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

Lesclous, Philippe; Najm, Semaan Abi; Carrel, Jean-Pierre; Baroukh, Brigitte; Tommaso, Lombardi; Willi, Jean-Pierre; Rizzoli, René; Saffar, Jean‐Louis; Samson, Jacky

doi:10.1016/j.bone.2009.07.011

Cited by 194 publications

(169 citation statements)

References 51 publications

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“…However, histological studies of tissue removed from patients with ONJ have demonstrated the presence both of osteoclasts and bone resorption. Lesclous et al [59] reported the presence of TRAP-positive mononuclear and multinucleate cells in perinecrotic tissue, and in other studies, the presence of increased numbers of osteoclasts and active bone resorption have been reported. Furthermore, isotope studies using technetium-labelled diphosphonate or F-18 FDG PET have shown increased uptake in the regions surrounding the necrotic jaw [60][61][62][63].…”

Section: Suppression Of Bone Turnovermentioning

confidence: 97%

“…However, histological studies of affected tissue from patients with ONJ have generally shown the presence of normal vasculature [59,69], and furthermore, there is no evidence that denosumab has effects on angiogenesis. ONJ has been described in a few patients treated for cancer with bevacizumab, an antiangiogenic agent that targets VEGF and is used in the treatment of advanced metastatic disease.…”

Section: Angiogenesismentioning

confidence: 99%

“…However, whether infection is a primary event or secondary to others has not been established. Lesclous et al [59] postulated that inflammation occurs first, weakening the mucosal barrier and hence predisposing to infection and necrosis. Alternatively, it is possible that necrosis is the primary event and is followed by infection, or that infection results in inflammation and necrosis.…”

Section: Infection/inflammationmentioning

confidence: 99%

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Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Compston

2011

Osteoporos Int

104

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In recent years, atypical femoral fractures and osteonecrosis of the jaw have emerged as potential complications of long-term bisphosphonate therapy; osteonecrosis of the jaw has also been reported in patients receiving high doses of denosumab. The pathophysiology of both conditions is poorly defined, and the underlying mechanisms are likely to differ. The initiation of atypical fractures in the lateral femoral shaft suggests that reduced tensile strength, possibly secondary to alterations in the material properties of bone resulting from low bone turnover, may be an important pathogenetic factor. Osteonecrosis of the jaw is characterised by infection, inflammation, bone resorption and bone necrosis, but the sequence in which these occur has not been established. However, the observation that bone resorption occurs in close proximity to microbial structures suggests that infection may be the most important trigger, often as a result of dental disease. Other possible pathogenetic factors include suppression of bone turnover, altered immune status and adverse effects of bisphosphonates on the oral mucosa.

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Section: Suppression Of Bone Turnovermentioning

confidence: 97%

Section: Angiogenesismentioning

confidence: 99%

Section: Infection/inflammationmentioning

confidence: 99%

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Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Compston

2011

Osteoporos Int

104

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“…1 It will be important to clarify whether zoledronate-mediated NK cell activation, as reported here, can contribute to the development of osteonecrosis of the jaw, which can be considered an inflammatory condition associated with substantial leukocyte infiltration. 48 Infiltrating leukocytes may encounter high concentrations of bisphosphonate, which have been shown previously to accumulate in the resorption space, where they may reach 0.1-1mM. 49 In summary, we have shown that the potent bisphosphonate zoledronate not only induces ␥␦ T-cell activation but can also induces NK cell activation.…”

Section: Discussionmentioning

confidence: 97%

DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Nussbaumer

Gruenbacher

Gander

et al. 2011

Blood

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Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce ␥␦ T-cell activation. Using IL-2-primed cultures of CD56 ؉ peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-␥ production not only in ␥␦ T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of ␥␦ T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-␥ production was silenced. Conversely, in the absence of ␥␦ T lymphocytes, DClike cells were spared, allowing NK cell IFN-␥ production to proceed. ␥␦ T cellindependent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1␤ for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-␥ production in NK cells and ␥␦ T lymphocytes, indicating that caspase-1-mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate. (Blood. 2011; 118(10):2743-2751) IntroductionThe bisphosphonates zoledronate and pamidronate are approved by the Food and Drug Administration for the treatment of metastatic bone disease of hematopoietic tumors such as multiple myeloma 1,2 and nonhematopoietic tumors such as breast 3 and prostate cancer. 4 Inhibition of farnesyl pyrophosphate synthase, an enzyme of the mevalonate pathway for cholesterol biosynthesis and protein prenylation, 5 is one important mechanism for bisphosphonate effects on bone resorption. 1,4 Inhibition of farnesyl pyrophosphate synthase leads to farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) deprivation and the subsequent failure to perform farnesylation and geranylgeranylation of small guanosine triphosphatases (GTPases) of the RAS superfamily. Inhibition of RAS signaling because of the disruption of membrane anchoring of these GTPases eventually prevents osteoclast-mediated bone resorption. 6,7 In addition to their effects on bone metabolism, bisphosphonates may have immunomodulatory effects, particularly on the innate immune system. [8][9][10][11] Evidence for the stimulation of ␥␦ T lymphocytes by bisphosphonates was obtained when expansion of ␥␦ T lymphocytes was observed in patients who had acute-phase reactions after their first treatment with pamidronate. 12 Inhibition of FPP synthase by bisphosphonates leads to the accumulation of isopentenyl pyrophosphate that can be specifically recognized by ␥␦ T lymphocytes expressing the V␦2V␥9 T-cell receptors. 13 Hematopoietic tumor cell lines such as Daudi (Burkitt lymphoma) or RPMI 8226 (myeloma) are specifically recognized and lysed by these ␥␦ T lymphocytes in vitro. 14,15 Moreover, ␥␦ T lymphocytes have recently been...

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“…Several types of inflammatory reactions have been observed in patients treated with NBPs, including flu-like symptoms, esophageal irritation, and osteonecrosis of the jaw (2). These side effects might be attributable to the immune-modulating effects of NBPs (3). Inhibition of the mevalonate pathway by NBPs causes isopentenyl-5-pyrophosphate accumulation in monocytes, augmenting γδ T-cell activation in vitro (4), but additional effects likely contribute to the in vivo inflammatory responses to NBPs (1).…”

mentioning

confidence: 99%

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

Norton¹,

Hayashi²,

Crain³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Nitrogen bisphosphonates (NBPs) are commonly prescribed for osteoporosis but have also been found to induce inflammatory reactions and to delay the progression of breast cancer. The inflammatory and anticancer effects of the NBPs might be associated with an ability to modulate innate immune signaling. In mice, intraperitoneal NBP administration causes a rapid influx of neutrophils and monocytes that is dependent on the myeloid differentiation primary response gene 88 (MyD88) mediator of Toll-like receptor (TLR) and IL-1 signaling. Bone marrow chimeras demonstrate that this inflammatory response is partially dependent on TLR4 expression by hematopoietic cells and the IL-1 receptor on radioresistant cells. In vitro, NBPs directly stimulate neither murine bone marrow-derived mononuclear cells nor human peripheral blood mononuclear cells, but rather prime them to produce increased amounts of cytokines when exposed to IL-1 or TLR ligands. This potentiation is mediated by a reduction in IL-1 receptor-associated kinase-M, a negative regulator of MyD88-dependent signaling. In vivo, this property renders the NBPs as effective adjuvants that enhance both cellular and antibody responses to antigens.

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

Cited by 194 publications

References 51 publications

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw

DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by γδ T lymphocytes

Role of IL-1 receptor-associated kinase-M (IRAK-M) in priming of immune and inflammatory responses by nitrogen bisphosphonates

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