Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells

Coxon, Fraser P.; Thompson, Keith; Roelofs, Anke J.; Ebetino, Frank H.; Rogers, Michael J.

doi:10.1016/j.bone.2007.12.225

Cited by 211 publications

(168 citation statements)

References 31 publications

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“…Unlike TRAP + /CTR + osteoclasts, these TRAP + / CTR − polykarions may not take up NBPs and would thus be less sensitive to their cellular toxicity. In fact, macrophages can internalize NBPs depending on their endocytic ability and on the soluble pool of NBP available [29], which is probably low in the medullary spaces. We suspect that the polykaryons are involved in clearing necrotic tissues.…”

Section: Discussionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

190

128

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Osteonecrosis of the jaw (ONJ) can be associated with nitrogen-containing bisphosphonates (NBPs) therapy. Various mechanisms of NBP-associated ONJ have been proposed and there is currently no consensus of the underlying pathogenesis. The detailed medical and dental histories of 30 ONJ patients treated with NBPs for malignant diseases (24) or osteoporosis (6) were analyzed. The necrotic bone was resected and analyzed histologically after demineralization. In 10 patients the perinecrotic bone was also resected and processed without demineralization. Alveolar bone samples from 5 healthy patients were used as controls. In 14 ONJ patients, serial technetium-99m-methylene diphosphonate scintigraphic scans were also available and confronted to the other data. Strong radionuclide uptake was detected in some patients several months before clinical diagnosis of ONJ. The medullary spaces of the necrotic bone were filled with bacterial aggregates. In the perinecrotic bone, the bacteria-free bone marrow characteristically showed an inflammatory reaction. The number of medullary inflammatory cells taken as an index of inflammation allowed us to discriminate two inflammation grades in the ONJ samples. Low-grade inflammation, characterized by marrow fibrosis and low inflammatory cells infiltration, increased numbers of TRAP + monoand multineacleated cells was seen in patients with bone exposure b 2 cm 2 . High-grade inflammation, associated with larger lesions, showed amounts of tartrate-resistant acid phosphatase + /calcitonin receptor − mono-and multinucleated cells, osteocyte apoptosis, hypervascularization and high inflammatory cell infiltration. The clinical extent of ONJ was statistically linked to the numbers of inflammatory cell. Taken together these data suggest that bone necrosis precedes clinical onset and is an inflammation-associated process. We hypothesize that from an initial focus, bone damage spreads centrifugally, both deeper into the jaw and towards the mucosa before the oral bone exposure and the clinical diagnosis of ONJ.

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Section: Discussionmentioning

confidence: 99%

Bisphosphonate-associated osteonecrosis of the jaw: A key role of inflammation?

Lesclous

Najm

Carrel

et al. 2009

Bone

190

128

View full text Add to dashboard Cite

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“…Given this, FRFP can be used to monitor factors such vascular delivery and available binding surfaces independent of bisphosphonate type. Other fluorescent bisphosphonate analogues have been described (30) but have not yet been tested against FRFP to determine whether heterogeneous site-specific binding of different bisphosphonates occurs. This technique will be useful for examining side effects that have been associated with bisphosphonate treatment.…”

Section: Discussionmentioning

confidence: 99%

“…(25,(27)(28)(29) Similar fluorescent bisphosphonate probes have been used to monitor bisphosphonate-osteoclast interactions in vitro. (30) Using a nearinfrared imaging strategy allows for deep signal penetration through tissues in a region of the spectrum where tissue autofluorescence is low, providing high signal-to-noise values. (31) Despite demonstration of this imaging strategy in a variety of disease contexts, the potential of FRFP as a tracer compound for bisphosphonate delivery and retention in vivo has yet to be established.…”

Section: J Jbmrmentioning

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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“…The pharmacologic action of nitrogen-containing BPs (N-BPs) to inhibit bone resorption depends on (1) their binding affinity for bone mineral (hydroxyapatite) crystals and (2) their inhibitory effect on osteoclast function. (40)(41)(42) The latter is accomplished by inhibiting the enzyme, farnesyl pyrophosphate synthase (FPPS), a step in the mevalonate pathway, preventing biosynthesis of molecules used for the post-translational modification of small proteins essential for osteoclast function and survival. (43) The position of the nitrogen atom in the side chain of NBPs is critical for the inhibition of FPPS and subsequently for their antiresorptive potency.…”

Section: Mechanisms Of Bisphosphonate Actionmentioning

confidence: 99%