Farnesyl diphosphate synthase/FPPS

Alendronate is the most often prescribed medication among the bisphosphonates, which are frequently used to treat osteoporosis. The process of bone grinding, which impedes fracture healing, is strongly inhibited by bisphosphonates [2].

Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic techniques and their solubility in water and biological fluids was determined. An evaluation of the toxicity towards human healthy cells and also human breast, lung and bone (osteosarcoma) cell lines was performed. Globally, it was observed that the monoanionic OSILs showed lower toxicity than the corresponding dianionic structures to all cell types. The highest cytotoxic effect was observed in OSILs containing a [C2OHMIM] cation, in particular [C2OHMIM][ALN]. The latter showed an improvement in IC50 values of ca. three orders of magnitude for the lung and bone cancer cell lines as well as fibroblasts in comparison with ALN. The development of OSILs with high cytotoxicity effect towards the tested cancer cell types, and containing an anti-resorbing molecule such as ALN may represent a promising strategy for the development of new pharmacological tools to be used in those pathological conditions[1].

Absorption, Distribution and Excretion
The mean oral bioavailability of alendronate sodium is 0.64% in women and 0.59% in men. Bioavailability can be reduced by up to 40% when taken within one hour after a meal. Following administration of radiolabeled alendronate sodium, 50% is recovered in urine within 72 hours. Alendronate sodium is not detected in feces. Men excrete alendronate sodium less than women, but race and age do not affect excretion. 28 liters. 71 ml/min. The mean oral bioavailability of alendronate sodium is 0.64% in women when taken 5 to 70 mg two hours before a standard breakfast after an overnight fast, relative to the intravenous reference dose. The oral bioavailability (0.59%) of a 10 mg alendronate sodium tablet in men is similar to that in women when taken 2 hours before breakfast after an overnight fast.
The bioavailability of alendronate sodium 70 mg oral solution and alendronate sodium 70 mg tablets is the same.
One study investigated the effect of mealtime on the bioavailability of alendronate sodium in 49 postmenopausal women. Results showed that compared to taking it 2 hours before a meal, taking 10 mg alendronate sodium 0.5 hours or 1 hour before a standard breakfast reduced bioavailability by approximately 40%. In studies on the treatment and prevention of osteoporosis, alendronate sodium was effective when taken at least 30 minutes before breakfast.
The bioavailability of alendronate sodium is negligible whether taken with a standard breakfast or within two hours after breakfast.
For more complete data on the absorption, distribution, and excretion of alendronate (10 items in total), please visit the HSDB records page.
Metabolism/Metabolites
Urinary excretion is the only route of elimination of alendronate; no metabolites were detected in urine collection.
There is no evidence that alendronate sodium is metabolized in animals or humans.
There is no evidence that alendronate sodium is metabolized in humans or animals.
Elimination route: Following a single intravenous injection of [14C] alendronate sodium, approximately 50% of the radioactivity is excreted in the urine within 72 hours, with the remainder being excreted in small amounts or completely. No radioactive material was detected in feces.
Half-life: >10 years

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Biological half-life
Because alendronate is integrated into the bone, its terminal half-life is estimated to be over 10 years.
In humans, the terminal half-life is estimated to be over 10 years, which may reflect the release of alendronate sodium from the bone. Based on the above information, it is estimated that after 10 years of oral treatment with alendronate sodium (10 mg daily), the amount of alendronate sodium released daily from the bone is approximately 25% of the amount absorbed from the gastrointestinal tract.

Toxicity Summary
Alendronate sodium's effects on bone tissue are partly based on its affinity for hydroxyapatite, a component of the bone mineral matrix. Alendronate sodium also targets farnesyl pyrophosphate (FPP) synthase. Nitrogenous bisphosphonates (such as pamidronate sodium, alendronate sodium, risedronate sodium, ibandronate sodium, and zoledronic acid sodium) appear to act as lipid analogs of isoprene diphosphate, thereby inhibiting an enzyme in the mevalonate pathway—FPP synthase. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprene lipids (FPP and GGPP), which are crucial for the post-translational farnesylation and geranylation of small GTPase signaling proteins. This activity inhibits osteoclast activity and reduces bone resorption and bone turnover. In postmenopausal women, it reduces elevated bone turnover and, on average, results in a net increase in bone mass.

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Limited evidence suggests that discontinuing breastfeeding after long-term bisphosphonate treatment appears to have no adverse effects on the infant. Since there is currently no information on the use of alendronate sodium during lactation, alternative medications may be preferred, especially for breastfed newborns or premature infants. However, breastfed infants are unlikely to absorb alendronate sodium. If the mother takes bisphosphonates during pregnancy or lactation, some experts recommend monitoring the infant's serum calcium levels in the first two months postpartum.
◉ Effects on breastfed infants
Because alendronate sodium can persist in the body for several years after long-term use, the following may be relevant. A woman received alendronate sodium treatment for 6 months one year before conception, followed by pamidronate sodium treatment every 4 months thereafter. Her infant was breastfed for 3 months (the extent of breastfeeding was not specified). The infant presented with mild hypocalcemia at 2 months of age, but calcium levels were normal at 5 months of age, and long bone development was also normal.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
78%. Rat studies showed that plasma protein binding increased with decreasing plasma alendronate concentration and increasing pH.

