

Type

Language

ETIDRONIC ACID MONOHYDRATE

Common Name

English

1-HYDROXYETHYLIDENE-1,1-DIPHOSPHONIC ACID MONOHYDRATE

Common Name

English

ETHANE-1-HYDROXY-1,1-DIPHOSPHONIC ACID MONOHYDRATE

Common Name

English

PHOSPHONIC ACID, (1-HYDROXYETHYLIDENE)BIS-, MONOHYDRATE

Common Name

English

HYDROXYETHYLIDENEBISPHOSPHONIC ACID MONOHYDRATE

Systematic Name

English

ETIDRONIC ACID MONOHYDRATE [USP-RS]

Common Name

English

ETIDRONIC ACID MONOHYDRATE [USP IMPURITY]

Common Name

English

Code System Code Type Description

EPA CompTox

DTXSID8040800