Retention of etidronate in human, dog, and rat

Kasting, Gerald B.; Francis, Marion D.

doi:10.1002/jbmr.5650070507

Cited by 70 publications

(18 citation statements)

References 20 publications

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“…Bisphosphonates are internalized by osteoclasts during bone resorption and can be transferred to adjacent cells by transcytosis, such that they may be passed to nonosteoclast host cells and tumour cells, thus directly modifying the bone microenvironment [7,8]. Bisphosphonates are rapidly cleared from the circulation after administration, but have a half-life in bone that is measurable in years [9].…”

Section: Preclinical Evidence For Disease-modifying Effects In Solid mentioning

confidence: 99%

Adjuvant bone-targeted therapy to prevent metastasis

Coleman

2012

Current Opinion in Supportive &Amp; Palliative Care

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Section: Preclinical Evidence For Disease-modifying Effects In Solid mentioning

confidence: 99%

Adjuvant bone-targeted therapy to prevent metastasis

Coleman

2012

Current Opinion in Supportive &Amp; Palliative Care

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“…Bisphosphonates show negligible biotransformation (Lin et al, 1994). The rate and extent of skeletal uptake and release of drug is dependent on the osseous turnover rate as well as the intrinsic bone affinity of the bisphosphonate (Kasting and Francis, 1992). The distribution of bisphosphonates within the skeleton is not homogeneous.…”

mentioning

confidence: 99%

Biodistribution and Plasma Protein Binding of Zoledronic Acid

Weiss

Pfaar²,

Schweitzer³

et al. 2008

Drug Metab Dispos

149

117

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ABSTRACT:The bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. To investigate drug biodistribution and elimination, 14 C-zoledronic acid was administered intravenously to rats and dogs in single or multiple doses and assessed for its in vitro blood distribution and plasma protein binding in rat, dog, and human. Drug exposure in plasma, bones, and noncalcified tissues was investigated up to 240 days in rats and 96 h in dogs using radiometry after dissection. Drug biodistribution in the rat and within selected bones from dog was assessed by autoradiography. Concentrations of radioactivity showed a rapid decline in plasma and noncalcified tissue but only a slow decline in bone, to ϳ50% of peak at 240 days post dose, whereas the terminal half-lives (50-200 days) were similar in bone and noncalcified tissues, suggesting redistribution of drug from the former rather than prolonged retention in the latter. Uptake was highest in cancellous bone and axial skeleton. At 96 h after dose, the fraction of dose excreted was 36% in rat and 60% in dog; 94 to 96% of the excreted radioactivity was found in urine. Blood/plasma concentration ratios were 0.52 to 0.59, and plasma protein binding of zoledronic acid was moderate to low in all species. The results suggest that a fraction of zoledronic acid is reversibly taken up by the skeleton, the elimination of drug is mainly by renal excretion, and the disposition in blood and noncalcified tissue is governed by extensive uptake into and slow release from bone.

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“…Their action is mediated by the inhibition of osteoclast recruitment and impairment of osteoclast function as evidenced by morphologic changes on osteoclast cytoskeleton, disruption of ruffle borders, and apoptosis (6,7). Bisphosphonates are stable in bone for prolonged times, and in vivo animal studies have shown a long half-life in the skeleton, with a terminal phase of ∼300 days (8,9). Their effects on cell types other than osteoclast have not been completely elucidated.…”

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confidence: 99%

High-Dose Zoledronic Acid Impacts Bone Remodeling with Effects on Osteoblastic Lineage and Bone Mechanical Properties

Pozzi

Vallet²,

Mukherjee³

et al. 2009

Clinical Cancer Research

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Purpose: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. Experimental Design: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. Results: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. Conclusions: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease. (Clin Cancer Res 2009;15(18):5829-39)

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Retention of etidronate in human, dog, and rat

Cited by 70 publications

References 20 publications

Adjuvant bone-targeted therapy to prevent metastasis

Adjuvant bone-targeted therapy to prevent metastasis

Biodistribution and Plasma Protein Binding of Zoledronic Acid

High-Dose Zoledronic Acid Impacts Bone Remodeling with Effects on Osteoblastic Lineage and Bone Mechanical Properties

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