Etidronic acid (Etidronate) (10 mM, 24 h) exhibits cytotoxicity, causing p53 alterations in MCF-7 cells as well as a decrease in the S phase population and an increase in the G2/M population [3]. Osteoclast apoptosis is induced by etipidric acid (100 nM, 24 h), and fluorescence microscopy reveals the features of this process, such as chromatin condensation and modifications to nuclear and cellular morphology [5].

Absorption, Distribution and Excretion
Etidronic acid has an oral bioavailability of 1-10%. Further data regarding pharmacokinetics of etidronic acid are not readily available.
Absorbed etidronic acid is eliminated in the urine, while the unabsorbed drug is eliminated in the feces.
Etidronic acid has a volume of distribution of 0.3-1.3L/kg.
Etidronic acid has a renal clearance of 0.09L/kg/h.
THE DISTRIBUTION OF TECHNETIUM-99M HEDP IN NORMAL HUMAN ORGANS WAS MEASURED.
THE BONE-SEEKING AGENT (99M)TC-SN-1-HYDROXYETHYLIDENE-1,1-DIPHOSPHONIC ACID UNEXPECTEDLY BINDS TO PARTICLES OF HUMAN ARTICULAR CARTILAGE AS WELL AS CORTICAL BONE IN VITRO. MECHANISMS ADDITIONAL TO THE SIMPLE IONIC ATTRACTION BETWEEN THE PHOSPHONATE GROUPS OF HEDP & METAL CATIONS SUCH AS CA2+ ARE RESPONSIBLE FOR THE UPTAKE OF (99M)TC-HEDP BY BODY TISSUES.
THE AFFINITY CONSTANT WHICH CHARACTERIZES THE BINDING OF (99)TC-HYDROXYETHYLENE DIPHOSPHONATE (TC-HEDP) WITH HUMAN SERUM ALBUMIN WAS 7.8X10+4. A SINGLE SLOPE WAS OBTAINED.

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Metabolism / Metabolites
Etidronic acid is not metabolized _in vivo_
Not metabolized.
Route of Elimination: Etidronate disodium is not metabolized. Within 24 hours, approximately half the absorbed dose is excreted in urine; the remainder is distributed to bone compartments from which it is slowly eliminated. Unabsorbed drug is excreted intact in the feces.
Half Life: In normal subjects, plasma half-life of etidronic acid, based on non-compartmental pharmacokinetics is 1 to 6 hours.

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Biological Half-Life
The half life of etidronate is approximately 1-6 hours.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of etidronate during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. However, absorption of etidronate by a breastfed infant is unlikely.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Dunn CJ, et al. Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs Aging. 1994 Dec;5(6):446-74.
[2]. Ariyoshi T, et al. Effect of etidronic acid on arterial calcification in dialysis patients. Clin Drug Investig. 2006;26(4):215-22.
[3]. Zhou Y, et al. Cytotoxicity of etidronic acid to human breast cancer cells. Ethn Dis. 2008 Spring;18(2 Suppl 2):S2-87-92.
[4]. Zhu S, et al. In-Depth Study of Heavy Metal Removal by an Etidronic Acid-Functionalized Layered Double Hydroxide. ACS Appl Mater Interfaces. 2022 Feb 9;14(5):7450-7463.
[5]. Kameda T, et al. Estrogen inhibits bone resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med. 1997 Aug 18;186(4):489-95.

Etidronic acid is a 1,1-bis(phosphonic acid) that is (ethane-1,1-diyl)bis(phosphonic acid) having a hydroxy substituent at the 1-position. It inhibits the formation, growth, and dissolution of hydroxyapatite crystals by chemisorption to calcium phosphate surfaces. It has a role as a bone density conservation agent, a chelator and an antineoplastic agent. It is a conjugate acid of an etidronic acid(2-).
Etidronic acid is a first generation bisphosphonate similar to [clodronic acid] and [tiludronic acid]. These drugs were developed to mimic the action of pyrophosphate, a regulator of calcification and decalcification. Etidronate’s use has decreased over the years in favor of the third generation, nitrogen containing bisphosphonate [zoledronic acid], [ibandronic acid], [minodronic acid], and [risedronic acid]. Etidronic acid was granted FDA approval on 1 September 1977.
Etidronic acid is a Bisphosphonate.
Etidronic Acid is as a member of the family of drugs known as bisphosphonates, etidronate differs from endogenous pyrophosphate in its resistance to enzymatic hydrolysis. This agent adsorbs to hydroxyapatite cells and reduces the number of osteoclasts, thereby inhibiting abnormal bone resorption. Etidronate may also directly stimulate bone formation by osteoblasts. (NCI)
Etidronic acid is only found in individuals that have used or taken this drug. It is a diphosphonate which affects calcium metabolism. It inhibits ectopic calcification and slows down bone resorption and bone turnover. [PubChem] 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 does not interfere with bone mineralization. In malignancy-related hypercalcemia, etidronic acid decreases serum calcium by inhibiting tumour-induced bone resorption and reducing calcium flow from the resorbing bone into the blood. Etidronic acid also reduces morbidity of osteolytic bone metastases by inhibiting tumour-induced bone resorption. 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.
A diphosphonate which affects calcium metabolism. It inhibits ectopic calcification and slows down bone resorption and bone turnover.
See also: Etidronic acid monohydrate (annotation moved to).

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Drug Indication
Etidronate is indicated to treat Paget's disease of bone, as well as the treatment and prevention of heterotropic ossification after total hip replacement of spinal cord injury.
FDA Label

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Mechanism of Action
Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. First generation bisphosphonates closely mimic the structure of pyrophosphate, which can be incorporated into ATP anologues that cannot be hydrolyzed, disrupting all ATP mediated actions of osteoclasts.
MALE RATS WERE INJECTED WITH VEHICLE (CONTROL GROUP), 0.4 OR 4.0 MG/KG/DAY OF ETHANE-1-HYDROXY-1,1-DIPHOSPHONATE (EHDP). AFTER 6 DAYS OF EHDP TREATMENT ALL RATS RECEIVED 6 SC INJECTIONS OF (3)H-THYMIDINE AT 8 HR INTERVALS. AFTER 6 DAYS OF EHDP PRE-TREATMENT THE MULTIPLE LABELING INDEX OF OSTEOPROGENITOR CELLS WAS REDUCED WITH 4.0 MG/KG/DAY DOSE OF EHDP. EHDP CAUSED INCR IN RATE OF INCORP & ACCUM OF (3)H-THYMIDINE NUCLEI IN OSTEOCLASTS. EHDP CAUSES AN ACCELERATED RATE OF OSTEOCLAST PRODN FROM PRECURSOR CELLS IN SPITE OF ITS ABILITY TO SLOW BONE RESORPTION.

C2H8O7P2

206.02832

205.974

2809-21-4

Etidronic acid disodium;7414-83-7

3305

White to off-white solid powder

2.1±0.1 g/cm3

578.8±60.0 °C at 760 mmHg

198~199℃

303.8±32.9 °C

0.0±3.6 mmHg at 25°C

1.586

-3.54

5

7

2

11

211

0

OC(P(O)(O)=O)(P(O)(O)=O)C

DBVJJBKOTRCVKF-UHFFFAOYSA-N

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

(1-hydroxy-1-phosphonoethyl)phosphonic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~485.37 mM)
H2O : ~100 mg/mL (~485.37 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.13 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.13 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (485.37 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)