At pamidronate concentrations ranging from 100 to 1000 μM, osteosarcoma cell viability was considerably reduced in a concentration- and time-dependent manner, with the greatest reductions occurring most consistently after 48 and 72 hours of exposure. After being exposed to 1000 μM pamidronate for 72 hours, the lowest cell viability percentage in treated osteosarcoma cells was found to be 34% [1]. The osteogenic development of BMMSCs is regulated by Wnt and β-catenin signaling, which is inhibited by pamidodate disodium. The osteogenic abnormalities of BMMSCs are rescued by Wnt3a, an activator of Wnt and β-catenin signaling, which counteracts the adverse effects of pamidronate disodium [2].

In cases of early osteoarthritis, pamidranate can effectively prevent or even reverse subchondral bone loss, which slows down the deterioration of cartilage. The process could be associated with the downregulation of RANKL, MMP-9, and TLR-4 and the upregulation of OPG [3].

Absorption, Distribution and Excretion
In patients with a creatinine clearance >90mL/min, a 90mg intravenous dose reached a Cmax of 1.92±1.08µg/mL, with a Tmax of 4h, and an AUC of 10.2±6.95µg\*h/mL. In patients with a creatinine clearance 61-90mL/min, a 90mg intravenous dose reached a Cmax of 1.86±0.50µg/mL, with a Tmax of 4h, and an AUC of 10.7—3.91µg\*h/mL.[A203264 In patients with a creatinine clearance 30-60mL/min, a 90mg intravenous dose reached a Cmax of 1.84±0.58µg/mL, with a Tmax of 4h, and an AUC of 10.1±3.38µg\*h/mL. In patients with a creatinine clearance <30mL/min, a 90mg intravenous dose reached a Cmax of 1.93±0.53µg/mL, with a Tmax of 4h, and an AUC of 34.0±8.37µg\*h/mL.
Pamidronate is exclusively eliminated in the urine. By 120 hours after administration, 46±16% of the dose has been eliminated in the urine.
The mean total clearance of pamidronate is 107±50mL/min and the mean renal clearance is 49±28mL/min.

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Metabolism / Metabolites
Pamidronate is not metabolized _in vivo_.
Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Route of Elimination: Pamidronate is not metabolized and is exclusively eliminated by renal excretion.
Half Life: The mean ± SD elimination half-life is 28 ± 7 hours

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Biological Half-Life
The mean elimination half life of pamidronate is 28±7 hours.

Toxicity Summary
The mechanism of action of pamidronate is inhibition of bone resorption. Pamidronate adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. Pamidronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of pamidronate of 30 mg intravenously produce very low levels in milk. Because pamidronate has a serum half-life of about 3 hours, is highly bound to calcium and is poorly absorbed orally (0.3 to 3% in adults), absorption of pamidronate by a breastfed infant is unlikely.[1] Until more data become available, withholding nursing for 12 to 24 hours after a dose should ensure that the breastfed infant is exposed to little or no pamidronate. Other evidence indicates that breastfeeding after cessation of long-term pamidronate treatment appears to have no adverse effects on the infant. Some experts recommend monitoring the infant's serum calcium during the first 2 months postpartum if the mother received pamidronate during pregnancy or nursing.[2]
◉ Effects in Breastfed Infants
A mother received intravenous pamidronate 30 mg once monthly beginning 6 months postpartum. She pumped her breasts and discarded the milk for 48 hours after each dose. The infant, who was about 80% breastfed throughout maternal pamidronate therapy, remained healthy and grew normally during this time.[1]
Because pamidronate can persist in the body for years after long-term administration, the following cases may be relevant. Three women received pamidronate intravenously for osteogenesis imperfecta or McCune-Albright syndrome in cumulative dosages of 6, 7.5 and 9 mg/kg annually for 2 years, 4 years, and 2.2 years, respectively. Their last doses were 3 months, 3 and 48 months (2 infants), and 21 months prior to conception, respectively. None of the women resumed pamidronate during breastfeeding, but they all breastfed their infants postpartum, one for 18 months, two for undetermined times, and one for 6 weeks. None of the infants had any evidence of adverse effects of pamidronate.[3]
Two other mothers received intravenous pamidronate infusions preconception and during pregnancy. On received a total of 240 mg with the final dose during the first trimester of pregnancy. She exclusively breastfed her infant for 6 months and continued breastfeeding until the infant was 12 months old. Her infant grew normally and had no adverse reactions.[4] Another woman received alendronate for 6 months, then pamidronate every 4 months for 1 year prior to conception. Her infant was breastfed (extent not stated) for 3 months. The infant had mild hypocalcemia at 2 months of age, but a normal calcium level and normal long bone development at 5 months of age.[5]
A woman developed transient osteoporosis with foot pain during pregnancy. On days 3 and 8 postpartum and 2 months later, she received 30 mg of pamidronate intravenously. She was instructed to discard her breastmilk for 24 hours after each dose. Her breastfed (extent not stated) infant had normal growth and development at 15 months of age.[6]
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Pamidronate is approximately 54% protein bound in serum.

[1]. Investigation of the effect of pamidronate disodium on the in vitro viability of osteosarcoma cellsfrom dogs. Am J Vet Res. 2005 May;66(5):885-91.

[2]. Pamidronate Disodium Leads to Bone Necrosis via Suppression of Wnt/β-Catenin Signaling in Human Bone Marrow Mesenchymal Stem Cells In Vitro. J Oral Maxillofac Surg. 2017 Mar 22.

[3]. Effects of pamidronate disodium on the loss of osteoarthritic subchondral bone and the expression of cartilaginous and subchondral osteoprotegerin and RANKL in rabbits. BMC Musculoskelet Disord. 2014 Nov 6;15:370.

Pharmacodynamics
Pamidronic acid is a second generation, nitrogen containing bisphosphonate that inhibits osteoclast mediated bone loss It has a wide therapeutic index and a long duration of action as it can be given every 3-4 weeks for certain indications. Patients should be counselled regarding the risk of elevated blood urea nitrogen, renal tubular necrosis, and nephrotoxicity.

C3H11NO7P2

235.0695

235.001

40391-99-9

Pamidronate Disodium;57248-88-1

4674

White to off-white solid powder

1.998 g/cm3

658.7ºC at 760 mmHg

226-228ºC

352.2ºC

1.611

-6.9

6

8

4

13

243

0

WRUUGTRCQOWXEG-UHFFFAOYSA-N

InChI=1S/C3H11NO7P2/c4-2-1-3(5,12(6,7)8)13(9,10)11/h5H,1-2,4H2,(H2,6,7,8)(H2,9,10,11)

(3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

H2O : ~5 mg/mL (~21.27 mM)
DMSO : ~1 mg/mL (~4.25 mM)

Solubility in Formulation 1: 2 mg/mL (8.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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