Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo

Endo, Yasuo; Nakamura, Masanori; Kikuchi, Takashi; Satoh, Hisashi; Takeda, Yoshikazu; Nitta, Yoshio; Kumagai, Katsuo

doi:10.1007/bf00298728

Cited by 87 publications

(71 citation statements)

References 30 publications

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“…In the first situation, the inflammatory reaction was mild, and its hallmarks were bone marrow fibrosis and moderate inflammatory cell infiltration without vascular change. The observed stimulation of osteoclast recruitment despite ongoing bisphosphonate treatment may result from this inflammatory state; accordingly, Endo et al reported that NBP injections in mice increased marrow macrophage and osteoclast numbers [22]. Other Fig.…”

Section: Discussionmentioning

confidence: 96%

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

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

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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: 96%

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

Lesclous

Najm

Carrel

et al. 2009

Bone

194

140

View full text Add to dashboard Cite

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“…Nitrogen-containing bisphosphonates (such as alendronate) induce various inflammatory reactions via interleukin dependent mechanisms. [27][28][29][30] Bisphosphonate-induced inflammation exacerbates pathologic conditions such as arthritis 31 and atherosclerosis. 32 Blockage of matrix metalloproteinases improves anterior cruciate graft healing in the bone tunnels.…”

Section: Discussionmentioning

confidence: 99%

Alendronate prevents bone loss and improves tendon‐to‐bone repair strength in a canine model

Thomopoulos

Matsuzaki

Zaegel

et al. 2007

Journal Orthopaedic Research

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Previously we showed a loss of bone and a concomitant decrease in mechanical properties in the first 21 days after flexor tendon insertion site injury and repair in a canine model. The goal of this short-term study was to suppress bone loss after insertion site repair using alendronate in an attempt to prevent the reduction in biomechanical properties. Flexor tendons of the second and fifth digits of the right forelimbs of canines were injured and repaired. Dogs received a daily oral dose of alendronate (2 mg/kg). One digit in each dog also received a local dose of alendronate in the bone tunnel at the time of surgery. The repair was evaluated for bone mineral density (BMD) and biomechanical properties and compared to data from a previous study in which no alendronate was used. Alendronate was effective in protecting the distal phalanx from resorption during tendonto-bone healing (BMD was 94 and 104% of control for systemic alendronate and for systemic plus local alendronate, respectively). Alendronate treatment prevented much of the decrease in ultimate load that occurs in the first 21 days. Without treatment, ultimate load was 42% of control. With systemic alendronate treatment and systemic plus local alendronate treatment, ultimate load was 78 and 69% of control, respectively. Failure mode was significantly different when comparing alendronate treatment to repair alone. A lower incidence of suture pull through was found in alendronate treated dogs, suggesting less tendon degeneration. Ultimate load can be improved in association with preventing the bone loss that normally occurs during the early period following tendon-to-bone repair. These initial short-term data demonstrate the potential for a clinical treatment that could enhance tendon-to-bone healing. ß

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“…Among these derivatives, aminobisphosphonates (aminoBPs) are particularly potent. We have reported that aminoBPs with a free amino group in their molecule, when injected into mice, enhanced the activity of histidine decarboxylase (HDC), the enzyme forming histamine, in the bone marrow, spleen, lung and liver (Endo et al, 1993). However, non-aminoBPs showed no such activity.…”

Section: Introductionmentioning

confidence: 99%

Contrast between effects of aminobisphosphonates and non‐aminobisphosphonates on collagen‐induced arthritis in mice

Nakamura

Ando

Abe

et al. 1996

British J Pharmacology

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1 Bisphosphonates (BPs) are inhibitors of bone resorption, and many derivatives have been developed for the treatment of enhanced bone resorption. Aminobisphosphonates (aminoBPs) are particularly potent in this respect. We have shown previously that aminoBPs, such as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP), induce histidine decarboxylase, the enzyme forming histamine, and increase macrophages, granulocytes and osteoclast numbers. Non-aminoBPs do not show this activity. 2 In the present study, an additional aminoBP, cycloheptyl-aminomethylene bisphosphonate (CHAMBP), was shown to have similar properties to AHBuBP suggesting that these actions are common among aminoBPs. 3 In experiments carried out to determine if aminoBPs affect immune responses, we found that CHAMBP and AHBuBP each exacerbated the arthritis induced in mice by the co-injection of type II collagen and an adjuvant, a model for rheumatoid arthritis. In contrast, dichloromethylene bisphosphonate (C12MBP), a typical non-aminoBP, did suppress the arthritis. 4 On the basis of these results, and those obtained previously, we propose that the exacerbating effects of CHAMBP and AHBuBP may be related to their ability to stimulate the synthesis of histamine and to increase macrophages and granulocytes. Conversely, we propose that the suppressive effect of C12MBP on arthritis is related to its cytotoxic action on macrophages or granulocytes.

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Aminoalkylbisphosphonates, potent inhibitors of bone resorption, induce a prolonged stimulation of histamine synthesis and increase macrophages, granulocytes, and osteoclasts in vivo

Cited by 87 publications

References 30 publications

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

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

Alendronate prevents bone loss and improves tendon‐to‐bone repair strength in a canine model

Contrast between effects of aminobisphosphonates and non‐aminobisphosphonates on collagen‐induced arthritis in mice

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