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Interactions
Intravenous ranitidine doubled the bioavailability of oral alendronate sodium. The clinical significance of this increased bioavailability, and whether a similar increase would occur in patients taking oral H2 receptor antagonists, is currently unclear.
In healthy subjects, oral prednisone (20 mg three times daily for five days) did not cause a clinically significant change in the oral bioavailability of alendronate sodium (mean increase of 20% to 44%).
Calcium supplements, antacids, and certain oral medications may interfere with the absorption of alendronate sodium. Therefore, patients should wait at least half an hour after taking alendronate sodium before taking other oral medications. Taking alendronate sodium with coffee or orange juice reduces bioavailability by approximately 60%. For more complete data on drug interactions of alendronates (8 types in total), please visit the HSDB record page.

[1]. Teixeira S, et al. Alendronic Acid as Ionic Liquid: New Perspective on Osteosarcoma. Pharmaceutics. 2020 Mar 24;12(3). pii: E293.
[2]. Duckworth AD, et al. Effect of Alendronic Acid on Fracture Healing: A Multicenter Randomized Placebo-Controlled Trial. J Bone Miner Res. 2019 Jun;34(6):1025-1032.

Therapeutic Uses

Bone Mineral Degradation Protectant
Alendronate Sodium Tablets are indicated for the treatment of osteoporosis. Alendronate Sodium Tablets increase bone mass and reduce the incidence of fractures, including hip and spinal fractures (vertebral compression fractures). The diagnosis of osteoporosis is based on low bone mass (e.g., below the premenopausal mean by at least 2 standard deviations) or the presence or history of osteoporotic fractures. /US Product Label/
Alendronate Sodium Tablets are indicated for the prevention of osteoporosis. Alendronate Sodium Tablets may be considered for postmenopausal women at risk of osteoporosis who expect clinical efficacy in maintaining bone mass and reducing the risk of future fractures. /US Product Label/
Alendronate Sodium Tablets are indicated for the treatment of osteoporosis in men to increase bone mass. /Included in US Product Label/
For more complete data on the therapeutic uses of alendronate (7 types), please visit the HSDB record page.
Drug Warning
The FDA has notified healthcare professionals and patients that it is reviewing published research data to assess whether the use of oral bisphosphonates is associated with an increased risk of esophageal cancer. The FDA has not concluded that taking oral bisphosphonates increases the risk of esophageal cancer. There is currently insufficient data to recommend endoscopic screening for asymptomatic patients. The FDA will continue to evaluate all existing data supporting the safety and efficacy of bisphosphonates and will update the public as more information becomes available.
Bone loss is particularly rapid in postmenopausal women under the age of 60. Common risk factors associated with the development of postmenopausal osteoporosis include: early menopause; moderately low bone mass (e.g., at least one standard deviation below the mean for healthy young adult women); lean body type; Caucasian or Asian appearance; and a family history of osteoporosis. The presence of these risk factors may be important when considering the use of alendronate sodium tablets for osteoporosis prevention.
/Alendronate sodium is contraindicated in: esophageal abnormalities causing delayed esophageal emptying, such as esophageal stricture or achalasia; inability to stand or sit upright for at least 30 minutes; hypersensitivity to any component of this product; hypocalcemia.
As with other bisphosphonates, alendronate sodium may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse reactions, such as esophagitis, esophageal ulceration, and esophageal erosion, have been reported in patients treated with alendronate sodium, with occasional bleeding, and in rare cases, progression to esophageal stricture or perforation. In some cases, these adverse reactions are severe and require hospitalization. Therefore, physicians should be alert to any signs or symptoms that may indicate an esophageal reaction and should inform patients that alendronate sodium should be discontinued immediately and medical attention sought if dysphagia, dysphagia, retrosternal pain, or new or worsening heartburn occurs.
For more complete data on drug warnings for alendronate (18 in total), please visit the HSDB record page.

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Pharmacodynamics
The oral bioavailability of alendronate tablets is extremely low. After administration, the drug is distributed in soft tissues and bones, or excreted in the urine. Alendronate is not metabolized.

C4H13NO7P2

249.09612

249.017

C, 19.29; H, 5.26; N, 5.62; O, 44.96; P, 24.87

66376-36-1

Alendronate sodium hydrate;121268-17-5;Alendronic acid-d6;1035437-39-8;Alendronate sodium;129318-43-0; 66376-36-1 (free acid); 137504-90-6 (calcium); 138624-11-0 (free acid hydrate)

2088

Fine white powder

1.857 g/cm3

616.7ºC at 760 mmHg

230-235ºC

326.7ºC

-6.5

6

8

5

14

257

0

C(CC(O)(P(=O)(O)O)P(=O)(O)O)CN

OGSPWJRAVKPPFI-UHFFFAOYSA-N

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)

(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid

ALENDRONIC ACID; alendronate; 66376-36-1; Fosamax; (4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid; Acido alendronico; Acide alendronique; Acidum alendronicum;

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)

H2O : ~3.7 mg/mL (~14.85 mM)

Solubility in Formulation 1: 6.67 mg/mL (26.78 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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