Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy

Leu, Chih‐Tai; Luegmayr, Eva; Freedman, Leonard P.; Rodan, Gideon A.; Reszka, Alfred A.

doi:10.1016/j.bone.2005.07.023

Cited by 130 publications

(101 citation statements)

References 33 publications

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“…One possible explanation for the short-term effect of the pre-OVX treatment with risedronate is that risedronate, which has a high affinity to bone [9,13], administered before OVX, might be retained in the bone and act on the osteoclasts after OVX. Stopping treatment with risedronate may not promptly reverse its benefit, because of the long residence time of risedronate in the bone.…”

Section: Discussionmentioning

confidence: 99%

Effect of Pre- and Post-Surgery Treatment with Risedronate on Trabecular Bone Loss in Ovariectomized Rats

et al. 2006

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The purposes of the present study were to differentiate the effects of pre-surgery treatment with risedronate and post-surgery treatment with a reduced dosing frequency of risedronate on trabecular bone loss in ovariectomized rats and to determine whether postsurgery treatment with a reduced dosing frequency of risedronate would have a beneficial effect on trabecular bone loss after pre-surgery treatment Materials and Methods Treatment of animalsOne hundred female Sprague-Dawley rats, 3 months of age, were purchased from Charles River Lab (Wilmington, MA, USA). The animals were housed under local vivarium conditions (temperature 23.8°C and 12 h on/off light cycle), and were fed a pelleted standard chow diet (Purina Mills Prolab RMH 2500 Rodent diet #5P14, ON, USA), with free access to water. The rats were used after allowing one-month adaptation to the new environment.The present study included short-term (6 weeks) and long-term (10 weeks) experiments. The short-term experiment was performed on fifty rats. Rats were randomized by the stratified weight method into five groups of 10 rats each (Fig. 1). In detail, 40 rats were divided into two groups with 20 rats in each group. Twenty rats were treated with vehicle for 4 weeks before ovariectomy (OVX) (Vehicle-OVX), and another 20 rats were treated with risedronate for 4 weeks before OVX (Risedronate-OVX). Then, 20 rats in each group were subdivided into two groups of 10 rats each. The 20 rats treated with vehicle before OVX were treated with vehicle (10 rats) or risedronate (10 rats) for 2 weeks following OVX (the Vehicle-OVX-Vehicle [OVX control] and Vehicle-OVX-Risedronate [post-OVX treatment with risedronate] groups, respectively), and the 20 rats treated with risedronate before OVX were treated with vehicle (10 rats) or risedronate (10 rats) for 2 weeks following OVX (the Risedronate-OVX-Vehicle [pre-OVX treatment with risedronate] and Risedronate-OVX-Risedronate [continuous treatment with risedronate] groups, respectively). The remaining 10 rats were treated with vehicle for 6 weeks, with a sham operation performed 4 weeks after the start of the experiment (the Vehicle-Sham-Vehicle [Sham control] group). During the 4 weeks prior to surgery, risedronate (Aventis Pharma, Tokyo, Japan) was dissolved in 0.1

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Section: Discussionmentioning

confidence: 99%

Effect of Pre- and Post-Surgery Treatment with Risedronate on Trabecular Bone Loss in Ovariectomized Rats

et al. 2006

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“…Previous works have shown that different bisphosphonates vary in their affinity for bone surfaces and their level of bone penetration. (12,40) The use of medium-or low-affinity bisphosphonates as the targeting molecule may better reflect changes in osteoclast activity because of their relatively greater uptake in regions of bone resorption compared with quiescent surfaces. (12) Additional histological analyses will be needed to more precisely define subregions within the bone with more rapid uptake of high-versus low-affinity bisphosphonates.…”

Section: Discussionmentioning

confidence: 99%

Binding Kinetics of a Fluorescently Labeled Bisphosphonate as a Tool for Dynamic Monitoring of Bone Mineral Deposition In Vivo

Tower

Campbell

Müller

et al. 2014

Journal of Bone and Mineral Research

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Bone mineral deposition during the modeling of new bone and remodeling of old bone can be perturbed by several pathological conditions, including osteoporosis and skeletal metastases. A site-specific marker depicting the dynamics of bone mineral deposition would provide insight into skeletal disease location and severity, and prove useful in evaluating the efficacy of pharmacological interventions. Fluorescent labels may combine advantages of both radioisotope imaging and detailed microscopic analyses. The purpose of this study was to determine if the fluorescent bisphosphonate OsteoSense could detect localized changes in bone mineral deposition in established mouse models of accelerated bone loss (ovariectomy) (OVX) and anabolic bone gain resulting from parathyroid hormone (PTH) treatment. We hypothesized that the early rate of binding, as well as the total amount of bisphosphonate, which binds over long periods of time, could be useful in evaluating changes in bone metabolism. Evaluation of the kinetic uptake of bisphosphonates revealed a significant reduction in both the rate constant and plateau binding after OVX, whereas treatment with PTH resulted in a 36-fold increase in the bisphosphonate binding rate constant compared with untreated OVX controls. Localization of bisphosphonate binding revealed initial binding at sites of ossification adjacent to the growth plate and, to a lesser extent, along more distal trabecular and cortical elements. Micro-computed tomography (CT) was used to confirm that initial bisphosphonate binding is localized to sites of low tissue mineral density, associated with new bone mineral deposition. Our results suggest monitoring binding kinetics based on fluorescently labeled bisphosphonates represents a highly sensitive, site-specific method for monitoring changes in bone mineral deposition with the potential for translation into human applications in osteoporosis and bone metastatic processes and their treatment.

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“…In vitro, alendronate and pamidronate were comparable in displacing FRFP, consistent with similar binding constants found between these drugs in (14) C-labeled bisphosphonate studies. (44) In vivo, nearly 90% of the fluorescent signal from FRFP localized to bone within 2 to 6 hours of injection. This compares favorably with studies of (14) C-labeled pamidronate, in which skeletal distribution is rapid initially, slows after 6 hours, and yields peak binding after 24 hours.…”

Section: Discussionmentioning

confidence: 99%

Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo

Kozloff

Volakis

Marini

et al. 2010

Journal of Bone and Mineral Research

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Bisphosphonate use has expanded beyond traditional applications to include treatment of a variety of low-bone-mass conditions. Complications associated with long-term bisphosphonate treatment have been noted, generating a critical need for information describing the local bisphosphonate-cell interactions responsible for these observations. This study demonstrates that a fluorescent bisphosphonate analogue, far-red fluorescent pamidronate (FRFP), is an accurate biomarker of bisphosphonate deposition and retention in vivo and can be used to monitor site-specific local drug concentration. In vitro, FRFP is competitively inhibited from the surface of homogenized rat cortical bone by traditional bisphosphonates. In vivo, FRFP delivery to the skeleton is rapid, with fluorescence linearly correlated with bone surface area. Limb fluorescence increases linearly with injected dose of FRFP; injected FRFP does not interfere with binding of standard bisphosphonates at the doses used in this study. Long-term FRFP retention studies demonstrated that FRFP fluorescence decreases in conditions of normal bone turnover, whereas fluorescence was retained in conditions of reduced bone turnover, demonstrating preservation of local FRFP concentration. In the mandible, FRFP localized to the alveolar bone and bone surrounding the periodontal ligament and molar roots, consistent with findings of osteonecrosis of the jaw. These findings support a role for FRFP as an effective in vivo marker for bisphosphonate site-specific deposition, turnover, and long-term retention in the skeleton. ß

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Relative binding affinities of bisphosphonates for human bone and relationship to antiresorptive efficacy

Cited by 130 publications

References 33 publications

Effect of Pre- and Post-Surgery Treatment with Risedronate on Trabecular Bone Loss in Ovariectomized Rats

Effect of Pre- and Post-Surgery Treatment with Risedronate on Trabecular Bone Loss in Ovariectomized Rats

Binding Kinetics of a Fluorescently Labeled Bisphosphonate as a Tool for Dynamic Monitoring of Bone Mineral Deposition In Vivo

Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo

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